Retatrutide-Associated Improvements in Cardiovascular Risk Biomarkers in Adults With Obesity With or Without Type 2 Diabetes.

AIMS: To further characterise the effects of retatrutide on cardiometabolic risk, lipoprotein and inflammatory biomarkers were assessed post hoc in phase 2 trials of adults with obesity/overweight with or without type 2 diabetes (T2D). MATERIALS AND METHODS: Data were analysed from two randomised, double-blind, placebo-controlled phase 2 trials. In Study 1, adults with obesity/overweight and T2D received once-weekly retatrutide (0.5/4/8/12 mg), dulaglutide (1.5 mg) or placebo for 36 weeks; in Study 2, adults with clinical obesity without T2D received retatrutide (1/4/8/12 mg) or placebo for 48 weeks. Fasting blood samples were collected at baseline and during treatment to assess lipids, apolipoproteins, lipoprotein particle subclasses and inflammatory biomarkers. Mixed models for repeated measures estimated placebo-adjusted change from baseline. Statistical significance was defined as a false discovery rate-adjusted p < 0.05. RESULTS: Mean body mass index was 35.4 kg/m2 (Study 1) and 37.4 kg/m2 (Study 2). In both studies, retatrutide was associated with significant reductions in non-high-density lipoprotein cholesterol (Study 1: up to -21.0%, Study 2: up to -26.9%), apolipoprotein B (-21.4%, -24.2%), total triglyceride-rich lipoprotein particles (-22.5%, -33.7%), large triglyceride-rich lipoprotein particles (-84.4%, -76.6%), triglyceride-rich lipoprotein cholesterol (-29.4%, -38.6%), total low-density lipoprotein particles (-19.7%, -23.5%) and small low-density lipoprotein particles (-32.6%, -32.3%). Retatrutide was associated with significant reductions in high-sensitivity C-reactive protein (-54.8%) and interleukin-6 (-29.6%) in Study 2 but not Study 1. CONCLUSIONS: In adults with obesity/overweight, with or without T2D, retatrutide treatment was associated with reductions in atherogenic lipoproteins and inflammatory biomarkers linked to cardiovascular disease risk. TRIAL REGISTRATION: ClinicalTrials.gov numbers NCT04881760 and NCT04867785.