Safety and efficacy of oral non-peptide GLP-1 receptor agonist in non- diabetic obese patients; systematic review and meta-analysis of randomized controlled trials

Abstract Background Oral glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been developed as a needle-free alternative of subcutaneous injectables GLP-1 RAs. This systematic review and meta-analysis evaluated whether oral GLP-1 receptor agonists improve body weight and metabolic outcomes, and characterized their safety and tolerability, compared with placebo in adults with obesity or overweight. Methods PubMed, Embase, the Cochrane Library, Scopus, and ClinicalTrials.gov were systematically searched for randomized controlled trials comparing oral GLP-1 receptor agonists with placebo in adults with obesity or overweight without diabetes. Study selection followed Cochrane handbook guidelines and PRISMA checklist 2020, and quality was assessed using the Cochrane RoB 2 tool. Analysis was done using random-effects models in R version 4.5.2 (meta package). Certainty of evidence was assessed using the GRADE framework. Results Six randomized controlled trials comprising 31 treatment arms of five oral GLP-1 receptor agonists (danuglipron, elecoglipron, lotiglipron, orforglipron, and aleniglipron) versus placebo were included, spanning phase 2 to phase 3 designs of 26 to 72 weeks. Four trials had a low risk of bias, one raised some concerns, and one had a high risk. Oral GLP-1 receptor agonists significantly reduced body weight from baseline compared with placebo (MD −7.61%, 95% CI −8.59 to −6.62; p<0.0001; I²=74.0%), an effect that remained stable on leave-one-out sensitivity analysis and differed significantly by drug, escalation intensity, and placebo run-in. Significant reductions were also observed for alanine aminotransferase (MD −9.53 U/L, 95% CI −11.88 to −7.18; p<0.0001; I²=0%), aspartate aminotransferase (MD −5.48 U/L, 95% CI −6.99 to −3.97; p<0.0001; I²=0%), systolic blood pressure (MD −5.49 mmHg, 95% CI −6.17 to −4.82; p<0.0001; I²=0%), and diastolic blood pressure (MD −1.54 mmHg, 95% CI −1.99 to −1.09; p<0.0001; I²=8.6%). However, oral GLP-1 receptor agonists were associated with an increased risk of any adverse event (RR 1.07, 95% CI 1.04–1.11; p<0.0001), treatment discontinuation due to adverse events (RR 2.85, 95% CI 2.07–3.92; p<0.0001), nausea (RR 3.04, 95% CI 2.29–4.04; p<0.0001), vomiting (RR 3.38, 95% CI 2.19–5.21; p<0.0001), constipation (RR 2.48, 95% CI 1.64–3.75; p<0.0001), and gastroesophageal reflux (RR 1.92, 95% CI 1.15–3.19; p=0.0124), with no significant differences in diarrhea, dyspepsia, headache, or fatigue. Heterogeneity was low (I²≤8.6%) for all outcomes except body weight. GRADE certainty of evidence was high for seven outcomes and moderate for the remaining eight, with no outcome rated below moderate certainty. Conclusion Oral GLP-1 receptor agonists significantly reduce body weight and improve liver enzymes and blood pressure compared with placebo in adults with obesity or overweight, but are associated with a higher incidence of gastrointestinal adverse events and treatment discontinuation.