Associations between statins and adverse events in primary prevention of cardiovascular disease: systematic review with pairwise, network, and dose-response meta-analyses

Abstract

Objective To assess the associations between statins and adverse events in primary prevention of cardiovascular disease and to examine how the associations vary by type and dosage of statins. Design Systematic review and meta-analysis. Data sources Studies were identified from previous systematic reviews and searched in Medline, Embase, and the Cochrane Central Register of Controlled Trials, up to August 2020. Review methods Randomised controlled trials in adults without a history of cardiovascular disease that compared statins with non-statin controls or compared different types or dosages of statins were included. Main outcome measures Primary outcomes were common adverse events: self-reported muscle symptoms, clinically confirmed muscle disorders, liver dysfunction, renal insufficiency, diabetes, and eye conditions. Secondary outcomes included myocardial infarction, stroke, and death from cardiovascular disease as measures of efficacy. Data synthesis A pairwise meta-analysis was conducted to calculate odds ratios and 95% confidence intervals for each outcome between statins and non-statin controls, and the absolute risk difference in the number of events per 10 000 patients treated for a year was estimated. A network meta-analysis was performed to compare the adverse effects of different types of statins. An E max model based meta-analysis was used to examine the dose-response relationships of the adverse effects of each statin. Results 62 trials were included, with 120 456 participants followed up for an average of 3.9 years. Statins were associated with an increased risk of self-reported muscle symptoms (21 trials, odds ratio 1.06 (95% confidence interval 1.01 to 1.13); absolute risk difference 15 (95% confidence interval 1 to 29)), liver dysfunction (21 trials, odds ratio 1.33 (1.12 to 1.58); absolute risk difference 8 (3 to 14)), renal insufficiency (eight trials, odds ratio 1.14 (1.01 to 1.28); absolute risk difference 12 (1 to 24)), and eye conditions (six trials, odds ratio 1.23 (1.04 to 1.47); absolute risk difference 14 (2 to 29)) but were not associated with clinically confirmed muscle disorders or diabetes. The increased risks did not outweigh the reduction in the risk of major cardiovascular events. Atorvastatin, lovastatin, and rosuvastatin were individually associated with some adverse events, but few significant differences were found between types of statins. An E max dose-response relationship was identified for the effect of atorvastatin on liver dysfunction, but the dose-response relationships for the other statins and adverse effects were inconclusive. Conclusions For primary prevention of cardiovascular disease, the risk of adverse events attributable to statins was low and did not outweigh their efficacy in preventing cardiovascular disease, suggesting that the benefit-to-harm balance of statins is generally favourable. Evidence to support tailoring the type or dosage of statins to account for safety concerns before starting treatment was limited. Systematic review registration PROSPERO CRD42020169955.

Statin treatment effectiveness and the SLCO1B1*5 reduced function genotype: long-term outcomes in women and men

“…This could be due to underreporting of statinassociated pain (by the patients themselves, or under-recording by GPs in the clinical record; 3.4% of participants prescribed simvastatin or atorvastatin received a relevant GP diagnosis (including myalgia, myositis), compared to previous studies with systematic ascertainment of muscle effects that reported up to 25% of patients with muscle symptoms (5,9,43). A recent systematic review of RCTs reported that statins were not associated with clinically confirmed muscle disorders, consistent with our results (patients may report muscle symptoms, but these are not clinically confirmed) (44). Additionally, our ability to analyse dose was limited due to data availability, and SLCO1B1*5 has been linked to muscular complaints (and atorvastatin intolerance) especially in patients receiving high doses of atorvastatin (45).…”

“…Trials are showing that genotype-guided treatment for antiplatelet therapy reduces adverse events (48). Though a recent systematic review reported that safety concerns were limited in statin therapy (44) this was in the general population; in sub-populations carrying the SLCO1B1*5 decreased function variant, especially women, tailoring the specific statin or dose may improve outcomes, and could highlight patients to target with novel agents for cholesterol lowering (49).…”

Systematic Review and Meta-Analysis of the Effect of Statins on Circulating E-Selectin, L-Selectin, and P-Selectin

“…One of these agents, the monoclonal antibody against P-selectin inclacumab, has shown some promise in minimizing cardiac damage in patients with acute coronary syndrome undergoing percutaneous coronary intervention [95,96]. The results of our systematic review and meta-analysis suggest that soluble selectin-lowering might also be important in the context of statin therapy, an established treatment option in primary and secondary cardiovascular prevention [97][98][99]. Whist the exact mechanisms of action involved in the statin-mediated reduction in soluble selectin concentrations remain elusive, in vitro studies have shown that atorvastatin significantly prevents the overexpression of E-Selectin induced by cigarette smoking extract in human umbilical vein endothelial cells through inhibiting the NF-K B signal pathway, a critical pathway involved in inflammatory processes [100,101].…”

A Systematic Review and Meta-Analysis of the Effect of Statins on Glutathione Peroxidase, Superoxide Dismutase, and Catalase

“…Elevations in circulating cholesterol concentrations significantly increase the risk of atherosclerosis and its clinical manifestations, particularly myocardial infarction, ischemic stroke, and peripheral arterial disease [ 1 , 2 ]. Statins, through the inhibition of the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting step in the mevalonate pathway through which cells synthesize cholesterol, are the most commonly prescribed drugs for the treatment of hypercholesterolaemia and the management of cardiovascular risk worldwide in view of their favourable efficacy and safety profile [ 3 ]. However, while the main action is mediated by lowering the concentrations of specific cholesterol fractions, particularly low-density lipoprotein (LDL) [ 4 ], the atheroprotective effects of statins involve other mechanisms, normally described as pleiotropic effects [ 5 , 6 , 7 ].…”