Aims Statin intolerance (SI) represents a significant public health problem for which precise estimates of prevalence are needed. Statin intolerance remains an important clinical challenge, and it is associated with an increased risk of cardiovascular events. This meta-analysis estimates the overall prevalence of SI, the prevalence according to different diagnostic criteria and in different disease settings, and identifies possible risk factors/conditions that might increase the risk of SI. Methods and results We searched several databases up to 31 May 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. The overall prevalence of SI was 9.1% (95% confidence interval 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% (4.0–6.0%) vs. 17% (14–19%)]. The prevalence of SI in studies including both primary and secondary prevention patients was much higher than when primary or secondary prevention patients were analysed separately [18% (14–21%), 8.2% (6.0–10%), 9.1% (6.0–11%), respectively]. 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. Conclusion 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. Key question What is the overall prevalence of statin intolerance (SI) worldwide? What are the main risk factors of SI? Key finding The overall prevalence of SI is 9.1% and even lower using the international definitions: National Lipid Association, International Lipid Expert Panel, European Atherosclerosis Society (7.0, 6.7, 5.9%). Female gender, hypothyroidism, high statin dose, advanced age, antiarrhythmics, and obesity are the main factors that increase the risk of SI. Take-home message Clinicians should use these results to encourage adherence to statin therapy in the patients they treat.

The sirtuins, silent mating-type information regulation 2 (SIRTs), are a family of nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylases with important roles in regulating energy metabolism and senescence. Activation of SIRTs appears to have beneficial effects on lipid metabolism and antioxidants, prompting investigation of the roles of these proteins in atherogenesis. Although clinical data are currently limited, the availability and safety of SIRT activators such as metformin and resveratrol provide an excellent opportunity to conduct research to better understand the role of SIRTs in human atherosclerosis. Encouraging observations from preclinical studies necessitate rigorous large, prospective, randomized clinical trials to determine the roles of SIRT activators on the progression of atherosclerosis and ultimately on cardiac outcomes, such as myocardial infarction and mortality.

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BackgroundThe ‘placebo effect’ and ‘nocebo effect’ are phenomena whereby beneficial (placebo) or adverse (nocebo) effects result from the expectation that an inert substance will relieve or cause a particular symptom. These terms are often inappropriately applied to effects experienced on drug therapy. Quantifying the magnitude of placebo and nocebo effects in clinical trials is problematic because it requires a ‘no treatment’ arm. To overcome the difficulties associated with measuring the nocebo effect, and the fact that its definition refers to inert compounds, rather than drugs, we introduce the concept of ‘drucebo’ (a combination of DRUg and plaCEBO or noCEBO) to relate to beneficial or adverse effects of a drug, which result from expectation and are not pharmacologically caused by the drug. As an initial application of the concept, we have estimated the contribution of the drucebo effect to statin discontinuation and statin‐induced muscle symptoms by performing a systematic review of randomized controlled trial of statin therapy.MethodsThis preferred reporting items for systematic reviews and meta‐analysis‐compliant systematic review was prospectively registered in PROSPERO (CRD42017082700). We searched PubMed and Cochrane Central from inception until 3 January 2018 using a search strategy designed to detect studies including the concepts (Statins AND Placebo AND muscle pain). We included studies that allowed us to quantify the drucebo effect for adverse muscle symptoms of statins by (i) comparing reported rates of muscle symptoms in blinded and unblinded phases of randomized controlled trials and (ii) comparing rates of muscle symptoms at baseline and during blinded therapy in trials that included patients with objectively confirmed statin intolerance at baseline. Extraction was performed by two researchers with disagreements settled by a third reviewer.ResultsFive studies allowed the estimation of the drucebo effect. All trials demonstrated an excess of side effects under open‐label conditions. The contribution of the drucebo effect to statin‐associated muscle pain ranged between 38% and 78%. The heterogeneity of study methods, outcomes, and reporting did not allow for quantitative synthesis (meta‐analysis) of the results.ConclusionsThe drucebo effect may be useful in evaluating the safety and efficacy of medicines. Diagnosis of the drucebo effect in patients presenting with statin intolerance will allow restoration of life‐prolonging lipid‐lowering therapy. Our study was limited by heterogeneity of included studies and lack of access to individual patient data. Further studies are necessary to better understand risk factors for and clinical management of the drucebo effect.