Efficacy and Safety of Oral Non-Statin Lipid-Lowering Therapies in Dyslipidaemia: A Systematic Review and Network Meta-Analysis

Abstract

Introduction

Dyslipidaemia remains a major contributor to atherosclerotic cardiovascular disease (ASCVD), and many patients fail to achieve recommended low-density lipoprotein cholesterol (LDL-C) targets despite statin therapy or are unable to tolerate statins. Oral non-statin therapies have emerged as important alternatives; however, their comparative efficacy and safety remain unclear.

Methods

We systematically searched PubMed, Embase, Web of Science, and Cochrane Central up to December 2025 for clinical trials evaluating these medications in adults with dyslipidaemia. Primary outcomes were percent and absolute changes in LDL-C, while secondary outcomes included other lipid parameters and safety profile. A frequentist random-effects network meta-analysis was performed.

Results

Forty-three trials comprising 17,021 participants were included. Combination therapies showed the greatest efficacy, with obicetrapib 10 mg plus ezetimibe 10 mg achieving the largest reduction in percent LDL-C (−49.15%; 95% CI: −59.42 to −38.89), followed by bempedoic acid plus ezetimibe (−36.90%; 95% CI: −44.65 to −29.15). Obicetrapib also showed substantial improvements in HDL-C and ApoB. Safety outcomes were generally reassuring, with no significant increase in serious adverse events, myalgia, headache, or elevated liver enzymes; however, treatment discontinuation was higher with bempedoic acid 180 mg and colesevelam 3.75 g. The certainty of evidence was low to very low for many efficacy outcomes, primarily because of heterogeneity and imprecision.

Conclusions

Oral non-statin combination therapies, particularly obicetrapib plus ezetimibe and bempedoic acid plus ezetimibe, provide the most effective LDL-C lowering and are valuable for patients with statin intolerance or residual risk. Ezetimibe remains a well-tolerated option. Long-term cardiovascular outcome trials are needed to confirm clinical benefit.