This is the largest comparison of obesity drugs assembled so far: 262 randomized trials, 99,791 participants, 19 drugs, 24 outcomes, with certainty of evidence graded throughout[1]. It supersedes the pooled figures reported in the earlier weight-loss averages on coverage, though not on the caveats.
On weight at one year, measured against lifestyle modification alone, tirzepatide led at -14.9% (95% CI -16.0% to -13.9%), followed by cagrilintide-semaglutide at -14.8%, oral semaglutide at -10.9%, orforglipron at -9.9%, injected semaglutide at -9.8%, and phentermine-topiramate at -8.1%. All of those carry moderate to high certainty.
The newer agents are a separate category and should be read as one. Ecnoglutide, mazdutide and retatrutide may produce similar or larger reductions, in the range of 13.1% to 14.6%, but the certainty attached is very low to low. A number with low certainty and a number with high certainty are not two entries on the same list, and the drugs that have not yet reached the market are covered in what is not for sale yet.
That overlap is the practical finding, and it reframes what a top-of-table position means. A ranking built on weight loss among the people who completed a trial answers a different question from the one a person starting treatment is asking, which is closer to how much weight they will have lost in a year given some chance of stopping along the way. The tolerability route out of treatment is described from the dosing side in titration and nausea.
Two structural limits apply to every figure above. The comparator is lifestyle modification, so these are not head-to-head contests, and most differences between two drugs here are inferred through the network rather than measured in a trial that randomized people between them. And trial follow-up ran from 12 to 172 weeks, which for a condition managed over decades is short — the question of what the weight is made of, and what returns, sits outside this analysis entirely and is taken up in what these drugs do to muscle.