GLP-1 drugs and weight loss in patients without diabetes

Background

Treatments involving glucagon-like peptide 1 (GLP-1), mostly GLP-1 receptor agonists (GLP-1 RAs) and dual-acting GLР-1 and glucose-dependent insulinotropic polypeptide receptor agonists (GIP-RAs), mediate glycemic control by enhancing glucose-dependent insulin secretion, slowing gastric emptying, and reducing postprandial glucagon secretion and food intake. These drugs are not associated with hypoglycemia. The present review assessed the efficacy and safety of GLP-1 RAs and coagonists for weight loss in patients with overweight or obesity and without diabetes mellitus.

Methods

The MEDLINE, Embase, and Cochrane CENTRAL databases were searched until 4 October 2024 to identify placebo-controlled randomized controlled trials (RCTs) in patients with overweight or obesity. The primary outcome was the change in body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, any adverse events, serious adverse events, and gastrointestinal adverse events.

Results

This study included 26 RCTs with 15,491 patients (72% female; mean body mass index, 30-41 kg/m²; mean age, 34-57 years) and assessed 12 drugs, focusing on commercially available GLP-1 RAs (semaglutide, liraglutide) and the dual-acting GLP-1/GIP-RA agonist (tirzepatide). The treatment duration was between 16 and 104 weeks (median, 43 weeks). Most patients followed a restricted-calorie diet to reduce their intake by at least 500 kcal/d.

Compared with placebo, for semaglutide (2.4 mg weekly) there was a weight loss of up to 13.9% (confidence interval [CI], 11.0%-16.7%) after 68 weeks of treatment; for liraglutide (3.0 mg daily), up to 5.8% (CI, 3.6%-8.0%) after 26 weeks; and for tirzepatide (15 mg weekly), up to 17.8% (95% CI, 16.3%-19.3%) after 72 weeks.

Most adverse events were gastrointestinal and mainly involved nausea, vomiting, diarrhea, and constipation. They occurred in both active treatment and placebo-receiving patients (47%-84% vs 13%-63%). Adverse events requiring treatment discontinuation also occurred in both groups (active drug, 0%-26%; placebo, 0%-9%).

A major limitation of this analysis was no head-to-head drug comparisons and across-study heterogeneity that precluded meta-analysis.

Conclusions

The commercially available GLP-1 RAs and GLP-1/GIP-RA agonist are effective for weight loss when used in patients with overweight or obesity and without diabetes. The reported safety concerns are predominantly gastrointestinal.

McMaster editors’ commentary

Pharmacologic weight loss treatments have had a long and notorious history, with most drugs being removed from clinical use because of serious adverse effects. GLP-based drugs appear unique, as they have shown considerable effectiveness with an acceptable safety profile and have additional cardiometabolic benefits on cardiac, vascular, and renal function. An overarching issue with these RCTs, as in most other weight-loss intervention trials, is the lack of long-term follow-up of at least 5 years or longer (1-2 years in these trials), as there is the potential for weight loss recidivism. In addition, it is unclear what proportion of patients taking these drugs diminish or abandon complementary weight loss measures, especially dietary restrictions, after 1 to 2 years.