Detailed results from the phase 3 SURMOUNT-3 clinical trial evaluating tirzepatide in adults with obesity or overweight with weight-related comorbidities, excluding type 2 diabetes, have revealed Tirzepatide met both co-primary endpoints for the efficacy estimandi and treatment-regimenii estimand, demonstrating superiority to placebo during the 72-week double-blind treatment period. The full results of the SURMOUNT-3 trial were published in Nature Medicine, 'Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial', and simultaneously presented at ObesityWeek 2023.
SURMOUNT-3 was a multi-centre, randomised, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide to placebo for 72 weeks after a 12-week intensive lifestyle intervention lead-in period in adults with obesity or overweight with weight-related comorbidities, excluding type 2 diabetes. The trial enrolled 806 participants across the US, including Puerto Rico, Argentina and Brazil to a lead-in period with intensive lifestyle intervention.
After 12 weeks, 579 participants achieved at least 5% body weight reduction and were randomised in a 1:1 ratio to receive tirzepatide or placebo. The co-primary objectives of the study were to demonstrate that tirzepatide is superior in percent change in body weight from randomisation and percentage of participants achieving ≥5% body weight reduction from randomisation at 72 weeks compared to placebo.
SURMOUNT-3 utilized a maximum tolerated dose of 10 mg or 15 mg once-weekly. The starting dose of 2.5 mg tirzepatide was increased by 2.5 mg every four weeks until maximum tolerated dose was achieved. Participants who tolerated 15 mg continued on 15 mg as their maximum tolerated dose. Participants who tolerated 10 mg but did not tolerate 15 mg continued on 10 mg as their maximum tolerated dose.
Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist. Tirzepatide is a single molecule that activates the body's receptors for GIP and GLP-1, which are natural incretin hormones. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. Tirzepatide has been shown to decrease food intake and modulate fat utilisation.
At study entry, the mean body weight was 241.4 lb. (109.5 kg). At the end of the 12-week lead-in period, participants achieved 6.9% (7.6 kg or 16.8 lb.) mean weight loss. In a co-primary endpoint, following the lead-in period, participants taking tirzepatide achieved an additional 21.1% mean weight loss. In a secondary endpoint, participants achieved a total mean weight loss of 26.6% (29.2 kg or 64.4 lb.) from study entry over 84 weeks. Participants on placebo achieved a total mean weight loss of 3.8% (4.1 kg or 9.0 lb.) from study entry over 84 weeks.
Table 1: Primary and secondary endpoints week 0 - 72
"In this study, people who added tirzepatide to diet and exercise saw greater, longer-lasting weight reduction than those taking placebo," said Dr Jeff Emmick, senior vice president, product development, Lilly. "While intensive lifestyle intervention is an important part of obesity management, these results underscore the difficulty some people face maintaining weight loss with diet and exercise alone."
The overall safety profile of tirzepatide in SURMOUNT-3 was similar to previously reported SURMOUNT and SURPASS trials. The most commonly reported adverse events in SURMOUNT-3 were gastrointestinal-related and generally mild to moderate in severity. The most frequent events reported by those on tirzepatide compared with placebo, respectively, were nausea (39.7% vs. 14.0%), diarrhoea (31.0% vs. 9.2%), constipation (23.0% vs. 6.8%), COVID-19 (23.0% vs. 25.3%) and vomiting (18.1% vs. 1.4%). Adverse events led to discontinuation of study treatment in 10.5% of participants taking tirzepatide and 2.1% taking placebo.
Tirzepatide is under review by the FDA and the European Medicines Agency for adults living with obesity or overweight with weight-related comorbidities. It is also being studied as a potential treatment for people with obesity and/or overweight with heart failure with preserved ejection fraction, obstructive sleep apnoea and non-alcoholic steatohepatitis. Studies of tirzepatide in chronic kidney disease and in morbidity/mortality in obesity are also ongoing.
To access the paper, 'Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial', please click here