Updated Annals of Internal Medicine Review Adds Orforglipron and Amycretin Data to GLP-1 Weight-Loss Evidence

Annals of Internal Medicine published an updated systematic review online on September 1, 2026, evaluating the efficacy and safety of GLP-1 receptor agonists and co-agonists for weight loss in adults without diabetes. The review, led by Areesha Moiz and Mark J. Eisenberg at the Lady Davis Institute, Jewish General Hospital, and McGill University in Montreal, updates the same research group's earlier review of the field, incorporating trial data published through March 2026.

The authors searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from October 5, 2024 through March 25, 2026, for randomized controlled trials lasting 16 weeks or longer. Two reviewers independently extracted data. The update added 14 new trials, covering roughly 11,000 participants, to the prior review, bringing the combined evidence base to 38 randomized controlled trials and 25,816 participants.

Among commercially available therapies, the review reported placebo-subtracted weight loss reaching up to -5.8% (95% CI, -8.0% to -3.6%) for liraglutide, -14.8% (CI, -16.2% to -13.4%) for subcutaneous semaglutide, -14.3% (CI, -17.2% to -11.4%) for oral semaglutide, -12.4% (CI, -15.1% to -9.7%) for orforglipron, and -19.0% (CI, -21.6% to -16.4%) for tirzepatide. All five of these agents are approved for weight management or type 2 diabetes in at least one major jurisdiction, though approval status varies by country and indication.

A separate group of emerging multiagonist drugs showed numerically larger reductions in the pooled data, including -23.9% (CI, -29.3% to -18.5%) with amycretin and -22.1% (CI, -24.9% to -19.3%) with retatrutide. The authors rated this evidence very low to low certainty, reflecting the smaller and less mature trial base behind those two drugs compared with the approved options. Both amycretin and retatrutide remain investigational and are not approved by the FDA, the European Medicines Agency, or Australia's Therapeutic Goods Administration; the review's numbers should be read as preliminary rather than as confirmed comparative effectiveness.

On safety, gastrointestinal adverse events remained common with active treatment compared with placebo (76.0% versus 40.1%). Discontinuation because of adverse events was low overall (10.7% versus 3.4%) but numerically higher with some oral agents, according to the review. Serious adverse events (6.5% versus 5.2%) and deaths (0.1% versus 0.0%) were rare in both groups, and the authors reported identifying no new safety signals. The review noted that safety outcomes were inconsistently reported across the included trials, which limited direct comparison.

Head-to-head trial data included in the review showed greater weight loss with semaglutide and the investigational oral agent JNJ-64565111 compared with liraglutide, and greater weight loss with tirzepatide and with the cagrilintide-semaglutide combination known as CagriSema compared with semaglutide alone. CagriSema is not yet approved by the FDA; cagrilintide, its amylin-analogue component, remains investigational on its own.

The authors acknowledged that heterogeneity across trials precluded a full quantitative synthesis for some outcomes, and that inconsistent safety reporting limited some comparisons. Their overall conclusion states that GLP-1 receptor agonists demonstrate substantial weight loss in adults without diabetes, alongside an expanding range of therapeutic options that now includes oral and multiagonist therapies. The review reports no primary funding source and was registered in advance with PROSPERO (registration CRD42024505558). It synthesizes existing randomized trial evidence rather than presenting new original trial results, and nothing in it constitutes medical, treatment, or dosing advice.