Updated GLP-1 Review Finds Large Weight Loss but Cannot Reliably Rank Emerging Drugs

A systematic review published September 1 in *Annals of Internal Medicine* found substantial weight loss across approved and emerging GLP-1–based treatments for adults with overweight or obesity who did not have diabetes. The largest numerical reductions appeared with experimental multiagonists, but the researchers could not formally combine the studies because their designs differed too much.

That limitation is central to interpreting the results. The review expands the evidence base for peptide and related metabolic medicines, but it does not establish a definitive ranking or show that an investigational drug is superior to an approved alternative.

What the researchers reviewed

Investigators from Jewish General Hospital and McGill University updated an earlier systematic review by searching MEDLINE, Embase and the Cochrane Central Register of Controlled Trials for studies published through March 25, 2026. Eligible studies were randomized controlled trials lasting at least 16 weeks.

The final review contained 38 trials involving 25,816 adults with overweight or obesity but without diabetes. Fourteen trials, representing 11,000 participants, were new to the update. Two reviewers independently extracted the data.

The outcomes included percentage change in body weight, body-mass index, waist circumference, blood pressure and adverse events. Most efficacy figures compared an individual treatment with placebo rather than directly comparing drugs within the same trial.

Large numbers do not create a league table

At the highest doses reported, placebo-subtracted weight loss reached 5.8% with liraglutide, 14.8% with injected semaglutide, 14.3% with oral semaglutide, 12.4% with orforglipron and 19.0% with tirzepatide.

Emerging multiagonists produced still larger numerical estimates: 23.9% with amycretin and 22.1% with retatrutide. Those figures have overlapping confidence intervals and came from separate development programs with different treatment durations, dose-escalation schedules and participant characteristics.

The authors concluded that heterogeneity prevented quantitative synthesis. In practical terms, the review could summarize the trials but could not perform the pooled statistical comparison needed to declare that amycretin beats retatrutide, or that either experimental therapy outperforms tirzepatide.

Some active-comparator evidence was available. Trials directly comparing treatments found greater weight loss with semaglutide and JNJ-64565111 than with liraglutide, and greater reductions with tirzepatide and the cagrilintide-semaglutide combination than with semaglutide. These comparisons are more informative than placing results from unrelated placebo-controlled trials side by side, although each remains bounded by its own population and follow-up period.

Tolerability remains part of the result

Gastrointestinal adverse events were reported in 76.0% of participants receiving a GLP-1 receptor agonist or coagonist, compared with 40.1% receiving placebo. Discontinuations attributed to adverse events occurred in 10.7% and 3.4%, respectively.

Serious adverse events were reported in 6.5% of treated participants and 5.2% of placebo recipients. Deaths were rare at 0.1% and 0.0%, respectively, and the reviewers identified no new safety signal. However, safety outcomes were reported inconsistently across the underlying trials, making reassurance about newer agents necessarily provisional.

FDA’s current public information also distinguishes established medicines from experimental candidates. The agency states that retatrutide has not been found safe and effective for any condition and is not a component of an FDA-approved drug. Results obtained with a sponsor’s controlled trial material therefore should not be extended to products marketed outside clinical research.

What the evidence means

The review strengthens the conclusion that this therapeutic class can produce clinically substantial weight loss in adults without diabetes. It also shows how quickly multi-receptor approaches are expanding beyond earlier GLP-1 medicines.

It does not settle which treatment offers the best long-term balance of weight reduction, tolerability and health outcomes. Trials lasting 16 weeks or longer can measure weight change, but the newest candidates still have limited exposure compared with established drugs. Longer comparative studies are needed to assess durability, uncommon harms and outcomes beyond the scale.

For now, the clearest finding is not that one emerging molecule has won. It is that efficacy estimates are becoming larger while the evidence needed for reliable cross-drug comparisons and mature safety assessment is still catching up.