This updated systematic review pooled 38 randomised trials of GLP-1 receptor agonists and co-agonists in 25,816 adults with overweight or obesity and without diabetes, adding 14 new trials since the previous version. It is the clearest current summary of where the field has reached, and non-specialists are being asked about these drugs constantly.
Placebo-subtracted weight loss reached -5.8% for liraglutide (95% CI -8.0 to -3.6), -14.8% for subcutaneous semaglutide (-16.2 to -13.4), -14.3% for oral semaglutide (-17.2 to -11.4), -12.4% for orforglipron (-15.1 to -9.7) and -19.0% for tirzepatide (-21.6 to -16.4). Investigational multiagonists went further: -23.9% for amycretin and -22.1% for retatrutide. Head-to-head data confirmed the ordering — semaglutide beat liraglutide, and tirzepatide and cagrilintide-semaglutide beat semaglutide.
The safety picture is stable rather than reassuring or alarming. Gastrointestinal adverse events occurred in 76.0% on active drug versus 40.1% on placebo. Discontinuation for adverse events was 10.7% versus 3.4%, numerically higher with some oral agents. Serious adverse events were 6.5% versus 5.2% and deaths were rare in both arms. No new safety signals emerged.
Two things follow. Oral semaglutide performing close to the injection matters most in settings where cold chain and injection training limit uptake. And the near-doubling of gastrointestinal side effects is the number to quote when a patient asks what it will feel like — three quarters of people get some, one in ten stops because of them.
- Quote real figures when counselling: roughly 15% body weight with semaglutide, 19% with tirzepatide, against placebo
- Warn that about three quarters experience gastrointestinal side effects and about one in ten stops because of them
- Oral semaglutide performed close to the injectable — relevant where cold chain or needle aversion limits use
- Liraglutide is now clearly the weakest of the licensed options at about 6%
- Treat amycretin and retatrutide figures as investigational, not as options to offer today
The statistics, in plain English
Placebo-subtracted means the weight loss attributable to the drug after removing what the placebo group achieved through diet, monitoring and trial participation — so the total weight a patient loses is usually larger than the figure quoted. The review's authors could not perform a formal quantitative synthesis because the trials were too heterogeneous, which means these are ranges across trials rather than a single pooled estimate, and cross-drug comparisons drawn from separate trials are weaker than the head-to-head data. Note also that safety outcomes were inconsistently reported, so the adverse event percentages are less reliable than the efficacy ones.
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