The primary weight-loss results from the SURMOUNT-3 and SURMOUNT-4 studies in a combined total of 1,249 randomized adults add to positive data previously reported from more than 3,400 randomized patients in SURMOUNT-1 and SURMOUNT-2, also in people with overweight or obesity. The results from these four trials collectively create a compelling picture of safety and efficacy as tirzepatide (Mounjaro, Lilly) nears a decision, expected later in 2023, from the U.S. Food and Drug Administration for approval as a weight-loss agent in people with or without type 2 diabetes.
Tirzepatide received FDA approval in May 2022 for the indication of improving glycemic control in people with type 2 diabetes.
SURMOUNT-3 included intensive lifestyle management
SURMOUNT-3 initially enrolled 806 adults with obesity or overweight plus one or more weight-related comorbidities who received a 12-week intensive lifestyle-intervention program. People who lost at least 5% of their baseline weight could continue, and in the second phase, investigators randomized 579 people to 72 weeks of treatment with weekly injections of tirzepatide or placebo while they continued the lifestyle intervention. In the intervention group, tirzepatide was gradually up-titrated to a 10-mg or 15-mg weekly dose, depending on tolerance.
People taking tirzepatide lost an average of 21.1% of body weight after 72 weeks from time of randomization, compared with an average weight gain of 3.3% among controls, an overall incremental loss of 24.5% of body weight with tirzepatide, compared with placebo, one of the trial’s two primary endpoints. The second primary endpoint was the percentage of people achieving at least a 5% weight loss from time of randomization, which occurred in 94.4% of people taking tirzepatide and 10.7% of controls.
SURMOUNT-4 tested tirzepatide discontinuation
SURMOUNT-4 started with a 36-week lead-in period during which 783 adults with obesity or overweight plus comorbidities received weekly injections of tirzepatide, which led to an average weight loss of 21.1% from baseline. Researchers then randomized 670 of these participants to continue weekly tirzepatide for another 52 weeks or continue placebo injections. At the end of the 1-year randomized phase, those who continued tirzepatide had an average additional weight loss of 6.7%, while those who switched to placebo had an average 14.8% weight gain during the 52-week phase, producing a placebo-adjusted weight loss with tirzepatide of 21.4% for this phase.
As a secondary endpoint, those who received tirzepatide continuously for 88 weeks (the 36-week run-in plus the 52-week randomized phase) had an overall average weight loss from baseline of 26.0%. In SURMOUNT-3, participants randomized to receive tirzepatide during the second phase had an overall average weight loss, compared with baseline, before the lifestyle-intervention lead-in of 26.6% during 84 total weeks of treatment. These weight-loss levels, 26.0% and 26.6%, were “the highest level of weight loss observed in the SURMOUNT program to date,” said a Lilly official in a written statement. The findings from this trial also highlighted the importance of ongoing tirzepatide treatment to maintain weight loss.
Safety findings from both trials were consistent with prior studies of tirzepatide, as well as other agents that act by mimicking the action of human incretin hormones, the glucagonlike peptide-1 (GLP-1) receptor agonists. The most common adverse effects with tirzepatide were gastrointestinal and were generally mild to moderate in severity. Tirzepatide is a twincretin that has agonist activity for both the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide receptor.
According to Lilly’s announcement, the SURMOUNT-3 results will be reported at Obesity Week, being held Oct. 14-17 in Dallas, and the SURMOUNT-4 findings will be reported at the European Association for the Study of Diabetes 2023 annual meeting, being held Oct. 2-6 in Hamburg, Germany.
The SURMOUNT trials have been funded by Lilly, the company that markets tirzepatide (Mounjaro).
A version of this article first appeared on Medscape.com.