New review maps GLP-1 weight loss across 38 trials—but it is not a league table

What the source reports

An updated systematic review published in Annals of Internal Medicine on 1 September 2026 examined the efficacy and safety of GLP-1 receptor agonists and related co-agonists for weight loss in adults with overweight or obesity who did not have diabetes.

The researchers included 38 randomized controlled trials involving 25,816 participants. Fourteen trials and approximately 11,000 people were new since the group’s previous review, reflecting how quickly oral treatments and dual- or triple-target candidates are expanding the evidence base.

The review found substantial weight reduction across the drug family, with gastrointestinal symptoms remaining the most frequently reported adverse effects. Its most eye-catching figures belong to newer multi-agonists—but the authors could not combine the studies into one formal quantitative synthesis because the trials were too different.

What the review included

Eligible studies were randomized trials lasting at least 16 weeks. They enrolled adults with overweight or obesity but without diabetes and compared GLP-1-based treatments with placebo or, in a smaller number of trials, another active medicine.

The treatments varied substantially. The review covered established single-receptor medicines, the dual GIP/GLP-1 agonist tirzepatide, oral small-molecule GLP-1 treatments, combinations involving amylin biology, and investigational multi-agonists such as retatrutide and zenagamtide, formerly called amycretin.

Trials also differed in dose, duration, participant characteristics, lifestyle support, discontinuation patterns and statistical handling of missing data. Those differences are why a systematic review can map the field without turning every reported percentage into a valid direct comparison.

The weight-loss figures attracting attention

At the highest doses and study time points reported, placebo-subtracted weight reduction reached up to 5.8% with liraglutide, 14.8% with injected semaglutide, 14.3% with oral semaglutide, 12.4% with orforglipron and 19.0% with tirzepatide.

The emerging multi-agonists produced numerically larger estimates in the trials included: 23.9% for zenagamtide and 22.1% for retatrutide. Their confidence intervals were wide—18.5% to 29.3% for zenagamtide and 19.3% to 24.9% for retatrutide—reflecting a less mature evidence base.

These are placebo-subtracted estimates, not the same as unadjusted weight change from the start of a trial. They also describe group averages at particular doses and time points, not an amount of weight loss that an individual can expect.

Why this is not a drug ranking

A larger percentage in one placebo-controlled trial does not prove that its medicine is better than a different medicine studied in another trial. A reliable comparative claim normally requires a randomized head-to-head study or a carefully conducted network meta-analysis with sufficiently compatible evidence.

This review explicitly reports that heterogeneity prevented quantitative synthesis. Its cross-treatment figures should therefore be read descriptively: they show the range of effects observed across an increasingly diverse pipeline, not a statistically tested finishing order.

The review did include some direct comparisons. Those data favoured tirzepatide and the cagrilintide–semaglutide combination over semaglutide in the particular head-to-head trials assessed. That conclusion is narrower and stronger than simply lining up the largest percentages from unrelated studies.

Approved treatments and experimental candidates are mixed together

A systematic review can include both marketed medicines and experimental candidates because its purpose is to evaluate evidence, not regulatory status. Readers should not interpret inclusion as approval or availability.

Tirzepatide, semaglutide, liraglutide and orforglipron have defined approved uses and prescribing information in relevant markets. Retatrutide and zenagamtide remain investigational; neither percentage in this review creates an approved product, recommended dose or established long-term safety profile.

This distinction is especially important when unapproved compounds are advertised online. A published trial result does not make a research product legitimate for personal use, and material sold outside an authorized supply chain may not match the substance or strength claimed.

What the safety results show—and do not show

Across the evidence summarized, gastrointestinal adverse events were common: the review reported them in 76.0% of participants receiving GLP-1-based treatment and 40.1% receiving placebo. Treatment discontinuation because of adverse events was 10.7% and 3.4%, respectively.

Serious adverse events were reported in 6.5% of treatment participants and 5.2% of placebo participants, while deaths were uncommon in both groups. The authors reported no new safety signal across the review.

That phrase does not mean every medicine has been proved equally safe or that rare harms have been ruled out. Safety outcomes were reported inconsistently, study follow-up did not exceed two years, and the newest candidates have far less exposure than established medicines used by large populations.

What the review says about the changing market

The evidence base is no longer centred only on daily or weekly injections that activate GLP-1 receptors. Oral semaglutide and small-molecule treatments change how therapy can be taken, while dual and triple agonists attempt to produce larger or broader metabolic effects through additional hormone pathways.

More options could eventually allow treatment choices to reflect cardiovascular or metabolic disease, desired weight reduction, tolerability, dosing preference, access and cost. The review itself cannot determine which option offers the best overall balance for a particular person.

Longer comparative trials will matter increasingly as percentage weight loss becomes only one part of the decision. Durability, physical function, cardiovascular outcomes, treatment discontinuation, quality of life and outcomes after stopping may distinguish treatments that look similar—or very different—on the scale.

What remains uncertain

The review could not establish a single comparative hierarchy across all medicines. Its authors also noted inconsistent safety reporting, while the available studies offered limited evidence about uncommon adverse effects and outcomes beyond two years.

The largest investigational-drug estimates need confirmation in larger, longer Phase III programmes and regulatory review. It remains uncertain how much of any apparent advantage will persist when treatments are compared directly, used in routine care or continued for many years.

The review focused on people without diabetes, so its estimates should not be transferred automatically to people with type 2 diabetes, who may lose different amounts of weight and have different treatment priorities. It also does not replace product-specific prescribing information or individualized medical assessment.

Bottom line

The new review provides a valuable snapshot of a fast-changing field: 38 randomized trials, 25,816 adults without diabetes, and a growing range of injectable, oral and multi-target approaches. It supports the conclusion that GLP-1-based medicines can produce substantial weight loss, with gastrointestinal effects remaining common.

Its biggest lesson is methodological as well as clinical. Newer agents produced striking numerical results, but the studies were too heterogeneous for a formal pooled comparison. The percentages identify promising directions; they do not by themselves crown a winner or tell an individual which treatment to choose.