Safety of ezetimibe in lipid-lowering treatment: systematic review and meta-analysis of randomised controlled trials and cohort studies

Abstract

ObjectiveTo determine the harms of ezetimibe in people who need lipid-lowering treatment.DesignSystematic review and meta-analysis.Data sourcesRandomised controlled trials and cohort studies.Eligibility criteria for selecting studiesStudies comparing ezetimibe with placebo, standard care, or other lipid-lowering agents in people who need lipid-lowering treatment with a follow-up duration of at least six months (or 24 weeks). The relative effects for potential harms of ezetimibe were pooled by use of random effect pairwise meta-analyses for randomised controlled trials and the evidence from observational studies was narratively summarised. The certainty of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation.Results48 randomised controlled trials with 28 444 participants (median follow-up 34 weeks, range 24-312 weeks) and four observational studies with 1667 participants (median follow-up 282 weeks, range 72-400 weeks) were included. The meta-analyses of randomised trials showed moderate to high certainty that ezetimibe was not associated with cancer (relative risk 1.01; 95% confidence interval 0.92 to 1.11), fractures (0.90; 0.74 to 1.10), discontinuation due to any adverse event (0.87; 0.74 to 1.03), gastrointestinal adverse events leading to discontinuation (1.34; 0.58 to 3.08), myalgia or muscular pain leading to discontinuation (0.82; 0.51 to 1.33), neurocognitive events (1.48; 0.58 to 3.81), or new-onset diabetes (0.88; 0.61 to 1.28). The narrative analysis of observational studies provided consistent findings. No credible subgroup effects were identified for the harm outcomes, including shorter versus longer follow-up duration of trials.ConclusionsEzetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents.Review registrationPROSPERO CRD42020187437.

Cost-effectiveness of adding ezetimibe and/or PCSK9 inhibitors to high-dose statins for secondary prevention of cardiovascular disease in Chinese adults

“…The latest evidence demonstrates the effectiveness and safety of PCSK9 inhibitors and ezetimibe in the primary and secondary prevention of CVD (17;18). Nevertheless, the stakeholders in choosing lipid-lowering drugs are beyond clinicians and patients.…”

“…Third, the current study did not consider the cost of the side effects, which is very different from other cost-effectiveness analyses. Nevertheless, high-quality systematic reviews demonstrated the safety of both drugs except for the injection-site reaction for PCSK9 inhibitors, which is not likely to cause additional costs (17;18). The study chose Markov model to simulate the disease development.…”

“…Although the Western major guidelines recommended the second lipid-lowering drugs only after the maximally tolerated dose of statins (8)(9)(10)(11)(12), most clinicians and patients adopt low-to moderate-dose statins by concerning the potential side effects in China (13;14). A recent global clinical practice guideline with its accompanied meta-analyses suggested that people with maximally tolerated statins at high risk of CVD may choose other lipid-lowering drugs including ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors based on the case-to-case benefit and harm balancing and values and preference of the patient (15)(16)(17)(18).…”

Personalized management of dyslipidemias in patients with diabetes—it is time for a new approach (2022)

“…In a metaanalysis of 48 RCTs by Wang et al ezetimibe did not influence the risk of NOD (RR = 0.88; 95% CI: 0.61-1.28) [39]. Despite inconsistent data, it is worth mentioning, that ezetimibe may reverse insulin resistance, reduce lipid dysmetabolism after a meal and improve endothelial function in patients with metabolic syndrome and coronary artery disease [40].…”

Chinese Expert Consensus on the Clinical Diagnosis and Management of Statin Intolerance

“…Score: < 7 points; 7-8 points;9-11 points The correlation between muscle symptoms and statins: Unlikely possible; Possible; Very likely cholesterol inhibitors (e.g., ezetimibe) reduce LDL-C by 15-22%, bile-acid sequestrants reduce LDL-C by 18-25%, PCSK9 inhibitors lower LDL-C by ~ 60%, and bempedoic acid reduces LDL-C by about 20% 2,71. Besides, ezetimibe, PCSK9 inhibitors, and bempedoic acid have lower rates of muscle adverse reactions.24,71,73,74 …”