An updated systematic review published in Annals of Internal Medicine on 1 September 2026 pooled 38 randomised trials covering 25,816 adults who had overweight or obesity but not diabetes. It is the cleanest single answer yet to the question most readers arrive with: how much weight does each of these drugs actually take off, above and beyond what the placebo group lost? Tirzepatide leads the drugs you can get today at 19.0% more than placebo. Oral semaglutide came close enough to the injection that the review cannot separate them.
What the review found
The authors searched MEDLINE, Embase and the Cochrane Central Register from 5 October 2024 through 25 March 2026, taking randomised trials that ran at least 16 weeks. That added 14 new trials and about 11,000 participants to their earlier review. Placebo-subtracted weight loss reached −5.8% for liraglutide (95% CI, −8.0% to −3.6%), −12.4% for orforglipron (−15.1% to −9.7%), −14.3% for oral semaglutide (−17.2% to −11.4%), −14.8% for subcutaneous semaglutide (−16.2% to −13.4%) and −19.0% for tirzepatide (−21.6% to −16.4%).
Those confidence intervals do real work. Tirzepatide’s range (−21.6% to −16.4%) does not overlap subcutaneous semaglutide’s (−16.2% to −13.4%), so the gap between them is unlikely to be noise. Oral and injected semaglutide overlap almost completely, so the review gives you no basis for preferring one on efficacy. In plain arithmetic, for someone starting at 100 kg, the difference between the two intervals’ midpoints is roughly 4 kg over the course of a trial. Side effects were near-universal but rarely disqualifying: gastrointestinal adverse events occurred in 76.0% on drug versus 40.1% on placebo, while stopping because of an adverse event happened in 10.7% versus 3.4%. Serious adverse events were 6.5% versus 5.2% and deaths 0.1% versus 0.0%, with no new safety signals identified.
What it changes, and what it does not
For the ordering of options on this site, very little — which is itself the finding. The head-to-head data the review collected point the same way as the individual trials we have covered: greater weight loss with tirzepatide and with cagrilintide–semaglutide than with semaglutide, and greater weight loss with semaglutide than with liraglutide. What is new is that the oral options now have enough evidence behind them to sit in the same table as the injections rather than in a footnote, and that orforglipron, a small-molecule pill, lands clearly below the injectable incretins rather than alongside them. Anyone weighing a pill against a pen should be doing it on tolerability, supply and what it costs without insurance, not on an efficacy gap the data do not support. The review also names two drugs that beat everything on the market — amycretin at −23.9% (−29.3% to −18.5%) and retatrutide at −22.1% (−24.9% to −19.3%) — neither of which is approved or legally purchasable in the United States.
The authors say plainly that heterogeneity prevented them from pooling the numbers quantitatively, so these are ranges assembled across trials, not a network meta-analysis. Comparing two drugs by their placebo-subtracted figures from different trials is weaker evidence than a trial that randomised people between them. Safety outcomes were inconsistently reported across studies, which limits what the adverse event percentages can settle. The multiagonist figures rest on fewer and earlier trials — amycretin’s interval spans nearly 11 percentage points — and the review labels those comparisons numerical rather than established. Nothing here speaks to what happens after treatment stops, or to the products sold online under these drug names, which are not the formulations that were studied in any of these trials.
Sources: Moiz A, et al. “Efficacy and Safety of Glucagon-like Peptide-1 Receptor Agonists and Co-agonists for Weight Loss Among Adults Without Diabetes: An Updated Systematic Review.” Annals of Internal Medicine, 1 September 2026. PubMed 42673585 · doi:10.7326/annals-25-05519 (PROSPERO CRD42024505558; no funding source reported).
