Does Statin Therapy Initiation Increase the Risk for Myopathy? An Observational Study of 32,225 Diabetic and Nondiabetic Patients

doi:10.1016/j.clinthera.2007.08.022

Clinical Therapeutics

Volume 29, Issue 8, August 2007, Pages 1761-1770

Presented in poster form at the American Diabetes Association 66th Annual Meeting, June 9–13, 2006, Washington, DC.

https://doi.org/10.1016/j.clinthera.2007.08.022 Get rights and content

Abstract

Background: Estimates of myopathy rates in the literature are based on adverse events reported in clinical trials, which may not be representative of the clinical practice setting.

Objective: The objective of this study was to estimate the prevalence of myopathic events, particularly myalgia, myositis, and rhabdomyolysis in a community-based practice among a cohort of subjects with or without diabetes, some of whom received statin treatment.

Methods: In this retrospective data analysis, we identified members of a health maintenance organization (HMO) who initiated statin treatment between 1997 and 2004 and classified them into 2 groups: those subjects with diabetes and those without. We matched them to an equal number of health plan members based on age group, diabetes diagnosis, and year of health plan enrollment. We defined 4 levels of myopathic events according to the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute's definitions as follows: myalgia, mild myositis, severe myositis, and rhabdomyolysis. Subjects were observed for ∼9 years. Prevalence rates were calculated by adjusting for known myopathic risk factors and also by utilizing Cox regression models to identify predictors of time for myopathic events.

Results: Of the 35,413 HMO members initially assessed for inclusion, 32,225 were identified and clas sified into the 2 cohorts: diabetes (n = 10,247) and nondiabetes (n = 21,978). A greater proportion of statin initiators in both the diabetes (7.9% vs 5.5%; P < 0.001) and nondiabetes cohorts (9.0% vs 3.7%; P < 0.001) experienced myopathic events. However, 95% of events were myalgia or mild myositis. The prevalence of severe myositis was 0.4 per 1000 person-years (95% CI, 0.2–0.7) and 0.8 per 1000 person-years (95% CI, 0.6-1.1) among statin initiators with or without diabetes, respectively. By comparison, rates were 0.3 (95% CI, 0.1–0.5) and 0.2 (95% CI, 0.1–0.4) per 1000 person-years among nonstatin users with or without diabetes, respectively. Rates of rhabdomyolysis were 0.1 (95% CI, 0.1–0.3) and 0.2 (95% CI, 0.1–0.5) per 1000 person-years among statin and non-statin users with diabetes, respectively, and 0.2 (95% CI, 0.1–0.4) in both groups without diabetes.

Conclusions: Statin initiation was associated with an approximate doubling of the risk for any myopathic event but did not appear to be associated with an increased risk for rhabdomyolysis in these patients. Because clinically significant elevations of creatine kinase levels were rare, statins appeared to be well tolerated in diabetic and nondiabetic patients who used them.

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Le risque de maladie cardiovasculaire chez le sujet âgé est nettement plus élevé que chez le sujet jeune ; paradoxalement, certaines molécules qui ont prouvé leur efficacité dans la réduction du risque cardiovasculaire sont souvent sous-prescrites dans cette tranche d’âge. La place des statines en prévention secondaire est indiscutable jusqu’à l’âge de 80 ans. En prévention primaire, ces molécules permettent de réduire le risque de survenue d’infarctus de myocarde et d’accident vasculaire cérébral, mais leurs effets sur la mortalité cardiovasculaire ou de toute cause restent non prouvés. Chez le sujet très âgé, nous ne disposons pas d’études randomisées concernant l’impact des statines sur la morbimortalité que ce soit en prévention primaire ou secondaire. Les effets indésirables chez le sujet âgé ne semblent pas être statistiquement différents du sujet jeune, cependant, la prescription chez les patients très âgés doit être individualisée, prenant en considération l’espérance et la qualité de vie, les comorbidités et surtout le risque d’interactions médicamenteuses.
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Statin Induced Myopathy Among Patients Attending the National Center for Diabetes, endocrinology, & genetics
2022, Annals of Medicine and Surgery
myopathy is a major side effect of statins that leads to statin intolerance and discontinuation. In this prospective cohort study, the main objective was to estimate the incidence of myopathy in patients receiving statins. In addition, we identified some risk factors associated with statin induced myopathy.
A prospective cohort study was conducted at the National Center for Diabetes, Endocrinology and Genetics [NCDEG] in Jordan from October 1, 2018 to January 31, 2021. All subjects who initiated statin therapy followed up during that period. Data was collected at time 0 (baseline), 3, 6, 9, and 12 months after enrollment. Demographic and clinical data were collected from medical records. Muscular symptoms were collected by conducting face-to-face interviews to all patients using a pre-structured questionnaire.
The overall incidence of myopathy among patients taking statins was 27.8%, 31.4% in males and 22.6% in females, the incidence of myopathy was higher in older people, being highest in patients ≥60 years (34%). Bivariate analyses showed no significant association between myopathy and hypothyroidism, diabetes or medications that are known to interact with statins. The incidence of myopathy was highest with Simvastatin 40 mg (50%) and lowest with Fluvastatin XL 80 mg (8%) and Rosuvastatin 10 mg (10.8%).
The overall incidence of myopathy in patients taking statins was 27.8%. Myopathy was directly related to dose and type of statin used. The use of Fluvastatin XL 80 mg and Rosuvastatin 10 mg showed less incidence of myopathy compared with other statins.
Regression discontinuity analysis for pharmacovigilance: statin example reflected trial findings showing little evidence of harm
2022, Journal of Clinical Epidemiology
The study aims to explore the use of regression discontinuity analysis (RDA) to examine effects of prescription of statins on total cholesterol and adverse outcomes (type 2 diabetes, rhabdomyolysis and myopathy, myalgia and myositis, liver disease, CVD, and mortality).
We conducted a prospective cohort study using the Clinical Practice Research Datalink including patients with QRISK scores of 10 to 30 in 2010 to 2013 who were last followed-up in October 2016. Comparing patients with QRISK≥20 and QRISK<20, we explored RDA assumptions, provided proof of concept analyses (total cholesterol as outcome), and investigated the effect of statins prescription on adverse outcomes.
RDA confirmed statin prescription reduced total cholesterol (Mean difference (MD) -1.33 mmol/L, 95%Confidence Interval (CI) -1.93 to -0.73). RDA provided little evidence for adverse effects on diabetes, myalgia and myositis, liver disease, CVD, or mortality. The RDA analysis findings are similar to RCT results. Findings from non-RDA analysis agree with published observational studies.
RDA can be used with large routine clinical datasets to provide evidence on effects of medications which are prescribed according to a threshold. Testable RDA assumptions were satisfied, but confidence intervals were wide, partly due to the low compliance with the prescribing threshold.
Tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients with muscle symptoms: A randomized controlled clinical trial
2020, Contemporary Clinical Trials Communications
Despite limited evidence, non-daily dosing of statins is recommended for managing muscle symptoms associated with statin therapy. We assessed the tolerability and effectiveness of every-other-day atorvastatin compared to daily atorvastatin in patients having muscle symptoms associated with atorvastatin therapy. A parallel-group, outcome-assessment-blinded, randomized controlled clinical trial was conducted at Colombo South Teaching Hospital, Sri Lanka. Patients with muscle pain, tenderness or cramps alone or in combination for ≥2 weeks while on daily atorvastatin for ≥1 month, with no alternative cause, were recruited. Patient's regular atorvastatin dose was given every-other-day to those in intervention group (IG) and daily to those in control group (CG). Primary outcomes were assessed at 24 weeks and included composite of myalgia and myositis, LDL-cholesterol level and percentage reduction of LDL-cholesterol from baseline. Number recruited was 49 to IG (women:79.6%; mean-age:60.6 ± 8.7years) and 52 to CG (women:73.1%; mean-age:61.7 ± 9.8years). Mean atorvastatin dose per day was 8.6 mg (SD = 4 mg) and 17.6 mg (SD = 8.4 mg) in IG and CG, respectively. Composite of myalgia and myositis at 24 weeks was 79.6% in IG and 69.2% in CG (OR = 1.7, 95% CI 0.7–4.3; p = 0.234). IG failed to show noninferiority for mean LDL-cholesterol (difference:0.31 mmol/L; upper limit 97.5% CI:0.61 mmol/L; p for noninferiority = 0.989) and for mean percentage reduction of LDL-cholesterol from baseline (difference:3.13%; upper limit 97.5% CI:15.5%; p for noninferiority = 0.718). At 24 weeks, mean creatine kinase and discomfort due to muscle symptoms (assessed with Visual Analogue Scale) were not different between the two groups. Findings of this study do not favor every-other-day atorvastatin as an option for managing patients with muscle symptoms associated with atorvastatin therapy.
Impact of pharmacogenetics on statin-induced myopathy in South-Indian subjects
2018, Indian Heart Journal
Citation Excerpt :
Statin therapy is limited with skeletal muscle toxicity associated with elevated systemic drug exposure, and up to 10% of statin-treated individuals will experience muscle pain or weakness, in rare cases.3,12,22 Studies have shown that muscle-related symptoms include muscle weakness (∼3%),23,24 myalgia (2%–22%),25,26 and life-threatening rhabdomyolysis (0.0004%),27 which tend to occur several months to years after statin initiation. In a randomized (JUPITER) clinical trial with rosuvastatin 20 mg daily or placebo and with an average follow-up of 17 months, they found that muscle symptoms (pain, stiffness, or weakness) was noted in 16.0% of the rosuvastatin group and 15.4% of the placebo group.10
Statins are the most commonly prescribed medications for the treatment of atherosclerotic cardiovascular disease. Statin-associated adverse effects occur in ∼10% of patients and are associated with polymorphisms in several key genes coding for transporters and metabolizing enzymes that affect statin pharmacokinetics. In the present study, we examine the association between cytochrome P450 3A5*3 (CYP3A5*3) T>C (rs776746), COQ G>C (rs4693075), and SLCO1B1 T>C (rs4149056) genetic variants with the risk of myopathy in South Indian patients on statin therapy.
A total of 202 patients on atorvastatin or rosuvastatin therapy for 12 years were recruited in the study. Genotyping of drug metabolic CYP3A5*3 gene variant and drug transporter genes COQ G>C (rs4693075) and SLCO1B1 T>C (rs4149056) was analyzed by Sanger's sequencing.
In our study subjects, the percentage of patients diagnosed to have statin-induced myopathy was 18%. The majority of the patients were on 10 mg/day dose of either atorvastatin or rosuvastatin. The homozygous nonexpressors genotype CYP3A5*3/3 frequency of the CYP3A5 polymorphism was higher in patients with myopathy. But we could not find association of CYP3A5, COQ, and SLCO1B1 gene polymorphisms with either rosuvastatin or atorvastatin.
Our results clearly demonstrate that the frequency of CYP3A5*3 splicing variant is higher in myopathy group than in the tolerant group. We did not find significant association of genetic polymorphisms in CYP3A5, COQ, and SLCO1B1 with atorvastatin- or rosuvastatin-induced myopathy.
The use of structured data elements to identify ASCVD patients with statin-associated side effects: Insights from the Department of Veterans Affairs
2019, Journal of Clinical Lipidology
Accurate identification of patients with statin-associated side effects (SASEs) is critical for health care systems to institute strategies to improve guideline-concordant statin use.
The objective of this study was to determine whether adverse drug reaction (ADR) entry by clinicians in the electronic medical record can accurately identify SASEs.
We identified 1,248,214 atherosclerotic cardiovascular disease (ASCVD) patients seeking care in the Department of Veterans Affairs. Using an ADR data repository, we identified SASEs in 15 major symptom categories. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed using a chart review of 256 ASCVD patients with identified SASEs, who were not on high-intensity statin therapy.
We identified 171,189 patients (13.71%) with documented SASEs over a 15-year period (9.9%, 2.7%, and 1.1% to 1, 2, or >2 statins, respectively). Statin use, high-intensity statin use, low-density lipoprotein cholesterol, and non–high-density lipoprotein cholesterol levels were 72%, 28.1%, 99 mg/dL, and 129 mg/dL among those with vs 81%, 31.1%, 84 mg/dL, and 111 mg/dL among those without SASEs. Progressively lower statin and high-intensity statin use, and higher low-density lipoprotein cholesterol and non–high-density lipoprotein cholesterol levels were noted among those with SASEs to 1, 2, or >2 statins. Two-thirds of SASEs were related to muscle symptoms. Sensitivity, specificity, PPV, NPV compared with manual chart review were 63.4%, 100%, 100%, and 85.3%, respectively.
A strategy of using ADR entry in the electronic medical record is feasible to identify SASEs with modest sensitivity and NPV but high specificity and PPV. Health care systems can use this strategy to identify ASCVD patients with SASEs and operationalize efforts to improve guideline-concordant lipid-lowering therapy use in such patients. The sensitivity of this approach can be further enhanced by the use of unstructured text data.

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Does Statin Therapy Initiation Increase the Risk for Myopathy? An Observational Study of 32,225 Diabetic and Nondiabetic Patients

Abstract

Lancet

Lancet

Am J Med

J Clin Epidemiol

Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S)

Lancet

Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia

N EnglJ Med

The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels

N Engl J Med

MRC/BHF Heart Protection Study ofantioxidant vitamin supplementation in 20,536 high-risk individuals: A randomised placebo-controlled trial

Lancet

Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)

JAMA

Reduction in cardiovascular events with atorvastatin in 2,532 patients with Wpe 2 diabetes: Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOTLLA)

Diabetes Care