Dual incretin agonism ‘enhances activity,’ says expert
Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.
Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.
Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.
The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.
“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.
Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked.
Weight-loss agents gain U.S. traction
There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.
His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.
With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels, an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.
“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.
SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m2 or more, or 27 kg/m2 or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.
The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.
The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively
The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”
Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”
Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.
SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.
A version of this article first appeared on Medscape.com.