EClinicalMedicine · Oct 28, 2026

Comparative effectiveness of lipid-lowering therapies for primary cardiovascular prevention: a network meta-analysis of randomised controlled trials

By Gnanavelou M, Ho GJK, Ng CH et al.

BACKGROUND: Comparative effectiveness across lipid-lowering drug classes in primary prevention remains uncertain. METHODS: We conducted a random-effects network meta-analysis of randomised trials of lipid-lowering therapy in adults without a prior coronary event, stratified by baseline atherosclerotic cardiovascular disease (ASCVD) risk. MEDLINE and EMBASE were searched from inception to July 25, 2026; included trials were published 1984-2026. Statin-containing regimens were classified by intensity, with no lipid-lowering therapy as reference. FINDINGS: 29 trials (218,657 unique participants) were included; hazard ratios are shown with 95% CIs. At high ASCVD risk, evolocumab plus statin (0.59, 0.49-0.71), bempedoic acid (0.64, 0.48-0.85) and high-intensity statin (0.80, 0.69-0.92) reduced 3-point major adverse cardiovascular events (MACE) vs. no lipid-lowering therapy. Against its statin comparator, evolocumab retained benefit (0.74, 0.65-0.83), whereas eicosapentaenoic acid (EPA) (0.81, 0.62-1.06) and fibrates (4-point MACE, low-to-moderate risk; 1.04, 0.80-1.36) did not. At low-to-moderate risk, benefit was graded by statin intensity (high 0.53, 0.37-0.75; moderate 0.76, 0.64-0.91); for 4-point MACE, ezetimibe (0.66, 0.50-0.87) and fibrates (0.81, 0.70-0.94) also reduced events. Heterogeneity was moderate in the 2-point and 3-point networks (I² 59-62%) and no network contained a closed loop, precluding consistency testing. Two trials were at high risk of bias; certainty was low or very low for 23 of 27 comparisons. No comparison contained enough trials to test for small-study effects. INTERPRETATION: Benefit in primary prevention tracked statin intensity rather than drug class. Evolocumab added to a statin conferred further benefit over that statin, whereas EPA and fibrates did not, and bempedoic acid is an option where statins are not tolerated. FUNDING: None.

doi.org/10.1016/j.eclinm.2026.104300 Open access PubMed 42991068 Interventions