Triple-hormone receptor agonist retatrutide significantly improves lipoprotein and apolipoprotein profiles in participants with obesity or overweight

Abstract Background In a phase 2 study in participants who have obesity or overweight but not type 2 diabetes (T2D) (n=338), retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, reduced body weight, glycated hemoglobin, triglycerides (TG), LDL-C and VLDL-C. Purpose To better understand the effects of RETA on the serum lipid profile we analyzed changes in apolipoprotein levels and distribution and size of lipoprotein particles. Methods Adult participants with obesity (BMI ≥30 kg/m2), or overweight (BMI ≥ 27 kg/m2 and < 30 kg/m2) with a weight-related comorbidity, and without T2D were randomized to receive RETA 1, 4, 8, 12 mg or placebo for 48 weeks. Lipids panel (including calculated non-HDL-C), apolipoproteins (apo) and NMR lipoprotein profiles were measured at baseline, 24 and 48 weeks in fasting plasma samples. Data were analyzed using a mixed model for repeated measures after log transformation. Results RETA dose-dependently reduced non-HDL-C up to 22.2% and 26.9% and apoB up to 19.6% and 24.2% at 24 and 48 weeks, respectively (Figure). At 48 weeks, RETA reduced TG and apoC-III levels up to 40.6% and 38.0%, respectively. RETA greatly reduced the total number of TG-rich lipoprotein particles (TRLP) and all subfractions of TRLP (large, medium and small) at 48 weeks (Table). Since the reduction in large and medium TRLP was greater than the reduction in small TRLP, the average size of TRLP was smaller following treatment with RETA. RETA reduced the number of total and highly atherogenic small LDL particles (LDLP), while total and small HDL particles (HDLP) were only slightly reduced. The average size of HDLP increased following treatment with RETA. At 48 weeks, the NMR-derived lipoprotein insulin resistance score was dose-dependently decreased by 27.4%, 31.7% and 32.5% with 4 mg, 8 mg and 12 mg, respectively, following RETA treatment. Conclusions RETA treatment for 48 weeks dose-dependently reduced levels of non-HDL-C and apoB and the number of total and small LDL particles, suggesting an improvement in atherogenic lipoprotein profile and cardiovascular risk in subjects who have obesity or overweight but not T2D.