SURMOUNT-1: Tirzepatide Provides Significant, Sustained Weight Loss in Obesity

Ania Jastreboff, MD

Data from the highly anticipated SURMOUNT-1 trial provide clinicians with an overview of the degree of weight loss achieved with use of tirzepatide versus placebo therapy in patients with obesity.

Presented at the American Diabetes Association (ADA) 82nd Scientific Sessions, results of the study indicate 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight, with a mean percentage change of -15% at week 72 and up to 22.5% with the 15 mg dose.

“Obesity should be treated like any other chronic disease—with effective and safe approaches that target underlying disease mechanisms, and these results underscore that tirzepatide may be doing just that,” said Ania Jastreboff, MD, PhD, associate professor Yale University School of Medicine, director of Weight Management and Obesity Prevention at the Yale Stress Center and co-director of the Yale Center for Weight Management, New Haven, Connecticut, in a statement. “These results are an important step forward in potentially expanding effective therapeutic options for people with obesity. Notably, about 9 out of 10 individuals with obesity lost weight while taking tirzepatide.”

Excitement and anticipation surrounding SURMOUNT-1 have continued to grow since Eli Lilly and Company announced topline results of the trial in a release on April 28. Further fuel was added to this far with the US FDA’s approval of the dual GIP/GLP-1 receptor agonist as an adjunct to diet and exercise for improving blood sugar on May 13.

A phase 3 double-blind, randomized, controlled trial, SURMOUNT-1 was conducted between December 2019 and April 2022 and 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. The 2539-patient cohort had a mean age of 44.9±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 or higher at baseline.

These patients were randomized in a 1:1:1:1 ratio to receive tirzepatide in 5 mg, 10 mg, or 15 mg doses or placebo therapy for 72 weeks, including a 20-week dose-escalation period. The trial had a pair of coprimary endpoints, which were the percentage change in weight from baseline and a weight reduction of 5% or more.

When assessing percentage change in weight, results suggested the mean percentage change in weight at week 72 was −15.0% (95% 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). When assessing the proportion of patients with a weight reduction of 5% or more, results suggested this was achieved by 85% (95% CI, 82 to 89) with tirzepatide 5 mg, 89% (95% CI, 86 to 92) with tirzepatide 10 mg, and 91% (95% CI, 88 to 94) with tirzepatide 15 mg compared to 35% (95% CI, 30 to 39) with placebo (P <.001 for all). Investigators also pointed out 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. Among those in the placebo arm, this degree of weight loss was achieved by just 3% (95% CI, 1 to 5) of those receiving placebo.

Additionally, at week 72, 95.3% of participants with prediabetes at baseline in the tirzepatide group had reverted to normoglycemia. Investigators also highlighted tirzepatide use was associated with positive changes in waist circumference, systolic and diastolic blood pressure, fasting insulin levels, and lipid levels.

When assessing safety outcomes, results indicated 78.9-81.8% of those receiving tirzepatide reported at least 1 adverse event during the treatment period compared to 72% in the placebo arm. The most common adverse events were gastrointestinal in nature. Overall, adverse events led to treatment discontinuation in 4.3%, 7.1%, and 6.2% of those receiving the 5 mg, 10 mg, and 15 doses of tirzepatide. In the placebo arm, the rate of discontinuation due to adverse events was 2.6%.

In an editorial published in the New England Journal of Medicine, Clifford Rosen, MD, of the Maine Medical Center Research Institute, and Julie Ingelfinger, MD, of Massachusetts General Hospital, write about their excitement surrounding the potential of the dual GIP/GLP-1 receptor agonist, but are quick to point out information related to long-term cardiovascular and renal outcomes are essential to optimal implementation as well as a better understanding of the mechanism of action.

“In the SURMOUNT-1 trial, the relatively large number of participants, the racial and ethnic balance, and the lack of major off-target side effects suggest that the results from this trial could have major ramifications for people with obesity,” wrote Rosen and Ingelfinger. “Of course, there remain unanswered questions. For example, is there a distinct mechanism of action for tirzepatide-induced weight loss relative to other first-generation incretin mimetics beyond the effects of GIP? Also, are major adverse cardiovascular events reduced with tirzepatide treatment?”

This study, “Tirzepatide Once Weekly for the Treatment of Obesity,” was presented at ADA 2022 and simultaneously published in the New England Journal of Medicine.