Impact of GLP-1 Receptor Agonists and Dual/Triple IncretinTherapies on Cardiometabolic Outcomes Beyond Glycemic Control:Evidence from Recent Randomized Trials

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists and emerging dual/triple incretin therapies, such as tirzepatide (a GLP-1/GIP dual agonist) and retatrutide (a GLP-1/GIP/glucagon triple agonist), have demonstrated significant cardiometabolic benefits beyond glycemic control in patients with type 2 diabetes (T2D) and obesity, as evidenced by recent randomized controlled trials (RCTs). These agents promote substantial weight loss, improve lipid profiles, reduce blood pressure, and lower the risk of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction (MI), and stroke, while also conferring renal protection through reductions in composite kidney outcomes such as kidney failure, sustained estimated glomerular filtration rate (eGFR) decline, and macroalbuminuria. For instance, in trials like SUSTAIN-6 and SELECT, semaglutide reduced MACE by 26% and 20%, respectively, with consistent benefits across subgroups regardless of baseline body mass index (BMI) or cardiovascular disease (CVD) history; similarly,
tirzepatide in SURPASS-2 outperformed semaglutide in weight reduction (up to 20.2% vs. 13.7%) and lipid improvements, including greater decreases in triglycerides (24% vs. 17%) and increases in high-density lipoprotein cholesterol (HDL-C) (6.8% vs. 4.4%). Renal outcomes were notably enhanced in the FLOW trial, where semaglutide lowered the risk of major kidney events by 24%, and post-hoc analyses from SURMOUNT-5 indicated tirzepatide's superior 10-year CVD risk reduction (2.4% absolute reduction vs. 1.4% with semaglutide), potentially preventing up to 2 million CVD events in eligible U.S. populations over a decade. Triple agonists like retatrutide showed promising phase 2 results with up to 24.2% weight loss at 48 weeks, alongside dose-dependent improvem ents in blood pressure and lipids, though long-term safety data remain limited. Overall, these therapies exhibited a favorable safety profile, with gastrointestinal adverse events being the most common but generally mild and transient during dose escalation, and no increased risk of severe hypoglycemia, retinopathy, or pancreatitis; however, low blood pressure events were slightly higher with tirzepatide. These findings underscore the potential of GLP-1-based and multi-incretin therapies to address residual cardiometabolic risk in T2D and obesity, supporting their integration into guidelines for comprehensive risk management, though further trials in non-diabetic populations and those with preserved ejection fraction heart failure (HFpEF) are warranted to broaden applicability.