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La terapia con niacina y el riesgo de diabetes de nueva aparición: un metanálisis de ensayos controlados aleatorios

Resultados: En 11 ensayos con 26 340 participantes no diabéticos, 1371 (725/13 121 asignados a niacina; 646/13 219 asignados a control) fueron diagnosticados con diabetes durante una media ponderada de seguimiento de 3,6 años. El tratamiento con niacina se asoció con un RR de 1,34 (IC del 95 %: 1,21 a 1,49) para la diabetes de nueva aparición, con una heterogeneidad limitada entre los ensayos (I(2)=0,0 %, p=0,87). Esto equivale a un caso adicional de diabetes por cada 43 (IC del 95 %: 30 a 70) personas inicialmente no diabéticas que reciben tratamiento con niacina durante 5 años. Los resultados fueron consistentes independientemente de si los participantes recibieron tratamiento de base con estatinas (p para interacción = 0,88) o tratamiento combinado con laropiprant (p para interacción = 0,52).

Conclusiones: La terapia con niacina se asocia con un riesgo moderadamente mayor de desarrollar diabetes, independientemente de la terapia de fondo con estatinas o laropiprant combinada.

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Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials - PubMed

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Niacin therapy is associated with a moderately increased risk of developing diabetes regardless of background statin or combination laropiprant therapy.

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Titulo: Eficacia y seguridad de la inhibición de PCSK9 en enfermedades cardiovasculares: un metanálisis de 45 ensayos controlados aleatorios.
Autor: Geng, Q; 2021.
Tipo de estudio: Meta-análisis

Resultados: Se trabajó con Medline, la Biblioteca Cochrane y Clinicaltrials.gov fueron buscados para 45 ensayos controlados aleatorios, en los que participaron 97 297 pacientes.

Conclusión: Alirocumab y evolocumab podrían mejorar el perfil lipídico y reducir el riesgo de trastornos cardíacos y accidentes cerebrovasculares con una seguridad y tolerabilidad satisfactorias. Sin embargo, se debe prestar atención a las reacciones en el lugar de la inyección.

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Early publication date: 2021-09-23

Qiang Geng ¹, Xuan Li ¹, Qingjiao Sun ¹, Zhengzhong Wang ¹

DOI: 10.5603/CJ.a2021.0110

Department of Cardiology, Qingdao Municipal Hospital, 1 road jiaozhou, 266011 qingdao, China

Early publication date: 2021-09-23

Abstract

Background: Safety concerns about proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors make physicians reluctant to prescribe agents for patients. The present aim was to assess the efficacy and safety of alirocumab, evolocumab and bococizumab in patients with atherosclerotic cardiovascular disease (ASCVD). Methods: Medline, the Cochrane Library and Clinicaltrials.gov were searched for 45 randomized controlled trials, involving 97,297 patients. Results: Compared with the control group, PCSK9 inhibitors could significantly reduce low-density lipoprotein cholesterol, total cholesterol, triglycerides and increase high-density lipoprotein cholesterol. Alirocumab was associated with lower incidence of unstable angina (p < 0.05) and myocardial infarction (p < 0.05), compared with the control group. Alirocumab (odds ratio [OR] 0.76, 95% conﬁdence interval [CI] 0.60-0.97, p < 0.05), evolocumab (OR 0.79, 95% CI 0.66-0.95, p < 0.05) and bococizumab (OR 0.60, 95% CI 0.42-0.84, p < 0.05) were associated with lower incidence of stroke, compared with control group. The incidence of injection-site reactions was significantly higher in alirocumab (OR 1.68, 95% CI 1.45-1.93, p < 0.05), evolocumab (OR 1.64, 95% CI 1.41-1.91, p < 0.05) and bococizumab (OR 8.03, 95% CI 6.85-9.41, p < 0.05) group than in the control group. Conclusions: Alirocumab and evolocumab could ameliorate lipid profile and reduce the risk of cardiac disorders and stroke with satisfactory safety and tolerability. However, injection-site reactions should be paid attention to.

Abstract

Background: Safety concerns about proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors make physicians reluctant to prescribe agents for patients. The present aim was to assess the efficacy and safety of alirocumab, evolocumab and bococizumab in patients with atherosclerotic cardiovascular disease (ASCVD). Methods: Medline, the Cochrane Library and Clinicaltrials.gov were searched for 45 randomized controlled trials, involving 97,297 patients. Results: Compared with the control group, PCSK9 inhibitors could significantly reduce low-density lipoprotein cholesterol, total cholesterol, triglycerides and increase high-density lipoprotein cholesterol. Alirocumab was associated with lower incidence of unstable angina (p < 0.05) and myocardial infarction (p < 0.05), compared with the control group. Alirocumab (odds ratio [OR] 0.76, 95% conﬁdence interval [CI] 0.60-0.97, p < 0.05), evolocumab (OR 0.79, 95% CI 0.66-0.95, p < 0.05) and bococizumab (OR 0.60, 95% CI 0.42-0.84, p < 0.05) were associated with lower incidence of stroke, compared with control group. The incidence of injection-site reactions was significantly higher in alirocumab (OR 1.68, 95% CI 1.45-1.93, p < 0.05), evolocumab (OR 1.64, 95% CI 1.41-1.91, p < 0.05) and bococizumab (OR 8.03, 95% CI 6.85-9.41, p < 0.05) group than in the control group. Conclusions: Alirocumab and evolocumab could ameliorate lipid profile and reduce the risk of cardiac disorders and stroke with satisfactory safety and tolerability. However, injection-site reactions should be paid attention to.

Keywords

proprotein convertase subtilisin/kexin type 9, efficacy, safety, meta-analysis

Title

Efficacy and safety of PCSK9 inhibition in cardiovascular disease: a meta-analysis of 45 randomized controlled trials

Journal

Cardiology Journal

Issue

Ahead of print

Article type

Original Article

Early publication date

2021-09-23

DOI

10.5603/CJ.a2021.0110

Pubmed

Keywords

proprotein convertase subtilisin/kexin type 9
efficacy
safety
meta-analysis

Authors

Qiang Geng
Xuan Li
Qingjiao Sun
Zhengzhong Wang

1. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Medicine. 2009; 6(7): e1000097.

2. Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 [updated March 2011]. The Cochrane Collaboration. 2011. http://www.cochrane-handbook.org (accessed 21 March 2011).

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Efficacy and safety of PCSK9 inhibition in cardiovascular disease: a meta-analysis of 45 randomized controlled trials | Geng | Cardiology Journal

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Early publication date: 2021-09-23 Qiang Geng 1, Xuan Li 1, Qingjiao Sun 1, Zhengzhong Wang 1 DOI: 10.5603/CJ.a2021.0110 Department of Cardiology, Qingdao Municipal Hospital, 1 road jiaozhou, 266011 qingdao, China Early publication date: 2021-09-23 Abstract Background: Safety concerns about proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors make physicians reluctant to prescribe agents for patients.

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TUTULO: Eficacia y seguridad a largo plazo de evolocumab en pacientes con hipercolesterolemia

TIPO DE ESTUDIO: Ensayo Controlado Aleatorio
AÑO: 2019
AUTOR: Michael J.
RESULTADOS: Las tasas anuales de EA graves durante evolocumab + SOC oscilaron entre el 6,9 % y el 7,9 %, en comparación con la tasa del 6,8 % en pacientes con SOC durante el año 1. La interrupción de evolocumab debido a EA se produjo en el 5,7 % de los pacientes.
CONCLUSIONES: El ensayo OSLER-1 demostró una eficacia, tolerancia y seguridad de evolocumab para reducir el LDL-C consistentemente excelentes, sin que se detectaran anticuerpos neutralizantes, a lo largo del estudio de mayor duración de un inhibidor de PCSK9 informado hasta la fecha.

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Affiliations

¹ Jacksonville Center for Clinical Research, Jacksonville, Florida. Electronic address: mkoren@encoredocs.com.

² Thrombolysis In Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

³ Lipid Clinic, Oslo University Hospital, Oslo, Norway.

⁴ Amgen, One Amgen Center Drive, Thousand Oaks, California.

⁵ The Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Free article

Randomized Controlled Trial

Free article

Affiliations

¹ Jacksonville Center for Clinical Research, Jacksonville, Florida. Electronic address: mkoren@encoredocs.com.

² Thrombolysis In Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

³ Lipid Clinic, Oslo University Hospital, Oslo, Norway.

⁴ Amgen, One Amgen Center Drive, Thousand Oaks, California.

⁵ The Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Abstract

Background: Evolocumab and other anti-PCSK9 antibodies reduced adverse cardiovascular outcomes in clinical trials of high-risk patients over <3 years median treatment duration.

Objectives: The OSLER-1 trial (Open Label Study of Long Term Evaluation Against LDL-C Trial) evaluated longer-term effects of evolocumab during open-label hypercholesterolemia treatment for up to 5 years.

Methods: Patients randomized to standard of care (SOC) or evolocumab 420 mg monthly (evolocumab + SOC) for year 1. After year 1, patients could enter the all-evolocumab period and receive evolocumab + SOC for an additional 4 years. The authors analyzed the persistence of lipid effects and exposure-dependent safety focusing on yearly rates of adverse events (AEs) and anti-drug antibodies over 4.951 patient-years of observation.

Results: A total of 1,255 patients (safety analysis population) randomized into the year 1 SOC-controlled period and received ≥1 evolocumab dose (mean ± SD age 57 ± 12 years; 53% female). A total of 1,151 patients (efficacy analysis population) progressed to the all-evolocumab period (year 2 and beyond). Evolocumab + SOC persistently lowered mean ± SE low-density lipoprotein cholesterol (LDL-C) by 56% ± 0.6% (n = 1,071), 57% ± 0.8% (n = 1,001), 56% ± 0.8% (n = 943), and 56% ± 0.8% (n = 803) after approximately 2, 3, 4, and 5 years, respectively, from randomization. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment. Yearly serious AE rates during evolocumab + SOC ranged from 6.9% to 7.9%, comparable to the 6.8% rate in SOC patients during year 1. Evolocumab discontinuation due to AEs occurred in 5.7% of patients. Two SOC and 2 evolocumab + SOC patients developed new, transient, binding anti-drug antibodies; no neutralizing antibodies were observed.

Conclusions: The OSLER-1 trial demonstrated consistently excellent LDL-C-lowering efficacy, tolerance, and safety of evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OSLER-1]; NCT01439880).

Keywords: LDL-cholesterol; PCSK9; evolocumab; lipoproteins; randomized controlled trial.

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anticholesteremic agents / therapeutic use

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The OSLER-1 trial demonstrated consistently excellent LDL-C-lowering efficacy, tolerance, and safety of evolocumab, with no neutralizing antibodies detected, throughout the longest-duration study of a PCSK9 inhibitor reported to date. (Open Label Study of Long Term Evaluation Against LDL-C Trial [OS ...

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2732783/

Titulo: Eficacia y seguridad comparativas de la monoterapia con estatinas y fibratos: una revisión sistemática y un metanálisis de ensayos controlados aleatorios directos.

Tipo: Metanálisis de ensayos controlados aleatorios directos
Resultados: Se incluyeron 19 ensayos elegibles que compararon directamente la monoterapia con estatinas y fibratos e informaron la mortalidad o un evento cardiovascular. Los estudios tuvieron una duración limitada del seguimiento (rango de 10 semanas a 2 años). No encontramos ninguna evidencia de una diferencia entre las estatinas y los fibratos para la mortalidad cardiovascular (OR 2,35, IC del 95 %: 0,94-5,86, I2 = 0 %; diez estudios, n = 2657; certeza baja), eventos cardiovasculares mayores (OR 1,15, IC 95 % 0,80-1,65, I2 = 13 %; 19 estudios, n = 7619; certeza baja) y mialgia (OR 1,32, IC 95 % 0,95-1,83, I2 = 0 %; diez estudios, n = 6090; certeza baja ). Las estatinas tuvieron efectos adversos menos graves (OR 0,57, IC del 95 % 0,36-0,91, I2 = 0 %; nueve estudios, n = 3749; certeza moderada), menos elevaciones de la creatinina sérica (OR 0,17, IC del 95 % 0,08-0,36, I2 = 0%; seis estudios, n = 2553; certeza alta).
Conclusiones: Los ensayos aleatorios elegibles de estatinas versus fibratos se diseñaron para evaluar los resultados de lípidos a corto plazo, lo que dificulta tener certeza sobre el efecto comparativo directo sobre los resultados cardiovasculares y la mortalidad. Con la excepción de la mialgia, el uso de una estatina pareció tener una menor incidencia de efectos adversos en comparación con el uso de un fibrato.

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INTRODUCTION

Dyslipidemia, a major complication in renal transplant patients, increases the risk of cardiovascular disease (CVD) [ 1, 2], which is a major cause of morbidity and mortality in the renal transplant population [ 3]. The clinical practice guidelines of the National Kidney Foundation Work Group recommend a target low-density lipoprotein cholesterol (LDL-C) level of less than 100 mg/dL [ 4], and the use of a statin as the first-line treatment. Nevertheless, in clinical practice, many patients fail to reach the target LDL-C level. The reasons for this may be multifactorial, but include a tendency to reduce the statin dose because of concerns about the adverse effects related to higher doses and drug interactions between the statin and calcineurin inhibitors (CNIs) [ 4, 5].

Ezetimibe lowers cholesterol levels by inhibiting the intestinal absorption of cholesterol [ 6] so ezetimibe is especially useful for patients who are statin-intolerant or resistant to high-dose statin monotherapy [ 7]. The incremental lipid-lowering effect of ezetimibe has been observed in both non-transplant [ 8- 18] and renal transplant populations [ 19- 22]. However, no report has examined the use of ezetimibe combined with a low-dose statin as the initial treatment in renal transplant patients.

This study prospectively evaluated the efficacy and safety of ezetimibe and low-dose simvastatin therapy as primary treatment for dyslipidemia in renal transplant recipients. Our results revealed that primary treatment of renal transplant recipients with ezetimibe and low-dose simvastatin lowers lipid levels dramatically without significant adverse reactions.

METHODS

Study population

A prospective study examined renal transplant recipients receiving a single combination tablet of ezetimibe (10 mg) and simvastatin (10 mg) daily. The inclusion criteria were the passage of at least 4 months after renal transplantation, fasting LDL-C levels over 100 mg/dL despite therapeutic lifestyle changes, and informed consent of the patient. Patients who had one or more of the following criteria were excluded: use of other lipid-lowering drugs (including statin monotherapy) within 4 weeks of the start of ezetimibe and simvastatin therapy, an episode of unstable angina or myocardial infarction within the past 6 months, preexisting malignancy with a life expectancy of less than 1 year, abnormal liver enzymes (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) ≥2× the upper limit of normal, and pregnant or breast-feeding women.

Study protocol

After a 1-month screening period, eligible patients were enrolled in the study. The doses of simvastatin and ezetimibe were not changed during the study period. Study visits were scheduled before initiating treatment and after 2 weeks and 1, 3, and 6 months. Fasting lipid profiles (total cholesterol [TC], triglyceride [TG], LDL-C, and high-density lipoprotein cholesterol [HDL-C]), creatinine kinase (CK), and trough immunosuppressant levels (cyclosporin A [CsA], tacrolimus [Tac], and sirolimus [SRL]) were measured at all scheduled visits. The urine protein-to-creatinine ratio in a spot urine sample, liver transaminase (AST, ALT), and high sensitivity C-reactive protein (hsCRP) were measured before initiating treatment and after 1, 3, and 6 months. Adverse drug reactions, such as myalgia and skin rash, were monitored at all scheduled visits. Treatment compliance was assessed after 1, 3, and 6 months. The study protocol was approved by the institutional review board.

Data and statistical analysis

The following variables were analyzed before and after ezetimibe and low-dose simvastatin treatment: fasting lipid profiles (TC, TG, LDL-C, and HDL-C), estimated glomerular filtration rate (eGFR), urine protein-to-creatinine ratio in a spot urine sample, liver transaminase (AST, ALT), hsCRP, CK, trough immunosuppressant levels (CsA, Tac, and SRL), and adverse drug reactions. LDL-C was calculated using Friedewald's equation (LDL-C=TC-[TG/5]-[HDL-C] and eGFR was calculated using the abbreviated Modification of Diet and Renal Disease (MDRD) equation [ 23].

Continuous data are presented as the median and range or mean±SD and were compared using the paired t-test. In a subgroup analysis of patients with proteinuria (≥500 mg/g) or high hsCRP levels (≥0.5 mg/dL), data including proteinuria and hsCRP levels were compared using the Wilcoxon signed-rank test.

RESULTS

Patient characteristics

Seventy-seven patients were enrolled in this study. The patient characteristics are summarized in . Three patients were on CNI-free regimens (SRL and prednisolone) and two patients were on corticosteroid-free regimens (CsA and mycophenolate mofetil). Fifty-six patients were on a triple immunosuppressive regimen and 21 patients were on a dual immunosuppressive regimen. Sixty-three patients (81.8%) continued on ezetimibe and low-dose simvastatin therapy for the full 6 months.

Table 1

Effects of ezetimibe and low-dose simvastatin on lipid panels

The overall effects of treatment on the fasting lipid profiles are shown in . The TC, TG, and LDL-C levels were reduced significantly after treatment with mean percentage changes of 34.6±9.5, 16.0±27.4, and 47.6±13.7%, respectively. After 6 months of treatment, 52 patients (82.5%) reached the target of LDL-C <100 mg/dL.

Table 2

An analysis of subgroups divided according to the type of CNI showed that the lipid-lowering effect was significant in both the CsA and Tac groups (). In CsA-treated patients, the levels of TC, TG, and LDL-C were reduced significantly with mean percentage changes of 33.9±6.5, 12.0±29.5, and 47.2±9.9%, respectively. In Tac-treated patients, the TC, TG, and LDL-C levels were significantly reduced with mean percentage changes of 35.8±12.0, 21.4±24.5, and 48.8±16.7%, respectively. Stable trough CsA and Tac levels were maintained. One patient was on SRL and had a trough level of 8.9 ng/mL before treatment and 9.5 ng/mL after treatment.

Table 3

Effect of ezetimibe and low-dose simvastatin therapy on allograft function, proteinuria, and hsCRP levels

As shown in , no significant change occurred in the eGFR, urine protein-to-creatinine ratio, or hsCRP concentration after treatment. In a subgroup analysis of patients with proteinuria of at least 500 mg/g (n=16), the median urine protein-to-creatinine ratio was reduced from 1558.5 (range 500.4-5985.5) to 869.5 (range 93.2-6857.1) mg/g, but the difference was not significant ( p=0.14). In a subgroup analysis of patients with hsCRP levels ≥0.5 mg/dL (n=6), the median hsCRP concentration was reduced from 0.7 (range 0.5-1.0) to 0.3 (range 0.02-2.2) mg/dL, but statistical significance was not achieved ( p= 0.6).

Adverse drug reactions

Fourteen patients (18.2%) discontinued the ezetimibe and low-dose simvastatin treatment. The most common reason was muscle pain or weakness (n=8, 11.7%) without a significant increase in CK levels. Two patients (2.6%) had greater than twofold increases in the upper limit levels of AST and ALT. Other reasons were skin rash, dizziness, pregnancy, and concomitant administration of itraconazole.

DISCUSSION

Our results clearly demonstrate the lipid-lowering efficacy of a combination of ezetimibe and low-dose statin in renal transplant recipients with dyslipidemia. Four reports on the lipid-lowering efficacy of ezetimibe in renal transplant patients have been published [ 19- 22], but these studies focused mainly on patients who were statin-intolerant or resistant to high-dose statin monotherapy. Compared to previous reports, our study provides evidence of the potential advantage of the combination of ezetimibe and low-dose statin as the initial treatment for dyslipidemia in this population.

The most important finding of this study is that treatment with a combination of ezetimibe and low-dose statin effectively lowered the LDL-C level in renal transplant recipients. With ezetimibe (10 mg) and simvastatin (10 mg), the LDL-C level was reduced 47.6% on average and 82.5% of the patients reached the LDL-C goal of <100 mg/dL (). Our results (47.6% reduction in the LDL-C level) are better than those of a study on statin monotherapy (fluvastatin, 40 mg) in a large number of renal transplant patients (32% reduction in the LDL-C level) [ 24]. Furthermore, we obtained better results than studies reporting an average 31% reduction (range 22-41%) in the LDL-C level using ezetimibe with or without high-dose statin treatment [ 19- 22]. The reason for the enhanced lipid-lowering effect seen in our study may be explained partially by the higher pretreatment LDL-C levels [ 20, 22]. Nevertheless, it suggests that initial treatment with ezetimibe and low-dose statin has a more potent lipid-lowering effect than other regimens, such as statin monotherapy or the secondary addition of ezetimibe to a statin. This presumption is supported by the excellent results (45-54%) in non-transplant patients initially treated with ezetimibe and a statin [ 11- 13, 16, 18].

In addition to its excellent effect on dyslipidemia, renal transplant patients receiving a CNI would benefit from ezetimibe and low-dose statin therapy. The effective dose of ezetimibe is higher in patients receiving CsA than in patients not receiving CsA [ 25- 27]. The mechanism of the interaction between ezetimibe and CsA is not fully understood, but CsA is thought to alter the glucuronidation of ezetimibe in gastrointestinal tissue, which alters the pharmacokinetics of ezetimibe and its metabolites [ 27]. Therefore, patients on CsA may have a higher lipid-lowering effect with lower doses of ezetimibe than those not receiving CsA.

Another advantage of the combination treatment with ezetimibe and low-dose statin is safety. In this study, the incidence of adverse reactions associated with statins was quite low. Only 2.6% of the patients developed elevated transaminase levels, which is a rate similar to that in the non-transplant population [ 28]. Muscle pain or weakness occurred in 11.7% of the patients, but it was nonspecific and was not associated with increased CK levels. The blood trough CNI levels and allograft function measured using the estimated GFR were stable during the 6-month treatment. This suggests that combination treatment with ezetimibe and low-dose statin has fewer adverse effects and induces less allograft dysfunction than high-dose statin therapy.

Our study has some limitations. First, it lacks randomization to compare ezetimibe plus low-dose statin with high-dose statin monotherapy. Second, the observation period was short and the study population was relatively small, which meant that we did not observe a beneficial effect of statin on reducing proteinuria or hsCRP levels.

In conclusion, the combination of ezetimibe and low-dose statin is an effective primary lipid-lowering therapy in renal transplant patients. This treatment may help more transplant patients to achieve the optimal LDL-C target compared to statin monotherapy.

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The Efficacy and Safety of Ezetimibe and Low-Dose Simvastatin as a Primary Treatment for Dyslipidemia in Renal Transplant Recipients

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Dyslipidemia, a major complication in renal transplant patients, increases the risk of cardiovascular disease (CVD) [ 1, 2], which is a major cause of morbidity and mortality in the renal transplant population [ 3].

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Título:

Efectos de la terapia combinada de reducción de lípidos sobre la variabilidad del colesterol de lipoproteínas de baja densidad y los eventos adversos cardiovasculares en pacientes con síndrome coronario agudo

Año:2021
Tipo de estudio : Ensayo controlado aleatorizado
Resultados: antes del tratamiento, no hubo diferencias significativas en el colesterol total (CT), colesterol de lipoproteínas de alta densidad (HDL-C), CK, ALT, MMP-9, hsCRP y LDL-C entre los dos grupos (P > 0,05) . Después de 6 meses, 12 meses y 24 meses de tratamiento, TC, HDL-C, CK, ALT, MMP-9, hsCRP y LDL-C mejoraron en ambos grupos, y TC, HDL-C, CK, ALT, MMP- 9, hsCRP y LDL-C en el grupo de observación obtuvieron mejores resultados que los del grupo de control con una diferencia significativa (P < 0,05). En el transcurso del tratamiento, se comparó la seguridad del fármaco de los dos grupos (P > 0,05), y la incidencia de eventos adversos cardiovasculares en el grupo de observación fue significativamente menor que en el grupo de control (6,59 % frente a 11,96 %) ( p < 0,05).

Conclusión: La terapia combinada con atorvastatina y ezetimiba potencialmente proporciona efectos notables en términos de tratamiento del síndrome coronario agudo, controlando la variación de LDL-C, aliviando el estado inflamatorio y reduciendo la incidencia de eventos adversos cardiovasculares con un perfil seguro. Los fármacos hipolipemiantes combinados se consideran enfoques válidos y alternativos para la práctica clínica amplia.

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References

1. 2.
Haraldsson I, Gan LM, Svedlund S, Torngren K, Westergren HU, Redfors B, et al. PROspective evaluation of coronary FLOW reserve and molecular biomarkers in patients with established coronary artery disease the PROFLOW-trial: cross-sectional evaluation of coronary flow reserve. Vasc Health Risk Manag. 2019;15:375-84.

Article Google Scholar

2. 3.
Nardin M, Verdoia M. Impact of active smoking on the immature platelet fraction and its relationship with the extent of coronary artery disease. Eur J Clin Investig. 2019;50:e13181.

Google Scholar

3. 7.
Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG, Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 23;64(24):e139-e228. https://doi.org/10.1016/j.jacc.2014.09.017. Epub 2014 Sep 23. Erratum in: J Am Coll Cardiol. 2014 Dec 23;64(24):2713-4. Dosage error in article text. PMID: 25260718.

4. 15.
Liu P, Jiang J, Li J, Hong T, Zhang Y, Yu R, et al. Intensive statin therapy for Chinese patients with coronary artery disease undergoing percutaneous coronary intervention (ISCAP study): rationale and design. Catheter Cardiovasc Interv. 2012;79(6):967-71.

Article Google Scholar

5. 17.
Zhu Y, Hu H, Yang J, Yao Q, Xu H, Yu Y, et al. The efficacy and safety of statin in combination with ezetimibe compared with double-dose statin in patients with high cardiovascular risk: a meta-analysis. Bosn J Basic Med Sci. 2019;20:169.

Google Scholar

Download references

Acknowledgements

We thank the participants of the study.

Funding

This study was supported by 2017 Clinical Medicine Excellent Talents Training Fund from Hebei Provincial Government (No. HBWJ2017BJ50).

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Compliance with Ethics Guidelines

The study was approved by the ethics committee of the First Hospital of Hebei University (no. 20190589). All participants signed informed consent. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.

Disclosures

Huilian Tan, Ling Liu, Qinghou Zheng, Dahong Zhang, Qian Liu, Dong Cui, Lei Gao, Zhen Wang, Wen-Lei Wang and Jun Liu have nothing to disclose.

Authorship Contributions

HTL, LL and JL contributed to the design of the study. QZ, DZ, QL, DC and ZW dealt with patients' follow-up and contributed to the analysis. QZ, DZ and QL contributed to the interpretation of data. HTL and WW drafted the manuscript. All the authors critically revised the manuscript and gave final approval and agree to be accountable for all aspects of the work, ensuring both its integrity and accuracy.

Data Availability

All data generated or analyzed during this study are included in this published article/as supplementary information files.

Author information

Author notes

Huilian Tan and Ling Liu contributed equally to this paper.

Affiliations

1. Department of Cardiology, First Hospital of Hebei Medical University, Shijiazhuang, China

Huilian Tan, Ling Liu, Qinghou Zheng, Dahong Zhang, Qian Liu, Dong Cui, Lei Gao, Zhen Wang & Jun Liu

2. Department of Neurosurgery, Emergency General Hospital, Beijing, China

Wen-Lei Wang

Corresponding author

Correspondence to Jun Liu.

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Tan, H., Liu, L., Zheng, Q. et al. Effects of Combined Lipid-Lowering Therapy on Low-Density Lipoprotein Cholesterol Variability and Cardiovascular Adverse Events in Patients with Acute Coronary Syndrome. Adv Ther 38, 3389-3398 (2021). https://doi.org/10.1007/s12325-021-01741-7
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Keywords

Atorvastatin

Ezetimibe

Acute coronary syndrome

LDL-C variability

Cardiovascular adverse events

# data[].attributes.attachment_link.title
Effects of Combined Lipid-Lowering Therapy on Low-Density Lipoprotein Cholesterol Variability and Cardiovascular Adverse Events in Patients with Acute Coronary Syndrome - Advances in Therapy

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Introduction To investigate the effect of combined lipid-lowering therapy on low-density lipoprotein cholesterol (LDL-C) variability and cardiovascular adverse events in patients with acute coronary syndrome (ACS).

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https://www.tandfonline.com/doi/abs/10.1185/03007995.2013.842165?journalCode=icmo20

TITULO: Seguridad y eficacia del tratamiento con estatinas solas y en combinación con fibratos en pacientes con dislipidemia: metaanálisis

OBJETIVO: Comparar la seguridad y la eficacia de las estatinas solas versus estatinas más fibratos en pacientes con dislipidemia.

TIPO DE ESTUDIO: Metaanálisis

AÑO: 2014

RESULTADOS: En el análisis de eficacia, una combinación de estatinas y fibratos proporcionó reducciones significativamente mayores en el colesterol total (SE = 0,430; IC 95% 0,315-0,545), colesterol LDL (SE = 0,438; IC 95% 0,321-0,555) y triglicéridos ( SE = 0,747; IC 95% 0,618-0,876), y un aumento significativamente mayor del colesterol HDL (SE = 0,594; IC 95% 0,473-0,715) que el tratamiento con estatinas solas. En el análisis de seguridad, el tratamiento con estatinas solas se asoció con una reducción significativa en el número de eventos adversos totales (RR = 0,665; IC 95 % 0,539-0,819), eventos adversos relacionados con el hígado (RR = 0,396; IC 95 % 0,206- 0,760) y eventos adversos relacionados con el riñón (RR = 0,146; IC 95% 0,075-0,285).

CONCLUSIONES: Sugerimos que el tratamiento con estatinas más fibratos proporciona beneficios clínicos sobre el tratamiento con estatinas solas, pero el aumento de los riesgos, especialmente de efectos secundarios hepáticos o renales, debe controlarse cuidadosamente.

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Safety and efficacy of statin treatment alone and in combination with fibrates in patients with dyslipidemia: a meta-analysis

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(2014). Safety and efficacy of statin treatment alone and in combination with fibrates in patients with dyslipidemia: a meta-analysis. Current Medical Research and Opinion: Vol. 30, No. 1, pp. 1-10.

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TITULO:Eficacia y seguridad comparativas de ciprofibrato y bezafibrato de liberación sostenida en pacientes con hiperlipidemia tipo II

TIPO DE ESTUDIO: ENSAYO CLINICO
AÑO: 1996
La eficacia hipolipemiante y la seguridad del ciprofibrato se compararon con una formulación de liberación sostenida de bezafibrato (Bezalip Mono) en 174 pacientes con hiperlipidemia tipo II.
Las concentraciones de colesterol de lipoproteínas de alta densidad aumentaron significativamente con ambos fármacos (19,6 % con ciprofibrato, 24,9 % con bezafibrato), pero las diferencias entre los fármacos no fueron significativas. Ambos fármacos fueron bien tolerados, siendo el dolor de cabeza el evento adverso más informado.
https://pubmed.ncbi.nlm.nih.gov/9015467/

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Abstract

The hypolipidaemic efficacy and safety of ciprofibrate were compared with a sustained-release formulation of bezafibrate (Bezalip Mono) in 174 patients with type II hyperlipidaemia. This multicenter, open, parallel-group study was conducted in general practice. A total of 83 patients received 100 mg ciprofibrate once daily and 91 received 400 mg bezafibrate once daily for eight weeks. Concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured at baseline (after stabilisation on a lipid-lowering diet) and after eight weeks. Safety was assessed from reports of adverse events and by measuring haematological and biochemical parameters. After eight weeks, ciprofibrate produced a significantly greater decrease in total cholesterol (-17.8% vs -12.5%), low-density lipoprotein cholesterol (-22.4% vs -17.2%), and triglycerides (-33.9% vs -26.1%). High-density lipoprotein cholesterol concentrations were increased significantly by both drugs (19.6% with ciprofibrate, 24.9% with bezafibrate) but the differences between drugs were non-significant. Both drugs were well tolerated, with headache the most widely reported adverse event.

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hyperlipoproteinemia type ii / drug therapy*

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national center for biotechnology information

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Comparative efficacy and safety of ciprofibrate and sustained-release bezafibrate in patients with type II hyperlipidaemia - PubMed

# data[].attributes.attachment_link.description
The hypolipidaemic efficacy and safety of ciprofibrate were compared with a sustained-release formulation of bezafibrate (Bezalip Mono) in 174 patients with type II hyperlipidaemia. This multicenter, open, parallel-group study was conducted in general practice. A total of 83 patients received 100 mg ...

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126440/?fbclid=IwAR0-%20apcR_yidV5Z3nIToN8SJxtsoI5CMectmY_0BPIEUAAru4r73TnzLzQk

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Abstract

Keywords: Dyslipidemia, Hypercholesterolemia, Statin

INTRODUCTION

Hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors (commonly known as statins) have been one of the most widely prescribed groups of drugs in the world since their introduction to the market more than twenty years ago. Currently, there are six statin drugs available on the market - pitavastatin, atorvastatin, rosuvastatin, pravastatin, simvastatin and fluvastatin. Because pitavastatin is more commonly prescribed in Asian patients, trial results are more generalizable to the wider Asian population.

Statins inhibit HMG-CoA, which is a rate limiting step in cholesterol biosynthesis. Statin therapy has been shown to be effective in lowering low density lipoprotein cholesterol (LDL-C) levels 20-50%, as well as lowering triglyceride levels 10-20% and causing a possible rise in serum high density lipoprotein cholesterol (HDL-C) levels (5-10%).⁻ Despite growing interest in the non-cardiovascular benefits of statins, there has so far been little evidence to support their use in this setting.

There is a strong body of evidence supporting the cardiovascular benefits of stating therapy. A January 2013 Cochrane Review article based on 18 randomised control trials with a total of 56,934 participants found that statin therapy reduced all-cause mortality [odds ratio (OR) 0.86, 95% confidencre Interval (CI) 0.79-0.94], reduced fatal and non-fatal cardiovascular events [relative risk (RR) 0.75 95% CI 0.67-0.80], and reduced the incidence of fatal and non-fatal stroke (RR 0.78, 95% CI 0.68-0.89). The Cholesterol Treatment Trialists' (CTT) Collaboration in 2010 performed a meta-analysis of 26 trials (21 comparing statins to placebo and five comparing low and high intensity statin therapy), with a total of more than 170,000 participants and a median follow-up of nearly five years. This meta-analysis found an overall reduction in all-cause mortality of 10% for every 1.0 mmol/L reduction in LDL-C levels (RR 0.90, 95% CI 0.87-0.93) (p < 0.001). Additionally, there were significant reductions in major vascular events including both myocardial infarction and ischaemic stroke. Due to the overwhelming body of evidence supporting its use, statin therapy is recommended according to the guidelines of the American Heart Association and the European Society of Cardiology.

Recently, concern has been expressed regarding the over-prescription of statin drugs as well as the potential for severe adverse effects from statin therapy. This has resulted in several patients ceasing statin therapy amid questions about the potential risk of long-term statin use. The aim of this article is to the review the current literature regarding the overall safety of statin therapy.

COMPARISON OF PITAVASTATIN TO OTHER STATINS

Pitavastatin is a fully synthetic HMG-CoA reductase inhibitor, and one of the most widely prescribed statins in Asia. Compared to other statin drugs, pitavastatin use showed a greater increase in patient HDL-C levels compared to atorvastatin in a head-to-head randomized controlled trial at 52 weeks in female patients with glucose intolerance and high LDL-C levels. The CHIBA trial assessed the efficacy of pitavastatin 2 mg vs. atorvastatin 10 mg in 201 Japanese patients with hypercholesterolemia, finding an equivalent reduction in LDL-C levels in both statins. A head-to-head trail comparing pitavastatin (2 mg/day) to atorvastatin (10 mg/day) and rosuvastatin (2.5 mg/day) in patients with high LDL-C levels showed that pitavastatin was comparable to the other two statins with regards to both LDL-C reduction and safety. The LIVES study is the largest post-market surveillance investigation assessing real world outcomes and safety in over 20,000 Japanese patients subsequent to treatment with pitavastatin, with follow-up at 104 weeks. The authors found that pitavastatin demonstrated a consistent reduction in LDL-C (31.3%) and triglycerides (21%), and an increase in HDL-C levels (5.9%) with no significant adverse events.

MUSCULOSKELETAL

Nearly all of the statin drugs are associated with musculoskeletal side effects. Myalgia is the most common symptom, and myositis is less common and associated with a rise in creatine kinase (CK). Rhabdomyolysis is the most severe musculoskeletal form observed, with a rise in CK greater than 10x the upper limit of normal with associated features including myoglobinuria, renal impairment and serum electrolyte abnormalities.

Overall, the rates of severe musculoskeletal side effects from the current statin drugs are low., There are variable rates of myopathy reported in the literature ranging from 0.1-10%, but it must be noted that many of these studies use different definitions, have variable methods of data collection and have high rates of reporting bias. Khan et al. (2015) assessed the patient characteristics of more than 10,000 statin users in the United States. Myalgia was a common cause of discontinuation, with over 60% of patients who had ceased statin therapy reporting musculoskeletal side effects compared with only 25% in current statin users.

Of the nine trials included in the Cochrane Review which reported musculoskeletal side effects, 3551 participants out of a total of 37,939 patients developed symptoms of myalgia (9.4%). There was no evidence of excess risk with a pooled estimate of 1.03 (95% CI, 0.97-1.09). Rhabdomyolysis occurred very rarely, affecting just 3 out of 19,410 participants in a total of six trials (0.02%). The Heart Protection Study which investigated the use of simvastatin compared with placebo in a group of more than 20,000 patients reported an annual myopathy risk of 0.01%, with a total of five cases of rhabdomyolysis in the treatment arm compared with three in the placebo arm. Forty-nine patients (0.5%) in the statin arm and 50 (0.5%) in the placebo arm had ceased therapy due to side effects. The large Cholesterol Treatment Trialists' meta-analyses found overall rates of rhabdomyolysis were 1 per 10,000 patients in both the statin and placebo groups. The more intensive statin group had a slightly higher risk of rhabdomyolysis (4 per 10,000) compared with 2 per 10,000 in the less intensive group. The LIVES observational study reported only one case of rhabdomyolysis and one case of muscle weakness amongst 20,000 patients treated with pitavastatin. Although the overall incidence of adverse effects was 10.4%, the proportion of patients who had myalgia and other musculoskeletal side effects was not reported.

All of the major statin trials including large meta-analyses have concluded that severe musculoskeletal side effects from statin use are rare, and that the overall benefits of statin therapy outweigh this small risk (with current recommendations for close clinical monitoring of patients. The exact mechanism of statin-related myopathy is unknown, though it involves a complex interplay of drug, patient-related factors and concomitant therapy. Statins have been associated with mitochondrial dysfunction associated with a reduction in co-enzyme Q10 levels., Another mechanism is the lowering of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, which are end products of the mevalonate pathway and thus involved in maintenance of cell growth. Statins have also been shown to alter cholesterol content in skeletal muscle cells which alters the flow of ion channels including calcium, making them vulnerable to cell injury and death. Drug-related factors increase the risk of statin toxicity; more intensive statin therapies and higher doses have been associated with higher rates of toxicity. Although more potent statins were assumed to have higher rates of myopathy, this phenomenon has not been clearly demonstrated. The interactions between statins and other drugs is a very strong risk factor in the development of toxicity.

Statin rechallenge remains a clinical dilemma in patients who develop musculoskeletal side effects. Importantly, such statin use has to be individualised to every patient, and there are several factors which warrant consideration. A recent study found that increased age, body mass index and female gender were all associated with poor tolerance to statin rechallenge. Statin-related myalgia should only be diagnosed following clinical assessment to exclude other causes of myalgia and weakness. It is not uncommon for elderly patients to have underlying arthritis, tendonitis or neuropathy which may be misdiagnosed as myalgia related to statins, and rare inflammatory myopathy should also be excluded. The overall cardiovascular risk for each patient should be assessed so clinicians have a better understanding of the larger risk vs. benefit analysis, which is crucial for informed consent. A recent randomised trial did not find any improvement in statin-related myalgia with the addition of co-enzyme Q10. Fung et al. (2012) reported outcomes in patients attending a large lipid clinic, describing overall rates of statin-related myopathy in 108/1056 patients. However, further clinical assessment showed that 55 other patients had musculoskeletal symptoms that were unrelated to statin therapy. Interestingly, the patients with statin-related myopathy were more likely to be female (62%), with a higher median erythrocyte sedimentation rate (14 vs. 8 mm/hr, p = 0.035) and were more likely to be prescribed simvastatin (98.1%). There were similar rates of myopathy with rechallenge using atorvatstain, rosuvastatin, pravastatin and fluvastatin (between 60-80%), although the study was not sufficiently large to conclusively answer this clinical question. Monotherapy with ezetimibe or fibrates was associated with lower rates of myopathy (between 17-31%). The authors commented that "...atorvatstain and rosuvastatin were both reasonable choices. They have an added advantage of long half-lives enabling alternate day or twice weekly dosing strategy further minimizing the occurrence of statin myopathy."

Based on currently available evidence, it is reasonable for patients with mild musculoskeletal complaints or established mild rises in CK to continue with statin therapy at lower dosing regimens, with close clinical monitoring. Patients with serious adverse effects such as rhabdomyolysis should not continue with statin therapy, and monotherapy with ezetimibe could be considered. For the spectrum of patients whose circumstances fall in between these two categories, we would suggest careful clinical assessment to exclude other causes of myalgia. Treatment decisions need to be based on the cardiovascular risk of each patient. If cardiovascular risk is high then we would suggest rechallenging with another statin such as atorvatstatin or rosuvastatin with a modified dosing regimen (such as twice weekly) with close clinical observation ().

Table 1

Female gender

Hypothyroidism

Alcohol abuse

Polypharmacy

Multisystem diseases e.g. chronic kidney disease, diabetes mellitus, chronic liver disease

Specific drug interactions (see section of pharmacokinetics)

HEPATIC DYSFUNCTION

Statin therapy has been associated with elevated hepatic transaminases in up to 1-3% of patients. This usually is dose dependent and occurs within the first three months of commencing therapy, and is not usually associated with any long-term hepatic dysfunction. There also appears to be no significant differences amongst the different statin drugs with regards to rates of hepatotoxicity.

Russo et al. reported a total of 22 cases involving statin use in a prospective registry of 1188 patients with drug-induced liver injury between 2004 and 2012. Of these patients, the majority were female (68%), with a varied latency of onset from 34 days to 10 years (median 155 days) associated with a variety of cellular injury mechanisms. Interestingly, they reported that the condition of four of these patients progressed to chronic liver disease, mainly of the autoimmune phenotype. A Cochrane Review more than 18 trials examining the role of statin therapy in primary prevention reported weak evidence of an increased risk of elevated hepatic enzymes with statin use (RR 1.16 95% CI 0.87-1.54). Another large meta-analyses focusing on the side effect profile of 35 statin trials found a slightly increased rate of elevation in liver enzymes with statin use compared with placebo (1.4% vs. 1%, 4.2 patients per 1000 cases). The LIVES study reported liver function test derangement in two patients while another seven patients had liver disorders or hepatic dysfunction of a different nature related to pitavastatin use (of the 20,000 patients included).

The clinical significance of this "transaminitis" is uncertain, with the vast majority of patients being asymptomatic. Cases of hepatic failure due to statin use have otherwise been exceedingly rare, with case reports providing the primary bulk of evidence. Although it is useful to assess baseline liver function, routine monitoring of liver function tests is not recommended. Patients with mild derangement of LFT's use can safely continue statin therapy with close monitoring.

DIABETES MELLITUS

Statins have been shown to increase the risk of diabetes mellitus in that they can disrupt insulin signalling pathways, affect pancreatic beta cell function and may contribute to increased insulin resistance., A meta-analysis by Satter et al. of 13 trials found an increased risk of new onset diabetes after a median four-year follow up of 9% (HR 1.09, 95% CI 1.02-1.17). This correlated to a new case of diabetes mellitus for every 255 patients treated for at least four years with statin therapy., A meta-analyses in 2011 by Preiss et al. of five large randomised control trials with 32,752 patients found increased rates of diabetes with intensive dose statin regimen compared with moderate dose regimen (1449 vs. 1300 patients). Overall statin therapy was associated with an increased risk of new onset diabetes (OR 1.12 95% CI 1.04-1.22). A recent meta-analysis found that the risk of diabetes mellitus was increased with the use of more potent statins at higher doses. Hyun et al. (2015) reported an increased insulin resistance in non-dyslipidemic Asian patients following statin use.

Interestingly, not all statin drugs have been shown to be diabetogenic. Of the 1197 patients in the LIVES study who had diabetes mellitus as well as hypercholesterolemia, treatment with pitavastatin was not found to affect glucose metabolism. However, 1 patient had new onset diabetes mellitus during follow-up. A reduction in HbA1c at 104 weeks was noted in patients who were on treatment for diabetes at baseline (reduction of 0.28%, p < 0.001). Multivariate analysis showed that the percentage change in LDL and triglyceride levels were all clinical factors which influenced the decrease in HbA1c.

There is evidence to suggest that some statins are potentially diabetogenic, and the risk appears to be dose-related. However, diabetic patients are one of the groups that benefits most from statin therapy with regards to cardiovascular risk. There is no convincing evidence indicating that statin therapy in diabetics may contribute to worsening glycaemic control. Overall, the cardiovascular protective benefits of statins outweigh the concerns associated with risk of diabetes mellitus. It is important that patients are informed of this risk prior to commencing therapy and routine monitoring of blood glucose levels is recommended.

RENAL

Statins can influence the kidney in two main pathways. Rhabdomyolysis can induce tubular obstruction causing tubular injury and ischaemia. Statin therapy can be associated with a benign proteinuria due to inhibition of the tubular reabsorption of small molecular weight proteins. The clinical significance of this mild proteinuria is unknown, as the protein differs from that of other glomerular diseases. There has been no evidence of long-term renal dysfunction from statin therapy.

There is some evidence regarding the protective effects of statin therapy. A large meta-analysis examining 27 studies with over 39,000 patients conducted by Sandhu et al. (2006) found a statistically significant reduction in the decline of glomerular filtration rate (GFR) (0.93 ml/min per year, 95% CI 0.10-1.76) in patients on statin therapy compared to controls in patients with cardiovascular disease. There was no significant difference in patients with diabetic or hypertensive kidney disease. Bianchi et al. (2004) also noted a reduction in proteinuria with the addition of atorvastatin to the combination with angiotensin converting enzyme inhibitors and angiotensin-converting enzymes. The LIVES study noted a rise in eGFR of 5.4 ml/min) at the end of the follow-up period with the use of pitavastatin. Multivariate analysis showed that the absence of proteinuria at baseline and an increase in HDL levels were associated with improvement in GFR. More recently there have been negative trials, primarily the PREVEND-IT, ESPLANADE and PLANET trials, that all found no reduction in proteinuria with statin use.

There remains concern regarding possible acute kidney injury following the introduction of statin therapy. Dormuth et al. conducted a large real-world retrospective observational analysis of more than 2 million patients on statin therapy with no prior history of chronic kidney disease, and another 59,636 patients with chronic kidney disease. Within 4 months of statin therapy there were 4691 hospitalisations for acute kidney injury (AKI) in patients with no prior kidney disease (0.2%), and 1896 hospitalisations in those patients with known chronic kidney disease (3%). Patients with high potency statins were 34% more likely to be hospitalised with AKI for patients with no prior kidney disease compared to low intensity regimens. A similar finding was not significant in patients with chronic kidney disease. The authors found that this increase in AKI risk was strongest in the first 4 months following initiation of statin therapy.

There is a large proportion of patients on statin therapy with underlying chronic kidney disease (CKD). Chronic kidney disease is a strong predictor and risk factor for cardiovascular disease. Based on the large 4-D and AURORA trials, there is currently no significant evidence to suggest a protective role of statin therapy for patients on dialysis. Both of these trials found no significant benefit in overall mortality or cardiovascular outcomes., However, in patients who are not dialysis-dependent, statins have been shown to improve cardiovascular outcomes. Overall, statins are well-tolerated in patients with CKD with no significant increase in adverse events. The UK-HARP-1 study which investigated the safety of statin use in the CKD population found no significant increase in CK levels or LFT derangement. Other large trials investigating statin use in this population have also reported similar findings., It is worth noting that combination therapy with ezetimibe was associated with higher rates of myalgia in the SHARP study. We would suggest continued statin therapy in patients with CKD with clinical monitoring for adverse effects similar to non-CKD patients. We would avoid the use of high dose statin therapy or combination therapy with fibrates or ezetimibe unless patients have increased cardiovascular risk, or have not achieved adequate LDL level reduction. In the dialysis population we would not suggest commencing statin therapy in patients with mildly elevated LDL levels. Statin therapy should be considered in patients following acute coronary syndrome or in patients with high cardiovascular risk, although vigilance is required to monitor for adverse effects. We would avoid the use of high dose statins or combination therapy with fibrates/ezetimibe, despite the lack of conclusive evidence suggesting an increase in complication rates.

MALIGNANCY

The role of statins in malignancy is somewhat clouded by an array of mixed evidence suggesting both a protective role as well as being a potential risk factor. Animal studies have shown the link between high dose statin therapy and liver tumours in rodent models. However a recent clinical trial showed a reduction in liver cancers with statin use. Both the Cochrane Review of statin therapy in primary prevention and the Cholesterol Treatment Trialists' meta analyses have not shown any increase in cancer risk with statin therapy., The Heart Protection study and the West Scotland Coronary Prevention Study (WOSCOPS), which have extended follow-up periods of more than 10 years, have also not shown any difference in the rates of malignancy with long-term statin therapy., A recent meta-analysis suggested that long-term statin use reduced the risk of some haematological malignancies. Statin use was associated with a reduction in malignancy risk in post-menopausal women in the Women's Health Initiative. The sources of evidence will continue to improve once long-term follow-up data of the early statin trials are published. However, it is reassuring that long-term statin therapy appears to be safe for the majority of patients.

NEUROLOGICAL

There have been case reports of statin use associated with peripheral neuropathy, mood symptoms and irritability. To date, there is no proven association between statin use and increase in suicide. Despite some early reports of an increase in haemorrhagic stroke with statin use, this has not been substantiated in larger clinical trials and the protective aspects from recurrent ischaemic stroke outweigh these potential risks.,

There has been some concern regarding cognitive dysfunction in patients on long-term statin therapy. Interestingly, statins have also been shown in some retrospective studies to reduce the risk of Alzheimer's disease. The mechanisms that may be involved include the interaction with cholesterol and amyloid processing, as well as the indirect effect via stroke prevention. A recent systematic review did not find any overall increased risk of dementia with long-term statin use.

RESPIRATORY

There have been case reports of interstitial lung disease associated with statin use. The mechanism for cellular injury is not well understood, and patients have usually responded to corticosteroid or immunosuppressive therapy. A recent cohort study did not demonstrate any increased risk of interstitial lung disease with statin use. Statins can safely be prescribed in patients with chronic respiratory diseases, and routine monitoring of lung function is not recommended in the absence of symptoms.

DRUG INTERACTIONS

Clinically, it is important to note that statin drugs have multiple potential drug interactions which may increase the risk of myopathy and other drug toxicities. All statin drugs other than pravastatin are metabolised by the cytochrome p450 group of enzymes. Inhibitors of these enzymes may increase levels of statins and may be associated with an increased risk of toxicity. Atorvastatin, simvastatin and pravastatin are also substrates for P-glycoprotein, which are active transport drug channels in the gastrointestinal tract. A summary of common drug interactions and pharmacokinetic properties is provided in .

COMMON DRUG INTERACTIONS

* The combined use of statin and fibrate drugs for mixed dyslipidemia is associated with an increased risk of myopathy up to 5%. Gemfibrozil interacts with multiple statin drugs via the CYP3A4 enzyme and glucuronidation pathways, and should be avoided.

* Grapefruit juice is a potent inhibitor of cytochrome p450 3A4 and can increase the risk of toxicity with atorvastatin, lovastatin and simvastatin. Patients should be advised to avoid grapefruit juice if on these medications.

* Pravastatin has the least drug interactions amongst the statin drugs and should be considered in patients who are on immunosuppression post-transplantation and in HIV patients on protease inhibitors. Due to the interaction with cyclosporine, other statin drugs if prescribed should be low dosing regimens with frequent clinical monitoring for side effects.

* Anti-epileptic drugs such as phenytoin, carbamazepine and phenobarbitone are potent inducers of cytochrome p450 enzymes and may be associated with reduced statin drug levels. A dose adjustment or a switch to pravastatin may be required in these patients.

SUMMARY

* Hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors, commonly called statins are one of the most commonly prescribed medications in Asia.

* Statins are the most potent drugs that lower LDL cholesterol.

* There is extensive evidence to suggest that statin therapy has significant mortality and morbidity benefit for both primary and secondary prevention from cardiovascular disease.

* Myalgia is the most common side effect from statin use with rates from 1-10% of patients.

* Rhabdomyolysis is the most serious adverse effect from statin use and is very rare (less than 0.1%).

* The most common risk factors for statin-related myopathy include hypothyroidism, polypharmacy, alcohol abuse and patients with multiple medical co-morbidities.

* Derangement in liver function tests is common, affecting up to 1% of patients; however the clinical significance of this is unknown.

* Some statin drugs are potentially diabetogenic and the risk appears to increase in those on higher doses. Pitavastatin is not associated with an increased risk of diabetes mellitus.

* Statins have not be proven to increase the risk of malignancy, dementia, mood disorders, interstitial lung disease and acute interstitial nephritis.

* Statins have multiple drug interactions, primarily those which interact with the cytochrome p450 enzymes.

* Statins can safely be used in patients with CKD, although clinicians should be cautious in using high-dose statins and combination therapy with fibrates/ezetimibe.

* Pravastatin has the least drug interactions amongst the statin drugs.

* Overall statin drugs appear to be safe in the vast majority of patients and the protective benefits of statin therapy far outweigh the potential risks.

CONFLICTS OF INTEREST

None to declare.

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Statin Therapy: Review of Safety and Potential Side Effects

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Keywords: Dyslipidemia, Hypercholesterolemia, Statin Hydroxymethyl glutaryl coenzyme A reductase (HMG-CoA) inhibitors (commonly known as statins) have been one of the most widely prescribed groups of drugs in the world since their introduction to the market more than twenty years ago. Currently, there are six statin drugs available on the market - pitavastatin, atorvastatin, rosuvastatin, pravastatin, simvastatin and fluvastatin.

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https://www.bmj.com/content/bmj/374/bmj.n1537.full.pdf
TITULO: Asociaciones entre estatinas y eventos adversos en la prevención primaria de enfermedades cardiovasculares: revisión sistemática con metanálisis por pares, en red y de dosis-respuesta
AURTOR: Ting C, et al; 2021
TIPO DE ESTUDIO: Revisión sistemática con metanálisis.
RESULTADOS: Las estatinas se asociaron con un mayor riesgo de síntomas musculares autoinformados (21 ensayos, razón de probabilidad 1,06 (intervalo de confianza del 95 %: 1,01 a 1,13); diferencia de riesgo absoluto 15 (intervalo de confianza del 95 %: 1 a 29)), disfunción hepática (21 ensayos , razón de probabilidad 1,33 (1,12 a 1,58); diferencia de riesgo absoluta 8 (3 a 14)), insuficiencia renal (ocho ensayos, razón de probabilidad 1,14 (1,01 a 1,28); diferencia de riesgo absoluta 12 (1 a 24)) y afecciones oculares (seis ensayos, razón de probabilidad 1,23 (1,04 a 1,47); diferencia de riesgo absoluto 14 (2 a 29)) pero no se asociaron con trastornos musculares clínicamente confirmados o diabetes. El aumento de los riesgos no superó la reducción del riesgo de eventos cardiovasculares importantes. Atorvastatina, lovastatina, y rosuvastatina se asociaron individualmente con algunos eventos adversos, pero se encontraron pocas diferencias significativas entre los tipos de estatinas.
CONCLUSIONES:  Para la prevención primaria de enfermedades cardiovasculares, el riesgo de eventos adversos atribuibles a las estatinas fue bajo y no superó su eficacia en la prevención de enfermedades cardiovasculares, lo que sugiere que el balance beneficio-daño de las estatinas es generalmente favorable.

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TÍTULO: Incidencia de rabdomiólisis hospitalizada con uso de estatinas y fibratos en una población asegurada de EE. UU.

TIPO DE ESTUDIO: Estudio comparativo

AÑO: 2011

RESULTADOS: Hubo 1.116.805 pacientes que iniciaron la terapia con estatinas y/o fibratos, con 2,4 millones de años-persona de observación. Se confirmaron setenta casos de rabdomiólisis hospitalizada. Los análisis ajustados mostraron un aumento persistente del riesgo de rabdomiólisis con la terapia combinada, mientras que la terapia con estatinas y fibratos sola mostró aumentos similares y no significativos en el riesgo. La TIR(razones de tasa de incidencia) ajustada para una estatina y fenofibrato fue de 3,26 (IC del 95%: 1,21 a 8,80), mientras que la TIR(razones de tasa de incidencia) ajustada para una estatina y gemfibrozilo fue de 11,93 (IC del 95%: 3,96 a 35,93) versus el tratamiento con estatinas sola.

CONCLUSIONES: La incidencia de rabdomiólisis hospitalizada es rara, pero mayor en pacientes con tratamiento concomitante con estatinas-fibrato que en pacientes con tratamiento con estatinas sola.

# data[].attributes.attachment_link.title
Incidence of hospitalized rhabdomyolysis with statin and fibrate use in an insured US population - PubMed

# data[].attributes.attachment_link.description
The incidence of hospitalized rhabdomyolysis is rare, but higher in patients with concomitant statin-fibrate treatment than in patients on statin therapy alone. The rate found in this study is consistent with the known profile of the statin-fibrate treatment option for mixed dyslipidemia.

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https://pubmed.ncbi.nlm.nih.gov/18425988/
TÍTULO: La seguridad de la rosuvastatina en comparación con otras estatinas en más de 100 000 usuarios de estatinas en la atención primaria del Reino Unido.
AÑO DE PUBLICACIÓN: 2008
TIPO DE ESTUDIO: Comparativo
RESULTADOS: Estudiamos a 10 289 pacientes que tomaban rosuvastatina y 117 102 que tomaban otras estatinas. En los que tomaban estatinas distintas de rosuvastatina, la incidencia de miopatía fue de 0,4 (intervalo de confianza (IC) del 95 %: 0,1-0,9), de rabdomiólisis de 0,4 (IC del 95 %: 0,1-0,9) y de daño hepático agudo de 0,4 (95 % %IC: 0,2-1,0), por 10 000 años-persona. Se identificaron catorce casos de insuficiencia renal aguda (dos entre usuarios de rosuvastatina y 12 entre usuarios de otras estatinas).
CONCLUSIONES: No encontramos evidencia de que los pacientes a los que se les prescribió rosuvastatina tuvieran un mayor riesgo de estos resultados que los pacientes a los que se les prescribieron otras estatinas. No hubo evidencia de aumento de la mortalidad entre los pacientes que tomaban rosuvastatina, incluso después de tener en cuenta la edad, el sexo y el uso previo de estatinas.

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Abstract

Purpose: To compare mortality and the incidence of hospitalization for myopathy, rhabdomyolysis, acute renal failure and acute liver injury in patients receiving rosuvastatin and those taking other statins.

Methods: Patients prescribed a statin that they had not used before were selected from the UK General Practice Research Database (GPRD) and followed up from 1 April 2003 to 31 December 2005.

Results: We studied 10 289 patients on rosuvastatin and 117 102 taking other statins. No cases of myopathy, rhabdomyolysis or acute liver injury occurred among rosuvastatin users. In those taking statins other than rosuvastatin, the incidence of myopathy was 0.4 (95% confidence interval (CI): 0.1-0.9), of rhabdomyolysis was 0.4 (95%CI: 0.1-0.9) and of acute liver injury was 0.4 (95%CI: 0.2-1.0), per 10 000 person-years. Fourteen cases of acute renal failure were identified (two among rosuvastatin users and 12 among other statin users). Among current users, the relative risk (RR) of acute renal failure in rosuvastatin users compared with other statin users was 1.16 (95%CI: 0.15-9.03).We identified 3232 deaths during the study period (173 in the rosuvastatin-treated group and 3059 in the other statin group). The RR of death associated with current use of rosuvastatin compared with other statins was 0.55 (95%CI: 0.44-0.68).

Conclusions: We found no evidence that patients prescribed rosuvastatin were at greater risk of these outcomes than patients prescribed other statins. There was no evidence of increased mortality among patients taking rosuvastatin, even after allowing for age, sex and prior statin use.

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primary health care / statistics & numerical data*

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national center for biotechnology information

# data[].attributes.attachment_link.title
The safety of rosuvastatin in comparison with other statins in over 100,000 statin users in UK primary care - PubMed

# data[].attributes.attachment_link.description
We found no evidence that patients prescribed rosuvastatin were at greater risk of these outcomes than patients prescribed other statins. There was no evidence of increased mortality among patients taking rosuvastatin, even after allowing for age, sex and prior statin use.

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Titulo:

Combinación de dosis fija de ácido bempedoico más ezetimiba en pacientes con hipercolesterolemia y alto riesgo de ECV tratados con terapia con estatinas máximamente tolerada

Autor: Christie Ballantyne; 2020
Tipo de estudio: Ensayo clínico
Resultados: Entre los 301 pacientes incluidos en el análisis primario, el nivel medio de colesterol de lipoproteínas de baja densidad inicial fue de 3,87 mmol/L (149,8 mg/dL). En la semana 12, la combinación de dosis fija redujo el colesterol de lipoproteínas de baja densidad (-36,2 %) significativamente más que el placebo (1,8 % (diferencia corregida con placebo -38,0 %); P < 0,001), ezetimiba sola (-23,2 %; P < 0,001) o ácido bempedoico solo (-17,2 %; P< 0,001). La combinación de dosis fija redujo los niveles de colesterol de lipoproteínas de baja densidad de manera similar en todos los subgrupos, incluidos los pacientes que recibieron terapia de alta intensidad, de otra intensidad o sin estatinas. También se observaron mejoras con la combinación de dosis fija en los criterios de valoración secundarios de la eficacia, incluida la proteína C reactiva de alta sensibilidad. En este ensayo, el tratamiento combinado de dosis fija tuvo un perfil de seguridad generalmente similar en comparación con el ácido bempedoico, la ezetimiba o el placebo.
Conclusiones: La combinación de dosis fija de ácido bempedoico y ezetimiba redujo significativamente el colesterol de lipoproteínas de baja densidad en comparación con el placebo u otras monoterapias orales y tuvo un perfil de seguridad favorable cuando se agregó a la terapia con estatinas máximamente tolerada en pacientes con hipercolesterolemia y alto riesgo de enfermedad cardiovascular.

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Affiliations

¹ Department of Medicine, Baylor College of Medicine, USA.

² Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Germany.

³ Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, UK.

⁴ Division of Endocrinology and Metabolism, St Michael's Hospital, Canada.

⁵ Louisville Metabolic and Atherosclerosis Research Center, USA.

⁶ Washington University School of Medicine, USA.

⁷ Department of Vascular Medicine, Academic Medical Centre, The Netherlands.

⁸ Esperion Therapeutics, Inc., USA.

⁹ Department of Pharmacological and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Italy.

Free PMC article

Free PMC article

Affiliations

¹ Department of Medicine, Baylor College of Medicine, USA.

² Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Germany.

³ Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, UK.

⁴ Division of Endocrinology and Metabolism, St Michael's Hospital, Canada.

⁵ Louisville Metabolic and Atherosclerosis Research Center, USA.

⁶ Washington University School of Medicine, USA.

⁷ Department of Vascular Medicine, Academic Medical Centre, The Netherlands.

⁸ Esperion Therapeutics, Inc., USA.

⁹ Department of Pharmacological and Biomolecular Sciences, University of Milan and Multimedica IRCCS, Italy.

Abstract

Aims: The aim of this study was to evaluate the low-density lipoprotein cholesterol lowering efficacy and safety of a bempedoic acid 180 mg and ezetimibe 10 mg fixed-dose combination in patients with hypercholesterolemia and a high risk of cardiovascular disease receiving maximally tolerated statin therapy.

Methods: This phase 3, double-blind clinical trial enrolled adult patients at high risk of cardiovascular disease due to atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or multiple cardiovascular disease risk factors. Patients were randomly assigned (2:2:2:1) to treatment with the fixed-dose combination, bempedoic acid 180 mg, ezetimibe 10 mg or placebo added to stable background statin therapy for 12 weeks. The primary efficacy endpoint was the percentage change from baseline to week 12 in low-density lipoprotein cholesterol.

Results: Among the 301 patients included in the primary analysis, the mean baseline low-density lipoprotein cholesterol level was 3.87 mmol/L (149.8 mg/dL). At week 12, the fixed-dose combination lowered low-density lipoprotein cholesterol (-36.2%) significantly more than placebo (1.8% (placebo-corrected difference -38.0%); P < 0.001), ezetimibe alone (-23.2%; P < 0.001) or bempedoic acid alone (-17.2%; P < 0.001). The fixed-dose combination lowered low-density lipoprotein cholesterol levels similarly across subgroups, including patients receiving high-intensity, other-intensity or no statin therapy. Improvements with the fixed-dose combination were also observed in secondary efficacy endpoints, including high-sensitivity C-reactive protein. In this trial, fixed-dose combination treatment had a generally similar safety profile compared with bempedoic acid, ezetimibe or placebo.

Conclusion: The bempedoic acid and ezetimibe fixed-dose combination significantly lowered low-density lipoprotein cholesterol versus placebo or other oral monotherapies and had a favourable safety profile when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk.

Trial registration: ClinicalTrials.gov identifier: NCT03337308.

Keywords: Bempedoic acid; LDL-cholesterol; ezetimibe; hydroxymethylglutaryl-CoA reductase inhibitors; hypercholesterolemia; hyperlipidemias; hypolipidemic agents; lipid-regulating agents.

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References

Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016; 316: 1289-1297. - PubMed

Menzin J, Aggarwal J, Boatman B, et al. Ezetimibe use and LDL-C goal achievement: a retrospective database analysis of patients with clinical atherosclerotic cardiovascular disease or probable heterozygous familial hypercholesterolemia. J Manag Care Spec Pharm 2017; 23: 1270-1276. - PubMed

Arca M, Ansell D, Averna M, et al. Statin utilization and lipid goal attainment in high or very-high cardiovascular risk patients: insights from Italian general practice. Atherosclerosis 2018; 271: 120-127. - PubMed

Ferrieres J, Gorcyca K, Iorga SR, et al. Lipid-lowering therapy and goal achievement in high-risk patients from French general practice. Clin Ther 2018; 40: 1484-1495; e22. - PubMed

Razek O, Cermakova L, Armani H, et al. Attainment of recommended lipid targets in patients with familial hypercholesterolemia: real-world experience with PCSK9 inhibitors. Can J Cardiol 2018; 34: 1004-1009. - PubMed

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anticholesteremic agents / administration & dosage*

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anticholesteremic agents / adverse effects

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cardiovascular diseases / prevention & control*

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dicarboxylic acids / administration & dosage*

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national center for biotechnology information

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Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy - PubMed

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1 Department of Medicine, Baylor College of Medicine, USA. 2 Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Germany. 3 Imperial Centre for Cardiovascular Disease Prevention, Imperial College London, UK. 4 Division of Endocrinology and Metabolism, St Michael's Hospital, Canada. 5 Louisville Metabolic and Atherosclerosis Research Center, USA.

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TITULO: Incidencia de rabdomiólisis hospitalizada con uso de estatinas y fibratos en una población asegurada de EE. UU.

AÑO: 2011
TIPO DE ESTUDIO: ECA
RESULTADOS:  Los análisis ajustados mostraron un aumento persistente del riesgo de rabdomiólisis con la terapia combinada, mientras que la terapia con estatinas y fibratos solos mostró aumentos similares no significativos en el riesgo.
CONCLUSIONES: La incidencia de rabdomiólisis hospitalaria es rara, pero es mayor en pacientes con tratamiento concomitante con estatinas y fibratos que en pacientes con tratamiento solo con estatinas.

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Incidence of hospitalized rhabdomyolysis with statin and fibrate use in an insured US population - PubMed

# data[].attributes.attachment_link.description
The incidence of hospitalized rhabdomyolysis is rare, but higher in patients with concomitant statin-fibrate treatment than in patients on statin therapy alone. The rate found in this study is consistent with the known profile of the statin-fibrate treatment option for mixed dyslipidemia.

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TITULO:

Un estudio fase IV aleatorizado, abierto, paralelo y multicéntrico para comparar la eficacia y seguridad de 10 y 20 mg de atorvastatina en pacientes asiáticos de alto riesgo con hipercolesterolemia.

TIPO DE ESTUDIO: Ensayo clínico
AÑO: 2021
RESULTADOS: Durante este ensayo clínico, ocho RAM en siete pacientes tuvieron una relación causal con el fármaco del estudio en el conjunto de seguridad (2,8 %, 7 de 249 pacientes). Se informaron dos RAM en dos pacientes del grupo de 10 mg de atorvastatina (1,6 %, 2 de 126 pacientes) y seis RAM en cinco pacientes del grupo de 20 mg de atorvastatina (4,1 %, 5 de 123 pacientes). Las RAM más frecuentes fueron mialgia (dos pacientes en el grupo de 20 mg de atorvastatina) y elevación de las enzimas hepáticas (dos pacientes en el grupo de 20 mg de atorvastatina). No hubo diferencia estadísticamente significativa en la incidencia de RAM entre los dos grupos.
CONCLUSIONES: La atorvastatina de 20 mg fue más eficaz para reducir los niveles de LDL-C en pacientes asiáticos con alto riesgo de ECV que la atorvastatina de 10 mg y también resultó en una mejoría estadísticamente significativa en la mayoría de los perfiles de lípidos. Atorvastatina 20 mg no aumentó la incidencia de RAM y fue más rentable que atorvastatina 10 mg. Por lo tanto, atorvastatina 20 mg puede ser una dosis de elección más apropiada que atorvastatina 10 mg en pacientes asiáticos con alto riesgo de ECV.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245481

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Ji Bak Kim,

Woo Hyuk Song,

Jong Sung Park,

Tae-Jin Youn,

Yong Hyun Park,

Shin-Jae Kim,

Sung Gyun Ahn,

Joon-Hyung Doh,

Yun-Hyeong Cho,

Jin Won Kim

Related PLOS Articles

has CORRECTION

Correction: A randomized, open-label, parallel, multi-center Phase IV study to compare the efficacy and safety of atorvastatin 10 and 20 mg in high-risk Asian patients with hypercholesterolemia

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Correction

Kim JB, Song WH, Park JS, Youn TJ, Park YH, et al. (2021) Correction: A randomized, open-label, parallel, multi-center Phase IV study to compare the efficacy and safety of atorvastatin 10 and 20 mg in high-risk Asian patients with hypercholesterolemia. PLOS ONE 16(10): e0259072. https://doi.org/10.1371/journal.pone.0259072 View correction

Abstract

Background

Although accumulating evidence suggests a more extensive reduction of low-density lipoprotein cholesterol (LDL-C), it is unclear whether a higher statin dose is more effective and cost-effective in the Asian population. This study compared the efficacy, safety, and cost-effectiveness of atorvastatin 20 and 10 mg in high-risk Asian patients with hypercholesterolemia.

Methods

A 12-week, open-label, parallel, multicenter, Phase IV randomized controlled trial was conducted at ten hospitals in the Republic of Korea between October 2017 and May 2019. High-risk patients with hypercholesterolemia, defined according to 2015 Korean guidelines for dyslipidemia management, were eligible to participate. We randomly assigned 250 patients at risk of atherosclerotic cardiovascular disease to receive 20 mg (n = 124) or 10 mg (n = 126) of atorvastatin. The primary endpoint was the difference in the mean percentage change in LDL-C levels from baseline after 12 weeks. Cost-effectiveness was measured as an exploratory endpoint.

Results

LDL-C levels were reduced more significantly by atorvastatin 20 mg than by 10 mg after 12 weeks (42.4% vs. 33.5%, p < 0.0001). Significantly more patients achieved target LDL-C levels (<100 mg/dL for high-risk patients, <70 mg/dL for very high-risk patients) with atorvastatin 20 mg than with 10 mg (40.3% vs. 25.6%, p < 0.05). Apolipoprotein B decreased significantly with atorvastatin 20mg versus 10 mg (−36.2% vs. −29.9%, p < 0.05). Lipid ratios also showed greater improvement with atorvastatin 20 mg than with 10 mg (total cholesterol/high-density lipoprotein cholesterol ratio, −33.3% vs. −29.4%, p < 0.05; apolipoprotein B/apolipoprotein A1 ratio, −36.7% vs. −31.4%, p < 0.05). Atorvastatin 20 mg was more cost-effective than atorvastatin 10 mg in terms of both the average and incremental cost-effectiveness ratios. Safety and tolerability of atorvastatin 20 mg were comparable to those of atorvastatin 10 mg.

Conclusion

In high-risk Asian patients with hypercholesterolemia, atorvastatin 20 mg was both efficacious in reducing LDL-C and cost-effective compared with atorvastatin 10 mg.

Citation: Kim JB, Song WH, Park JS, Youn T-J, Park YH, Kim S-J, et al. (2021) A randomized, open-label, parallel, multi-center Phase IV study to compare the efficacy and safety of atorvastatin 10 and 20 mg in high-risk Asian patients with hypercholesterolemia. PLoS ONE 16(1): e0245481. https://doi.org/10.1371/journal.pone.0245481

Editor: Giuseppe Danilo Norata, Universita degli Studi di Milano, ITALY

Received: September 8, 2020; Accepted: January 1, 2021; Published: January 22, 2021

Copyright: © 2021 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the papper and its Supporting Information files.

Funding: The sponsor (Chong Kun Dang Pharmacy Corp., Seoul, Korea) supported the supply of the investigational products, laboratory tests, and clinical research coordinator expenses.

Competing interests: This study is funded by Chong Kun Dang Pharmaceutical Corp, manufacture of; Lipilou® (atorvastatin calcium anhydrous). There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLoS ONE policies on sharing data and materials.

Introduction

Dyslipidemia is one of the most critical risk factors for cardiovascular disease (CVD) [ 1, 2]. Therefore, lipid-lowering therapy is undeniably essential for reducing cardiovascular adverse events (AEs), especially in patients with risk factors or established CVD [ 3]. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known as statins, are the most effective and widely used drugs for treating dyslipidemia and have been the cornerstone medication for lipid-lowering therapy [ 4, 5]. Studies conducted during the past few decades have confirmed the effectiveness and safety of statins through several large-scale clinical trials [ 6- 8]. Based on these studies, the latest international guidelines for dyslipidemia recommend increasingly intensive statin treatment to prevent CVD [ 1, 9]. However, the landmark statin trials were conducted in western countries. Therefore, some questions remain regarding statin treatment in the Asian population. Asians exhibit a higher response to statin treatment than Westerners [ 10, 11], and high-dose statin-related side effects are known to be more common in patients of Asian ethnicity due to variations in drug metabolism and clearance [ 12, 13]. In the same context, Health Canada and the US Food and Drug Administration refer to patients of Asian ethnicity as a higher risk group for statin-induced myopathy and recommend starting patients on lower statin doses [ 14, 15]. Therefore, there is still no clear information regarding the appropriate statin dose for Asian patients. Unlike the recommendations in the latest guidelines, low-dose statins are used widely and the achievement rate of target low-density lipoprotein cholesterol (LDL-C) levels and compliance with statin treatment are suboptimal in Asian countries [ 16- 20].

Because lipid-lowering therapy using statin should continue throughout the patient's life, it is important to select the appropriate dose of statin to maximize the effect and minimize the risk of side effects. Therefore, this study's objective was to compare the efficacy and safety of atorvastatin 10 mg versus those of atorvastatin 20 mg in Asian patients with high CVD risk, defined according to 2015 Korean guidelines for managing dyslipidemia. Also, cost-effectiveness, another essential factor for long-term drug maintenance [ 21, 22], was analyzed.

Methods

Ethics statement

The study protocol was designed with sufficient consideration of patient safety in accordance with the recommendations of The Korea University Guro Hospital Institutional Review Board. The Korea University Guro Hospital Institutional Review Board approved the study protocol (KUGH17199-001). Written informed consent was obtained from all participants before their inclusion in the study.

Study patients

Patients aged >19 years who had hypercholesterolemia with high CVD risk, according to the 2015 Korean guidelines for managing dyslipidemia, were eligible to participate in the study. Based on the guidelines, patients with carotid stenosis of >50%, abdominal aortic aneurysm, or diabetes were considered the high-risk group. Patients with coronary artery disease (CAD), ischemic stroke, transient ischemic attack (TIA), or peripheral arterial disease (PAD) were considered the very high-risk group. In case the patients were previously treated with lipid-lowering agents, a washout period was implemented (8 weeks for fenofibrate, four weeks for other lipid-lowering agents). If the patients were naïve to lipid-lowering agents or had already completed the washout period, a 1:1 randomization was performed when the following conditions were met: 1) LDL-C levels ≥100 mg/dL and triglyceride (TG) levels ≤500 mg/dL for high-risk patients, and 2) LDL-C levels ≥70 mg/dL and TG levels ≤500 mg/dL for very high-risk patients. Patients with uncontrolled diabetes mellitus (glycosylated hemoglobin, HbA1c, >9%, arbitrary threshold), uncontrolled hypertension (systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥110 mmHg at screening), and thyroid dysfunction (thyroid-stimulating hormone ≥1.5 times the upper limit of normal) were excluded. Patients with severe renal insufficiency (serum creatinine level ≥2 times the upper limit of normal), active liver diseases (serum aspartate or alanine aminotransferase levels more than twice the upper limit of normal), known history of myopathy, or elevated creatinine phosphokinase level (more than twice the upper limit of normal) were excluded from the study. Further exclusion criteria are listed in S1 Table. Use of other statins, fibrates, niacin, bile acid sequestrants, oral steroids, anti-obesity drugs, fish oil, cholestin, fiber-based laxatives, phytosterol margarine, cyclosporine, macrolide, and antifungal drugs was not permitted during the study.

Study design

This study was a 12-week, open-label, parallel, multicenter, Phase IV randomized controlled trial conducted at ten hospitals in the Republic of Korea between October 2017 and May 2019 (S2 Table). The study protocol was designed with sufficient consideration of patient safety. The institutional review board (IRB) of each hospital approved the study protocol. The study was not registered before subject enrollment, as it was not a requirement of the IRB. This trial has since been registered with Clinicaltrials.gov (NCT04511000, Aug 2020). All participants or their legal guardians provided written informed consent before their inclusion in the study. This trial has the following three phases: (1) Screening period; (2) Run-in period; and (3) Treatment period (Fig 1). All blood tests were conducted in the central laboratory. At visit 1, eligible and consenting patients underwent tests for baseline assessment (S3 Table) and were instructed to make therapeutic lifestyle changes. Patients on a statin or another lipid-lowering therapy underwent a washout period of 8 weeks for fenofibrate and four weeks for other lipid-lowering agents, including statins. At visit 2, patients were tested for reevaluation to determine whether they still met the inclusion criteria. If the eligible patients were naïve to lipid-lowering agents or did not take lipid-lowering agents for a specified period at the screening examination (8 weeks for fenofibrate, four weeks for other lipid-lowering agents), visit two was omitted. At visit 3, the patients were randomly assigned to the atorvastatin 10 mg or atorvastatin 20 mg groups in a 1:1 ratio using SAS version 9.3 (SAS Institute, Inc, Cary, North Carolina). We used the stratified block randomization method and the patients entered the 12-week treatment period. We used a generic atorvastatin drug (Atorvastatin calcium anhydrous; Lipilou ®; Chong Kun Dang Pharmacy Corp., Seoul, Korea) in this study. After the 12-week treatment period, we repeated all baseline measurements, conducted residual study drug retrieval, measured drug compliance, checked for concomitant medication, and evaluated adverse reactions.

Endpoints and safety assessment

We conducted an efficacy analysis on full analysis (FA) sets and per-protocol (PP) sets and a safety analysis on the safety analysis set. The FA set included all participants who had taken at least one dose of the study drug and underwent at least one efficacy assessment. The PP set consisted of all patients in the FA set who completed the study without major protocol deviation. Subjects who did not complete the period specified in the clinical trial protocol, or had medication adherence of <80% or >120%, and deviated from the inclusion/exclusion criteria were excluded from the study. The safety set consisted of participants who had taken at least one dose of the study drug and underwent at least one safety-related interview.

The primary efficacy endpoint was comparing the mean percentage change in LDL-C levels between atorvastatin 10 and 20 mg groups after 12 weeks of treatment. The secondary endpoint was the mean percentage change from baseline in the following parameters: (1) lipid parameters including total cholesterol (TC), TG, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apolipoprotein (Apo)-B, and Apo-A1; (2) LDL-C/HDL-C ratio, TC/HDL-C ratio, non-HDL-C/HDL-C ratio, and Apo-B/Apo-A1 ratio; and (3) rate of achievement of target LDL-C and non-HDL-C levels according to the patient's risk factors after 12 weeks of treatment. We also compared mean changes in fasting glucose and hemoglobin A1c (HbA1c) levels from baseline after 12 weeks of treatment. As an additional exploratory endpoint, we compared the cost-effectiveness between atorvastatin 10 and 20 mg in reducing the LDL-C levels. The reduction of LDL-C levels was defined as similar to that of the primary efficacy endpoint, i.e., the mean percentage change in LDL-C levels after 12 weeks of treatment. The cost-effective analysis results are presented as the average cost-effectiveness ratio (ACER) and the incremental cost-effectiveness ratio (ICER). The ACER was calculated by dividing the mean cost of each group by the mean percentage change in each group's LDL-C levels. The ICER was calculated by dividing the difference in the mean cost of each group by the difference in the mean percentage change in each group's LDL-C levels. The ACER implies the cost of reducing the LDL-C level for each alternative, and the lower the ACER, the better the cost-effectiveness. The ICER indicates the additional cost of further reducing the LDL-C level when comparing the two options.

Safety assessments consisted of monitoring and recording all laboratory tests, vital signs, electrocardiograms, AEs, serious AEs, and possible association of AEs with the study drug. Adverse drug reactions (ADRs) were defined as drug-related AEs and classified as certain, probable/likely, possible, unlikely, conditional/unclassified, unassessable/unclassifiable, or not applicable to the study drug. We evaluated laboratory AEs by comparing baseline laboratory values with those measured at follow-up. AE severity was classified as mild for mild symptoms or signs not affecting activities of daily living, moderate for minor limitations in daily living activities, and severe for significant limitations in daily living activities. The investigators at each center decided whether the patients with drug-related AEs should withdraw from the study.

Statistical analysis

Data are expressed as mean, standard deviation (SD), median, minimum, and maximum values for continuous variables. The number and percentage of patients are presented for categorical variables. The normality of the data distribution as tested with the Shapiro-Wilk test, and homogeneity of variances was verified by F-test. Since the normality assumption was satisfied, we conducted independent two-sample t-test to compare continuous variables between two treatment groups and performed Pearson's χ2 test or Fisher's exact test to compare categorical variables between groups. Within each group, a paired t-test was used to compare the pre- and post-treatment measurements. All statistical analyses were two-sided, and p- values <0.05 were considered to be statistically significant. The SAS software package version 9.4 (SAS Institute Inc, Cary, North Carolina, USA) was used for all analyses.

Sample size calculation

The sample size of the study was calculated according to the estimated mean percentage changes in LDL-C levels obtained from the US Food and Drug Administration approval data for rosuvastatin. Using this reference, we assumed that the difference in the mean percentage change in LDL-C levels between rosuvastatin 20 and 10 mg was −6% [ 23]. Based on this assumption, a sample size of approximately 99 patients per treatment group was calculated to provide 90% power to detect a difference of 6% (assuming a SD of 13%) and to detect the superiority of atorvastatin 20 mg over 10 mg with a two-sided alpha level of 0.05. Using a 1:1 sampling ratio and a dropout rate of 20%, a final sample size of 124 patients per treatment group (total 248 patients) was determined to provide an adequate evaluation.

Results

Baseline characteristics

Of the 305 patients who agreed to participate in this clinical trial, 55 patients failed to meet the inclusion criteria and were excluded. The remaining 250 patients were randomly assigned to receive either atorvastatin 10 mg or atorvastatin 20 mg. We included 249 patients in the safety set (one patient who had never taken the experimental drug) and 244 patients (except for five patients who did not undergo efficacy evaluation) in the FA set. During the trial, an additional 17 patients were excluded due to dropout, major protocol deviation, and drug non-compliance. Thus, 227 patients were included in the PP set (Fig 2). The demographic and baseline characteristics of the study participants, according to the group, are presented in Table 1. The characteristics of the participants in the two intervention groups were well balanced. The baseline lipid profiles and risk group stratification according to the 2015 Korean guidelines for dyslipidemia management were similar between both groups.

FAS = full analysis set; PPS = per-protocol set.

Efficacy

Table 2 and Fig 3 present the lipid profile changes after 12 weeks of treatment. In the FA set analysis, the LDL-C level decreased from 142.1 to 80.3 mg/dl (−42.4%, p < 0.0001) in the atorvastatin 20 mg group and from 142.6 to 92.3 mg/dl (−33.5%, p < 0.0001) in the atorvastatin 10 mg group after the 12-week treatment period. In the intergroup comparison, atorvastatin 20 mg resulted in a statistically significant reduction of LDL-C levels after 12 weeks of treatment from the baseline level compared to the atorvastatin 10 mg (group difference: 8.85%, p < 0.0001). Moreover, there were significant improvements in the levels of non-HDL-C, TC, HDL-C, and Apo-B in both groups after the 12-week treatment period. The percentage changes in non-HDL-C, TC, and Apo B levels were significantly greater in the atorvastatin 20 mg group than in the atorvastatin 10 mg group. The changes in HDL-C and ApoA1 levels showed no significant differences between the two groups. Comparative analysis of lipid ratios revealed significant improvements in LDL-C/HDL-C ratio, non-HDL-C/HDL ratio, TC/HDL-C ratio, and Apo-B/Apo-A1 ratio in both groups after the 12-week treatment period, with a significantly greater improvement in these lipid ratios in the atorvastatin 20 mg group. The PP set analysis results were similar to those of the FA set analysis (S4 Table).

LDL-C = low density lipoprotein cholesterol; HDL-C = high density lipoprotein cholesterol; TC = total cholesterol; TG = triglyceride; Apo-B = apolipoprotein B; Apo-A1 = apolipoprotein A1.

In the very high-risk group (n = 207), significantly more patients achieved the target LDL-C level (<70 mg/dL) at the 12 th week in the atorvastatin 20 mg group (35.0%, 36 of 103 patients) than in the atorvastatin 10 mg group (17.3%, 18 of 104 patients, p = 0.0038, Table 3). Also, significantly more very high-risk patients achieved the target non-HDL-C level (<100 mg/dL) at the 12 th week in the atorvastatin 20 mg group than in the atorvastatin 10 mg group (44.2%, 46 of 104 patients in the atorvastatin 10 mg group versus 59.2%, 61 of 103 patients in the atorvastatin 20 mg group, p = 0.0309, Table 3). In the analysis of the high-risk group patients (n = 37), more patients in the atorvastatin 20 mg group achieved the target LDL-C level (<100 mg/dL) at the 12 th week. However, it was not statistically significant (66.7%, 14 of 21 patients in atorvastatin 10 mg group versus 75.0%, 12 of 16 patients in the atorvastatin 20 mg group, p = 0.7228). There was no significant difference between the two groups in achieving the target non-HDL-C level (<130mg/dL) in the high-risk group patients (90.5%, 19 of 21 patients in the atorvastatin 10 mg group versus 87.5%, 14 of 16 patients in the atorvastatin 20 mg group, p = 1.0000). The achievement rate of target LDL-C level, irrespective of the risk group among all patients, was also significantly higher (p = 0.0142) in the atorvastatin 20 mg group (40.3%, 48 of 119 patients) than in the atorvastatin 10 mg group (25.6%, 32 of 125 patients). The achievement rate of target non-HDL-C level, irrespective of the risk group among all patients, was also higher in the atorvastatin 20 mg group (63.0%, 75 of 119 patients) than in the atorvastatin 10 mg (52.0%, 65 of 125 patients). Still, the difference was not statistically significant (p = 0.0817). The achievement rate of target LDL-C and non-HDL-C levels in the PP set were similar to those of the FA set analysis (S5 Table).

Safety

After 12 weeks of atorvastatin treatment, the HbA1c level was slightly, but statistically significantly, increased in both treatment groups (Fig 4, Table 4). In the atorvastatin 20 mg group, the HbA1c level increased from a baseline value of 6.1% to 6.3% after 12 weeks (p = 0.0149). Similarly, in the atorvastatin 10 mg group, the HbA1c level was increased from a baseline value of 6.0% to 6.1% after 12 weeks (p = 0.0057). No intergroup differences were detected in the 12 th week between the two groups (p = 0.4525). There were also increments in fasting glucose levels in both groups at the 12 th week, although not statistically significant, and there were no intergroup differences. The results of the PP set analysis for HbA1c and fasting glucose levels were similar to those of the FA set analysis (S6 Table). In patients with low risk of diabetes defined as a body mass index of <30 kg/m ², a fasting glucose level of <100 mg/dL, and an HbA1c level of <6%, both the atorvastatin 20 and 10 mg groups showed small but significant increases in HbA1c levels. There was no difference between the two groups (S7 Table). The levels of creatine kinase were increased slightly but, significantly after 12 weeks of atorvastatin treatment compared to baseline in both the atorvastatin 10mg and 20mg group without exceeding the normal range in both groups. And there was no difference between the two groups in levels of creatine kinase (S8 Table).

(A) Change of HbA1c after treatment. (B) Change of fasting glucose after treatment.

During this clinical trial, eight ADRs in seven patients had a causal relationship with the study drug in the safety set (2.8%, 7 of 249 patients). Two ADRs were reported in two patients in the atorvastatin 10 mg group (1.6%, 2 of 126 patients), and six ADRs were reported in five patients in the atorvastatin 20 mg group (4.1%, 5 of 123 patients). The most frequent ADRs were myalgia (two patients in the atorvastatin 20 mg group) and hepatic enzyme elevation (two patients in the atorvastatin 20 mg group). There was no statistically significant difference in the incidence of ADRs between the two groups (Table 5).

Cost-effectiveness analysis

ACER and ICER were used to analyze the cost-effectiveness of atorvastatin 10 and 20 mg. The ACER value was significantly lower in the atorvastatin 20 mg group than in the atorvastatin 10 mg group. The costs required to reduce 1% of LDL-C levels were Korean Won (₩) 2604 in the atorvastatin 10 mg group and ₩2074 in the atorvastatin 20 mg group (Table 6). The ICER value analysis showed that atorvastatin 20 mg had an 8.9% greater LDL-C reduction effect than atorvastatin 10 mg, and the total cost was reduced to as much as ₩3480. Consequently, the cost required to reduce 1% of LDL-C levels was lower at ₩393, with atorvastatin 20 mg than with atorvastatin 10 mg (Table 6).

Discussion

High-quality evidence, from several randomized controlled trials, supports the benefits of statin therapy for the primary and secondary prevention of CVD. Although there are some differences in the criteria for initiating statin therapy and in the treatment goals according to the guideline used, the target of LDL-C is getting lower and more potent statins are recommended. However, the response to a statin in a particular individual is so unpredictable that it is not easy for physicians to choose the optimal statin for a specific patient. Thus, physicians need to refine the statin therapy beyond the general guideline recommendations on a case-by-case basis in their practice. However, in some cases, several factors such as unawareness of guideline recommendations, concern over adverse reactions, and therapeutic inertia can lead physicians to prescribe a suboptimal dose of statin [ 24, 25]. In particular, in the Asian population, the use of suboptimal dose statins and low achievement rates of target LDL-C levels are widespread issues. Both previous and recent studies report that a substantial proportion of individuals fail to achieve the recommended LDL-C target even among high-risk patients. In the REALITY-Asia study, conducted in 2622 patients from China, Korea, Malaysia, Singapore, Taiwan, and Thailand in 2008, only 38% of high-risk patients achieved ATP III target levels for LDL-C (<100 mg/dL) [ 26]. In a recent study published in 2020, 69,942 Korean patients with dyslipidemia were stratified according to the risk, based on the 2015 Korean guidelines as done in our research, and the achievement rate of target LDL-C levels was analyzed. In that study, similar to the previous research published 12 years ago, the achievement rate of target LDL-C levels was very suboptimal as only 17.6% of very high-risk patients and 47.2% of high-risk patients achieved the target [ 27]. Also, investigations conducted in other Asian countries reported low LDL-C target achievement rates [ 17, 19, 28]. This phenomenon is a bit disappointing since the Asian population has a lower baseline level of LDL-C and greater statin responsiveness than the Western population [ 29- 31]. However, the importance of optimal LDL-C goal attainment is no matter of debate to prevent future CVD. Attainment of the suboptimal LDL-C target is related to the increased risk of developing future CVD, and the benefit of statin treatment is more evident in high-risk patients [ 20, 32, 33]. Therefore, achieving the target LDL-C level is essential irrespective of ethnicity, and the most critical determinants for this achievement are lipid-lowering treatment with statin and adherence to the lipid-lowering treatment [ 24, 28]. But unconditional usage of high-dose statin cannot always be the best choice because even if the dose of statin is doubled, the additional LDL-C lowering effect is only 5%-7%. Furthermore, the risk of adverse reactions [ 34] and the costs increase along with the statin dose.

In the present study, treatments with atorvastatin 10 and 20 mg over a 12-week period were compared to explore the dose of atorvastatin that is more appropriate in high-risk Asian patients in terms of efficacy, safety, and cost-effectiveness. As reported by earlier studies regarding the effectiveness and safety of atorvastatin in Asian patients even at a high dose [ 35, 36], the present study also demonstrated that atorvastatin effectively improved various lipid profiles without increasing the rate of ADRs. The percentage change in LDL-C levels after atorvastatin therapy was comparable to that reported by previous studies [ 35, 37, 38]. The reduction of LDL-C, non-HDL-C, TC, and Apo-B levels was significantly higher in the atorvastatin 20 mg group than in the atorvastatin 10 mg group. Regarding the levels of TG, HDL-C, and Apo A-I, both groups displayed a tendency to improve after 12 weeks compared to the baseline levels. Still, there were no statistically significant differences between the groups. These relatively small and nonsignificant changes in TG, HDL-C, and Apo-A1 levels were also similar to those of previous studies [ 35, 37, 38]. Atorvastatin 20 was more efficient than atorvastatin 10 mg in for the very high-risk group patients in achieving target LDL-C and non-HDL-C levels. During the clinical trial, there were only a few ADRs, with no difference in the incidence of ADRs between the two groups. Overall, atorvastatin 20 mg exhibited a dose-dependent effect in improving lipid profiles without increasing the incidence of ADRs compared with atorvastatin 10 mg in the high-risk Asian patients.

Furthermore, atorvastatin 20 mg was more cost-effective than atorvastatin 10 mg in our study. Atorvastatin 20 mg has a low ACER value, implying that it costs less to reduce a certain amount of LDL-C when using atorvastatin 20 mg than using atorvastatin 10 mg. However, ACER alone may not be the best indicator for choosing a more cost-effective medicine in real practice because a low ACER value can arise in both cases when a medication has a small effect at low cost and a high effect at a high cost. Therefore, it is important to consider the size of the impact along with the cost. Hence, the ICER is another good indicator for choosing a more cost-effective medicine between two medications as it can compare the cost according to the size of the effect. In our study's ICER analysis, atorvastatin 20 mg demonstrated a more significant LDL-C-reducing effect at a lower cost, and the cost required to reduce 1% of LDL-C levels was found to be lower with atorvastatin 20 mg than with atorvastatin 10 mg. These results are remarkable, considering that the dose-effect relationship of statin is not linear, and that the LDL-C reduction effect is prominent at lower doses. In other words, although the administration of more moderate-dose statins is relatively advantageous in terms of cost, this could not offset the higher LDL-C reduction effect due to a higher dose of statin administration. Furthermore, using a lower dose of statin can increase the total cost because of repetitive monitoring and visiting that would be necessary due to the low achievement rate of target LDL-C levels. Therefore, avoiding the use of lower dose atorvastatin can be a cost-effective alternative to prevent CVD in a longer-term perspective.

In the present study, the HbA1c level increased significantly after 12 weeks of atorvastatin treatment. However, the mean elevation of the HbA1c level was not prominent, which was only around 0.1% irrespective of the atorvastatin dose. The elevated HbA1c level was commonly found in all patients as well as in nondiabetic patients with low risk of diabetes (BMI <30 kg/m ², fasting glucose level <100 mg/dL, and HbA1c level <6%). Although statins increase blood glucose levels and the risk of diabetes mellitus in a dose-dependent manner [ 39], there was no significant difference between the atorvastatin 10 and 20 mg groups. Also, our results revealed the elevation of HbA1c levels after a relatively short-term statin treatment of 12 weeks. As shown in our study, an increase in blood glucose level induced by a statin is not just a chronic, long-term change. Other studies on statin conducted for a relatively short period also demonstrated elevated blood glucose levels, and statin treatment for only a few days in the early phase of acute myocardial infarction also reduced insulin sensitivity [ 35, 40]. Therefore, although the benefit of LDL-C reduction is known to outweigh the harm from the elevation of blood glucose [ 41], it is necessary to monitor blood glucose levels from the early days of the statin treatment even in patients with low risk of diabetes.

Limitations

The present study has some limitations. First, high-dose statins recommended for high-risk patients in the latest guidelines were not used in this study. Although the atorvastatin dose used in this study may be closer to the dose frequently used in real-world practice, further investigation using higher doses of atorvastatin would be necessary. Second, as the proportion of patients with CAD was too high, the composition of the study patients was relatively homogenous, and most of the patients were considered very high risk. Consequently, the number of high-risk patients was too small for statistical analysis. Third, statins can affect the inflammatory process in atherosclerosis, which is one of the important effects of statin, but inflammatory marker such as high sensitivity C-reactive protein was not measured in this study. Fourth, the cost-effectiveness results cannot be generalized to other countries as it was calculated under the Korean healthcare system. Fifth, the incidence of AEs caused by statin treatment was lower than that in previous studies. This may be due to the small sample size neglecting the mild symptoms.

Conclusion

Atorvastatin 20 mg was more effective in reducing LDL-C levels in Asian patients with high risk for CVD than atorvastatin 10 mg and also resulted in statistically significant improvement in most of the lipid profiles. Atorvastatin 20 mg did not increase the incidence of ADRs and was more cost-effective than atorvastatin 10 mg. Therefore, atorvastatin 20 mg can be a more appropriate dose of choice than atorvastatin 10 mg in Asian patients with a high risk for CVD.

References

1. 3. Baigent C, Blackwell L, Emberson J, Holland L, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Elsevier; 2010.

2. 18. Wu N-Q, Guo Y-L, Ye P, Chen H, Li Y-F, Hua Q, et al. Statins usage and target achievement of LDL-C level in Chinese patients with coronary artery disease impacted by 2013 ACC/AHA cholesterol guideline. IJC Metabolic & Endocrine. 2017;14:33-7. https://doi.org/10.1016/j.ijcme.2016.11.002.

3. 23. Food, Administration D. Statistical review and evaluation, clinical studies. Media Release. 2009;NDA/Serial Number: 21-366 Appliction Supplement Number 17.

4. 24. Bittencourt MS, Cesena FH. Statin dose in primary prevention: aim for the target!: BMJ Publishing Group Ltd and British Cardiovascular Society; 2019.

# data[].attributes.attachment_link.title
A randomized, open-label, parallel, multi-center Phase IV study to compare the efficacy and safety of atorvastatin 10 and 20 mg in high-risk Asian patients with hypercholesterolemia

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Background Although accumulating evidence suggests a more extensive reduction of low-density lipoprotein cholesterol (LDL-C), it is unclear whether a higher statin dose is more effective and cost-effective in the Asian population. This study compared the efficacy, safety, and cost-effectiveness of atorvastatin 20 and 10 mg in high-risk Asian patients with hypercholesterolemia.

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Título:

Eficacia y seguridad de los anticuerpos monoclonales PCSK9 en pacientes con alto riesgo cardiovascular: revisión sistemática actualizada y metanálisis de 32 ensayos controlados aleatorios

Año: 2020
Tipo de estudio: Metaanálisis de ECA
Resultados: Treinta y dos ECA se incluyeron en la revisión sistemática y 25 de ellos (57 090 individuos) se incluyeron en el metanálisis. Los anticuerpos monoclonales PCSK9 mejoraron significativamente el LDL-C y otros perfiles lipídicos (P < 0,05), y no se encontraron diferencias raciales. Es probable que una dosis recomendada de 140 mg de evolocumab cada 2 semanas produzca un efecto relativamente más fuerte que 150 mg de alirocumab cada 2 semanas en términos del cambio absoluto (diferencias de medias ponderadas [DMP] - 0,36; intervalo de confianza [IC] del 95 %). - 0,71 a - 0,01; P = 0,041) y cambio porcentual (DMP - 19,53; IC del 95 % - 32,02 a - 7,04; P = 0,002) en los niveles de C-LDL. En general, los anticuerpos monoclonales PCSK9 fueron seguros, excepto por el aumento significativo del riesgo de reacciones en el lugar de la inyección (riesgos relativos (RR) 1,54; IC del 95 %: 1,38-1,71; P < 0,001). Ambos alirocumab (RR 0,89; IC 95% 0. 83-0,95; P < 0,001) y evolocumab (RR 0,86; IC 95 % 0,80-0,92; P < 0,001) se asociaron con un menor riesgo de eventos cardiovasculares mayores (MACE), especialmente en pacientes de prevención secundaria (grupo alirocumab: RR 0,88; IC 95 % 0,82-0,95; P < 0,001; grupo evolocumab: RR 0,86; IC 95% 0,80-0,92; P < 0,001). La reducción de MACE se observó en sujetos blancos pero no en asiáticos. No se encontró una reducción significativa de la mortalidad por todas las causas (RR 0,88; IC del 95%: 0,72-1,07; P = 0,182). La reducción de MACE se observó en sujetos blancos pero no en asiáticos. No se encontró una reducción significativa de la mortalidad por todas las causas (RR 0,88; IC del 95%: 0,72-1,07; P = 0,182). La reducción de MACE se observó en sujetos blancos pero no en asiáticos. No se encontró una reducción significativa de la mortalidad por todas las causas (RR 0,88; IC del 95%: 0,72-1,07; P = 0,182).
Conclusiones:

Los anticuerpos monoclonales PCSK9

generan un aumento significativo del riesgo de reacciones en el lugar de la inyección.
https://sci-hub.st/10.1007/s12325-020-01259-4

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https://pubmed.ncbi.nlm.nih.gov/30595326/
Titulo:

Estudiar el efecto de dosis altas de Atorvastatina 40 mg versus 80 mg en pacientes con dislipidemia.

TIPO: ECA
Conclusiones: este estudio concluyó que ambas dosis de atorvastatina (40 y 80 mg) son igualmente eficaces para mejorar la dislipidemia, pero una dosis más alta conduce a una mayor incidencia de mialgia.

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Randomized Controlled Trial

. 2018 Dec;70 Suppl 3(Suppl 3):S8-S12.

doi: 10.1016/j.ihj.2018.01.034.

Affiliations

¹ Department of Cardiology, Sir Ganga Ram hospital, 13/4, Upper ground floor, West Patel Nagar, New Delhi, 110008, India. Electronic address: drdeepakagrawal1984@gmail.com.

² Department of Cardiology, Sir Ganga Ram hospital, R-721, New Rajinder Nagar, New Delhi, 110 060, India. Electronic address: doctormanchanda@yahoo.com.

³ Department of Cardiology, Sir Ganga Ram hospital, House No.10, Road No.4 West Punjabi Bagh Extension, New Delhi, 110 026, India. Electronic address: jpssawhney@yahoo.com.

⁴ Department of Cardiology, Sir Ganga Ram hospital, 535, DDA Flats, Sector - 22, Dwarka, New Delhi, 110075, India. Electronic address: bhuwaneshk@yahoo.co.in.

⁵ Department of cardiology, Sir Ganga Ram hospital, S-455, Ground Floor Greater Kailash - 1, New Delhi, 110048, India. Electronic address: jainsaniya@yahoo.com.

⁶ Department of cardiology, Sir Ganga Ram hospital, 20/1 Old Rajinder Nagar, New Delhi, 110 060, India. Electronic address: drashwanimehta@gmail.com.

⁷ Department of Cardiology, Sir Ganga Ram hospital, B-101, Shivam Appt., Plot-14, Sec-12, Dwarka, New Delhi, 110078, India. Electronic address: arunmohanty25@hotmail.com.

⁸ Department of Cardiology, Sir Ganga Ram hospital, C-111 Preet Vihar, New Delhi, 110 092, India. Electronic address: drrpassey@yahoo.com.

⁹ Department of Cardiology, Sir Ganga Ram hospital, 56-B, Pocket-1, Mayur Vihar, Phase-I, New Delhi, 110091, India. Electronic address: amanmakhija@gmail.com.

¹⁰ Department of Cardiology, Sir Ganga Ram hospital, 8A/15, Old Rajinder Nagar, New Delhi, 110060, India. Electronic address: doctormanishksharma@gmail.com.

Free PMC article

Randomized Controlled Trial

Deepak Agrawal et al. Indian Heart J.

Free PMC article

. 2018 Dec;70 Suppl 3(Suppl 3):S8-S12.

doi: 10.1016/j.ihj.2018.01.034.

Affiliations

¹ Department of Cardiology, Sir Ganga Ram hospital, 13/4, Upper ground floor, West Patel Nagar, New Delhi, 110008, India. Electronic address: drdeepakagrawal1984@gmail.com.

² Department of Cardiology, Sir Ganga Ram hospital, R-721, New Rajinder Nagar, New Delhi, 110 060, India. Electronic address: doctormanchanda@yahoo.com.

³ Department of Cardiology, Sir Ganga Ram hospital, House No.10, Road No.4 West Punjabi Bagh Extension, New Delhi, 110 026, India. Electronic address: jpssawhney@yahoo.com.

⁴ Department of Cardiology, Sir Ganga Ram hospital, 535, DDA Flats, Sector - 22, Dwarka, New Delhi, 110075, India. Electronic address: bhuwaneshk@yahoo.co.in.

⁵ Department of cardiology, Sir Ganga Ram hospital, S-455, Ground Floor Greater Kailash - 1, New Delhi, 110048, India. Electronic address: jainsaniya@yahoo.com.

⁶ Department of cardiology, Sir Ganga Ram hospital, 20/1 Old Rajinder Nagar, New Delhi, 110 060, India. Electronic address: drashwanimehta@gmail.com.

⁷ Department of Cardiology, Sir Ganga Ram hospital, B-101, Shivam Appt., Plot-14, Sec-12, Dwarka, New Delhi, 110078, India. Electronic address: arunmohanty25@hotmail.com.

⁸ Department of Cardiology, Sir Ganga Ram hospital, C-111 Preet Vihar, New Delhi, 110 092, India. Electronic address: drrpassey@yahoo.com.

⁹ Department of Cardiology, Sir Ganga Ram hospital, 56-B, Pocket-1, Mayur Vihar, Phase-I, New Delhi, 110091, India. Electronic address: amanmakhija@gmail.com.

¹⁰ Department of Cardiology, Sir Ganga Ram hospital, 8A/15, Old Rajinder Nagar, New Delhi, 110060, India. Electronic address: doctormanishksharma@gmail.com.

Abstract

Objective: Primary objective was to compare the effects of atorvastatin 40mg vs 80mg on LDL-C in Indian patients with atherosclerotic dyslipidemia. Secondary objectives were to compare the effects of atorvastatin 40mg vs 80mg on HDL-C and triglycerides and also comparing of side effects (myopathy, hepatotoxicity and new onset diabetes mellitus) of both doses.

Method: This Study is A Prospective, randomized, open-label, comparative study. This study was conducted on 240 patients of dyslipidemia (as per ACC/AHA 2013 lipid guidelines) attending the OPD/wards/CCU of department of cardiology, Sir Ganga Ram Hospital. They were randomly divided into 2 groups of 120 each. Group A consisted patients who received Atorvastatin 40mg daily and Group B Atorvastatin 80mg daily. The follow up period was 6 months.

Results: At 3 and 6 month follow up, Atorvastatin 40mg leads to mean LDL cholesterol reduction of 47.18±20.81 & 50.03±18.06 respectively. While Atorvastatin 80mg results in LDL reduction as 50.11±15.85 & 52.30±13.72. The comparison between two doses revealed a non-significant difference (p=.118 & p=.149 respectively). At 6 months of follow up, few patients reported myalgia (2 in group A and 7 in Group B). The difference between groups was significant (p=.045). Although none of our patient had significant elevation of CPK.

Conclusion: This study concluded that both doses of atorvastatin (40 & 80mg) are equally efficacious in improving dyslipidemia but higher dose leads to more incidence of myalgia.

Keywords: Atherosclerosis; Atorvastatin; Dyslipidemia; Myalgia.

Figures

References

Enas E.A., Salim Yusuf Mehta J.L. Prevalence of coronary artery disease in Asian Indians. Am J Cardiol. 2018;70:945-949. - PubMed

Grundy S.M. Small LDL, atherogenic dyslipidemia and the metabolic syndrome. Circulation. 1997;95:1-4. - PubMed

Haffnar M. Diabetes, hyperlipidemia and coronary artery disease. Am J Cardiol. 1999;83:17F-21F. [Supplement] - PubMed

Joshi S.R., Anjana R.M., Deepa M. Prevalence of dyslipidemia in urban and rural India: the ICMR-INDIAB study. PLoS One. 2014;9:e96808. - PMC - PubMed

Newman C., Tsai J., Szarek M. Comparative safety of atorvastatin 80 mg vs 10 mg derived from analysis of 49 completed trials in 14236 patients. Am J Cardiol. 2006;97:61-67. - PubMed

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anticholesteremic agents / administration & dosage

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national center for biotechnology information

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To study the effect of high dose Atorvastatin 40mg versus 80mg in patients with dyslipidemia - PubMed

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Randomized Controlled Trial . 2018 Dec;70 Suppl 3(Suppl 3):S8-S12. doi: 10.1016/j.ihj.2018.01.034. 1 Department of Cardiology, Sir Ganga Ram hospital, 13/4, Upper ground floor, West Patel Nagar, New Delhi, 110008, India. Electronic address: drdeepakagrawal1984@gmail.com. 2 Department of Cardiology, Sir Ganga Ram hospital, R-721, New Rajinder Nagar, New Delhi, 110 060, India.

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Título:  Miopatía asociada a estatinas en la práctica clínica. Resultados del estudio DAMA]
Año: 2017
Autor: Jesús Millán ¹, juan pedro botet ², Elisenda Climent ², Joaquín Millán ³, joan rios ⁴
Tipo de Estudio: Estudio Multicéntrico
Objetivo: Evaluar las características clínicas de los pacientes tratados con estatinas que se quejaron de síntomas musculares e identificar posibles factores predictivos
Resultado: La mialgia estuvo presente en el 78,2% de los pacientes incluidos en el estudio, la miositis en el 19,3% y la rabdomiólisis en el 2,5%. Los pacientes informaron dolor muscular en el 77,5 % de los individuos tratados con estatinas, debilidad general en el 42,7 % y calambres en el 28,1 %. La insuficiencia renal, el ejercicio físico intenso, el consumo de alcohol (> 30 g/d en hombres y 20 g/d en mujeres) y la obesidad abdominal fueron las situaciones clínicas asociadas a la miopatía por estatinas.
Conclusiones:   La mialgia seguida de la miositis son los efectos secundarios más frecuentes relacionados con las estatinas. Se recomienda controlar los factores ambientales como el ejercicio intenso y la ingesta de alcohol, así como la obesidad abdominal y la función renal del paciente tratado con estatinas.

https://pubmed.ncbi.nlm.nih.gov/27717598/

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Affiliations

¹ Unidad de Lípidos, Hospital Universitario Gregorio Marañón, Universidad Complutense, Madrid, España. Electronic address: jesus.millan.nunezcortes@madrid.org.

² Unidad de Lípidos y Riesgo Vascular, Servicio de Endocrinología y Nutrición, Hospital del Mar, Universidad Autónoma de Barcelona, Barcelona, España.

³ Unidad de Lípidos, Hospital Universitario Gregorio Marañón, Universidad Complutense, Madrid, España.

⁴ Asesor Médico Cardiovascular. Medicina Familiar y Comunitaria, Barcelona, España.

Affiliations

¹ Unidad de Lípidos, Hospital Universitario Gregorio Marañón, Universidad Complutense, Madrid, España. Electronic address: jesus.millan.nunezcortes@madrid.org.

² Unidad de Lípidos y Riesgo Vascular, Servicio de Endocrinología y Nutrición, Hospital del Mar, Universidad Autónoma de Barcelona, Barcelona, España.

³ Unidad de Lípidos, Hospital Universitario Gregorio Marañón, Universidad Complutense, Madrid, España.

⁴ Asesor Médico Cardiovascular. Medicina Familiar y Comunitaria, Barcelona, España.

Abstract

Background and objective: Muscle symptoms, with or without elevation of creatin kinase are one of the main adverse effects of statin therapy, a fact that sometimes limits their use. The aim of this study was to evaluate the clinical characteristics of patients treated with statins who have complained muscle symptoms and to identify possible predictive factors.

Patients and methods: A cross-sectional one-visit, non-interventional, national multicenter study including patients of both sexes over 18 years of age referred for past or present muscle symptoms associated with statin therapy was conducted. 3,845 patients were recruited from a one-day record from 2,001 physicians.

Results: Myalgia was present in 78.2% of patients included in the study, myositis in 19.3%, and rhabdomyolysis in 2.5%. Patients reported muscle pain in 77.5% of statin-treated individuals, general weakness 42.7%, and cramps 28.1%. Kidney failure, intense physical exercise, alcohol consumption (>30g/d in men and 20g/d in women) and abdominal obesity were the clinical situations associated with statin myopathy.

Conclusions: Myalgia followed by myositis are the most frequent statin-related side effects. It should be recommended control environmental factors such as intense exercise and alcohol intake as well as abdominal obesity and renal function of the patient treated with statins.

Keywords: Estatinas; Intolerancia a estatinas; Mialgia; Miopatía; Miositis; Muscle symptoms; Myalgia; Myopathy; Myositis; Statin intolerance; Statins; Síntomas musculares.

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hydroxymethylglutaryl-coa reductase inhibitors / administration & dosage

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national center for biotechnology information

# data[].attributes.attachment_link.title
[Statin associated myopathy in clinical practice. Results of DAMA study] - PubMed

# data[].attributes.attachment_link.description
1 Unidad de Lípidos, Hospital Universitario Gregorio Marañón, Universidad Complutense, Madrid, España. Electronic address: jesus.millan.nunezcortes@madrid.org. 2 Unidad de Lípidos y Riesgo Vascular, Servicio de Endocrinología y Nutrición, Hospital del Mar, Universidad Autónoma de Barcelona, Barcelona, España. 3 Unidad de Lípidos, Hospital Universitario Gregorio Marañón, Universidad Complutense, Madrid, España. 4 Asesor Médico Cardiovascular.

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http://ve.scielo.org/scielo.php?script=sci_arttext&pid=S0798-04692004000200001

Título : ¿Estatinas para todos? Nuevas evidencias sobre la seguridad y eficacia de los inhibidores de la Hmg Co-A Reductasa. (Estatinas).

autores: Luis Alcocer, MD.
Tipo Estudio: ensayos clínicos controlados

RESULTADOS DE LOS GRANDES ESTUDIOS CON ESTATINAS: Recientemente se han completado seis grandes ensayos clínicos controlados, de desenlaces trascendentes (hard endpoints), empleando estatinas, The West of Scotland Coronary Prevention Study (WOSCOPS), The Scandinavian Simvastatin Survival Study (4S), The Colesterol and Recurrent Events trial (CARE), The Long-term Intervention with Pravastgatin in Ischemic Disease studty (LIPID), The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS), y the Heart Protection Study (HPS), que proporcionan importantes evidencias adicionales del beneficio del tratamiento para reducir los niveles de colesterol LDL. En dichos estudios se incluyeron sujetos sin cardiopatía coronaria con elevación limítrofe o elevación marcada del colesterol LDL, así como pacientes con cardiopatía coronaria manifiesta y elevación leve, moderada o marcada de dichos niveles, y pacientes con equivalentes de enfermedad coronaria (diabetes, enfermedad vascular periférica), con colesterol relativamente bajo.

Cada vez existe más evidencias fundadas de que los pacientes de más alto riesgo, definidos como aquellos que han padecido previamente enfermedad coronaria, los diabéticos y los hipertensos, obtienen un beneficio muy grande con el descenso del LDL-COLESTEROL, no sólo en aquellos en los cuales los niveles básales de lípidos son altos, como quedó demostrado en el estudio 4S, sino también en aquellos con niveles de lípidos llamados promedio (estudio CARE) o en aquellos con niveles promedio o relativamente bajos (estudio HPS). Más aún el estudio LIPID y el HPS demostraron que los pacientes con enfermedad coronaria manifiesta, obtienen beneficio de la reducción de sus niveles lípidos, aún en aquellos en quienes tienen niveles «deseables». También obtienen beneficios pacientes sin enfermedad coronaria manifiesta y que tienen niveles promedio de lípidos como quedó demostrado en el estudio AFCAPS/TEXCAPS. Sin embargo los pacientes con niveles más altos de lípidos y con descensos mas importantes, son los que parecen obtener los mejores resultados.

Existe una relación entre el riesgo absoluto y el beneficio obtenido por el tratamiento. El riesgo absoluto en los estudios controlados corresponde al por ciento de eventos en el grupo placebo, la disminución absoluta del riesgo es la diferencia entre el por ciento de eventos en el grupo placebo del riesgo. La disminución relativa del riesgo es la proporción que guarda la disminución absoluta del riesgo con el riesgo absoluto. La manera correcta de comparar estudios, no es mostrando la disminución relativa de riesgo, si no es calculando el número necesario de pacientes a tratar para evitar un evento, que corresponde 1/disminución absoluta del riesgo.

Si se grafica con los resultados de los 6 estudios el número necesario a tratar, contra el riesgo absoluto, se ve claramente que a más alto el riesgo, mejor es el resultado del tratamiento.

Los estudios 4S, CARE y LIPID y HPS, demostraron que en pacientes con enfermedad coronaria manifiesta, independientemente de los niveles lípidos se obtiene beneficio con el tratamiento con estatinas establecido en por lo menos tres meses después del diagnóstico de un evento coronario. La pregunta si las estatinas dan beneficios cuando se inician en las fases más tempranas de un evento coronario agudo se ha enfocado en el estudio The Myocardial Ischemia Reduction with Agressive Colesterol Lowering (MIRACL), cuyos resultados sugieren que si existe un beneficio con el tratamiento con estatinas prescritas en forma temprana, en pacientes con síndrome isquémico coronario agudo. Este estudio sugiere también que los beneficios son mayores cuando se alcanzan niveles de LDL-Colesterol tan bajos como <80 mg/dL.

Otro estudio que apoya el concepto de "tanto más bajo, mejor" (The lower the better) es el estudio Post-Coronary Artery Bypass Graft trial (Post-CABG), que mostró que después de un tratamiento agresivo por un promedio de 4.3 años, la mayor regresión de la aterosclerosis y su menor progresión se obtuvo en los pacientes que alcanzaron niveles de LDL-Colesterol <80 mg/dL.

El estudio Atorvastatin versus Revascularization Treatment (AVERT) sugiere que el tratamiento agresivo de la dislipidemia, (Atorvastatina 80 mgs diarios), después de 18 meses de tratamiento, con reducciones del LDL-Colesterol a 77 mg/dL, es capaz de reducir 36% la incidencia de eventos isquémicos, en comparación del grupo control en el cual los niveles de LDL-Col. Alcanzados fue de 119 mg/dL.

La respuesta definitiva a la pregunta de si es posible obtener mejores beneficios con el tratamiento agresivos de lípidos, se tendrá con los estudios: Treating to New Targets (TNT), Study of the Effectiveness of Adicional Reduction in Colesterol and Hocystiene (SEARCH) y Incremental Decrease in Endpoints Trough Agressive Lipid Lowering (IDEAL)

CONCLUSIONES: Debido a que se obtiene un beneficio claro con el uso de estatinas en la disminución de desenlaces duros (hard-endpoints), existen en la actualidad suficientes evidencias para indicarlas en las siguientes condiciones:

1. Pacientes con síndrome isquémico coronario agudo, con y sin desnivel del segmento ST, con prácticamente cualquiera que sea su nivel de Colesterol o LDL-Colesterol (con niveles de Colesterol o LDl-Colesterol muy elevados (4S), moderadamente elevado (LIPID), promedio, (CARE), promedio o bajo (HPS), independientemente de que sean mujeres o mayores de 75 años. (HPS). El tratamiento debe iniciarse inmediatamente después del diagnóstico del evento (MIRACL).

2. Pacientes con equivalentes de enfermedad coronaria: Diabetes, enfermedad arterial periférica, stroke, con niveles de colesterol o LDL-Colesterol promedio o bajo (HPS). Independientemente de que sean mujeres o mayores de 75 años. (HPS).

3. Personas sin evidencias de enfermedad coronaria, con niveles de Colesterol o LDl-Colesterol elevado. (WOSCOPS).

4. Personas sin evidencias de enfermedad coronaria, con niveles de Colesterol o LDl-Colesterol moderadamente elevado. (AFCAPS/TexCAPS).

Estas indicaciones para el uso de las estatinas implica su prescripción a cantidades muy grandes de personas, sin embargo cuando se emplean en pacientes con las características similares a aquellos incluidos en el estudio HPS, (Pacientes con enfermedad coronaria sintomática o con equivalentes de ella), por cada millón de tratados se pueden salvar 5.000 vidas por año, independientemente del nivel previo de lípidos en sangre.

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Similares en SciELO
¿Estatinas para todos? Nuevas evidencias sobre la seguridad y eficacia de los inhibidores de la Hmg Co-A Reductasa. (Estatinas).
Mexico City General Hospital, and National Autonomous University of Mexico.

Tuxpan 16, México D.F., 0676, México.

lalcocer@servidor.unam.mx

La aterosclerosis es la causa principal de muerte de la especie humana en la edad adulta. Existen múltiples evidencias en la actualidad que prueban que la prevención de la enfermedad y sus complicaciones es posible, al través de la modificación de algunos de sus factores de riesgo, como son la hipertensión arterial, el tabaquismo, la resistencia a la insulina / diabetes y la dislipidemia.

La calificación de riesgo coronario se ha basado por mucho tiempo en la medición de los niveles de Colesterol total, apoyándose en la teoría lípida clásica de la aterosclerosis, que muestra una clara relación directa entre los niveles de Colesterol total, y la presentación de morbilidad y mortalidad por enfermedad coronaria; entre más altas las cifras de colesterol, más eventos cardiovasculares suceden. Desde los primeros reportes del Framingham Heart Study se encontró que el nivel de colesterol está fuertemente relacionado al desarrollo posterior de enfermedad coronaria en la población.

Del análisis de la curva que relaciona al colesterol con los desenlaces cardiovasculares (MRFIT (Multiple Risk Factor Intervention Trial), se obtuvo el concepto que clasifica a los pacientes con distintos niveles de colesterol en:

* Niveles deseables: Menos de 200 mg/dL

* Riesgo moderado: entre 200 y 239 mg/dL

* Riesgo elevado: 240mg/dL o más

Una regla clínica muy conocida se desprendió del estudio de prevención primaria de la enfermedad coronaria en las clínicas de investigación sobre lípidos, estudio LRC-CPPT: es que una disminución en los niveles de colesterol de 1%, llevan a una disminución del 2 al 3% de la enfermedad coronaria.

No se concibe en la actualidad un enfoque aislado de los factores de riesgo y su modificación. La conducta correcta de prevención de la aterosclerosis, consiste en el cálculo del riesgo global, que comprende la valoración de cada uno de los factores, que en cada paciente participan en el desarrollo de la enfermedad y sus complicaciones y la atención de cada uno de ellos, con una visión global del problema. El cálculo del riesgo global de acuerdo al NCEP-III se hacen empleando las tablas de Framingham, y en las recomendations of the Task Force of the European Society Cardiology, European Atherosclerosis Society and European Society of Hypertension se hacen por medio the Coronary Risk Chart, basada también en el estudio Framingham.

El objetivo principal del tratamiento de las dislipidemias que constituyen un factor de riesgo para la aterosclerosis, es restaurar la esperanza y calidad de vida del paciente con riesgo para la aterosclerosis, a través de minimizar el impacto que tienen las alteraciones de los lípidos sobre este riesgo cardiovascular.

El manejo de las dislipidemias debe dirigirse primordialmente a la prevención de eventos cardiovasculares mediante el logro de unas metas de perfil lipídico que dependen de la categoría de riesgo del individuo. El tratamiento de las dislipidemias se hace con el manejo racional de los siguientes recursos:

2. Ejercicio

3. Abandono del tabaquismo

4. Medicamentos

Los medicamentos empleados en el tratamiento de las dislipidemias son:

* Inhibidores de la HMG CoA Reductasa. (Statins)

* Derivados del ácido fíbrico (Fibratos)

* Secuestrantes de Ácidos biliares

* Ácido nicotínico

Desde su introducción en la terapéutica, las estatinas se han convertido en los medicamentos más usados en el tratamiento de las dislipidemias. Las estatinas constituyen el primer paso en el tratamiento de los trastornos de los lípidos, en especial cuando se trata de hipercolesterolemia aislada, o de dislipidemia mixta con predominio de triglicéridos.

RESULTADOS DE LOS GRANDES ESTUDIOS CON ESTATINAS: Recientemente se han completado seis grandes ensayos clínicos controlados, de desenlaces trascendentes (hard endpoints), empleando estatinas, The West of Scotland Coronary Prevention Study (WOSCOPS), The Scandinavian Simvastatin Survival Study (4S), The Colesterol and Recurrent Events trial (CARE), The Long-term Intervention with Pravastgatin in Ischemic Disease studty (LIPID), The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS), y the Heart Protection Study (HPS), que proporcionan importantes evidencias adicionales del beneficio del tratamiento para reducir los niveles de colesterol LDL. En dichos estudios se incluyeron sujetos sin cardiopatía coronaria con elevación limítrofe o elevación marcada del colesterol LDL, así como pacientes con cardiopatía coronaria manifiesta y elevación leve, moderada o marcada de dichos niveles, y pacientes con equivalentes de enfermedad coronaria (diabetes, enfermedad vascular periférica), con colesterol relativamente bajo.

Cada vez existe más evidencias fundadas de que los pacientes de más alto riesgo, definidos como aquellos que han padecido previamente enfermedad coronaria, los diabéticos y los hipertensos, obtienen un beneficio muy grande con el descenso del LDL-COLESTEROL, no sólo en aquellos en los cuales los niveles básales de lípidos son altos, como quedó demostrado en el estudio 4S, sino también en aquellos con niveles de lípidos llamados promedio (estudio CARE) o en aquellos con niveles promedio o relativamente bajos (estudio HPS). Más aún el estudio LIPID y el HPS demostraron que los pacientes con enfermedad coronaria manifiesta, obtienen beneficio de la reducción de sus niveles lípidos, aún en aquellos en quienes tienen niveles "deseables". También obtienen beneficios pacientes sin enfermedad coronaria manifiesta y que tienen niveles promedio de lípidos como quedó demostrado en el estudio AFCAPS/TEXCAPS. Sin embargo los pacientes con niveles más altos de lípidos y con descensos mas importantes, son los que parecen obtener los mejores resultados.

Existe una relación entre el riesgo absoluto y el beneficio obtenido por el tratamiento. El riesgo absoluto en los estudios controlados corresponde al por ciento de eventos en el grupo placebo, la disminución absoluta del riesgo es la diferencia entre el por ciento de eventos en el grupo placebo del riesgo. La disminución relativa del riesgo es la proporción que guarda la disminución absoluta del riesgo con el riesgo absoluto. La manera correcta de comparar estudios, no es mostrando la disminución relativa de riesgo, si no es calculando el número necesario de pacientes a tratar para evitar un evento, que corresponde 1/disminución absoluta del riesgo.

Si se grafica con los resultados de los 6 estudios el número necesario a tratar, contra el riesgo absoluto, se ve claramente que a más alto el riesgo, mejor es el resultado del tratamiento.

Los estudios 4S, CARE y LIPID y HPS, demostraron que en pacientes con enfermedad coronaria manifiesta, independientemente de los niveles lípidos se obtiene beneficio con el tratamiento con estatinas establecido en por lo menos tres meses después del diagnóstico de un evento coronario. La pregunta si las estatinas dan beneficios cuando se inician en las fases más tempranas de un evento coronario agudo se ha enfocado en el estudio The Myocardial Ischemia Reduction with Agressive Colesterol Lowering (MIRACL), cuyos resultados sugieren que si existe un beneficio con el tratamiento con estatinas prescritas en forma temprana, en pacientes con síndrome isquémico coronario agudo. Este estudio sugiere también que los beneficios son mayores cuando se alcanzan niveles de LDL-Colesterol tan bajos como <80 mg/dL.

Otro estudio que apoya el concepto de "tanto más bajo, mejor" (The lower the better) es el estudio Post-Coronary Artery Bypass Graft trial (Post-CABG), que mostró que después de un tratamiento agresivo por un promedio de 4.3 años, la mayor regresión de la aterosclerosis y su menor progresión se obtuvo en los pacientes que alcanzaron niveles de LDL-Colesterol <80 mg/dL.

El estudio Atorvastatin versus Revascularization Treatment (AVERT) sugiere que el tratamiento agresivo de la dislipidemia, (Atorvastatina 80 mgs diarios), después de 18 meses de tratamiento, con reducciones del LDL-Colesterol a 77 mg/dL, es capaz de reducir 36% la incidencia de eventos isquémicos, en comparación del grupo control en el cual los niveles de LDL-Col. Alcanzados fue de 119 mg/dL.

La respuesta definitiva a la pregunta de si es posible obtener mejores beneficios con el tratamiento agresivos de lípidos, se tendrá con los estudios: Treating to New Targets (TNT), Study of the Effectiveness of Adicional Reduction in Colesterol and Hocystiene (SEARCH) y Incremental Decrease in Endpoints Trough Agressive Lipid Lowering (IDEAL)

EL EMPLEO SUBOPTIMO DE LAS MEDIDAS PARA LA PREVENCIÓN DE LA ATEROSCLEROSIS: El empleo subóptimo de las medidas para la prevención de la aterosclerosis es un fenómeno de enorme magnitud. En el estudio de salud nacional (NHNES III), se encontró que el 57% de pacientes con hiperlipidemia y dos o más factores de riesgo, no reciben tratamiento para el control de lípidos y lo que es aún mas preocupante, 85% de los pacientes norteamericanos con un infarto del miocardio, no se encuentran bajo control de la hiperlipidemia, todo esto a pesar de los magníficos resultados reportados en los 6 grandes estudios con estatinas (y de que existe la indicación precisa de su aplicación en las influyentes guías del ATPIII.

La explicación para este fenómeno puede estar en las siguientes infundadas preocupaciones en relación al uso de las estatinas:

* Toxicidad hepática y miositis /rabdiomiolisis.

LA HEPATOTOXICIDAD: La hepatotoxicidad caracterizada por: colestasis, ictericia, hepatitis, hígado graso, cirrosis o insuficiencia hepática, es un evento raro con el uso de estatinas y su tasa es de 0.2 por cada 100 000 individuos que la toman y su frecuencia resulta muy baja si se compara el 2/100 000 que se presenta con el uso de antinflamatorios no esteroideos o el 10/100 0000 con tiazolidinedionas o el elevadísimo de 100/ 100 000 en usarios de Bromfenac. La elevación leve a moderada de enzimas, que se presenta mucho más frecuentemente con el uso de hipolipemiantes no predicen hepatotoxicidad, la que parece ser una reacción idiosincrásica, que ocurre prácticamente solo con el uso de ácido nicotínico de liberación sostenida.

En el estudio HPS la elevación de ALT >3ULN se presentó en el 0.8% de los pacientes que tomaban la estatina y en 0.6% en el grupo placebo.

¿COSTO O INVERSIÓN EN EL TRATAMIENTO? La prevención secundaria es un procedimiento con muy buen rango de costo/efectividad, pues por ejemplo el tratamiento con estatinas para prevención secundaria tiene un costo por año de calidad de vida ajustado de $12.000,00 dólares americanos, siendo que cualquier intervención con un costo menor a $20.000,00 por año de calidad de vida ajustado, se considera altamente costo-efectivo. Por lo que en realidad cuando se trata a un paciente con estatinas, no se está gastando, se está invirtiendo en salud.

CONCLUSIONES: Debido a que se obtiene un beneficio claro con el uso de estatinas en la disminución de desenlaces duros (hard-endpoints), existen en la actualidad suficientes evidencias para indicarlas en las siguientes condiciones:

1. Pacientes con síndrome isquémico coronario agudo, con y sin desnivel del segmento ST, con prácticamente cualquiera que sea su nivel de Colesterol o LDL-Colesterol (con niveles de Colesterol o LDl-Colesterol muy elevados (4S), moderadamente elevado (LIPID), promedio, (CARE), promedio o bajo (HPS), independientemente de que sean mujeres o mayores de 75 años. (HPS). El tratamiento debe iniciarse inmediatamente después del diagnóstico del evento (MIRACL).

2. Pacientes con equivalentes de enfermedad coronaria: Diabetes, enfermedad arterial periférica, stroke, con niveles de colesterol o LDL-Colesterol promedio o bajo (HPS). Independientemente de que sean mujeres o mayores de 75 años. (HPS).

3. Personas sin evidencias de enfermedad coronaria, con niveles de Colesterol o LDl-Colesterol elevado. (WOSCOPS).

4. Personas sin evidencias de enfermedad coronaria, con niveles de Colesterol o LDl-Colesterol moderadamente elevado. (AFCAPS/TexCAPS).

Estas indicaciones para el uso de las estatinas implica su prescripción a cantidades muy grandes de personas, sin embargo cuando se emplean en pacientes con las características similares a aquellos incluidos en el estudio HPS, (Pacientes con enfermedad coronaria sintomática o con equivalentes de ella), por cada millón de tratados se pueden salvar 5.000 vidas por año, independientemente del nivel previo de lípidos en sangre.

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¿Estatinas para todos? Nuevas evidencias sobre la seguridad y eficacia de los inhibidores de la hmg co-a reductasa. (estatinas)

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Similares en SciELO ¿Estatinas para todos? Nuevas evidencias sobre la seguridad y eficacia de los inhibidores de la Hmg Co-A Reductasa. (Estatinas). Mexico City General Hospital, and National Autonomous University of Mexico. Tuxpan 16, México D.F., 0676, México. lalcocer@servidor.unam.mx La aterosclerosis es la causa principal de muerte de la especie humana en la edad adulta.

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TÍTULO: Terapia combinada de ezetimiba y estatina

TIPO DE ESTUDIO: Metaanálisis

AÑO: 2016

AUTOR: Nußbaumer, B, et al

RESULTADOS: Se incluyeron nueve ensayos controlados aleatorios con datos de un total de 19 461 pacientes. La terapia de combinación de ezetimiba y estatina se asoció con un menor riesgo de eventos cardiovasculares que la monoterapia con estatinas: el 33 % de los pacientes tratados con ezetimiba y una estatina, y el 35 % de los tratados con una estatina sola, tuvieron un evento cardiovascular dentro de los siete años (número necesarios para tratar [NNT]: 50 durante 7 años). La terapia combinada también fue significativamente más efectiva en la prevención de un criterio de valoración compuesto consistente en muerte por enfermedad cardiovascular, infarto de miocardio no fatal, angina de pecho inestable, revascularización coronaria y accidente cerebrovascular no fatal (hazard ratio [HR] 0,94, intervalo de confianza del 95% [0,89 ; 0,99]; p = 0,016). Los pacientes diabéticos se beneficiaron de la terapia combinada en lugar de la monoterapia con respecto a la morbilidad cardiovascular (HR 0,87 [0,78; 0,94]). Por otro lado, la adición de ezetimiba a la terapia con estatinas no disminuyó la mortalidad cardiovascular ni global. Se produjeron eventos no deseados graves en el 38 % de los pacientes que tomaban ezetimiba y una estatina y en el 39 % de los pacientes que tomaban una estatina sola (riesgo relativo 1,09 [0,77; 1,55]).

CONCLUSIÓN: En pacientes de alto riesgo con síndrome coronario agudo, la terapia combinada con ezetimiba y una estatina redujo el riesgo de eventos cardiovasculares en comparación con la monoterapia con estatina. El riesgo de morir o sufrir un efecto adverso del fármaco fue similar en los dos grupos de tratamiento.

https://pubmed.ncbi.nlm.nih.gov/27412989/

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Ezetimibe-Statin Combination Therapy - PubMed

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In high-risk patients with an acute coronary syndrome, combination therapy with ezetimibe and a statin lowered the risk of cardiovascular events in comparison to statin monotherapy. The risk of dying or suffering an adverse drug effect was similar in the two treatment groups.

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https://www.nature.com/articles/s41569-018-0098-5
TITULO:

Seguridad y eficacia de la terapia con estatinas

TIPO DE ESTUDIO: Revisión sistemática
Resultado: Se evidenció que el beneficio de un terapia de tratamiento en base a estatinas supera a los eventos adversos que puedan presentarse. Sin embargo se tiene entre los eventos mas graves: deterioro cognitivo e ictus hemorrágico

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Acknowledgements

Review criteria

We conducted a literature search using Medline, PubMed and Embase and limited the search to the years 2000-2017. Search terms included "statin adverse effects", "statin safety", "statin side effects" and "statin intolerance". In addition, search terms related to specific target organs and adverse events were also used, including "statin AND muscle, diabetes, glucose, cognitive function and stroke". Publications were fully reviewed if the abstract suggested that the study was relevant and used only human data.

Author information

Affiliations

1. Division of General Internal Medicine & Geriatrics, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

Bhavin B. Adhyaru & Terry A. Jacobson

2. Lipid Clinic and Cardiovascular Risk Reduction Program, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA

Terry A. Jacobson

Contributions

Both authors researched data for the article, contributed to the discussion of content, and wrote, reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Bhavin B. Adhyaru or Terry A. Jacobson.

Ethics declarations

Competing interests

T.A.J. is a consultant for Amgen and Regeneron/Sanofi. B.B.A. declares no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Statin-associated muscle symptoms

(SAMS). Muscle symptoms that are the most prevalent adverse effect reported with statin therapy.

Statin intolerance

A clinical syndrome characterized by the inability to tolerate multiple statins with either objectionable symptoms or abnormal laboratory determinations that are temporally related to statin treatment and reversible upon statin discontinuation but reproducible by rechallenge.

Creatine kinase

An enzyme that is found in skeletal muscle, the heart, and the brain, and increases in the blood due to muscle injury, inflammation or necrosis of skeletal or heart muscle.

Myalgia

A condition involving muscle aches, stiffness, soreness, tenderness or cramps.

Rhabdomyolysis

A rare, life-threatening condition, characterized by the rapid destruction of skeletal muscle typically with creatine kinase levels >10 times the upper limit of normal and which often leads to acute renal failure.

Statin-induced necrotizing autoimmune myopathy

(SINAM). A rare, immune-mediated myopathy characterized by proximal muscle weakness, muscle necrosis with markedly elevated creatine kinase levels, and the presence of autoantibodies to hydroxyl-methyl-glutaryl-coenzyme A reductase, in which muscle symptoms persist despite statin discontinuation.

About this article

Cite this article

Adhyaru, B.B., Jacobson, T.A. Safety and efficacy of statin therapy. Nat Rev Cardiol 15, 757-769 (2018). https://doi.org/10.1038/s41569-018-0098-5
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Safety and efficacy of statin therapy - Nature Reviews Cardiology

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The current guidelines recommending the use of higher-intensity statin therapy to reduce the risk of cardiovascular disease have raised concerns about potential adverse effects associated with long-term statin therapy. In this Review, Adhyaru and Jacobson discuss the evidence for the efficacy and safety of statins to help clinicians and patients make informed decisions about statin therapy.

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Titulo: Terapia con estatinas: revisión de la seguridad y los posibles efectos secundarios.

Tipo de Estudio: Revisión Sistemática
Año: 2016
Resultados: La mialgia es el efecto secundario más común del uso de estatinas, con tasas documentadas del 1 al 10%. La rabdomiolisis es el efecto adverso más grave del uso de estatinas, aunque ocurre muy raramente (menos del 0,1%).
Conclusiones: En general, las estatinas parecen ser seguras para su uso en la gran mayoría de los pacientes. Sin embargo, los pacientes con múltiples comorbilidades médicas tienen un mayor riesgo de efectos adversos por el uso prolongado de estatinas.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126440/

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Statin Therapy: Review of Safety and Potential Side Effects

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Hydroxymethyl glutaryl coenzyme A reductase inhibitors, commonly called statins, are some of the most commonly prescribed medications worldwide. Evidence suggests that statin therapy has significant mortality and morbidity benefit for both primary and ...

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TÍTULO: Eficacia y seguridad de alirocumab en la reducción de lípidos y eventos cardiovasculares
Estudio: Ensayo aleatorizado
AUTOR, AÑO: Robinson J; et al. 2015
RESULTADOS: En la semana 24, la diferencia entre los grupos de alirocumab y placebo en el cambio porcentual medio desde el inicio en el nivel de colesterol LDL calculado fue de -62 puntos porcentuales (P <0,001); el efecto del tratamiento se mantuvo constante durante un período de 78 semanas. El grupo de alirocumab, en comparación con el grupo de placebo, tuvo tasas más altas de reacciones en el lugar de la inyección (5,9 % frente a 4,2 %), mialgia (5,4 % frente a 2,9 %), eventos neurocognitivos (1,2 % frente a 0,5 %) y eventos oftalmológicos (2,9% vs. 1,9%). En un análisis post hoc, la tasa de eventos cardiovasculares adversos mayores (muerte por enfermedad coronaria, infarto de miocardio no fatal, accidente cerebrovascular isquémico fatal o no fatal o angina inestable que requiere hospitalización) fue menor con alirocumab que con placebo (1,7 % frente a 3,3 %). , razón de riesgo, 0,52, intervalo de confianza del 95%, 0,31 a 0,90, P nominal = 0,02).
CONCLUSION:Durante un período de 78 semanas, alirocumab, cuando se agregó a la terapia con estatinas a la dosis máxima tolerada, redujo significativamente los niveles de colesterol LDL. En un análisis post hoc, hubo evidencia de una reducción en la tasa de eventos cardiovasculares con alirocumab.
https://pubmed.ncbi.nlm.nih.gov/25773378/

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Abstract

Background: Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy.

Methods: We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.

Results: At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02).

Conclusions: Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).

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anticholesteremic agents / adverse effects

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anticholesteremic agents / therapeutic use*

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cardiovascular diseases / prevention & control*

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national center for biotechnology information

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Efficacy and safety of alirocumab in reducing lipids and cardiovascular events - PubMed

# data[].attributes.attachment_link.description
Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuti ...

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TITULO:

Seguridad y eficacia del tratamiento con estatinas solas y en combinación con fibratos en pacientes con dislipidemia.

AUTORES: Hye Pato Choi , wan gyoon shin

AÑO Y TIPO DE ESTUDIO: 2013,

metaanálisis

RESULTADOS:  En el análisis de eficacia, una combinación de estatinas y fibratos proporcionó reducciones significativamente mayores en el colesterol total (SE = 0,430; IC 95% 0,315-0,545), colesterol LDL (SE = 0,438; IC 95% 0,321-0,555) y triglicéridos ( SE = 0,747; IC 95% 0,618-0,876), y un aumento significativamente mayor del colesterol HDL (SE = 0,594; IC 95% 0,473-0,715) que el tratamiento con estatinas solas. En el análisis de seguridad, el tratamiento con estatinas solas se asoció con una reducción significativa en el número de eventos adversos totales (RR = 0,665; IC 95 % 0,539-0,819), eventos adversos relacionados con el hígado (RR = 0,396; IC 95 % 0,206- 0,760) y eventos adversos relacionados con el riñón (RR = 0,146; IC 95% 0,075-0,285).

CONCLUSIÓN: Sugerimos que el tratamiento con estatinas más fibratos proporciona beneficios clínicos sobre el tratamiento con estatinas solas, pero el aumento de los riesgos, especialmente de efectos secundarios hepáticos o renales, debe controlarse cuidadosamente.

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Abstract

Background: Dyslipidemia is a major risk factor for cardiovascular disease and is treated with many effective lipid-lowering agents. Statins are often used alone or in combination with fibrates. Combination therapy is more effective due to their comparative actions, but the increased incidence of side effects should be considered carefully.

Research design and methods: A meta-analysis of published data was conducted to compare the safety and efficacy of statins alone versus statins plus fibrates in patients with dyslipidemia. In total, nine articles were assessed for efficacy analysis and ten articles were assessed for safety analysis.

Results: In the efficacy analysis, a combination of statins and fibrates provided significantly greater reductions in total cholesterol (SE = 0.430; 95% CI 0.315-0.545), LDL cholesterol (SE = 0.438; 95% CI 0.321-0.555) and triglycerides (SE = 0.747; 95% CI 0.618-0.876), and a significantly greater increase in HDL cholesterol (SE = 0.594; 95% CI 0.473-0.715) than treatment with statins alone. In the safety analysis, treatment with statins alone was associated with a significant reduction in the numbers of total adverse events (RR = 0.665; 95% CI 0.539-0.819), liver-related adverse events (RR = 0.396; 95% CI 0.206-0.760) and kidney-related adverse events (RR = 0.146; 95% CI 0.075-0.285).

Conclusion: We suggest that treatment with statins plus fibrates provides clinical benefits over treatment with statins alone but increased risks, especially of hepatic or renal side effects, should be monitored carefully.

Similar articles

Safety and efficacy of fibrate-statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: a meta-analysis.

Choi HD, Shin WG, Lee JY, Kang BC. Choi HD, et al. Vascul Pharmacol. 2015 Feb-Mar;65-66:23-30. doi: 10.1016/j.vph.2014.11.002. Epub 2014 Nov 6. Vascul Pharmacol. 2015. PMID: 25451563

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national center for biotechnology information

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Safety and efficacy of statin treatment alone and in combination with fibrates in patients with dyslipidemia: a meta-analysis - PubMed

# data[].attributes.attachment_link.description
Background: Dyslipidemia is a major risk factor for cardiovascular disease and is treated with many effective lipid-lowering agents. Statins are often used alone or in combination with fibrates. Combination therapy is more effective due to their comparative actions, but the increased incidence of side effects should be considered carefully.

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Titulo: Seguridad y eficacia del tratamiento con estatinas solas y en combinación con fibratos en pacientes con dislipidemia
Año: 2013
Tipo de estudio: Metanalisis de ECA
Resultados: El tratamiento con estatinas solas se asoció con una reducción significativa en el número de eventos adversos totales (RR = 0,665; IC 95 % 0,539–0,819), eventos adversos relacionados con el hígado (RR = 0,396; IC 95 % 0,206– 0,760) y eventos adversos relacionados con el riñón (RR = 0,146; IC 95% 0,075-0,285).
Conclusiones: Se sugiere que el tratamiento con estatinas más fibratos proporciona beneficios clínicos sobre el tratamiento con estatinas solas, pero los riesgos aumentados, especialmente de efectos secundarios hepáticos o renales, deben controlarse cuidadosamente.

# data[].attributes.attachment_link.title
Safety and efficacy of statin treatment alone and in combination with fibrates in patients with dyslipidemia: a meta-analysis

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(2014). Safety and efficacy of statin treatment alone and in combination with fibrates in patients with dyslipidemia: a meta-analysis. Current Medical Research and Opinion: Vol. 30, No. 1, pp. 1-10.

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Titulo: Combinación de dosis fija de ácido bempedoico más ezetimiba en pacientes con hipercolesterolemia y alto riesgo de ECV tratados con terapia con estatinas máximamente tolerada

Año: 2020   tipo de estudio: ECA

Resultados:  Entre los 301 pacientes incluidos en el análisis primario, el nivel medio de colesterol de lipoproteínas de baja densidad inicial fue de 3,87 mmol/L (149,8 mg/dL). En la semana 12, la combinación de dosis fija redujo el colesterol de lipoproteínas de baja densidad (-36,2 %) significativamente más que el placebo (1,8 % (diferencia corregida con placebo -38,0 %); P < 0,001), ezetimiba sola (-23,2 %; P < 0,001) o ácido bempedoico solo (-17,2 %; P< 0,001). La combinación de dosis fija redujo los niveles de colesterol de lipoproteínas de baja densidad de manera similar en todos los subgrupos, incluidos los pacientes que recibieron terapia de alta intensidad, de otra intensidad o sin estatinas. También se observaron mejoras con la combinación de dosis fija en los criterios de valoración secundarios de la eficacia, incluida la proteína C reactiva de alta sensibilidad. En este ensayo, el tratamiento combinado de dosis fija tuvo un perfil de seguridad generalmente similar en comparación con el ácido bempedoico, la ezetimiba o el placebo.

Conclusiones:  La combinación de dosis fija de ácido bempedoico y ezetimiba redujo significativamente el colesterol de lipoproteínas de baja densidad en comparación con el placebo u otras monoterapias orales y tuvo un perfil de seguridad favorable cuando se agregó a la terapia con estatinas máximamente tolerada en pacientes con hipercolesterolemia y alto riesgo de enfermedad cardiovascular.

https://pubmed.ncbi.nlm.nih.gov/31357887/

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https://pubmed.ncbi.nlm.nih.gov/21498906/
TITULO: Comparación directa aleatorizada de pitavastatina, atorvastatina y rosuvastatina en cuanto a seguridad y eficacia (cantidad y calidad de LDL): el ensayo PATROL
AÑO: 2011
TIPO DE ESTUDIO: Ensayo controlado aleatorizado
RESULTADOS: La seguridad se evaluó en términos de tasas de eventos adversos, incluidas variables de laboratorio clínico anormales relacionadas con la función hepática y renal y el músculo esquelético. La eficacia se evaluó por los cambios en los niveles y patrones de lipoproteínas. Se inscribieron 302 pacientes (de 51 centros), y estas 3 estatinas potentes redujeron por igual las partículas de LDL-C y LDL, así como las LDL de migración rápida (LDL modificada) en un 40-45 %. La pitavastatina recientemente desarrollada no fue inferior a las otras 2 estatinas en la reducción del LDL-C.
CONCLUSIÓN:  La seguridad y la eficacia de estas 3 estatinas potentes son iguales. Se sugiere que el uso de estas 3 estatinas dependa completamente de la discreción del médico según los antecedentes del paciente.

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national center for biotechnology information

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Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial - PubMed

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The safety and efficacy of these 3 strong statins are equal. It is suggested that the use of these 3 statins be completely dependent on physician discretion based on patient background.

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Título:

Comparación de los efectos hipolipemiantes de pitavastatina 4 mg frente a pravastatina 40 mg en adultos con hiperlipidemia primaria o dislipidemia mixta (combinada): ensayo de superioridad de fase IV, prospectivo, estadounidense, multicéntrico, aleatorizado, doble ciego.

Año: 20214
Tipo de estudio: ECA
Resultados: La tasa general de eventos adversos emergentes del tratamiento fue del 47,6 % (78 de 164) para pitavastatina y del 44,5 % (73 de 164) para pravastatina. Se informó mialgia en 3 pacientes (1,8 %) en el grupo de pitavastatina y en 4 pacientes (2,4 %) en el grupo de pravastatina. No hubo informes de miositis o rabdomiólisis.

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Purpose

Results from a Phase III, European, noninferiority trial in elderly (age ≥65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18-80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia.

Methods

This was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels ≤400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg.

Findings

A total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged <65 years]; 49.4% women; mean body mass index, 30.2 kg/m ²) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was -38.1% for pitavastatin 4 mg and -26.4% for pravastatin 40 mg; the difference in median percent change between treatments was -12.5% ( P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non-HDL-C were also significant in favor of pitavastatin ( P < 0.001). Both treatments significantly ( P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis.

Implications

Pitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476.

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References

1. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines [Published correction appears in Circulation. 2004;110:763].

: 227-239

2. Prevalence of uncontrolled risk factors for cardiovascular disease: United States, 1999-2010. NCHS data brief, no 103.

National Center for Health Statistics, Hyattsville, MD August 2012 ()

3. Statins: have we found the Holy Grail?.

: w13515

4. Pitavastatin: a new HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia.

: 264-267

5. Drug-drug interactions with statins: will pitavastatin overcome the statins' Achilles' heel?.

: 1551-1562

6. Comparison of pitavastatin with simvastatin in primary hypercholesterolaemia or combined dyslipidaemia [Published correction appears in Curr Med Res Opin. 2010;26:1046. Dosage error in article text].

: 2755-2764

7. for the PATROL Trial Investigators. Randomized head-to-head comparison of pitavastatin, atorvastatin, and rosuvastatin for safety and efficacy (quantity and quality of LDL): the PATROL trial.

: 1493-1505

Jones P.H.

Davidson M.H.

Stein E.A.

et al.

for the STELLAR Study Group

Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial).

: 152-160

9. Pravachol [prescribing information].

Bristol-Myers Squibb Company, Princeton, NJ October 2012

Article Info

Publication History

Identification

DOI: https://doi.org/10.1016/j.clinthera.2014.06.009

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Comparison of the Lipid-Lowering Effects of Pitavastatin 4 mg Versus Pravastatin 40 mg in Adults With Primary Hyperlipidemia or Mixed (Combined) Dyslipidemia: A Phase IV, Prospective, US, Multicenter, Randomized, Double-blind, Superiority Trial

# data[].attributes.attachment_link.description
Results from a Phase III, European, noninferiority trial in elderly (age ≥65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively).

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TITULO: Eficacia y seguridad de la rosuvastatina frente a la atorvastatina para reducir el colesterol LDL: un metanálisis de ensayos con poblaciones de Asia oriental

TIPO DE ESTUDIO -AÑO: metanálisis-2020

RESULTADOS: En comparación con atorvastatina, los pacientes tratados con rosuvastatina tuvieron una reducción significativa en LDL-C: DMP = -7,15 mg/dl (95% intervalos de confianza [IC]: -10,71--3,60) mg/dl, p < 0,0001. Los análisis de metarregresión no revelaron una asociación significativa entre los beneficios superiores de la rosuvastatina y otras variables, como la edad, el sexo, el nivel inicial de LDL-C y la duración del seguimiento. Además, el grupo de pacientes con rosuvastatina, que fueron tratados con la mitad de la dosis de atorvastatina, logró una reducción significativamente mayor en los niveles de LDL-C (DMP = -3,57; IC 95%: -5,40--1,74 mg/dl, p < 0,001 ). Tanto la rosuvastatina como la atorvastatina fueron bien toleradas, con incidencias similares de eventos adversos.

CONCLUSIONES: De manera similar al metanálisis de VOYAGER, que informó una mayor eficacia de la rosuvastatina en comparación con la atorvastatina y la simvastatina en pacientes caucásicos, encontramos que la eficacia de la rosuvastatina fue superior a la de la atorvastatina en pacientes de Asia oriental con hipercolesterolemia.
https://pubmed.ncbi.nlm.nih.gov/30483816/

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Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

² Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.

³ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. jiang.hong@zs-hospital.sh.cn.

⁴ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. ge.junbo2@zs-hospital.sh.cn.

Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

² Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China.

³ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. jiang.hong@zs-hospital.sh.cn.

⁴ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. ge.junbo2@zs-hospital.sh.cn.

Abstract

Background: The VOYAGER meta-analysis reported on the low-density lipoprotein cholesterol (LDL-C)-lowering effect of commonly used statins in Caucasian subjects. As there is limited literature available on the efficacy of statins in Asian populations, the current meta-analysis compared the effects of rosuvastatin and atorvastatin on LDL-C levels in an East Asian population.

Methods: The MEDLINE, PubMed, Embase, Cochrane Library, and Web of Science databases were searched for randomized controlled trials comparing lipid-lowering effects of rosuvastatin and atorvastatin in an East Asian population. Data on the study design, participant characteristics, and outcomes were extracted. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences were calculated using the random-effects model.

Results: The meta-analysis comprised 16 randomized controlled trials with 5930 participants. Compared with atorvastatin, patients treated with rosuvastatin had a significant reduction in LDL-C: WMD = -7.15 mg/dl (95% confidence intervals [CI]: -10.71--3.60) mg/dl, p < 0.0001. Meta-regression analyses revealed no significant association between the superior benefits of rosuvastatin and other variables including age, sex, baseline LDL-C level, and follow-up duration. Additionally, the rosuvastatin group of patients, who were treated with half the dose of atorvastatin, achieved a significantly greater reduction in LDL-C levels (WMD = -3.57; 95% CI: -5.40--1.74 mg/dl, p < 0.001). Both rosuvastatin and atorvastatin were well tolerated, with similar incidences of adverse events.

Conclusion: Similar to the VOYAGER meta-analysis, which reported a greater efficacy of rosuvastatin in comparison with atorvastatin and simvastatin in Caucasian patients, we found that the efficacy of rosuvastatin was superior to atorvastatin in East Asian patients with hypercholesterolemia.

Keywords: Eastern Asia; Hypercholesterolemia; Low-density lipoprotein; Statins; Treatment efficacy.

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national center for biotechnology information

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Efficacy and safety of rosuvastatin vs. atorvastatin in lowering LDL cholesterol : A meta-analysis of trials with East Asian populations - PubMed

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1 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China. 2 Department of General Practice, Zhongshan Hospital, Shanghai Medical College of Fudan University, Shanghai, China. 3 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Medical College of Fudan University, 1069 Xietu Road, 200032, Shanghai, China.

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Estudio: https://sci-hub.st/10.1016/j.clinthera.2021.07.016
Título: Efectos de la combinación de dosis fija de rosuvastatina de baja intensidad y ezetimiba versus monoterapia con rosuvastatina de intensidad moderada en los perfiles lipídicos en pacientes con hipercolesterolemia: un estudio aleatorizado, doble ciego, multicéntrico, de fase III

Tipo de estudio: ECA
Resultados: Los eventos adversos ocurrieron en 7 (2,5%) pacientes, los cuales fueron: Distensión abdominal y dispepsia (1,5% en la monoterapia de rosuvastatina 2.5mg y ezetimiba 10mg), aumento de la AST y ALT (1.4% en la monoterapia de rosuvastatina 5mg), aumento de la creatina fosfoquinasa en sangre (1.4% en la monoterapia de rosuvastatina 5mg), mialgia, jaqueca y prurito (1.4% tanto en la combinación de rosuvastatina 2.5mg y ezetimibe 10mg como en la monoterapia de ambos).
Conclusión: La combinación de ezetimiba con rosuvastatina de baja intensidad fue bien tolerada, con un excelente perfil de seguridad. La mayoría de los eventos adversos fueron leves y no se informaron eventos adversos graves en ningún paciente. Los perfiles de eventos adversos observados en el grupo de rosuvastatina/ezetimiba de baja intensidad fueron similares a los del grupo de rosuvastatina de baja intensidad y ezetimiba.

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Titulo:

Monoterapia con ezetimiba para reducir el colesterol en 2722 personas: revisión sistemática y metanálisis de ensayos controlados aleatorios.

Tipo de Estudio: metanálisis de ensayos controlados aleatorios (ECA).
Resultados: Un metanálisis de ocho ensayos aleatorizados, doble ciego, controlados con placebo (todos de 12 semanas) mostró que la monoterapia con ezetimiba se asoció con una reducción media estadísticamente significativa del colesterol LDL (desde el inicio hasta el final) de -18,58 %, (95 % IC: −19,67 a −17,48, P  < 0,00001) en comparación con placebo.

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Abdullah Pandor, Health Economics and Decision Science, School of Health and Related Research, University of Sheffield, Sheffield, S1 4DA, UK.(fax: +44 0 114 272 4095; e-mail: a.pandor@sheffield.ac.uk ).

Abstract.

Objectives. To study the evidence on the efficacy and safety of ezetimibe monotherapy for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia.

Design. Systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods. Eleven electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception and supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of RCTs, with a minimum treatment duration of 12 weeks, which compared ezetimibe monotherapy (10 mg per day) with placebo.

Results. In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid concentrations were used as indicators of clinical outcomes. A meta-analysis of eight randomized, double-blind, placebo-controlled trials (all 12 weeks) showed that ezetimibe monotherapy was associated with a statistically significant mean reduction in LDL cholesterol (from baseline to endpoint) of −18.58%, (95% CI: −19.67 to −17.48, P < 0.00001) compared with placebo. Significant ( P < 0.00001) changes were also found in total cholesterol (−13.46%, 95% CI: −14.22 to −12.70), HDL cholesterol (3.00%, 95% CI: 2.06-3.94) and triglyceride levels (−8.06%, 95% CI: −10.92 to −5.20). Ezetimibe monotherapy appeared to be well tolerated with a safety profile similar to placebo.

Conclusions. In a meta-analysis restricted to short-term trials in hypercholesterolaemia, significant potentially favourable changes in lipid and lipoprotein levels relative to baseline occurred with ezetimibe monotherapy. Further long-term studies with cardiovascular and other clinical outcome data are needed to assess the efficacy and safety of ezetimibe more fully.

Introduction

Cardiovascular disease is the most common cause of death in the UK, accounting for over 208 000 deaths in 2005; about 49% of these from coronary heart disease and about 28% from stroke []. Cardiovascular disease is also a major cause of illness, disability and reduced quality of life []. There is a curvilinear relationship between LDL cholesterol and the risk of cardiovascular disease (coronary heart disease and non-haemorrhagic stroke) with no threshold below which the risk ceases to exist in the range of LDL cholesterol levels generally encountered in societies where cardiovascular disease is prevalent [].

The management of hypercholesterolaemia is constantly evolving. The main aim of treatment is to prevent or reduce the risk and complications of cardiovascular disease []. Although serum cholesterol is an important risk factor for cardiovascular disease, cholesterol lowering with medication is only one of a number of methods for reducing the risk of cardiovascular disease []. Dietary and lifestyle modifications are an integral part of risk management. The decision to initiate therapy with a lipid-regulating drug is generally based on an assessment of overall cardiovascular disease risk []. At present, statins (associated principally with lowering concentrations of total cholesterol and LDL cholesterol, with smaller effects in raising HDL cholesterol and decreasing triglyceride levels), are the cholesterol-regulating drugs of choice for both primary and secondary prevention of cardiovascular disease []. However, a small but significant proportion of patients (1-3%) are unable to tolerate statins (for example due to myalgia or gastrointestinal disturbances) or have contra-indications (for example active liver disease or, other drugs potentially interacting) []. Other lipid-regulating drug therapies such as fibrates, nicotinic acid derivatives or bile acid sequestrating agents are also available, but are infrequently prescribed for hypercholesterolaemia in the UK []. Despite some evidence that bile acid sequestrants and nicotinic acid [] can reduce cardiovascular disease risk they are poorly tolerated and in the case of fibrates, which have only moderate effects in lowering LDL cholesterol, evidence that they prevent cardiovascular disease is equivocal [].

Ezetimibe, a comparatively new treatment, lowers LDL cholesterol by blocking the intestinal absorption of dietary and biliary cholesterol and related plant sterols without affecting the uptake of triglycerides or fat soluble vitamins. This study evaluates the evidence for the clinical effectiveness of ezetimibe monotherapy versus placebo in hypercholesterolaemic patients. This study was undertaken to inform the UK National Institute for Health and Clinical Excellence on the appraisal of ezetimibe for the treatment of primary hypercholesterolaemia [].

Methods

Study search

Eleven electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception to September 2008 (including the Cochrane Library, MEDLINE, EMBASE and CINAHL). The search strategy used free text and thesaurus terms and combined synonyms relating to the intervention (e.g. ezetimibe, ezetrol, zetia, vytorin, inegy and Chemical Abstracts Service Registry number or Enzyme Commission number: 163222-33-1) with synonyms relating to the condition (e.g. hypercholesterolemia, hypercholesterolaemia). Language restrictions were not used on any database. Searches were supplemented by hand searching relevant journals, conference proceedings, and consulting experts in the field. Further details on the search strategies are available from the authors.

Study selection

Two reviewers independently screened the searches for potentially relevant studies. The full manuscript of all potentially relevant studies was retrieved and each study was assessed independently by two reviewers for inclusion using predetermined eligibility criteria. Any differences in selection were resolved through discussion to achieve consensus. Randomized controlled trials (RCTs) of ezetimibe monotherapy (10 mg per day) compared with placebo in individuals (over 18 years of age) with heterozygous familial and non-familial hypercholesterolaemia were included. The primary outcomes of interest were survival, fatal and non-fatal cardiovascular events, adverse effects of treatment, and health-related quality of life. In the absence of data from clinical outcome trials, surrogate endpoints such as changes in total serum cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were used as indicators of clinical outcomes. As current licensing authorities such as the European Medicines Agency require a minimum follow-up of 3 months for trials of surrogate endpoints in lipid lowering drug therapies [], and to minimize tachyphylaxis effects, studies of <12 weeks duration were excluded. Other exclusion criteria included adults with homozygous familial hypercholesterolaemia, homozygous sitosterolaemia, or mixed hyperlipidaemia, non RCTs (including reviews, comments and editorials) and studies with insufficient/inappropriate data.

Assessment of methodological quality

Study quality was assessed independently by two reviewers and discrepancies were resolved through discussion. RCTs were evaluated according to criteria based on those proposed by the NHS Centre for Reviews and Dissemination []. These included method of randomisation, details of allocation concealment, baseline comparability, blinding of participant, investigator, outcome assessors and data analysts, details of losses to follow-up and intention-to-treat analysis. Blinding of the quality assessors to author, institution or journal was not considered necessary [].

Data abstraction

Data relating to study design, quality, and results were extracted by one reviewer into a standardized data extraction form and independently checked for accuracy by a second. Any discrepancies were resolved through discussion to achieve agreement. Where multiple publications of the same study were identified, data were extracted and reported as a single study.

Data synthesis

For each study, data were tabulated and discussed in a narrative review. Where appropriate, meta-analyses were employed to estimate a summary measure of effect on relevant outcomes using the methods documented in the Cochrane Handbook []. All analyses were by intention-to-treat or modified intention-to-treat (analysis of subsets of patients who received treatment as planned or at least some treatment). Efficacy results were reported as least squares mean per cent change from baseline to study endpoint for each comparison group and were expressed as the weighted mean difference between treatments. The weighted mean difference is a method used to combine measures on continuous scales, where the mean, standard deviation (SD), and sample size in each group are known. The weight given to each study (for example, how much influence each study has on the overall results of the meta-analysis) is determined by the precision of its estimate of effect and is equal to the inverse of the variance. This method assumes that all of the trials have measured the outcome on the same scale.

Meta-analyses were carried out using fixed and random effect models, with the Cochrane Collaboration Review Manager 4.2.10 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The Z-statistic was used to assess overall effect and a P-value of <0.05 was considered significant. Statistical heterogeneity between trial results was assessed using the chi-squared test and I ²-measure. The chi-squared test measures the amount of variation in a set of trials. As this test has low power to detect heterogeneity when the number of included studies have small sample sizes or few in number, a P-value <0.1 was considered significant. The I ²-measure is the proportion of variation that is due to heterogeneity rather than sampling error (chance); a value >50% was considered as evidence of substantial heterogeneity [].

Results

Trial flow

Figure 1 presents a flow chart describing the process of identifying the relevant literature. To date, there have been no published clinical outcome trials examining the cardiovascular benefit of ezetimibe monotherapy. In the absence of data from hard clinical endpoint trials, eight RCTs of short-term duration (all 12 weeks) with surrogate endpoint data were included in this study []. A summary of each study is presented in Table 1.

Multi-centre, randomized double-blind, placebo-controlled trial

Adult men and women (aged ≥18 years) with a diagnosis of primary hypercholesterolaemia (LDL cholesterol concentration between 3.38 and 6.50 mmol L −1 and triglyceride level of ≤3.85 mmol L −1 after 6-12 weeks lipid lowering drug washout)

Ezetimibe, 10 mg per day ( n = 666) vs. placebo ( n = 226) (randomisation, 3 : 1 ratio)

LDL cholesterol

12 weeks

Multi-centre, randomized double-blind, placebo-controlled, balanced-parallel group trial

Adult men and women (aged ≥18 years) with a diagnosis of primary hypercholesterolaemia (LDL cholesterol concentration between 3.36 and 6.47 mmol L −1 and triglyceride level of ≤3.95 mmol L −1 after 6-12 weeks lipid lowering drug washout)

Ezetimibe, 10 mg per day ( n = 622) vs. placebo ( n = 205) (randomisation, 3 : 1 ratio)

LDL cholesterol

12 weeks

aInterventions not relevant and ignored from meta-analysis - atorvastatin (10, 20, 40, or 80 mg per day) or ezetimibe (10 mg per day) plus atorvastatin (10, 20, 40, or 80 mg per day). bInterventions not relevant and ignored from meta-analysis - simvastatin (10, 20, 40, or 80 mg per day) or ezetimibe (10 mg per day) plus simvastatin (10, 20, 40, or 80 mg per day). cInterventions not relevant and ignored from meta-analysis - lovastatin (10, 20, or 40 mg per day) or ezetimibe (10 mg per day) plus lovastatin (10, 20, or 40 mg per day). dInterventions not relevant and ignored from meta-analysis - pravastatin (10, 20, or 40 mg per day) or ezetimibe (10  mg per day) plus pravastatin (10, 20, or 40 mg per day).

Study and patient characteristics

All RCTs were published between 2002 and 2004. In total, 2,722 individuals were enrolled in the trials and included men (39-49%) and women over 18 years of age (mean ages ranged from 52.0 to 60.3 years), with a diagnosis of primary hypercholesterolaemia (mean baseline LDL cholesterol ranging from 3.36 to 6.50 mmol L −1 and triglyceride levels <4.0 mmol L −1). All eight studies included individuals with or at high-risk of cardiovascular disease. Approximately 33-48% of the participants had a known family history of cardiovascular disease; 27-38% had a history of hypertension, 2-8% had diabetes mellitus, and 3-9% had a history of coronary heart disease. All individuals were required to undergo a washout or discontinue all ongoing lipid altering drug therapy (in general, 6 weeks for statins, bile acid sequestrants and nicotinic acid and 8-12 weeks for fibrates) prior to randomisation and initiation of study treatments.

Quality assessment

Randomized treatment assignment sequences were computer generated in five studies [] (method of assignment not reported by three studies) []. Two studies used a 2 by 2 factorial design [], two used a 2 by 4 factorial design [], and two used a 2 by 5 factorial design []. None of the studies reported adequate methods of allocation concealment. All studies randomized equal numbers of individuals to treatment and control groups in a 1 : 1 ratio, except the studies by Dujovne et al. [] and Knopp et al. [], which assigned participants using a 3 : 1 ratio. Although all studies were reported to be double-blind (patient and investigator) it is unclear whether individuals who administered the intervention were blinded to the treatment in the studies by Davidson et al. [], Dujovne et al. [] and Kerzner et al. []. All outcome assessors were blinded to the treatment allocation except in the studies by Dujovne et al. [], Knopp et al. [] and Kerzner et al. [], where it is not reported or unclear.

The baseline demographic characteristics between treatment groups were generally well balanced and the eligibility criteria were clearly reported in all trials. The majority of the studies were adequately powered (80-90%) [] to detect a difference in the primary surrogate (LDL cholesterol) endpoint (data not reported by Bays et al. [], and Goldberg et al.) []. More than 88% of participants in each study were reported to have completed the full treatment duration and all withdrawals were accounted for (data not reported by Kerzner et al.) []. Efficacy analyses in all trials were conducted using the intention-to-treat [] or the modified intention-to-treat [] approach.

Quantitative data synthesis

2- 5 show the forest plots with weighted mean difference for each study and for the pooled data. In patients with primary hypercholesterolaemia, ezetimibe monotherapy significantly ( P < 0.00001) reduced LDL cholesterol concentrations by −18.58% (95% CI: −19.67 to −17.48) compared with placebo. Ezetimibe monotherapy also significantly ( P <0.00001) improved total cholesterol (−13.46%, 95% CI: −14.22 to −12.70), HDL cholesterol (3.00%, 95% CI: 2.06-3.94) and triglyceride concentrations (−8.06%, 95% CI: −10.92 to −5.20) compared with placebo. The test for statistical heterogeneity was not significant for any of these outcomes ( P > 0.05).

Adverse events reported in each of the included studies are summarized in Table 2. Meta-analyses were considered inappropriate because of insufficient data and low occurrences of adverse events. In the eight short-term studies, ezetimibe monotherapy was found to have a similar adverse event profile to placebo []. Adverse events (any) ranged from 53-74% in the ezetimibe monotherapy groups and 54-72% in the placebo groups. Of these, 9-18% were considered due to treatment in the ezetimibe monotherapy group and 9-24% in the placebo group (mainly gastrointestinal adverse events or musculoskeletal disorders). Clinically important elevations in creatine phosphokinase (≥10 times upper limit of normal) and liver enzymes (alanine aminotransferase and aspartate aminotransferase ≥3 times upper limit of normal) were not influenced by treatment (<1% in both groups). Discontinuation rates were comparable between both arms and serious adverse events were rare and occurred with similar frequency in the ezetimibe monotherapy and placebo groups. No cases of hepatitis, jaundice, or other clinical signs of liver dysfunction were observed in seven of the eight trials [] (data not reported by Dujovne et al.) []. No deaths were attributable to ezetimibe monotherapy in any of the included studies.

Discussion

This is the first comprehensive meta-analysis on the clinical effectiveness of ezetimibe monotherapy compared with placebo. Although there have been no published clinical outcome trials (with cardiovascular disease mortality and morbidity as outcome measures), our meta-analysis of eight RCTs with surrogate endpoint data demonstrated that ezetimibe monotherapy significantly reduced LDL cholesterol concentrations compared with placebo in patients with primary hypercholesterolaemia. Significant potentially favourable changes were also observed in total cholesterol, HDL cholesterol and triglyceride levels, and ezetimibe monotherapy appeared to be well tolerated with a safety profile similar to placebo.

The correlation and causal relationship between serum cholesterol values, particularly LDL cholesterol and the risk of cardiovascular disease, have been established in numerous epidemiological studies [] systematic reviews and meta-analyses of clinical outcome trials []. Reducing LDL cholesterol by various mechanisms (statins, partial ileal bypass surgery, bile acid sequestrants, niacin or diet alone) decreases the risk of cardiovascular disease in people with or at high risk of cardiovascular disease. However, evidence for the benefit of fibrates is less clear [], and the results of the 2 year ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression (ENHANCE) surrogate outcome trial [] showed that the daily addition of 10 mg ezetimibe to 80 mg simvastatin in patients with familial hypercholesterolaemia (many of whom had previously received statin therapy) had no benefit on carotid intima-media thickness when compared with 80 mg simvastatin alone. Therefore, caution must be exercised if assuming that the apparent favourable effects on lipids or other surrogate markers necessarily translate into clinical benefit []. Until the results from the long-term studies of ezetimibe emerge, the association between ezetimibe-induced changes in lipids and cardiovascular events remains uncertain. Similarly, whilst the short-term (12 weeks) safety profile of ezetimibe monotherapy appears to be similar to placebo, this systematic review cannot address the long-term safety of ezetimibe monotherapy.

The recent findings from the simvastatin and ezetimibe in aortic stenosis (SEAS) trial [], has led to controversy about the safety of ezetimibe. This randomized, double-blind trial involving 1873 patients with mild to moderate, asymptomatic aortic stenosis found that after a mean follow-up of approximately 4 years, dual lipid lowering therapy with simvastatin (40 mg per day) plus ezetimibe (10 mg per day) significantly increased the cancer rate compared with placebo (105 cases vs. 70, P = 0.01, respectively). Given that a large, high-quality meta-analysis found that prolonged statin therapy does not increase the risk of cancer [], a preliminary hypothesis-testing analysis of interim cancer data from two large ongoing trials - the study of heart and renal protection (SHARP) (NCT00125593), in which simvastatin plus ezetimibe is compared with placebo (9264 patients with mean follow-up of 2.7 years), and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878), in which simvastatin plus ezetimibe is compared with simvastatin plus placebo (11353 patients with mean follow-up of 1.0 years) - was undertaken by Peto et al. []. In this combined analysis there was no significant excess of cancer, either overall (313 active-treatment vs. 326 control, P = 0.61) or at any particular site and there was no suggestion of an emerging trend with longer treatment and follow-up periods. This analysis suggest that the findings of the SEAS trial were a chance effect as was once seen with statins []. However, an accompanying editorial [] raised concerns on the use of interim data and recommended additional data (meeting performance standards for safety trials) to adequately address whether simvastatin plus ezetimibe was associated with an increased risk of death from cancer.

Although statins are the most effective drugs for lowering surrogate endpoints (total cholesterol by approximately 20-30% and LDL cholesterol by about 25-50%) [] and reducing coronary events, all cardiovascular events and total mortality [], a small but significant portion of patients are unable to tolerate statins due to severe adverse effects such myalgia, myositis, myopathy and rhabdomyolysis. Such events, whilst rare or infrequent at standard doses, are more likely to occur at higher statin doses and in most cases, cessation or changing the dosage of (or) the statin, reverses the adverse effects and usually leads to a full recovery []. Other lipid regulating drugs such as bile acid sequestrants (decrease total cholesterol by approximately 8-24% [] and LDL cholesterol by approximately 15-30%) [] and nicotinic acid (decrease total cholesterol by approximately 7-15% and LDL cholesterol by approximately 10-20%) [] also reduce cardiovascular disease risk [] (very limited trial evidence in comparison to statins on cardiovascular outcomes); however, they are rarely prescribed for hypercholesterolaemia [] as they are generally unpalatable and poorly tolerated [] and in the case of fibrates (decrease total cholesterol by approximately 7-13% and LDL cholesterol by approximately 1-13%) [], evidence that they prevent cardiovascular disease is uncertain [].

In this study, all the included trials lacked data on previous treatment outcomes; therefore, it was not possible to determine in what proportion of the study populations there was statin intolerance or contraindication. Thus we cannot say whether the response to ezetimibe treatment would be as good as or better than that reported here in individuals who are intolerant of statin treatment or on other medications. Nevertheless, in individuals who are strictly intolerant of statins (defined by the presence of clinically severe adverse effects from statin therapy, which are considered to represent an unacceptable risk to the patient or that may result in compliance with statin therapy being compromised) [] or in whom statins are considered inappropriate, ezetimibe monotherapy offers a treatment option for hypercholesterolaemia. This must be weighed against the unknown long-term efficacy and safety profile of ezetimibe and, with limited healthcare resources, its cost-effectiveness should also be considered. Assuming that the ezetimibe-induced decrease in LDL cholesterol translates into the same decrease in cardiovascular event rates as a similar statin induced decrease in LDL cholesterol, it has, however recently been reported that ezetimibe monotherapy could be a cost-effective alternative for subgroups of patients with high baseline LDL cholesterol levels [].

Certain limitations are inherent in meta-analysis [], of which the most important relates to the synthesis of data from trials that may be heterogeneous. Although there was no statistical evidence of significant heterogeneity in the included trials, differences between studies in factors such as patient characteristics or trial design may still have influenced the results. It was not possible to determine the direction of any such influence or bias.

Although an extensive literature search was conducted, it is possible that some relevant studies may have been missed. However, such omissions are likely to have been minimal, as the search included all identifiable publications in the grey literature (including contact with clinical experts in the field).

The results of the meta-analysis were dominated by the results of two major trials: Dujovne et al. [], and Knopp et al. []. A possible type II error may have prevented the smaller trials from detecting significant intergroup differences. Therefore, the possibility exists that the two larger trials found a true effect. None of the other studies suggest a trend towards a differential effect in mean total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides. Moreover, concealment of treatment allocation and blinding are important safeguards against bias in RCTs. Although the studies included in the meta-analysis were double-blind, none of the studies adequately reported the method of allocation concealment. It is not known what effect this may have had on the findings of the analyses. However, empirical evidence suggests that publications of trials in which allocation concealment is unclear or inadequate over-estimate the treatment effect, on average [].

In summary, this systematic review and meta-analysis demonstrates that ezetimibe monotherapy provides a clinical benefit for individuals with primary hypercholesterolaemia compared with placebo; thus, it may be considered as an alternative option in the management of individuals with hypercholesterolaemia in whom statin therapy is considered inappropriate or is not tolerated. However, to elucidate the efficacy and safety of ezetimibe monotherapy fully and to justify its use in a lipid management programme, further research is required including long-term studies reporting clinical outcome data, direct comparisons with other lipid-lowering treatments (such as nicotinic acid, resins or fibrates), and data from patients who are truly intolerant of statins.

Ethical approval

Not required.

Funding

This work was funded by the UK National Coordinating Centre for Health Technology Assessment (NCCHTA) and was undertaken on behalf of the National Institute of Health and Clinical Excellence (NICE). The views and opinions expressed are those of the authors and do not necessarily reflect those of the UK Department of Health.

Conflict of interest

PND has served as consultant to and received travel expenses, payment for speaking at meetings, or funding for research from pharmaceutical companies marketing lipid-lowering drugs, including Merck Sharp & Dohme - Schering Plough Ltd, the manufacturer of ezetimibe. AP, RMA, IT, SP, AJW, AD and JC have no competing interest.

Acknowledgements

We would like to thank Andrea Shippam, Project Administrator, ScHARR, for her help in the retrieval of papers and in preparing and formatting the paper.

Abstract.

Objectives. To study the evidence on the efficacy and safety of ezetimibe monotherapy for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia.

Design. Systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods. Eleven electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception and supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of RCTs, with a minimum treatment duration of 12 weeks, which compared ezetimibe monotherapy (10 mg per day) with placebo.

Results. In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid concentrations were used as indicators of clinical outcomes. A meta-analysis of eight randomized, double-blind, placebo-controlled trials (all 12 weeks) showed that ezetimibe monotherapy was associated with a statistically significant mean reduction in LDL cholesterol (from baseline to endpoint) of −18.58%, (95% CI: −19.67 to −17.48, P < 0.00001) compared with placebo. Significant ( P < 0.00001) changes were also found in total cholesterol (−13.46%, 95% CI: −14.22 to −12.70), HDL cholesterol (3.00%, 95% CI: 2.06-3.94) and triglyceride levels (−8.06%, 95% CI: −10.92 to −5.20). Ezetimibe monotherapy appeared to be well tolerated with a safety profile similar to placebo.

Conclusions. In a meta-analysis restricted to short-term trials in hypercholesterolaemia, significant potentially favourable changes in lipid and lipoprotein levels relative to baseline occurred with ezetimibe monotherapy. Further long-term studies with cardiovascular and other clinical outcome data are needed to assess the efficacy and safety of ezetimibe more fully.

Introduction

Cardiovascular disease is the most common cause of death in the UK, accounting for over 208 000 deaths in 2005; about 49% of these from coronary heart disease and about 28% from stroke []. Cardiovascular disease is also a major cause of illness, disability and reduced quality of life []. There is a curvilinear relationship between LDL cholesterol and the risk of cardiovascular disease (coronary heart disease and non-haemorrhagic stroke) with no threshold below which the risk ceases to exist in the range of LDL cholesterol levels generally encountered in societies where cardiovascular disease is prevalent [].

The management of hypercholesterolaemia is constantly evolving. The main aim of treatment is to prevent or reduce the risk and complications of cardiovascular disease []. Although serum cholesterol is an important risk factor for cardiovascular disease, cholesterol lowering with medication is only one of a number of methods for reducing the risk of cardiovascular disease []. Dietary and lifestyle modifications are an integral part of risk management. The decision to initiate therapy with a lipid-regulating drug is generally based on an assessment of overall cardiovascular disease risk []. At present, statins (associated principally with lowering concentrations of total cholesterol and LDL cholesterol, with smaller effects in raising HDL cholesterol and decreasing triglyceride levels), are the cholesterol-regulating drugs of choice for both primary and secondary prevention of cardiovascular disease []. However, a small but significant proportion of patients (1-3%) are unable to tolerate statins (for example due to myalgia or gastrointestinal disturbances) or have contra-indications (for example active liver disease or, other drugs potentially interacting) []. Other lipid-regulating drug therapies such as fibrates, nicotinic acid derivatives or bile acid sequestrating agents are also available, but are infrequently prescribed for hypercholesterolaemia in the UK []. Despite some evidence that bile acid sequestrants and nicotinic acid [] can reduce cardiovascular disease risk they are poorly tolerated and in the case of fibrates, which have only moderate effects in lowering LDL cholesterol, evidence that they prevent cardiovascular disease is equivocal [].

Ezetimibe, a comparatively new treatment, lowers LDL cholesterol by blocking the intestinal absorption of dietary and biliary cholesterol and related plant sterols without affecting the uptake of triglycerides or fat soluble vitamins. This study evaluates the evidence for the clinical effectiveness of ezetimibe monotherapy versus placebo in hypercholesterolaemic patients. This study was undertaken to inform the UK National Institute for Health and Clinical Excellence on the appraisal of ezetimibe for the treatment of primary hypercholesterolaemia [].

Methods

Study search

Eleven electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception to September 2008 (including the Cochrane Library, MEDLINE, EMBASE and CINAHL). The search strategy used free text and thesaurus terms and combined synonyms relating to the intervention (e.g. ezetimibe, ezetrol, zetia, vytorin, inegy and Chemical Abstracts Service Registry number or Enzyme Commission number: 163222-33-1) with synonyms relating to the condition (e.g. hypercholesterolemia, hypercholesterolaemia). Language restrictions were not used on any database. Searches were supplemented by hand searching relevant journals, conference proceedings, and consulting experts in the field. Further details on the search strategies are available from the authors.

Study selection

Two reviewers independently screened the searches for potentially relevant studies. The full manuscript of all potentially relevant studies was retrieved and each study was assessed independently by two reviewers for inclusion using predetermined eligibility criteria. Any differences in selection were resolved through discussion to achieve consensus. Randomized controlled trials (RCTs) of ezetimibe monotherapy (10 mg per day) compared with placebo in individuals (over 18 years of age) with heterozygous familial and non-familial hypercholesterolaemia were included. The primary outcomes of interest were survival, fatal and non-fatal cardiovascular events, adverse effects of treatment, and health-related quality of life. In the absence of data from clinical outcome trials, surrogate endpoints such as changes in total serum cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were used as indicators of clinical outcomes. As current licensing authorities such as the European Medicines Agency require a minimum follow-up of 3 months for trials of surrogate endpoints in lipid lowering drug therapies [], and to minimize tachyphylaxis effects, studies of <12 weeks duration were excluded. Other exclusion criteria included adults with homozygous familial hypercholesterolaemia, homozygous sitosterolaemia, or mixed hyperlipidaemia, non RCTs (including reviews, comments and editorials) and studies with insufficient/inappropriate data.

Assessment of methodological quality

Study quality was assessed independently by two reviewers and discrepancies were resolved through discussion. RCTs were evaluated according to criteria based on those proposed by the NHS Centre for Reviews and Dissemination []. These included method of randomisation, details of allocation concealment, baseline comparability, blinding of participant, investigator, outcome assessors and data analysts, details of losses to follow-up and intention-to-treat analysis. Blinding of the quality assessors to author, institution or journal was not considered necessary [].

Data abstraction

Data relating to study design, quality, and results were extracted by one reviewer into a standardized data extraction form and independently checked for accuracy by a second. Any discrepancies were resolved through discussion to achieve agreement. Where multiple publications of the same study were identified, data were extracted and reported as a single study.

Data synthesis

For each study, data were tabulated and discussed in a narrative review. Where appropriate, meta-analyses were employed to estimate a summary measure of effect on relevant outcomes using the methods documented in the Cochrane Handbook []. All analyses were by intention-to-treat or modified intention-to-treat (analysis of subsets of patients who received treatment as planned or at least some treatment). Efficacy results were reported as least squares mean per cent change from baseline to study endpoint for each comparison group and were expressed as the weighted mean difference between treatments. The weighted mean difference is a method used to combine measures on continuous scales, where the mean, standard deviation (SD), and sample size in each group are known. The weight given to each study (for example, how much influence each study has on the overall results of the meta-analysis) is determined by the precision of its estimate of effect and is equal to the inverse of the variance. This method assumes that all of the trials have measured the outcome on the same scale.

Meta-analyses were carried out using fixed and random effect models, with the Cochrane Collaboration Review Manager 4.2.10 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). The Z-statistic was used to assess overall effect and a P-value of <0.05 was considered significant. Statistical heterogeneity between trial results was assessed using the chi-squared test and I ²-measure. The chi-squared test measures the amount of variation in a set of trials. As this test has low power to detect heterogeneity when the number of included studies have small sample sizes or few in number, a P-value <0.1 was considered significant. The I ²-measure is the proportion of variation that is due to heterogeneity rather than sampling error (chance); a value >50% was considered as evidence of substantial heterogeneity [].

Results

Trial flow

Figure 1 presents a flow chart describing the process of identifying the relevant literature. To date, there have been no published clinical outcome trials examining the cardiovascular benefit of ezetimibe monotherapy. In the absence of data from hard clinical endpoint trials, eight RCTs of short-term duration (all 12 weeks) with surrogate endpoint data were included in this study []. A summary of each study is presented in Table 1.

Multi-centre, randomized double-blind, placebo-controlled trial

Adult men and women (aged ≥18 years) with a diagnosis of primary hypercholesterolaemia (LDL cholesterol concentration between 3.38 and 6.50 mmol L −1 and triglyceride level of ≤3.85 mmol L −1 after 6-12 weeks lipid lowering drug washout)

Ezetimibe, 10 mg per day ( n = 666) vs. placebo ( n = 226) (randomisation, 3 : 1 ratio)

LDL cholesterol

12 weeks

Multi-centre, randomized double-blind, placebo-controlled, balanced-parallel group trial

Adult men and women (aged ≥18 years) with a diagnosis of primary hypercholesterolaemia (LDL cholesterol concentration between 3.36 and 6.47 mmol L −1 and triglyceride level of ≤3.95 mmol L −1 after 6-12 weeks lipid lowering drug washout)

Ezetimibe, 10 mg per day ( n = 622) vs. placebo ( n = 205) (randomisation, 3 : 1 ratio)

LDL cholesterol

12 weeks

aInterventions not relevant and ignored from meta-analysis - atorvastatin (10, 20, 40, or 80 mg per day) or ezetimibe (10 mg per day) plus atorvastatin (10, 20, 40, or 80 mg per day). bInterventions not relevant and ignored from meta-analysis - simvastatin (10, 20, 40, or 80 mg per day) or ezetimibe (10 mg per day) plus simvastatin (10, 20, 40, or 80 mg per day). cInterventions not relevant and ignored from meta-analysis - lovastatin (10, 20, or 40 mg per day) or ezetimibe (10 mg per day) plus lovastatin (10, 20, or 40 mg per day). dInterventions not relevant and ignored from meta-analysis - pravastatin (10, 20, or 40 mg per day) or ezetimibe (10  mg per day) plus pravastatin (10, 20, or 40 mg per day).

Study and patient characteristics

All RCTs were published between 2002 and 2004. In total, 2,722 individuals were enrolled in the trials and included men (39-49%) and women over 18 years of age (mean ages ranged from 52.0 to 60.3 years), with a diagnosis of primary hypercholesterolaemia (mean baseline LDL cholesterol ranging from 3.36 to 6.50 mmol L −1 and triglyceride levels <4.0 mmol L −1). All eight studies included individuals with or at high-risk of cardiovascular disease. Approximately 33-48% of the participants had a known family history of cardiovascular disease; 27-38% had a history of hypertension, 2-8% had diabetes mellitus, and 3-9% had a history of coronary heart disease. All individuals were required to undergo a washout or discontinue all ongoing lipid altering drug therapy (in general, 6 weeks for statins, bile acid sequestrants and nicotinic acid and 8-12 weeks for fibrates) prior to randomisation and initiation of study treatments.

Quality assessment

Randomized treatment assignment sequences were computer generated in five studies [] (method of assignment not reported by three studies) []. Two studies used a 2 by 2 factorial design [], two used a 2 by 4 factorial design [], and two used a 2 by 5 factorial design []. None of the studies reported adequate methods of allocation concealment. All studies randomized equal numbers of individuals to treatment and control groups in a 1 : 1 ratio, except the studies by Dujovne et al. [] and Knopp et al. [], which assigned participants using a 3 : 1 ratio. Although all studies were reported to be double-blind (patient and investigator) it is unclear whether individuals who administered the intervention were blinded to the treatment in the studies by Davidson et al. [], Dujovne et al. [] and Kerzner et al. []. All outcome assessors were blinded to the treatment allocation except in the studies by Dujovne et al. [], Knopp et al. [] and Kerzner et al. [], where it is not reported or unclear.

The baseline demographic characteristics between treatment groups were generally well balanced and the eligibility criteria were clearly reported in all trials. The majority of the studies were adequately powered (80-90%) [] to detect a difference in the primary surrogate (LDL cholesterol) endpoint (data not reported by Bays et al. [], and Goldberg et al.) []. More than 88% of participants in each study were reported to have completed the full treatment duration and all withdrawals were accounted for (data not reported by Kerzner et al.) []. Efficacy analyses in all trials were conducted using the intention-to-treat [] or the modified intention-to-treat [] approach.

Quantitative data synthesis

2- 5 show the forest plots with weighted mean difference for each study and for the pooled data. In patients with primary hypercholesterolaemia, ezetimibe monotherapy significantly ( P < 0.00001) reduced LDL cholesterol concentrations by −18.58% (95% CI: −19.67 to −17.48) compared with placebo. Ezetimibe monotherapy also significantly ( P <0.00001) improved total cholesterol (−13.46%, 95% CI: −14.22 to −12.70), HDL cholesterol (3.00%, 95% CI: 2.06-3.94) and triglyceride concentrations (−8.06%, 95% CI: −10.92 to −5.20) compared with placebo. The test for statistical heterogeneity was not significant for any of these outcomes ( P > 0.05).

Adverse events reported in each of the included studies are summarized in Table 2. Meta-analyses were considered inappropriate because of insufficient data and low occurrences of adverse events. In the eight short-term studies, ezetimibe monotherapy was found to have a similar adverse event profile to placebo []. Adverse events (any) ranged from 53-74% in the ezetimibe monotherapy groups and 54-72% in the placebo groups. Of these, 9-18% were considered due to treatment in the ezetimibe monotherapy group and 9-24% in the placebo group (mainly gastrointestinal adverse events or musculoskeletal disorders). Clinically important elevations in creatine phosphokinase (≥10 times upper limit of normal) and liver enzymes (alanine aminotransferase and aspartate aminotransferase ≥3 times upper limit of normal) were not influenced by treatment (<1% in both groups). Discontinuation rates were comparable between both arms and serious adverse events were rare and occurred with similar frequency in the ezetimibe monotherapy and placebo groups. No cases of hepatitis, jaundice, or other clinical signs of liver dysfunction were observed in seven of the eight trials [] (data not reported by Dujovne et al.) []. No deaths were attributable to ezetimibe monotherapy in any of the included studies.

Discussion

This is the first comprehensive meta-analysis on the clinical effectiveness of ezetimibe monotherapy compared with placebo. Although there have been no published clinical outcome trials (with cardiovascular disease mortality and morbidity as outcome measures), our meta-analysis of eight RCTs with surrogate endpoint data demonstrated that ezetimibe monotherapy significantly reduced LDL cholesterol concentrations compared with placebo in patients with primary hypercholesterolaemia. Significant potentially favourable changes were also observed in total cholesterol, HDL cholesterol and triglyceride levels, and ezetimibe monotherapy appeared to be well tolerated with a safety profile similar to placebo.

The correlation and causal relationship between serum cholesterol values, particularly LDL cholesterol and the risk of cardiovascular disease, have been established in numerous epidemiological studies [] systematic reviews and meta-analyses of clinical outcome trials []. Reducing LDL cholesterol by various mechanisms (statins, partial ileal bypass surgery, bile acid sequestrants, niacin or diet alone) decreases the risk of cardiovascular disease in people with or at high risk of cardiovascular disease. However, evidence for the benefit of fibrates is less clear [], and the results of the 2 year ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression (ENHANCE) surrogate outcome trial [] showed that the daily addition of 10 mg ezetimibe to 80 mg simvastatin in patients with familial hypercholesterolaemia (many of whom had previously received statin therapy) had no benefit on carotid intima-media thickness when compared with 80 mg simvastatin alone. Therefore, caution must be exercised if assuming that the apparent favourable effects on lipids or other surrogate markers necessarily translate into clinical benefit []. Until the results from the long-term studies of ezetimibe emerge, the association between ezetimibe-induced changes in lipids and cardiovascular events remains uncertain. Similarly, whilst the short-term (12 weeks) safety profile of ezetimibe monotherapy appears to be similar to placebo, this systematic review cannot address the long-term safety of ezetimibe monotherapy.

The recent findings from the simvastatin and ezetimibe in aortic stenosis (SEAS) trial [], has led to controversy about the safety of ezetimibe. This randomized, double-blind trial involving 1873 patients with mild to moderate, asymptomatic aortic stenosis found that after a mean follow-up of approximately 4 years, dual lipid lowering therapy with simvastatin (40 mg per day) plus ezetimibe (10 mg per day) significantly increased the cancer rate compared with placebo (105 cases vs. 70, P = 0.01, respectively). Given that a large, high-quality meta-analysis found that prolonged statin therapy does not increase the risk of cancer [], a preliminary hypothesis-testing analysis of interim cancer data from two large ongoing trials - the study of heart and renal protection (SHARP) (NCT00125593), in which simvastatin plus ezetimibe is compared with placebo (9264 patients with mean follow-up of 2.7 years), and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878), in which simvastatin plus ezetimibe is compared with simvastatin plus placebo (11353 patients with mean follow-up of 1.0 years) - was undertaken by Peto et al. []. In this combined analysis there was no significant excess of cancer, either overall (313 active-treatment vs. 326 control, P = 0.61) or at any particular site and there was no suggestion of an emerging trend with longer treatment and follow-up periods. This analysis suggest that the findings of the SEAS trial were a chance effect as was once seen with statins []. However, an accompanying editorial [] raised concerns on the use of interim data and recommended additional data (meeting performance standards for safety trials) to adequately address whether simvastatin plus ezetimibe was associated with an increased risk of death from cancer.

Although statins are the most effective drugs for lowering surrogate endpoints (total cholesterol by approximately 20-30% and LDL cholesterol by about 25-50%) [] and reducing coronary events, all cardiovascular events and total mortality [], a small but significant portion of patients are unable to tolerate statins due to severe adverse effects such myalgia, myositis, myopathy and rhabdomyolysis. Such events, whilst rare or infrequent at standard doses, are more likely to occur at higher statin doses and in most cases, cessation or changing the dosage of (or) the statin, reverses the adverse effects and usually leads to a full recovery []. Other lipid regulating drugs such as bile acid sequestrants (decrease total cholesterol by approximately 8-24% [] and LDL cholesterol by approximately 15-30%) [] and nicotinic acid (decrease total cholesterol by approximately 7-15% and LDL cholesterol by approximately 10-20%) [] also reduce cardiovascular disease risk [] (very limited trial evidence in comparison to statins on cardiovascular outcomes); however, they are rarely prescribed for hypercholesterolaemia [] as they are generally unpalatable and poorly tolerated [] and in the case of fibrates (decrease total cholesterol by approximately 7-13% and LDL cholesterol by approximately 1-13%) [], evidence that they prevent cardiovascular disease is uncertain [].

In this study, all the included trials lacked data on previous treatment outcomes; therefore, it was not possible to determine in what proportion of the study populations there was statin intolerance or contraindication. Thus we cannot say whether the response to ezetimibe treatment would be as good as or better than that reported here in individuals who are intolerant of statin treatment or on other medications. Nevertheless, in individuals who are strictly intolerant of statins (defined by the presence of clinically severe adverse effects from statin therapy, which are considered to represent an unacceptable risk to the patient or that may result in compliance with statin therapy being compromised) [] or in whom statins are considered inappropriate, ezetimibe monotherapy offers a treatment option for hypercholesterolaemia. This must be weighed against the unknown long-term efficacy and safety profile of ezetimibe and, with limited healthcare resources, its cost-effectiveness should also be considered. Assuming that the ezetimibe-induced decrease in LDL cholesterol translates into the same decrease in cardiovascular event rates as a similar statin induced decrease in LDL cholesterol, it has, however recently been reported that ezetimibe monotherapy could be a cost-effective alternative for subgroups of patients with high baseline LDL cholesterol levels [].

Certain limitations are inherent in meta-analysis [], of which the most important relates to the synthesis of data from trials that may be heterogeneous. Although there was no statistical evidence of significant heterogeneity in the included trials, differences between studies in factors such as patient characteristics or trial design may still have influenced the results. It was not possible to determine the direction of any such influence or bias.

Although an extensive literature search was conducted, it is possible that some relevant studies may have been missed. However, such omissions are likely to have been minimal, as the search included all identifiable publications in the grey literature (including contact with clinical experts in the field).

The results of the meta-analysis were dominated by the results of two major trials: Dujovne et al. [], and Knopp et al. []. A possible type II error may have prevented the smaller trials from detecting significant intergroup differences. Therefore, the possibility exists that the two larger trials found a true effect. None of the other studies suggest a trend towards a differential effect in mean total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides. Moreover, concealment of treatment allocation and blinding are important safeguards against bias in RCTs. Although the studies included in the meta-analysis were double-blind, none of the studies adequately reported the method of allocation concealment. It is not known what effect this may have had on the findings of the analyses. However, empirical evidence suggests that publications of trials in which allocation concealment is unclear or inadequate over-estimate the treatment effect, on average [].

In summary, this systematic review and meta-analysis demonstrates that ezetimibe monotherapy provides a clinical benefit for individuals with primary hypercholesterolaemia compared with placebo; thus, it may be considered as an alternative option in the management of individuals with hypercholesterolaemia in whom statin therapy is considered inappropriate or is not tolerated. However, to elucidate the efficacy and safety of ezetimibe monotherapy fully and to justify its use in a lipid management programme, further research is required including long-term studies reporting clinical outcome data, direct comparisons with other lipid-lowering treatments (such as nicotinic acid, resins or fibrates), and data from patients who are truly intolerant of statins.

Ethical approval

Not required.

Funding

This work was funded by the UK National Coordinating Centre for Health Technology Assessment (NCCHTA) and was undertaken on behalf of the National Institute of Health and Clinical Excellence (NICE). The views and opinions expressed are those of the authors and do not necessarily reflect those of the UK Department of Health.

Conflict of interest

PND has served as consultant to and received travel expenses, payment for speaking at meetings, or funding for research from pharmaceutical companies marketing lipid-lowering drugs, including Merck Sharp & Dohme - Schering Plough Ltd, the manufacturer of ezetimibe. AP, RMA, IT, SP, AJW, AD and JC have no competing interest.

Acknowledgements

We would like to thank Andrea Shippam, Project Administrator, ScHARR, for her help in the retrieval of papers and in preparing and formatting the paper.

# data[].attributes.attachment_link.title
Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta‐analysis of randomized controlled trials

# data[].attributes.attachment_link.description
Abdullah Pandor, Health Economics and Decision Science, School of Health and Related Research, University of Sheffield, Sheffield, S1 4DA, UK.(fax: +44 0 114 272 4095; e-mail: a.pandor@sheffield.ac.uk ). Objectives. To study the evidence on the efficacy and safety of ezetimibe monotherapy for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia.

# data[].attributes.body
Título: Tolerabilidad comparativa y daños de las estatinas individuales: un metanálisis en red a nivel de estudio de 246 955 participantes de 135 ensayos controlados aleatorios

Tipo de estudio: Metaanálisis
Año: 2013
Autor: Naci H, Brugts J, Ades T.
Resultados: Las estatinas como clase dieron como resultado probabilidades significativamente mayores de diabetes mellitus (odds ratio, 1,09; intervalo de confianza del 95 %, 1,02-1,16) y elevaciones de transaminasas (odds ratio, 1,51; intervalo de confianza del 95 %, 1,24-1,84) en comparación con el control. No hubo ninguna inconsistencia detectable en la red. y la simvastatina se asociaron con mayores probabilidades de elevaciones de transaminasas. La simvastatina en sus dosis más altas se asoció con elevaciones de la creatina cinasa (odds ratio, 4,14; intervalo creíble del 95 %, 1,08-16,24). Los análisis de metarregresión que ajustaron la edad del nivel de estudio al inicio, el nivel de colesterol de lipoproteínas de baja densidad y el año de publicación no explicaron la heterogeneidad. No hubo ninguna inconsistencia detectable en la red.
Conclusión: Las estatinas no están asociadas con el riesgo de cáncer, pero dan como resultado una mayor probabilidad de diabetes mellitus. Entre las estatinas individuales, la simvastatina y la pravastatina parecen más seguras y tolerables que otras estatinas.

https://pubmed.ncbi.nlm.nih.gov/23838105/

# data[].attributes.attachment_link.title
Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials - PubMed

# data[].attributes.attachment_link.description
As a class, adverse events associated with statin therapy are not common. Statins are not associated with cancer risk but do result in a higher odds of diabetes mellitus. Among individual statins, simvastatin and pravastatin seem safer and more tolerable than other statins.

# data[].attributes.body
Titulo:  Ezetimibe/simvastatin

Tipo de estudio: Revisión sistematica.
Año: 2009.
Resultados:  Los estudios de cohortes sugirieron que los tratamientos con simvastatina en dosis bajas y altas indujeron miotoxicidad y otros eventos adversos con una tasa similar a la de otras estatinas. En una gran cohorte de Japón que incluía a 51 000 personas seguidas durante un período de seguimiento promedio de 3,4 años, 5 mg/día de simvastatina no indujo ningún caso de rabdomiólisis [102]. Por otro lado, el ensayo A-to-Z, que comparó el uso de simvastatina 80 mg con simvastatina 20 mg en 4497 ​​pacientes con SCA, mostró un ligero aumento en el riesgo de miopatía durante el tratamiento con dosis altas [103]. Aunque el tratamiento con dosis altas indujo una mayor incidencia de efectos adversos, el riesgo de elevación de las enzimas hepáticas y musculares asociado con la simvastatina no parece estar relacionado con la eficacia para reducir el LDL-C.
Conclusiones: Datos recientes basados en evidencia sugieren que una reducción más intensa de LDL-C, particularmente en la población de alto riesgo, continúa reduciendo el riesgo cardiovascular. Las pautas actualizadas para que los médicos alcancen niveles objetivo más bajos de LDL-C para sus pacientes de mayor riesgo requerían el uso de estatinas más eficaces o terapias combinadas. La terapia combinada de ezetimiba/simvastatina ofrece una terapia eficaz con una mayor probabilidad de lograr los objetivos de LDL y con una seguridad similar, en comparación con dosis equivalentes de simvastatina en monoterapia. Sin embargo, se necesitan estudios clínicos que investiguen los resultados cardiovasculares para establecer si la terapia combinada con ezetimiba/simvastatina reduce significativamente no solo los niveles de LDL-C, sino también la inflamación aterosclerótica, la ateroprogresión y los eventos agudos en comparación con la monoterapia con simvastatina.

# data[].attributes.attachment_link.description
Combined therapy with ezetimibe/simvastatin has been shown to improve lipid profile inducing a very rapid reduction of low-density lipoprotein cholesterol levels in clinical trials. In the near future, potential clinical benefits could be observed in the IMPROVE-IT or SHARP trials. Although clinical…

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Inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (PCSK9) y el riesgo de eventos adversos neurocognitivos: una revisión sistemática, metanálisis y metarregresión.

Año: 2021
Tipo de estudio: Revisión Sistémica
Resultados:
Entre 59.733 pacientes, 31.611 fueron tratados con inhibidores de PCSK9. El período de seguimiento varió de 24 semanas a 48 meses. No se identificaron diferencias significativas en la incidencia de efectos adversos neurocognitivos entre los grupos (RR = 1,01, IC del 95 %: 0,86-1,19, I2 = 3 %). Se observaron resultados similares en el análisis de subgrupos para cada uno de los medicamentos (alirocumab- RR = 0,88, IC 95 %: 0,72-1,08, I2 = 0 %, evolocumab- RR = 1,42, IC 95 %: 0,74-2,73, I2 = 55 % ). Un análisis de metarregresión para evolocumab reveló que la duración prolongada del estudio se asoció con un menor riesgo de eventos adversos neurocognitivos (βsemana = -0,0037, valor de p = 0,03).
Conclusiones: Los resultados combinados de nuestro metanálisis y metarregresión muestran que la exposición a los inhibidores de PCSK9 no está asociada con un mayor riesgo de efectos adversos neurocognitivos.

# data[].attributes.attachment_link.title
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors and the risk for neurocognitive adverse events: A systematic review, meta-analysis and meta-regression.

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BACKGROUND: It has been suggested that lipid lowering therapy causes impaired cognitive changes. The association between the use of Proprotein Convertase Sub...

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TITULO: ODYSSEY EAST: Eficacia y seguridad de alirocumab frente a ezetimiba en pacientes de alto riesgo cardiovascular con hipercolesterolemia y con estatina máximamente tolerada en China, India y Tailandia
TIPO DE ESTUDIO: ECA
AÑO: 2019
RESULTADOS:  Los eventos adversos emergentes del tratamiento ocurrieron en el 68,5 % de los pacientes tratados con alirocumab y en el 63,1 % de los pacientes tratados con ezetimiba, siendo la infección del tracto respiratorio superior la más frecuente (alirocumab: 13,3 %; ezetimiba: 14,1 %). Las reacciones en el lugar de la inyección ocurrieron con mayor frecuencia en pacientes tratados con alirocumab (2,7 %) que en pacientes tratados con ezetimiba (1,0 %).
CONCLUSIONES: Alirocumab redujo significativamente el LDL-C frente a ezetimiba en pacientes de alto riesgo cardiovascular de Asia y, en general, fue bien tolerado.

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Affiliations

¹ Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China. Electronic address: hanyaling@263.net.

² Department of Cardiology, Guangdong General Hospital, Guangdong, China.

³ Department of Cardiology, Medanta - The Medicity, Delhi, India.

⁴ Department of Cardiology, Peking Union Medical College Hospital, Beijing, China.

⁵ Institute of Translational Medicine, Jinan Central Hospital, Jinan, China.

⁶ Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

⁷ Division of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

⁸ Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China.

⁹ Department of Cardiology, Tianjin Union Medical Center, Tianjin, China.

¹⁰ Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

¹¹ Department of Cardiac Surgery, Ruijin Hospital of Shanghai, Jiaotong University School of Medicine, Shanghai, China.

¹² Department of Internal Medicine, Faculty of Medicine, Chiang Mai Hospital, Chiang Mai, Thailand.

¹³ Clinical Development, R&D, Sanofi, Montpellier, France.

¹⁴ Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA.

¹⁵ R&D, Sanofi, China.

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Affiliations

¹ Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China. Electronic address: hanyaling@263.net.

² Department of Cardiology, Guangdong General Hospital, Guangdong, China.

³ Department of Cardiology, Medanta - The Medicity, Delhi, India.

⁴ Department of Cardiology, Peking Union Medical College Hospital, Beijing, China.

⁵ Institute of Translational Medicine, Jinan Central Hospital, Jinan, China.

⁶ Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

⁷ Division of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

⁸ Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China.

⁹ Department of Cardiology, Tianjin Union Medical Center, Tianjin, China.

¹⁰ Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

¹¹ Department of Cardiac Surgery, Ruijin Hospital of Shanghai, Jiaotong University School of Medicine, Shanghai, China.

¹² Department of Internal Medicine, Faculty of Medicine, Chiang Mai Hospital, Chiang Mai, Thailand.

¹³ Clinical Development, R&D, Sanofi, Montpellier, France.

¹⁴ Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA.

¹⁵ R&D, Sanofi, China.

Abstract

Background: The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab significantly reduces low-density lipoprotein cholesterol (LDL-C).

Objective: This study (ODYSSEY EAST) assessed the efficacy and safety of alirocumab vs ezetimibe in high cardiovascular risk patients from Asia.

Methods: Patients (n = 615) from China, India, and Thailand with hypercholesterolemia at high cardiovascular risk on maximally tolerated statin were randomized (2:1) to alirocumab (75 mg every 2 weeks [Q2W]; with dose increase to 150 mg Q2W at week 12 if week 8 LDL-C was >1.81 mmol/L [>70 mg/dL]) or ezetimibe (10 mg daily) for 24 weeks. The primary efficacy endpoint was percentage change in calculated LDL-C from baseline to week 24. Safety was assessed throughout.

Results: Baseline data were similar in both groups. LDL-C levels were reduced from baseline to week 24 by 56.0% and 20.3% in the alirocumab and ezetimibe groups, respectively (P < .0001 vs ezetimibe). Overall, 18.8% of alirocumab-treated patients received a dose increase to 150 mg Q2W. At week 24, 85.1% of alirocumab-treated and 40.5% of ezetimibe-treated patients reached LDL-C <1.81 mmol/L (<70 mg/dL, P < .0001 vs ezetimibe). Treatment-emergent adverse events occurred in 68.5% of alirocumab-treated and 63.1% of ezetimibe-treated patients, with upper respiratory tract infection the most common (alirocumab: 13.3%; ezetimibe: 14.1%). Injection-site reactions occurred more frequently in alirocumab-treated patients (2.7%) than in ezetimibe-treated patients (1.0%).

Conclusions: Alirocumab significantly reduced LDL-C vs ezetimibe in high cardiovascular risk patients from Asia and was generally well tolerated. These findings are consistent with previous ODYSSEY studies.

Trial registration: ClinicalTrials.gov NCT02715726.

Keywords: Alirocumab; Hypercholesterolemia; LDL-C; Lipid-lowering therapy; PCSK9.

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national center for biotechnology information

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ODYSSEY EAST: Alirocumab efficacy and safety vs ezetimibe in high cardiovascular risk patients with hypercholesterolemia and on maximally tolerated statin in China, India, and Thailand - PubMed

# data[].attributes.attachment_link.description
1 Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, China. Electronic address: hanyaling@263.net. 2 Department of Cardiology, Guangdong General Hospital, Guangdong, China. 3 Department of Cardiology, Medanta - The Medicity, Delhi, India. 4 Department of Cardiology, Peking Union Medical College Hospital, Beijing, China. 5 Institute of Translational Medicine, Jinan Central Hospital, Jinan, China.

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Título:  La eficacia y seguridad de estatinas en combinación con ezetimiba en comparación con estatinas en dosis doble en pacientes con alto riesgo cardiovascular: un metaanálisis
Autor: Yunyun Zhu , et al.
Año: 2020
Tipo de estudio: Metaanálisis
Resultados:  Los parámetros de lípidos cambiaron más significativamente en pacientes a los que se les administró ezetimiba y estatinas (colesterol de lipoproteínas de baja densidad [LDL-C]: DM = -9,39, IC del 95 %: -13,36 a -5,42; colesterol de lipoproteínas de no alta densidad [no-HDL-C]: DM = -10,36, IC del 95 %: -14,23 a -6,50; colesterol total [TC]: DM = -8,11, IC del 95 %: -10,95 a -5,26; y triglicéridos [TG]: DM = -5,96, IC del 95 %: -9,12 a -2,80). Nuestro análisis de subgrupos mostró que, en comparación con la monoterapia de atorvastatina en dosis doble, la terapia combinada de ezetimiba y atorvastatina redujo significativamente los niveles de LDL-C, no-HDL-C, TC y TG en un 14,16 %, 14,01 %, 11,06 % y 5,96 %. respectivamente ( con heterogeneidad moderada a alta entre los estudios.
Conclusiones: En general, este metanálisis indicó que, en comparación con la monoterapia con estatinas en dosis doble, la ezetimiba y las terapias de combinación de estatinas, especialmente la terapia de combinación de ezetimiba y atorvastatina, mostraron una mayor eficacia para reducir los niveles de LDL-C, no-HDL-C, TC y TG en pacientes con alto riesgo cardiovascular. Además, la seguridad del tratamiento combinado con ezetimiba y estatinas frente al tratamiento con estatinas en dosis doble no fue significativamente diferente.

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Abstract

Currently, statins are the first-line therapies for dyslipidemia and atherosclerotic cardiovascular disease, however, their hypolipidemic effects have not been satisfactory. We performed a meta-analysis to compare lipid-lowering efficacy and safety of ezetimibe and statin combination therapy with double-dose statin monotherapy in patients with high cardiovascular risk. Fourteen studies involving 3105 participants were included in the final analysis; 1558 (50.18%) participants received ezetimibe and statin combination therapy and 1547 (49.82%) received double-dose statin monotherapy. Eight studies reported the percentages of changes in several lipid parameters from baseline to endpoint in both groups. Lipid parameters changed more significantly in patients coadministered with ezetimibe and statin (low-density lipoprotein cholesterol [LDL-C]: MD = -9.39, 95% CI -13.36 to -5.42; non-high-density lipoprotein cholesterol [non-HDL-C]: MD = -10.36, 95% CI -14.23 to -6.50; total cholesterol [TC]: MD = -8.11, 95% CI -10.95 to -5.26; and triglyceride [TG]: MD = -5.96, 95% CI -9.12 to -2.80), with moderate to high heterogeneity among the studies. Two out of fourteen studies investigated several different statins. Our subgroup analysis showed that, compared with double-dose atorvastatin monotherapy, ezetimibe and atorvastatin combination therapy significantly decreased LDL-C, non-HDL-C, TC, and TG levels by 14.16%, 14.01%, 11.06%, and 5.96%, respectively ( p < 0.001). No significant difference was found in the incidence of laboratory-related adverse events (AEs) between statin combination therapy and monotherapy. Overall, ezetimibe and statin combination therapy significantly decreased LDL-C, non-HDL-C, and TC levels in patients with high cardiovascular risk, among which ezetimibe combined with atorvastatin had the best therapeutic effect. Compared with ezetimibe and statin combination therapy, double-dose statin monotherapy did not increase the risk of AEs.

Keywords: Efficacy, safety, statin, ezetimibe, combination therapy

INTRODUCTION

Cardiovascular disease is one of the main causes of mortality around the world [ 1]. Among diverse etiological factors, dyslipidemia is the most important reversible risk factor for cardiovascular diseases [ 2]. Previous studies showed that serum cholesterol levels were directly correlated with coronary heart disease (CHD)-related mortality [ 3- 5]. A meta-analysis of individual data obtained from 174,000 participants in 27 randomized trials showed that every 1.0 mmol/L reduction of low-density lipoprotein cholesterol (LDL-C) level resulted in a 12% reduction in vascular mortality [ 6]. Thus, developing effective and safe therapies for treating dyslipidemia is crucial for the prevention and treatment of cardiovascular diseases.

In general, hypolipidemic drugs are classified into the following categories: hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), niacin, cholic acid chelating agents, ezetimibe, and PCSK9 monoclonal antibody. Notably, statins are the first-line therapeutic approach for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD) [ 7]. Unfortunately, the recommended LDL-C levels cannot be reached in partial patients receiving statin monotherapy. Thus, the current clinical hypolipidemic guidelines recommend powerful lipid-lowering drugs, such as statins at high doses, for treating patients with ultrahigh risk of ASCVD [ 7- 9]. However, high doses of statins may cause side effects in patients, especially in the elderly. Some clinical trials showed that the risks of adverse events (AEs), such as myopathy and liver injury, generally increased with increasing doses of statins [ 10]. It remains controversial whether high doses of statins are good for treating patients with high cardiovascular risk.

In the current study, the primary efficacy endpoint was the percentage of change in lipid parameters. Moreover, the safety of two treatment strategies was assessed by reviewing adverse experiences and laboratory values. According to the 2018 Cholesterol Clinical Practice Guidelines, a high cardiovascular risk is defined as a history of multiple major ASCVD events or one major ASCVD event and multiple other high-risk conditions [ 11].

A meta-analysis is an effective statistical tool for overcoming the limitations of individual studies with different sample sizes. Thus, we performed a meta-analysis to compare lipid-lowering efficacy and safety between ezetimibe and statin combination therapy and double-dose statin monotherapy in patients with high cardiovascular risk.

MATERIALS AND METHODS

Search strategy

The meta-analysis was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [ 12]. In December 2018, two of the authors searched six databases independently, including PubMed, Cochrane Central, EMBASE, Medline, CNKI, and Wanfang. The search terms, deliberately generic, included ("Ezetimibe" OR "Ezetrol" OR "SCH-58235" OR " SCH58235 " OR "Zetia") AND ("Hydroxymethylglutaryl-CoA Reductase Inhibitors" OR "HMG-CoA Statins" OR "HMG-CoA Reductase Inhibitors" OR "Hydroxymethylglutaryl-CoA Inhibitors" OR "Statins" OR "Hydroxymethylglutaryl-Coenzyme A Inhibitors").

Inclusion criteria

1. Comparisons of the efficacy or safety of double-dose statin monotherapy vs. statin and ezetimibe combination therapy;

2. Reports on the percentages of changes in lipid parameters from baseline to endpoint, including LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), and triglyceride (TG);

3. Information on clinical AEs;

4. Randomized control trials.

Exclusion criteria

1. Abstracts, letters, case reports, reviews, or nonclinical studies;

2. Studies with insufficient data to estimate standard deviation (SD) and 95% confidence interval (CI);

3. Studies that contained duplicate data or repeated analyses;

4. Studies that excluded original data to calculate the percentages of changes in lipid parameters.

Data extraction and quality assessment

All candidate articles were independently evaluated and extracted by two authors (Yunyun Zhu and Shaoyi Lin). Extracted data were further verified by a senior author, and any discrepancies were resolved by a consensus agreement. Data items to be collected were determined before the literature search. The risk of bias in each individual trial was assessed using the Cochrane Collaboration's tool ( and ).

Statistical analysis

The meta-analysis was performed using Review Manager Version 5.3. (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen) and Stata SE12.0 Software (StataCorp LLC, Texas, USA). Summary estimates were represented as mean difference (MD) and 95% CI. Continuous variables were reported as mean and SD, with nonparametric data transformed to mean (SD) as previously described [ 13]. Cochran's Q test and Higgins I ² statistic were performed to assess the heterogeneity of included trials. Heterogeneity was considered significant when p < 0.10 or I ² value > 50%, where a random-effect model was applied. Otherwise, a fixed-effect model was applied. Subgroup analysis and sensitivity analysis were performed to explore the sources of heterogeneity. For all analyses, two-sided p < 0.05 was considered statistically significant. The quality of outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Publication bias was assessed visually by funnel plots and statistically by Egger's test.

RESULTS

Search results

A total of 2493 initial citations were retrieved through electronic searches, among which 45 studies were identified as potential candidates after screening. Further, 107 studies that involved non-ezetimibe intervention (n = 17), non-double-dose statin intervention (n = 33), or different primary endpoints (n = 57) were excluded from our study. The details of the study selection process are shown in .

Fourteen studies [ 14- 27] involving 3105 participants were included for final quantitative analysis, among which 1558 (50.18%) participants received ezetimibe and statin combination therapy and 1547 (49.82%) received double-dose statin monotherapy. The average age of participants was 68.2 years with 30.9%-78.9% males. The follow-up duration in these studies ranged from 42 days to 365 days. All research subjects were high-risk population for cardiovascular diseases based on their medical histories of cardiovascular diseases (i.e., CHD) or related diseases (i.e., diabetes, hypertension, etc.). Among the fourteen studies, two studies investigated multiple statins of different types. The statins used in the study by Nakamura et al. [ 18] included atorvastatin, pravastatin, rosuvastatin, and pitavastatin, and the statins used in the study by Yu et al. [ 27] included simvastatin, atorvastatin, and pravastatin. Additional baseline and patient characteristics are listed in .

TABLE 1

The Primary efficacy variable - the percentages of changes in lipid parameters from baseline to endpoint

A total of eight studies reported data about the percentages of changes in lipid parameters from baseline to endpoint, including LDL-C, HDL-C, non-HDL-C, TC, and TG, in both 10-mg ezetimibe plus statin group and double-dose statin group.

Combination of ezetimibe and statin was correlated with a greater percentage of LDL-C change from baseline (MD = -9.39, 95% CI -13.36 to -5.42). However, there was greater heterogeneity among the studies (I ² = 75%, p < 0.001) (). Then, statins were classified into subgroups for a subgroup analysis (). In rosuvastatin subgroup, the point estimation of MD (95% CI) was -3.30 (-7.45, 0.86) ( p = 0.12), suggesting that there was no statistical significance between rosuvastatin in combination with ezetimibe and double-dose rosuvastatin. The results obtained with Q-test and I ²-test showed that there was no heterogeneity among the studies in rosuvastatin subgroup (I ² = 0%, p = 0.59). Compared with double-dose atorvastatin treatment, LDL-C levels after ezetimibe plus atorvastatin treatment decreased by 14.16%, with a statistically significant difference (MD = -14.16, 95% CI -16.01 to -12.31; p < 0.001), and no heterogeneity was observed between the studies (I ² = 0.00%, p = 0.90). While no significant differences in the lipid-lowering efficacies were observed between the two subgroups (rosuvastatin vs. atorvastatin; p = 0.12), high heterogeneity (I ² = 55%) was observed, suggesting multiple statin subgroups were the main source of heterogeneity.

The results for non-HDL-C and TC were similar to the results for LDL-C. The changes in non-HDL-C and TC from baseline were more significant in patients receiving ezetimibe and statin combination therapy vs. double-dose statin monotherapy (non-HDL-C: MD = -10.36, 95% CI -14.23 to -6.50, p < 0.001; TC: MD = -8.11, 95% CI -10.95 to -5.26, p < 0.001) (Figures and ). However, there was greater heterogeneity among the studies (non-HDL-C: I ² = 75%, TC: I ² = 73%). Compared with double-dose atorvastatin subgroup, non-HDL-C and TC levels declined by 14.01% ( p < 0.001) and 11.06% ( p < 0.001), respectively, in ezetimibe plus atorvastatin group, with statistically significant differences (non-HDL-C: 95% CI -15.85 to -12.18; TC: 95% CI -12.61 to -9.50) (Figures and ), and there was no heterogeneity between the studies (I ² = 0%). There was significant heterogeneity in rosuvastatin subgroup (I ² = 61%), suggesting that rosuvastatin subgroup was the main source of heterogeneity for TC.

For TG levels, as shown in , the point estimation and 95% CI of MD were -5.96 (95% CI -9.12 to -2.80, p = 0.0002) and z-value was 3.70, which indicated that compared with double-dose statin monotherapy, the combination therapy significantly decreased TG levels, by 5.96%. The results obtained from Q-test and I ²-test showed that there was moderate heterogeneity for TG (I ² = 42%, p = 0.08). Notably, the results from atorvastatin subgroup showed a statistical significance (MD = -5.74, 95% CI -10.28 to -1.19, z = 2.47, p = 0.01) and lower heterogeneity between atorvastatin in combination with ezetimibe and double-dose atorvastatin (I ² = 0%, p = 0.59, ). However, there was great heterogeneity in rosuvastatin subgroup (I ² = 42%), indicating that rosuvastatin subgroup was the single source of heterogeneity for TG.

In terms of the percentages of changes in HDL, the point estimation of combined MD was 0.49 (95% CI -0.73 to 1.72), suggesting that there was no statistical significance. Also, there was no heterogeneity between the studies (I ² = 0%, ).

Safety and tolerability assessment

Indicators of AEs include: elevated levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST), i.e., more than threefold of the upper limit of normal [ULN] for two successive measurements; elevated levels of transaminases, i.e., more than threefold of the ULN during the final laboratory examination (considered as "presumed consecutive"); or elevated creatine phosphokinase (CPK) levels, i.e., more than tenfold of the ULN. In this study, there was no significant difference in the incidence of laboratory-related AEs between the two therapies (I ² = 0%, p = 0.91, RR = 0.63, 95% CI 0.31 to 1.26, z = 1.31, p = 0.19) ().

Publication bias

For TG, HDL-C, and laboratory-related AEs, the Egger's test showed no statistically significant publication bias ( p > 0.05), while the funnel plots were symmetrically distributed, suggesting that publication bias could not be excluded (-). For TC, LDL-C, and non-HDL-C the Egger's test showed statistically significant publication bias ( p < 0.05), and the funnel plots were unsymmetrically distributed, suggesting that there was publication bias (-).

DISCUSSION

Multiple studies have investigated the lipid-lowering efficacy and safety of ezetimibe and statin combination therapy and double-dose statin monotherapy in patients with high cardiovascular risk, however, the results of those studies are inconsistent and inconclusive (). In this study, we reviewed the relevant published studies and performed a meta-analysis to estimate the value of two distinct statin-based therapies. We analyzed the outcomes of 3105 patients from fourteen individual studies. Our results indicated that the efficacy of 10-mg ezetimibe and statin combination therapy to reduce LDL-C, non-HDL-C, TC, and TG levels was significantly better than the efficacy of double-dose statin monotherapy in patients with hypercholesterolemia with high risk of cardiovascular diseases. Notably, the subgroup analyses showed that, compared with double-dose atorvastatin monotherapy, ezetimibe and atorvastatin combination therapy caused significant reductions in the levels of LDL-C, non-HDL-C, TC, and TG, with no heterogeneity between the studies.

TABLE S1

Our results are consistent with the results of previous studies comparing ezetimibe and atorvastatin combination therapy with atorvastatin monotherapy, which showed that statin administration alone could not properly control the LDL-C levels of patients with moderate to high cardiovascular risk [ 28, 29]. Compared with 40-mg atorvastatin therapy, coadministration of 10-mg ezetimibe with 20-mg atorvastatin resulted in more significant decreases in LDL-C levels in hypercholesterolemic patients at moderately high risk for CHD [ 28]. In hypercholesterolemia patients with high risk of CHD, 10-mg ezetimibe combined with 40-mg atorvastatin had a more potent effect than 80-mg atorvastatin in lowering LDL-C levels and could even reduce LDL-C levels to less than 70 mg/dL [ 29]. In our analysis, compared with 40-mg atorvastatin monotherapy, atorvastatin and ezetimibe combination therapy caused a higher decrease in non-HDL-C and TC levels. All these results suggest that the lipid-lowering efficacy of ezetimibe plus statin therapy is more potent.

We did not observe a significant difference between double-dose rosuvastatin monotherapy and ezetimibe and rosuvastatin combination therapy in lowering the levels of LDL-C, non-HDL-C, TC, and TG. However, it should be noted that an increase in the basal dose of rosuvastatin in combination therapy could impair the efficacy of this therapy, causing only a mild decrease in LDL-C levels. Moreover, our results are inconsistent with the ACTE study in which 10-mg ezetimibe in combination with stable starting doses of rosuvastatin decreased LDL-C more significantly in patients with hypercholesterolemia compared with rosuvastatin uptitration, which caused a 21% reduction in LDL-C levels from the baseline [ 13]. The inconsistent results could be associated with the different dosages of rosuvastatin between the studies. The dosage applied in the ACTE study was 5 mg or 10 mg, while the dosage of rosuvastatin in the studies included in this meta-analysis ranged from 5 mg to 40 mg.

When comparing the overall curative effects between ezetimibe and statin combination therapy and double-dose statin monotherapy, we found that the percentages of changes in HDL-C levels were not significantly different.

Notably, our meta-analysis showed no significant difference in the laboratory AEs between double-dose statin-treated patients and ezetimibe-statin-treated patients. ALT, AST, and CPK are sensitive biomarkers for consecutive hepatocyte or muscle cell injury. Compared with ezetimibe and statin combination therapy, there was no significant difference in the levels of these indicators in patients receiving double-dose statin monotherapy. Randomized trials generally involve limited numbers of cases, which poses a limitation on obtaining a realistic overview of patients with poly-medications and comorbidities. Myalgia generally occurs in 5% to 10% of patients and the incidence of severe rhabdomyolysis is <0.07% in clinical practice [ 30]. In addition, due to the different durations of therapies in the included studies (the duration ranged from 42 days to 365 days), we could not draw a solid conclusion about the tolerability of regimens. Studies involving longer treatment durations are needed for collecting more specific data on drug safety.

The main focus of the current therapeutic guidelines is to reach the recommended LDL-C levels and to ensure drug safety. In our meta-analysis, ezetimibe and statin combination therapy significantly lowered LDL-C, non-HDL-C, and TC levels, especially when ezetimibe was administrated in combination with atorvastatin. Moreover, the application of double-dose statin monotherapy did not increase the risk of ALT, AST, and CPK elevation, compared with ezetimibe and statin combination therapy. The results suggested that ezetimibe and statin combination therapy could be more effective than double-dose statin monotherapy when the classical treatments fail to reduce LDL-C levels. However, more clinical trials are required for specifying the incidence of major cardiac AEs between two groups, i.e., ezetimibe plus statin therapy and double-dose statin monotherapy.

Limitations

There are several limitations to our study. First, significant heterogeneity was observed among the studies due to the different types of HMG-CoA reductase inhibitors used in each trial. The type of HMG-CoA reductase inhibitors was the only significant variable defined by meta-regression. In addition, the dosages of statins varied significantly among these studies, which partially affected the endpoints. Third, this meta-analysis was based on published data. In the future, more real-world data need to be included to draw a more comprehensive conclusion. Finally, although a large proportion of raw data was obtained from original authors in this study, a small portion of related data was incomplete.

CONCLUSION

Overall, this meta-analysis indicated that compared with double-dose statin monotherapy, ezetimibe and statin combination therapies, especially ezetimibe and atorvastatin combination therapy, showed higher efficacies in lowering LDL-C, non-HDL-C, TC, and TG levels in patients with high cardiovascular risk. In addition, the safety of ezetimibe and statin combination therapy vs. double-dose statin therapy was no significantly different.

ACKNOWLEDGMENTS

The research is supported by Ningbo Municipal Natural Science Foundation (grant no.2017A610209) and by Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (grant no.2020KY822).

Footnotes

Conflict of interest statement: The authors declare no conflict of interests

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The efficacy and safety of statin in combination with ezetimibe compared with double-dose statin in patients with high cardiovascular risk: A meta-analysis

# data[].attributes.attachment_link.description
Currently, statins are the first-line therapies for dyslipidemia and atherosclerotic cardiovascular disease, however, their hypolipidemic effects have not been satisfactory. We performed a meta-analysis to compare lipid-lowering efficacy and safety of ezetimibe and statin combination therapy with double-dose statin monotherapy in patients with high cardiovascular risk.

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https://pubmed.ncbi.nlm.nih.gov/25773378/
titulo

Eficacia y seguridad de alirocumab en la reducción de lípidos y eventos cardiovasculares.

Resultados: En la semana 24, la diferencia entre los grupos de alirocumab y placebo en el cambio porcentual medio desde el inicio en el nivel de colesterol LDL calculado fue de -62 puntos porcentuales (P <0,001); el efecto del tratamiento se mantuvo constante durante un período de 78 semanas. El grupo de alirocumab, en comparación con el grupo de placebo, tuvo tasas más altas de reacciones en el lugar de la inyección (5,9 % frente a 4,2 %), mialgia (5,4 % frente a 2,9 %), eventos neurocognitivos (1,2 % frente a 0,5 %) y eventos oftalmológicos (2,9% vs. 1,9%). En un análisis post hoc, la tasa de eventos cardiovasculares adversos mayores (muerte por enfermedad coronaria, infarto de miocardio no fatal, accidente cerebrovascular isquémico fatal o no fatal o angina inestable que requiere hospitalización) fue menor con alirocumab que con placebo (1,7 % frente a 3,3 %). , razón de riesgo, 0,52, intervalo de confianza del 95%, 0,31 a 0,90, P nominal = 0,02).

Conclusiones: Durante un período de 78 semanas, alirocumab, cuando se agregó a la terapia con estatinas a la dosis máxima tolerada, redujo significativamente los niveles de colesterol LDL. En un análisis post hoc, hubo evidencia de una reducción en la tasa de eventos cardiovasculares con alirocumab

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Abstract

Background: Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy.

Methods: We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24.

Results: At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02).

Conclusions: Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).

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anticholesteremic agents / adverse effects

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anticholesteremic agents / therapeutic use*

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cardiovascular diseases / prevention & control*

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national center for biotechnology information

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Efficacy and safety of alirocumab in reducing lipids and cardiovascular events - PubMed

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Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuti ...

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TÍTULO:

Ciprofibrate versus gemfibrozil in the treatment of primary
hyperlipidaemia

TIPO DE ESTUDIO: ECA con alto riesgo de sesgo
AÑO: 1996
RESULTADOS: El número de lesiones gastrointestinales reportadas fue mayor en el grupo gemfibrozil (n 12; 26.7%) en comparación con el ciprofibrato (n= 6; 11,8%), mientras que las quejas musculoesqueléticas fueron más frecuentes en pacientes tratados con ciprofibrato que en pacientes tratados con gemfibrozil.

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https://sci-hub.st/10.1016/j.clinthera.2021.07.016
Título: Efectos de la combinación de dosis fija de rosuvastatina de baja intensidad y ezetimiba versus monoterapia con rosuvastatina de intensidad moderada en los perfiles lipídicos en pacientes con hipercolesterolemia: un estudio aleatorizado, doble ciego, multicéntrico, de fase III

Tipo de estudio: ECA
Resultados: Los eventos adversos ocurrieron en 7 (2,5%) pacientes, los cuales fueron: Distensión abdominal y dispepsia (1,5% en la monoterapia de rosuvastatina 2.5mg y ezetimiba 10mg), aumento de la AST y ALT (1.4% en la monoterapia de rosuvastatina 5mg), aumento de la creatina fosfoquinasa en sangre (1.4% en la monoterapia de rosuvastatina 5mg), mialgia, jaqueca y prurito (1.4% tanto en la combinación de rosuvastatina 2.5mg y ezetimibe 10mg como en la monoterapia de ambos).
Conclusión: La combinación de ezetimiba con rosuvastatina de baja intensidad fue bien tolerada, con un excelente perfil de seguridad. La mayoría de los eventos adversos fueron leves y no se informaron eventos adversos graves en ningún paciente. Los perfiles de eventos adversos observados en el grupo de rosuvastatina/ezetimiba de baja intensidad fueron similares a los del grupo de rosuvastatina de baja intensidad y ezetimiba.

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Vereau Carmona Fanny Saray https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2008.02062.x

Vereau Carmona Fanny Saray https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2008.02062.x

Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta‐analysis of randomized controlled trials

Titulo:

Monoterapia con ezetimiba para reducir el colesterol en 2722 personas: revisión sistemática y metanálisis de ensayos controlados aleatorios.

Tipo de Estudio: metanálisis de ensayos controlados aleatorios (ECA).
Resultados: Un metanálisis de ocho ensayos aleatorizados, doble ciego, controlados con placebo (todos de 12 semanas) mostró que la monoterapia con ezetimiba se asoció con una reducción media estadísticamente significativa del colesterol LDL (desde el inicio hasta el final) de -18,58 %, (95 % IC: −19,67 a −17,48, P  < 0,00001) en comparación con placebo.

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RAMOS OLIVA ERICK MARIO

RAMOS OLIVA ERICK MARIO

Ezetimibe/simvastatin - PubMed

Titulo:  Ezetimibe/simvastatin

Tipo de estudio: Revisión sistematica.
Año: 2009.
Resultados:  Los estudios de cohortes sugirieron que los tratamientos con simvastatina en dosis bajas y altas indujeron miotoxicidad y otros eventos adversos con una tasa similar a la de otras estatinas. En una gran cohorte de Japón que incluía a 51 000 personas seguidas durante un período de seguimiento promedio de 3,4 años, 5 mg/día de simvastatina no indujo ningún caso de rabdomiólisis [102]. Por otro lado, el ensayo A-to-Z, que comparó el uso de simvastatina 80 mg con simvastatina 20 mg en 4497 ​​pacientes con SCA, mostró un ligero aumento en el riesgo de miopatía durante el tratamiento con dosis altas [103]. Aunque el tratamiento con dosis altas indujo una mayor incidencia de efectos adversos, el riesgo de elevación de las enzimas hepáticas y musculares asociado con la simvastatina no parece estar relacionado con la eficacia para reducir el LDL-C.
Conclusiones: Datos recientes basados en evidencia sugieren que una reducción más intensa de LDL-C, particularmente en la población de alto riesgo, continúa reduciendo el riesgo cardiovascular. Las pautas actualizadas para que los médicos alcancen niveles objetivo más bajos de LDL-C para sus pacientes de mayor riesgo requerían el uso de estatinas más eficaces o terapias combinadas. La terapia combinada de ezetimiba/simvastatina ofrece una terapia eficaz con una mayor probabilidad de lograr los objetivos de LDL y con una seguridad similar, en comparación con dosis equivalentes de simvastatina en monoterapia. Sin embargo, se necesitan estudios clínicos que investiguen los resultados cardiovasculares para establecer si la terapia combinada con ezetimiba/simvastatina reduce significativamente no solo los niveles de LDL-C, sino también la inflamación aterosclerótica, la ateroprogresión y los eventos agudos en comparación con la monoterapia con simvastatina.