SURMOUNT-2: Tirzepatide Demonstrates Body Weight-Lowering Effects in T2D

W. Timothy Garvey, MD
Credit: University of Alabama at Birmingham

Use of tirzepatide in people with overweight or obesity and type 2 diabetes was associated with a 14.7% mean reduction in total body weight while also providing meaningful benefit on HbA1c over a 72-week treatment course, according to the SURMOUNT-2 trial.

Presented at the 83rd Scientific Sessions of the American Diabetes Association (ADA 2023), just a year after SURMOUNT-1 results stole headlines at ADA 2022, results of the phase 3 trial demonstrate use of tirzepatide was associated with an overall mean weight reduction of 33 pounds, with 49% of participants receiving tirzepatide achieving a normal HbA1c below 5.7% without signs of severe hypoglycemia.^1,2

"People living with type 2 diabetes in many cases have been exposed to excess weight for years and often face increased difficulties in achieving weight loss results, typically losing 30% less weight than those who have obesity without type 2 diabetes. They need options to help overcome those challenges and achieve meaningful weight reductions," said W. Timothy Garvey, MD, professor of Medicine and director of the Diabetes Research Center at the University of Alabama at Birmingham.³

As the obesity epidemic continues to balloon in the US and abroad, excitement has reached a fever pitch as agents emerge from the pipeline and produced results from phase 2 or phase 3 trials, with the anticipation and reception of data from both SURMOUNT trials serving as examples of this excitement.

In SURMOUNT-1, enrolled 2539 patients with a BMI of 30 kg/m2 or greater or 27 kg/m2 plus at least 1 weight-related complication, excluding diabetes, and randomized them in a 1:1:1:1 ratio to 5 mg, 10 mg, or 15 mg tirzepatide or placebo therapy. This cohort had a mean age of 44.9 (SD, 12.5) years, mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 kg/m2 or higher at baseline.²

Results of the study, which were originally presented by lead investigator Anna Jastreboff, MD, PhD, co-director of the Yale Center for Weight Management, at ADA 2022, suggested the mean percentage change in weight at week 72 was −15.0% (95% Confidence Interval [CI], −15.9 to −14.2) with tirzepatide 5 mg, −19.5% (95% CI, −20.4 to −18.5) with tirzepatide 10 mg, and −20.9% (95% CI, −21.8 to −19.9) with tirzepatide 15 mg compared to −3.1% (95% CI, −4.3 to −1.9) with placebo (P <.001 for all). Further analysis suggested 50% (95% CI, 46 to 54) of the tirzepatide 10 mg arm and 57% (95% CI, 53 to 61) of the tirzepatide 15 mg arm had a reduction in body weight of 20% or more compared to just 3% (95% CI, 1 to 5) among the placebo arm.²

Unlike SURMOUNT-1, the SURMOUNT-2 trial enrolled a population of patients who had type 2 diabetes and were obese or overweight. In total 938 participants underwent randomization in a 1:1:1 ratio to placebo therapy or tirzepatide 10 or 15 mg. The overall trial cohorthad a mean age of 54.2 (SD, 10.6) years, 50.7% were female, and 75.7% were White. Investigators pointed out, at baseline, the cohort had a mean bodyweight of 100.7 kg (SD, 21.1), BMI 36.1 kg/m² (SD, 6.6), and HbA1c 8.02% (SD, 0.89; 64.1 mmol/mol [SD, 9.7]).¹

Per trial protocol, patients received tirzepatide for 72 weeks, with at least 52 weeks of use recorded after dose escalation. For the purpose of analysis, the trial was designed with coprimary endpoints of percent change from randomization in body weight and percentage of participants who achieve body weight reduction from randomization of at least 5%.¹

Upon analysis, results of the trial suggested the least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12.8% (SE, 0.6) and -14.7% (SE, 0.5), respectively, compared to -3.2% (SE, 0.5) with placebo therapy. Investigators pointed out this correlated with estimated treatment differences relative to placebo of -9.6 percentage points (95% CI, –11.1 to -8.1) with tirzepatide 10 mg and -11.6 percentage points (-13.0 to -10.1) with tirzepatide 15 mg (all P < .0001). Further analysis suggested 79-83% of patients receiving tirzepatide achieved a reduction in body weight of 5% or greater compared to 32% of the trial’s placebo arm.¹

When assessing safety endpoints, results indicated the most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhea, and vomiting. Investigators pointed out most events were mild to moderate in severity, with less than 5% leading to discontinuation. Investigators noted 2 deaths occurred in the tirzepatide 10 mg group, but these were not considered to be related to study treatment.¹

"At Lilly, bringing new treatments to people with obesity is a priority and we are proud to share more evidence that solidifies our belief in tirzepatide as a treatment that will impact the way patients manage this disease," said Mike Mason, executive vice president and president of Diabetes and Obesity with Eli Lilly and Company.³ "With these results in hand, we have completed our submission for chronic weight management to the U.S. FDA. We look forward to the future of obesity care and the opportunity to bring potential new treatments, like tirzepatide, to people with obesity and overweight."

References:

1. le Roux, C., Zhang, S., Aronne, L. et. al. Tirzepatide for the Treatment of Obesity: Rationale and Design of the SURMOUNT Clinical Development Program 2022 Obesity doi: 10.1002/oby.23612
2. Campbell P. Surmount-1: Tirzepatide provides significant, sustained weight loss in obesity. HCP Live. June 4, 2022. Accessed June 24, 2023. https://www.hcplive.com/view/surmount-1-tirzepatide-provides-significant-sustained-weight-loss-in-obesity.
3. Lilly’s surmount-2 results published in the Lancet show Tirzepatide achieved a mean weight reduction of 15.7% at the highest dose (15 mg) in adults with obesity or overweight and type 2 diabetes. Eli Lilly and Company. June 24, 2023. Accessed June 24, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-surmount-2-results-published-lancet-show-tirzepatide.