Tirzepatide edges out semaglutide in a cross-trial weight loss comparison

Semaglutide 2.4 mg and tirzepatide are the two headline drugs approved for chronic use in obesity, and both have reshaped expectations of what medication can do for weight. Anyone starting treatment, and any clinician prescribing it, faces an obvious question: which one works better, and which is easier to tolerate? Remarkably, the literature has lacked any direct comparison of the two in people with obesity or overweight, whether or not they also have type 2 diabetes. This review set out to fill that gap using the best available substitute, a structured comparison across the drugs' separate Phase 3 trials.

The authors systematically searched PubMed up to 15 December 2024 for Phase 3 randomised controlled trials of either drug. They then paired the most closely matched trials: STEP-1 for semaglutide against SURMOUNT-1 for tirzepatide in obese or overweight people without type 2 diabetes, and STEP-2 against SURMOUNT-2 in overweight people with the condition. Because the trial populations were almost entirely comparable on the characteristics that modify treatment outcomes, they ran an unadjusted indirect comparison, working without individual patient data and using the intention-to-treat results from each trial.

Tirzepatide came out ahead across the board. At the 10 mg and 15 mg doses it produced 4% and 5.4% additional weight loss respectively compared with semaglutide 2.4 mg. It also lowered HbA1c, the standard marker of longer term blood sugar control, by an additional 0.4%. Perhaps most surprisingly, tirzepatide was associated with fewer gastrointestinal side effects, the complaint that most often troubles people on these medicines. The authors are explicit, however, that these figures come from comparing separate trials rather than from a direct contest between the drugs.

Until now there has been a lack of literature systematically comparing these two agents, so this review addresses a genuine gap. Cross-trial comparisons are a recognised but imperfect tool: even well matched trials can differ in ways that bias the result, which is why the authors call for a well powered head-to-head randomised trial to confirm the findings. It is also worth noting that two of the authors have received speaker honoraria from Novo Nordisk and Eli Lilly, the manufacturers of the two drugs. Until a direct trial reports, this ranking remains provisional.

If you are taking, or considering, one of these medicines, this review offers a tentative ranking rather than a final answer: tirzepatide at its higher doses looked more effective for weight and blood sugar, and gentler on the gut, than semaglutide 2.4 mg. That is useful context for a conversation with a prescriber, not grounds for switching on its own. Individual response, availability, cost and tolerability all differ from person to person, and the head-to-head trial that would settle the question has not yet been run.