Comparative Cardiovascular, Lipid, and Safety Effects of Lipid-Modifying Therapies in Diabetes: An Agent-, Class-, and Dose-Level Network Meta-Analysis

AIMS: Comprehensive and fine-grained evidence of lipid-lowering drugs in patients with diabetes is lacking. This study aims to compare the efficacy and safety of lipid-modifying agents in this population across agent-, class-, and dose-levels. METHODS: We systematically searched PubMed, Web of Science, Scopus, the Cochrane Central Register of Controlled Trials, Embase, and ClinicalTrials.gov from inception to October, 2025, for randomized controlled trials (RCTs) evaluating lipid-modifying therapies in patients with diabetes. A frequentist network meta-analysis was performed across multiple levels. Primary outcomes included major adverse cardiovascular events (MACE), stroke, myocardial infarction (MI), revascularization, cardiovascular death, and all-cause death. Secondary outcomes were lipid profile parameters. Safety outcomes were also assessed. RESULTS: Eighteen RCTs involving 14 lipid-modifying agents and 89,717 participants were included. Statins, ezetimibe, PCSK9i and bempedoic acid each reduced the risk of MACE, with distinct agent-specific profiles across cardiovascular and lipid endpoints. Atorvastatin is associated with a strong reduction in multiple cardiovascular outcomes. Reduction in revascularization risk was specifically observed with atorvastatin at both moderate and high dose, while pravastatin was associated with a great reduction in stroke risk. Ezetimibe and evolocumab, with comparable efficacy, were associated with reductions in MI risk. PCSK9i significantly improved TC and LDL-C, while exerting mild effects on TG and HDL-C. Pemafibrate showed a pronounced benefit of TG-lowering efficacy. The renal safety of fibrates and bempedoic acid, and glycometabolism safety of EPA-DHA warrants monitoring. CONCLUSION: Lipid-modifying therapies were associated with beneficial and specific cardiovascular and lipid effects in diabetes. The results provide more granular and tailored lipid management strategies. TRIAL REGISTRATION: PROSPERO CRD420251163974.