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

Yang Wang; Shipeng Zhan; Heyue Du; Jing Li; Safi U Khan; Bert Aertgeerts; Gordon Guyatt; Qiukui Hao; Geertruida Bekkering; Ling Li; Nicolas Delvaux; Na Su; Irbaz Riaz; Per Olav Vandvik; Haoming Tian; Sheyu Li

doi:10.1136/bmjmed-2022-000134

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

BMJ Med. 2022 May 3;1(1):e000134. doi: 10.1136/bmjmed-2022-000134. eCollection 2022.

Authors

Yang Wang^#¹, Shipeng Zhan^#², Heyue Du^#^{1

3}, Jing Li¹, Safi U Khan⁴, Bert Aertgeerts⁵, Gordon Guyatt⁶, Qiukui Hao^{6

7

8}, Geertruida Bekkering⁵, Ling Li¹, Nicolas Delvaux⁵, Na Su⁹, Irbaz Riaz¹⁰, Per Olav Vandvik^{11

12}, Haoming Tian¹, Sheyu Li¹

Affiliations

¹ Department of Endocrinology and Metabolism, Chinese Evidence-based Medicine Centre, Cochrane China Centre, and MAGIC China Centre, West China Hospital, Sichuan University, Chengdu, China.
² Department of Pharmacy, Southwest Hospital, Army Medical University, Chongqing, China.
³ Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China.
⁴ Department of Cardiology, Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, USA.
⁵ Department of Public Health and Primary Care, Leuven, Leuven, Belgium.
⁶ Department of Clinical Epidemiology and Biostatistics, and Department of Medicine, McMaster University, Hamilton, ON, Canada.
⁷ Centre of Gerontology and Geriatrics/National Clinical Research Centre for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
⁸ School of Rehabilitation Science, McMaster University, Hamilton, Ontario, Canada.
⁹ Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China.
¹⁰ Mayo Clinic, Rochester, MN, USA.
¹¹ Department of Medicine, Norwegian Institute of Public Health, Oslo, Norway.
¹² Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway.

^# Contributed equally.

Abstract

Objective: To determine the harms of ezetimibe in people who need lipid-lowering treatment.

Design: Systematic review and meta-analysis.

Data sources: Randomised controlled trials and cohort studies.

Eligibility criteria for selecting studies: Studies 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.

Results: 48 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.

Conclusions: Ezetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents.

Review registration: PROSPERO CRD42020187437.

Keywords: Coronary disease; Pharmacology.