A post hoc analysis of the SURMOUNT-5 study reveals more tirzepatide-treated individuals with obesity achieving all body weight (BW) reduction thresholds than semaglutide-treated participants, with rapid responders showing a greater magnitude of weight loss.
“Early rapid response led to greater end-of-study BW reductions, with more tirzepatide participants reaching all BW reduction thresholds, mostly as rapid responders,” said the researchers, who defined rapid responders and non-rapid responders as those obtaining ≥15-percent and <15-percent BW reduction by week 24, respectively.
The research team also assessed baseline characteristics and the proportion of participants who achieved BW reduction thresholds by week 72. They then summarized the end-of-study safety and gastrointestinal adverse events (AEs) measures.
Of the 740 participants, 239 (32.3 percent) were rapid responders (tirzepatide: n=162; semaglutide: n=77) and 501 were non-rapid responders (tirzepatide: n=205; semaglutide: n=296). [Am J Med 2026;139:913-921]
At week 72, mean BW reductions from baseline were 33.1 kg with tirzepatide and 28.7 kg with semaglutide (30 percent vs 28 percent) among rapid responders and 19.0 vs 14.8 kg (16 percent vs 13 percent) among non-rapid responders.
Among rapid responders, a greater proportion of tirzepatide-treated participants achieved BW reductions ≥30 percent than semaglutide-treated counterparts (48 percent vs 29 percent; risk difference, 16.8, 95 percent confidence interval [CI], 4.4‒29.1; p=0.008).
Safety profile
Tirzepatide and semaglutide both demonstrated safety, with trends being similar between responder groups. Rapid responders, however, had a higher number of gastrointestinal and hepatobiliary AEs than non-rapid responders.
Furthermore, treatment completion did not significantly differ between rapid responders and non-rapid responders for both medications.
“Although the rapid responders experienced more gastrointestinal and hepatobiliary AEs in both treatments, this generally did not affect their ability to complete treatment vs non-rapid responders,” the researchers said.
“Findings of this study may help clinicians proactively tailor treatment plans and highlight that optimizing effectiveness and safety of obesity management requires comprehensive care and adjustment of interventions and monitoring based on patient responses, similar to other chronic diseases,” they added.
Predictor
The observation among rapid responders of greater BW reduction efficacy supports the findings from previous studies, which showed that “the greater the early BW loss response, the greater the overall BW reduction efficacy with obesity management medications.” [Diabetes Obes Metab 2025;27:5064-5071; Obesity (Silver Spring) 2016;24:2278-2288; Obesity (Silver Spring) 2024;32(suppl 1):5-308]
Likewise, early BW loss response has been shown to predict beneficial long-term BW reductions in other types of obesity treatments, including bariatric surgery and lifestyle interventions. [Eur J Clin Nutr 2010;64:994-999; Obes Surg 2016;26:1173-1177]
“Currently, there is no universally accepted definition of excessively rapid BW reduction, though it is often discussed in relation to biliary event risks,” the researchers said.
“The commonly cited target of >1.5 kg/week comes from an older report that analysed weight loss interventions of 4 to 16 weeks in duration and found that when the mean rate of weight loss was >1.5 kg/week there was a substantial increase in the rate of gallstone formation,” they added. [Am J Med 1995;98:115-117]