BACKGROUND: Tirzepatide and semaglutide are highly effective medications for obesity management. The efficacy and safety of tirzepatide as compared with semaglutide in adults with obesity but without type 2 diabetes is unknown.

METHODS: In this phase 3b, open-label, controlled trial, adult participants with obesity but without type 2 diabetes were randomly assigned in a 1:1 ratio to receive the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or the maximum tolerated dose of semaglutide (1.7 mg or 2.4 mg) subcutaneously once weekly for 72 weeks. The primary end point was the percent change in weight from baseline to week 72. Key secondary end points included weight reductions of at least 10%, 15%, 20%, and 25% and a change in waist circumference from baseline to week 72.

RESULTS: A total of 751 participants underwent randomization. The least-squares mean percent change in weight at week 72 was -20.2% (95% confidence interval [CI], -21.4 to -19.1) with tirzepatide and -13.7% (95% CI, -14.9 to -12.6) with semaglutide (P<0.001). The least-squares mean change in waist circumference was -18.4 cm (95% CI, -19.6 to -17.2) with tirzepatide and -13.0 cm (95% CI, -14.3 to -11.7) with semaglutide (P<0.001). Participants in the tirzepatide group were more likely than those in the semaglutide group to have weight reductions of at least 10%, 15%, 20%, and 25%. The most common adverse events in both treatment groups were gastrointestinal, and most were mild to moderate in severity and occurred primarily during dose escalation.

CONCLUSIONS: Among participants with obesity but without diabetes, treatment with tirzepatide was superior to treatment with semaglutide with respect to reduction in body weight and waist circumference at week 72. (Funded by Eli Lilly; SURMOUNT-5 ClinicalTrials.gov number, NCT05822830.).

Endocrine rater

These highly important study results would help physicians/policy makers make a paradigm shift in managing patients with obesity. Tirzepatide and the newer incretin poly-agonists are currently revolutionizing obesity management and might replace the role of bariatric surgery as a treatment option for obesity in the near future. An extra weight loss potential of about 7%, improvement in waist circumference of 5.4 cm, and 20% more people achieving 10% weight loss compared with semaglutide makes tirzepatide unique in managing obesity. The amount of weight loss with tirzepatide would result in reversal or remission of several adiposity-related diseases such as type 2 diabetes, fatty liver, sleep apnea, polycystic ovary syndrome, and osteoarthritis. Better GI side effects compared with semaglutide also makes this drug attractive. I sometimes label tirzepatide as a medical bariatric intervention. Data on CVD protection with massive weight loss is expected soon.

Family Medicine (FM)/General Practice (GP) rater

This unblinded study confirms the "buzz" that tirzepatide is superior to semaglutide for weight loss. There are many questions this study does not answer: Will patients' insurance cover GLP1s? If so, which drug will they cover? Will the covered drug be available in the pharmacy? And how did we arrive at our current state in which obesity is so prevalent and lifestyle interventions to combat it is so challenging to consistently follow?

Special Interest - Obesity -- Physician rater

This is the first long-term randomized trial comparing semaglutide and tirzepatide at weight-loss doses for both. This provides clear evidence that tirzepitide results in greater weight loss by all measures, but we are still waiting for the results of the trial evaluating cardiovascular disease outcomes for tirzepitide.