Efficacy and safety of orforglipron, an oral small-molecule GLP-1 receptor agonist, on cardiometabolic outcomes: a meta-analysis and systematic review

Obesity and type 2 diabetes are the primary drivers of atherosclerotic cardiovascular disease (ASCVD), the leading cause of death worldwide. Injectable GLP-1 receptor agonists reduce major adverse cardiovascular events. Yet for many individuals, injection hesitancy remains a significant barrier to long-term adherence. Orforglipron is a novel once-daily oral non-peptide GLP-1 receptor agonist designed to provide comprehensive cardiometabolic risk reduction. PRISMA-compliant systematic review and meta-analysis (PROSPERO CRD420251229397) of placebo-controlled phase 2 and phase 3 trials of orforglipron. Random-effects models were used to pool mean differences (MD) and risk ratios (RR) with 95% confidence intervals. Across four large trials, orforglipron produced dose-dependent, clinically meaningful improvements in major modifiable cardiovascular risk factor compared with placebo: body weight − 6.08% (95% CI − 7.68 to − 4.47; up to − 9.31% at higher doses), HbA1c − 0.85% (95% CI − 1.53 to − 0.18; up to − 1.36%), systolic blood pressure − 4.32 mmHg (95% CI − 5.61 to − 3.03; up to − 5.78 mmHg at 45 mg), LDL-cholesterol − 4.14% (95% CI − 6.38 to − 1.91), triglycerides − 10.90% (95% CI − 14.36 to − 7.43), VLDL-cholesterol − 10.81% (95% CI − 14.10 to − 7.51), and HDL-cholesterol + 3.31% (95% CI + 1.66 to + 4.97). Notably, heterogeneity was very low to absent (I² = 0%) for systolic blood pressure and all lipid outcomes. Gastrointestinal side effects were common but typical of the GLP-1 class (nausea RR 5.22, vomiting RR 3.24, eructation RR 6.80). Orforglipron provides highly consistent reductions across the full spectrum of ASCVD risk factors, with effect sizes on lipids and blood pressure comparable to those linked to MACE reduction in trials of injectable GLP-1 receptor agonists. As a novel small-molecule GLP-1 agonist in its class, Orforglipron offers a transformative option for comprehensive cardiometabolic risk reduction and ASCVD prevention in patients with obesity and type 2 diabetes.