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DALLAS -- People who started taking a dual GLP-1/GIP receptor agonist after losing at least 5% of weight through intensive lifestyle intervention shed an additional 18.4% with the drug, the phase III SURMOUNT-3 trial found.

Combined with an average 2.5% increase in the placebo group following the diet and exercise intervention, participants on tirzepatide (Mounjaro) shed 20.8% more of their body weight (95% CI -23.2 to -18.5) over 72 weeks, Ariana Chao, PhD, RN, of Johns Hopkins University School of Nursing in Baltimore, and coinvestigators reported at the ObesityWeek annual meeting.

This represented an additional 21.5 kg (47.4 lb) loss for tirzepatide participants compared with a 3.5 kg (7.7 lb) gain in the placebo group.

In total, the 12-week intensive lifestyle intervention followed by 72 weeks of tirzepatide led to a total loss of 26.6% of body weight compared with a loss of 3.8% with intensive lifestyle intervention followed by placebo (estimated treatment difference -22.8%, 95% CI -24.3 to -21.2).

"What this means essentially is that participants were able to move from a class II obesity status down two levels to an overweight obesity status at the end of the trial with tirzepatide," Chao said.

Findings from the phase III trial were simultaneously published in .

Substantially more patients on tirzepatide also achieved body weight reductions of 10% or more (76.7% vs 8.9%), 15% or more (65.4% vs 4.2%) and 20% or more (44.7% vs 2.2%). BMI dropped an average of 7.7 points with tirzepatide versus a 1.2-point rise with placebo.

This cohort only included a subset of participants (579 of 972) who were deemed responders to an intensive lifestyle intervention phase directly prior to randomization, losing 5% or more of their body weight with diet, exercise, and behavioral counseling. On average, participants lost 6.9% of body weight (7.6 kg, or 16.8 lb) during this lead-in period.

"We have to be very clear here -- these are people who are already responding," said study co-author Sriram Machineni, MD, of Albert Einstein College of Medicine in New York City. "Is there a point of adding a medication after they respond? Absolutely ... But if they fail, it's a really good reason for putting them on medication, because there's nothing else that will help them."

But it's not necessary to involve a pre-period of intensive lifestyle intervention in order to set patients up for success, argued co-author Robert Kushner, MD, of Northwestern University Feinberg School of Medicine in Chicago.

"The data suggests that yes, you do lose more weight with lifestyle modification, but it's not as necessary as with the first [generation of] medications," he explained. "I hope that will allow obesity care to be provided at the primary care level without that need that I have to have a dietitian on staff, the frequency of visits every week, and so forth."

Kushner added that this particular trial design -- only including responders to intensive lifestyle intervention -- is probably why there was more weight loss seen here than in the first trial in the clinical program. SURMOUNT-1 participants on the 15-mg injectable experienced a 17.8% difference in weight loss compared with the placebo group over 72 weeks. Following this, the SURMOUNT-2 results reported a 12.4% difference in body weight loss with the 15-mg dose versus placebo in people with obesity who had type 2 diabetes.

Drugmaker Eli Lilly already submitted findings from the SURMOUNT clinical program to the FDA in hopes of an obesity indication, and that decision is expected by the end of 2023. Two further installments in the trial series focusing on 88-week weight maintenance results and a head-to-head comparison with semaglutide 2.4 mg (Wegovy) have yet to be published.

As for SURMOUNT-3, most of the participants in the study were female (62.9%), their average age was 46, and 86% were white. All had a BMI of at least 30, or at least 27 along with one or more weight-related comorbidities, plus at least one unsuccessful attempt at weight loss through diet.

After the lead-in lifestyle intervention period, 287 participants were randomized to tirzepatide. The starting dose was 2.5 mg, which increased by 2.5 mg every 4 weeks until a maximum dose of 10 or 15 mg was reached.

During this tirzepatide dose-escalation phase was when gastrointestinal side effects occurred more frequently. As expected with an agent containing a GLP-1 receptor agonist, the most common adverse events were gastrointestinal: nausea (39.7% vs 14%), diarrhea (31% vs 9.2%), and constipation (23% vs 6.8%). Nearly 11% of tirzepatide-treated participants discontinued treatment due to adverse events, compared with 2.1% of placebo-group participants.

Benefits beyond just weight reduction were noted as well. Significantly more participants on tirzepatide than placebo saw improvements in the following cardiometabolic parameters and physical functioning scores:

• SF-36v2 physical functioning: 3.3 with tirzepatide vs -0.6 with placebo
• Waist circumference: -14.6 vs 0.2 cm
• Systolic blood pressure: -5.1 vs 4.1 mm Hg
• Total cholesterol: -0.3 vs 5.2 mmol/L
• Triglycerides: -25.8 vs 3.0 mmol/L
• Fasting glucose: -8.8 vs 2.4 mg/dL
• HbA1c: -0.5% vs 0% change with placebo

Of note, diabetes was a key exclusion criterion. Tirzepatide is already FDA-approved for type 2 diabetes, based on the SURPASS clinical program.

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