Efficacy and Safety of Orforglipron in Obese Adults With or Without Diabetes: A Systematic Review and Meta‐Analysis
Ravi Kumar Pandey, Mahnoor Jan, Aqsa Mohammad, Khawaja Arham Jawaid, Muhammad Asif Naveed, Muhammad Ali Abid, Abdelrahman Amir, Shafique Ahmed, Muhammad Safiullah, Muhammad Imaz Bhatti, Sana Iftikhar, Muhammad Nabeel Saddique, Widyan Alfalh, Razali Omar, Husam Abu Dawood
Abstract
BACKGROUND: Obesity represents a major global health challenge, contributing substantially to cardiovascular disease and metabolic complications. Orforglipron, a novel oral non-peptide GLP-1 receptor agonist, has emerged as a promising therapeutic option for weight management and glycemic control. This meta-analysis evaluated the efficacy and safety of orforglipron in obese patients with or without type 2 diabetes mellitus (T2DM). METHODS: A comprehensive literature search was conducted across PubMed, Embase, Cochrane Library and ClinicalTrials.gov from inception to October 2025 to identify randomised controlled trials (RCTs) evaluating orforglipron in obese patients. Mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. RESULTS: , waist circumference from 1.57 to 6.9 cm, and HbA1c from 0.76% to 1.04% compared with placebo. Favourable lipid changes included reductions in total cholesterol (MD: -4.51% [95% CI: -6.91 to -2.11]), LDL-C (MD: -5.34% [95% CI: -7.10 to -3.58]), and triglycerides (MD: -10.07% [95% CI: -12.33 to -7.80]), with increased HDL-C (MD: 2.94% [95% CI: 1.38 to 4.49]). However, gastrointestinal adverse events were significantly more frequent at doses of 12 mg or higher and treatment discontinuation rates were highest at 24 mg (RR:4.61 [95% CI:1.6 to 13.33]) and 36 mg (RR:3.68 [95% CI:2.48 to 5.44]) doses. Serious adverse events and mortality rates were comparable to those with placebo. CONCLUSION: Orforglipron significantly improved glycemic and lipid parameters in patients with obesity, demonstrating dose-dependent efficacy with maximal benefits at higher doses. While gastrointestinal tolerability remains a clinically important limitation requiring mitigation strategies, orforglipron represents a promising oral therapeutic option for comprehensive obesity and metabolic management.