Prevalence of Statin Intolerance: A Meta-Analysis
- About 1 in every 10-12 patients have statin intolerance (SI). There is about a 30% increase in SI associated with age >65 years, obesity, females, diabetics, alcohol consumption, Asian and Black race, high-dose statins, use of calcium channel blockers and antiarrhythmic drugs, chronic renal failure and liver disease, and hypothyroidism. Depression is negatively associated with SI.
- The prevalence of SI is considerably lower in randomized trials than cohort observational studies, 5% vs. 17%; possibly related to selection bias.
- Statin lipid solubility is not related to SI.
What is the overall prevalence of statin intolerance (SI), the prevalence according to different diagnostic criteria and in different disease settings, and possible risk factors/conditions that might increase the risk of SI?
The authors performed a meta-analysis of several databases up to May 31, 2021, for studies that reported the prevalence of SI. The primary endpoint was overall prevalence and prevalence according to a range of diagnostic criteria (National Lipid Association [NLA], International Lipid Expert Panel [ILEP], and European Atherosclerosis Society [EAS]) and in different disease settings. The secondary endpoint was to identify possible risk factors for SI. A random-effects model was applied to estimate the overall pooled prevalence.
A total of 176 studies (112 randomized controlled trials [RCTs]; 64 cohort studies) with 4,143,517 patients were ultimately included in the analysis. With a mean follow-up of 19 ± 7.3 months, the overall prevalence of SI was 9.1% (95% confidence interval [CI], 8.0–10%). The prevalence was similar when defined using NLA, ILEP, and EAS criteria (7.0% [6.0–8.0%], 6.7% [5.0–8.0%], 5.9% [4.0–7.0%], respectively). The prevalence of SI in RCTs was significantly lower compared with cohort studies (4.9% vs. 17%). The prevalence of SI in studies including both primary and secondary prevention patients was much higher than when primary or secondary prevention patients were analyzed separately. Statin lipid solubility did not affect the prevalence of SI (4.0% [2.0–5.0%] vs. 5.0% [4.0–6.0%]). Age (odds ratio [OR], 1.33; p = 0.04), female gender (OR, 1.47; p = 0.007), Asian and Black race (p > 0.05 for both), obesity (OR, 1.30; p = 0.02), diabetes mellitus (OR, 1.26; p = 0.02), hypothyroidism (OR, 1.37; p = 0.01), chronic liver, and renal failure (p < 0.05 for both) were significantly associated with SI in the meta-regression model. Antiarrhythmic agents, calcium channel blockers, alcohol use, and increased statin dose were also associated with a higher risk of SI.
Based on the present analysis of >4 million patients, the prevalence of SI is low when diagnosed according to international definitions. These results support the concept that the prevalence of complete SI might often be overestimated, and highlight the need for the careful assessment of patients with potential symptoms related to SI.
Statin intolerance and patient discontinuation of statins ranges from 2-3% to as high as 50% and is associated with a marked increase in atherosclerotic cardiovascular disease events. The worldwide prevalence of SI is 9.1% regardless of the definition. Notably, in randomized trials, SI occurred in about 5% of participants and 17% in cohort studies. The threefold difference may be related to pre-trial tolerance or intolerance to statins.
The approximate 30% increase in incident SI with associated factors (triggers?) is impressive. Amongst the important unappreciated factors include alcohol, exercise, calcium channel blockers, antiarrhythmic drugs, and Black race. Those factors not related include duration of statin therapy, Hispanic race, warfarin, smoking, and hypertension. Surprisingly, depression had a negative association with SI. One that I have seen in several patients is markedly worse muscle pain and even rhabdomyolysis associated with influenza.
Keywords: Alcohol Drinking, Anti-Arrhythmia Agents, Atherosclerosis, Calcium Channel Blockers, Depression, Diabetes Mellitus, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperthyroidism, Lipids, Liver Diseases, Obesity, Prevalence, Primary Prevention, Renal Insufficiency, Rhabdomyolysis, Risk Factors, Secondary Prevention
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