Tirzepatide safe, effective for weight loss, preventing diabetic progression at 3 years

Nov 06, 2024

SAN ANTONIO — Tirzepatide demonstrated long-term weight-loss benefits and prevention of diabetes progression in patients with obesity and prediabetes, but only so long as they continued the weight-loss medication, a speaker reported.

The SURMOUNT-1 trial was a randomized, double-blind, placebo-controlled study for which patients with overweight plus one weight-related comorbidity or obesity and without diabetes were randomly assigned to 72 weeks of tirzepatide 5 mg, 10 mg or 15 mg doses (Mounjaro/Zepbound, Eli Lilly) or placebo.

As Healio previously reported, adults with overweight or obesity without diabetes experienced an approximately 20.9% weight loss at 72 weeks with 15 mg tirzepatide.

The top-line results from the SURMOUNT-1 3-year study were previously reported in August 2024.

At ObesityWeek, Leigh Perreault, MD, associate clinical professor of medicine in the division of endocrinology, metabolism and diabetes at the University of Colorado Hospital, moderated a session overviewing the full 3-year efficacy and safety results of the SURMOUNT-1 trial.

The objective of the SURMOUNT-1 3-year trial was to evaluate the impact of tirzepatide on change in body weight and glycemia in participants with prediabetes and whether the drug prevented progression to type 2 diabetes.

“Here in the U.S., according to the CDC, approximately 40 million Americans live with diabetes,” Perreault said during a presentation. “The epidemic in diabetes, whether here in the U.S. or abroad, is clearly being driven in large part by prediabetes.”

Louis J. Aronne, MD, FACP, FTOS, DANOM, the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medical College, discussed the baseline characteristics of the 1,032 SURMOUNT-1 3-year participants, all of whom were diagnosed with prediabetes upon trial enrollment (mean age, 48 years; 64% women; 73.4% white).

Aronne said all participants also had obesity or overweight with one additional weight-related comorbidity. Diagnosis of prediabetes was defined by the American Diabetes Associations cutoffs and required at least two abnormal tests, according to the presentation.

The trial consisted of a 20-week dose-escalation period. Participants with prediabetes who remained on tirzepatide during the first 72 weeks underwent a further 104-week treatment period on tirzepatide 5 mg, 10 mg or 15 mg for a total treatment period of 176 weeks, after which participants were followed up 17 more weeks off-treatment to assess safety for the totality of trial duration, according to the presentation.

Ania M. Jastreboff, MD, PhD, associate professor of medicine and pediatrics at Yale School of Medicine, director of the Yale Obesity Research Center and co-director of the Yale Center for Weight Management, presented the main efficacy data on tirzepatide for weight loss at 3 years.

Key endpoints included mean percentage change in body weight from randomization to week 176 and time to type 2 diabetes onset at week 176 — during treatment period — and week 193 — during posttreatment follow-up.

Among the original SURMOUNT-1 cohort of 2,539 participants, 40.6% had prediabetes at randomization and were eligible to continue into the SURMOUNT-1 3-year trial.

Jastreboff reported that the average 3-year weight reduction with tirzepatide 15 mg was approximately 22.9%, translating to an average weight reduction of 34.6 lb to 54.2 lb, depending on the dose of tirzepatide (based on a baseline weight of 236.8 lb).

During 3 years of follow-up, 12.6% of participants assigned to placebo developed type 2 diabetes compared with 1.2% of participants assigned to tirzepatide, which correlated to an HR for diabetes of 0.06 (P < .001), or a 94% reduction in risk for developing diabetes among patients with prediabetes taking tirzepatide. The reported number of SURMOUNT-1 participants needed to treat to prevent one new case of diabetes was nine, according to the presentation.

During the on-drug treatment period, up to 94.5% of participants assigned to tirzepatide had reversion to normoglycemia compared with 60.4% of those assigned to placebo and lifestyle intervention.

Jastreboff and colleagues estimated that approximately 55.2% of diabetes risk reduction was mediated by the weight-loss effects of tirzepatide.

In addition, participants assigned to tirzepatide 15 mg long term also experienced:

Upon treatment discontinuation after 176 weeks on tirzepatide, the researchers reported reversals toward baseline in weight, type 2 diabetes risk and blood pressure during the ensuing 17-week off-drug period.

“Treatment with all three doses of tirzepatide demonstrated statistically significant and sustained body weight reduction compared with placebo over more than 3 years,” Jastreboff said during the presentation. “Diabetes prevention with tirzepatide over 3 years resulted in a 94% reduction in progression to diabetes ... and nearly 95% reverted from prediabetes to normoglycemia. There was improvement in all cardiometabolic measures. Improvements in all domains of health-related quality of life. Off-drug weight regain was observed and was accompanied by worsening glycemia and increase in progression to type 2 diabetes.”

Sean Wharton, MD, FRCPC, PharmD, medical director of the Wharton Medical Clinic, adjunct professor at McMaster University in Hamilton, Ontario, and York University in Toronto, academic staff at Women’s College Hospital and clinical staff at Hamilton Health Sciences, presented the main safety results of the 3-year trial.

Wharton reported no significant difference between placebo and any of the tirzepatide doses in mortality rate; however, early discontinuation due to treatment-emergent adverse events was higher among those assigned to tirzepatide compared with placebo.

The most common adverse events reported were gastrointestinal (GI)-related, and those reported were of generally mild to moderate severity. The most common GI-related events included were diarrhea, nausea, constipation and vomiting.

Cholelithiasis was also more frequently observed in the tirzepatide group compared with placebo, a finding consistent with prior studies.

These results were consistent with previously published safety and tolerability of tirzepatide at 72 weeks in SURMOUNT-I and other clinical studies of tirzepatide, according to the presentation.

“The tolerability and safety profile of tirzepatide in this study of 3 years and 9 months duration was generally consistent with incretin-based therapies in people with obesity. The most common adverse events were GI symptoms, generally mind to moderate in severity, occurring primarily during dose escalation. Among adverse events, the most common reasons for discontinuation of the medication were GI adverse events. Gallbladder disease events were reported more frequently in participants from the tirzepatide 10 mg and 15 mg groups compared to the placebo. The finding was mainly due to the increased incidence of cholelithiasis.”

After the presentation of the SURMOUNT-1 3-year safety results, Carel Le Roux, MBChB, MSC, FRCP, FRCPath, PhD, director of the metabolic medicine group at the University College Dublin, summarized the trial as a way to “shift focus from weight loss to health gain.”

“In people with obesity with prediabetes treatment of the disease of obesity, treatment could achieve control of the disease, but not cure. Metabolic complications of obesity got better and stayed better. Functional complications of obesity got better and stayed better. Mental complications of obesity got better but may return close to baseline. Uncertainty remains regarding what happened with appetitive behavior,” Le Roux said. “We can now shift the focus away from weight loss to health gain. When treating patients with prediabetes and obesity we can realize substantial health and functional goals.”

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Perreault L, et al. SURMOUNT-1 three-year outcomes: Clinical trials orals session. Presented at: ObesityWeek; Nov. 3-6, 2024; San Antonio.