Safety outcomes of statin vs non-statin lipid-lowering interventions in patients with prior statin-associated muscle symptoms: A systematic review and meta-analysis

Background: Statin-associated muscle symptoms (SAMS) are an obstacle in the prevention of cardiovascular events. A systematic assessment of the evidence of interventions in the setting of SAMS is lacking. Objective: To assess the evidence of strategies of statin-based vs non-statin based therapies in patients with a history of SAMS. Methods: MEDLINE, EMBASE, Cochrane Central Register of Controlled Clinical Trials, Scopus, Clinicaltrials.gov and Proquest databases were searched from inception up to February 2024.We included randomized controlled trials (RCTs) and non-randomized studies involving patients with history of prior SAMS, comparing statin-based therapy to a comparator. We followed the PRISMA guideline with multiple authors involved at each stage. A random-effect model was used in the meta-analysis. We defined the primary outcome as incidence of muscle symptoms. The secondary outcomes were proportion of statin discontinuation of statin-based therapy within patients with history of SAMS. The protocol was registered on PROSPERO (CRD42020202619). Results: In 23 studies (13 RCTs, 2 prospective and 8 retrospective studies) there were in total 1868 participants in RCTs and 47’628 participants in non-RCTs (follow-up 12 weeks – 31 months). Our confidence in the body of evidence using GRADE was moderate for the primary outcome and low-moderate for the secondary outcome. In RCTs among patients with history of SAMS, there was high heterogeneity in the statin regimens and controls (placebo/non-daily dosing/ezetimibe/PCSK9 inhibitors). In RCTs, the meta-analysis showed no difference between statin-based and control groups in the incidence of muscle symptoms (OR 1.19, 95%CI 0.86–1.64, I2: 46.3%)). Therapy discontinuation due to muscle symptoms in RCTs was higher in the statin-based than the comparator groups (OR 1.48, 95%CI 1.03–2.12, I2 = 17.6%). Conclusion: Our findings suggest that patients with a history of SAMS can be re-challenged with statins. More high-quality evidence is needed to strengthen guidelines regarding the management of SAMS.