Tirzepatide Provides 'Meaningful' Weight Loss in SURMOUNT-3

In the phase 3 SURMOUNT-3 trial, tirzepatide (Mounjaro) demonstrated clinically meaningful added weight loss in adults with obesity without diabetes who already had at least 5% weight loss after a 12-week intensive lifestyle intervention, researchers report.

The full trial results were reported in a packed, large ballroom at ObesityWeek, and the study was simultaneously published in Nature Medicine on October 15.

Topline findings on this dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide 1 (GLP-1) receptor agonist were reported in July, building on earlier results reported from SURMOUNT-1 and SURMOUNT-2. The full results of SURMOUNT-4 were just presented at the European Association for the Study of Diabetes (EASD) meeting.

Tirzepatide has been approved by the US Food and Drug Administration for glycemic control since May 2022, based on the SURPASS trial program.

The company anticipates a decision about tirzepatide for chronic weight management, based on the SURMOUNT trials, by the end of this year.

'Similar to Weight Loss With Bariatric Surgery'

In SURMOUNT-3, the "20% weight loss attained with 72 weeks of tirzepatide following 12 weeks of a successful intensive lifestyle program is similar to weight loss attained with bariatric surgery," lead author Thomas A. Wadden, PhD, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, told Medscape in an email.

"Tirzepatide (15 mg) reliably induces a mean reduction in body weight of 20%, which is equal to 50 pounds in a patient who weighs 250 pounds," he added.

This "provides much better control of sleep apnea, osteoarthritis, nonalcoholic steatohepatitis (NASH), type 2 diabetes, and other obesity-related complications that are only marginally improved with a traditional 5-10% weight loss," he added, and "patients will also have greater improvements in mobility, energy level, and daily physical function."

"Medications like tirzepatide — and others potentially to follow — could provide an alternative to metabolic and bariatric surgery, which is clearly the most effective treatment we now have for managing obesity and its complications," Wadden speculates.

More Tools for the Toolbox

Before the presentation, two spokespeople from The Obesity Society (TOS) who were not involved with the trials weighed in.

Always having a larger armamentarium to treat patients who have obesity is a good thing, because some may respond poorly to a particular medication, Ivania Rizo, MD, director of obesity medicine, Boston Medical Center, Massachusetts commented.

"Obesity is a disease with much heterogeneity, so because of that, it's positive that we have more tools in the toolbox," Amanda Velazquez, MD, director of obesity medicine, Cedars-Sinai, Los Angeles, California, echoed. "With dual agonists, we see patients who are telling us that they feel greater satiety"; there is "less food noise."

Tirzepatide is so effective "that you can see the pendulum swing where people are now potentially not getting enough nutrition. We are actually having conversations with patients" stressing their need to eat more, nourish more, and make sure to get all their macronutrients, especially protein and water intake, she said.

Trial Rationale, Results, and Implications

Presenting the study, co-author Sriram Machineni, MD, noted that "expert panels have suggested the use of antiobesity medications after patients lose weight with intensive lifestyle intervention to induce additional weight reduction or the prevent weight regain."

The study was therefore designed with this treatment sequence, said Machineni, from Albert Einstein College of Medicine, New York.

Ania Jastreboff, MD, PhD, who is not a study author, explained that SURMOUNT-3 enrolled 806 individuals with either obesity (BMI ≥ 30) or overweight (BMI ≥ 27) and at least one weight-related comorbidity — hypertension, dyslipidemia, sleep apnea, or cardiovascular disease — but without diabetes.

The patients received 12 weeks of an intensive lifestyle intervention, said Jastreboff, who is associate professor at Yale University, New Haven, Connecticut. The intervention consisted of eight counseling sessions about diet (aiming for 1200 kcal/d for women or 1500 kcal/d for men) and exercise (aiming for 150 minutes of moderate exercise a week) plus behavior modification strategies.

Following this, the 579 individuals who achieved ≥ 5% weight reduction were randomized in a 1:1 ratio to receive tirzepatide (escalated every 4 weeks, from 2.5 mg/wk to a maximum tolerated dose of 10 or 15 mg/wk) or placebo for the following 72 weeks.

Co-author Ariana M. Chao, PhD, CRNP, reported that the co-primary endpoint of greater percent change in weight from randomization to 72 weeks was met (a loss of 18.4% with tirzepatide vs a gain of 2.5% with placebo; treatment difference, -20.9%; P < .001).

The other co-primary endpoint, the percentage of participants achieving additional weight reduction ≥ 5%, was also met (87.5% of patients receiving tirzepatide vs 16.5% of patients receiving placebo; P < .001), said Chao, from Johns Hopkins School of Nursing, Baltimore, Maryland.

In addition, tirzepatide led to improvements in cardiometabolic risk factors and health-related quality of life, including waist circumference, systolic and diastolic blood pressure, lipids, A1c, fasting glucose, fasting insulin, and patient-reported physical functioning.

Co-author and TOS president-elect Jamy D. Ard, MD, reported that the safety profile of tirzepatide in SURMOUNT-3 was consistent with that of GLP-1 receptor agonists.

Adverse events were mostly mild to moderate gastrointestinal events, occurring primarily during dose escalation, said Ard, from Wake Forest University School of Medicine, Winston-Salem, North Carolina.

"Given the more effective biologic impact of incretin-based medications on appetite," said co-author Robert Kushner, MD, "this presents an opportunity [for clinicians] to reexamine the purpose, components, and implementation of lifestyle counseling in patients who are using pharmacological management."

There is a need for "more focus on health outcomes versus weight loss, more emphasis on dietary protein and healthy eating patterns," said Kushner, from Northwestern University, Chicago.

'Shift from Weight Loss to Health Improvement'

Ard invited the speakers to summarize how the data will change or reaffirm their clinical practice.

Chao said that these are "really exciting times," as clinicians figure out what will work best for a particular patient, taking into account patient preference, such as "whether the patient wants to start with intensive lifestyle intervention and then consider medication."

In reply to a question from the audience, Ard said that historically, patients needed to first try lifestyle intervention and then fail. "This [study] says you don't have to fail lifestyle intervention before taking anti-obesity medication."

The study was funded by Eli Lilly. The author disclosures are listed with the article. Jastreboff is on an advisory board for Eli Lilly and has relationships with multiple other pharmaceutical companies.

Nat Med. Published online October 15, 2023. Full text

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