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Obesity Medications Semaglutide, Tirzepatide, and Retatrutide: New Data and Concerns


By Pan-American Life Insurance Group

Key Points

  • Semaglutide and tirzepatide are hormone-mimicking drugs originally used to treat diabetes.
  • There are questions about the sustainability of weight loss.
  • And potential health consequences.

Medications to treat obesity have been at the front and center of medical discussions ever since new drugs appeared on the market, full of promise and questions. Some of these medications, along with new research results on them, were presented at the recent ObesityWeek conference, held in Dallas, Texas in October. Specialists’ data and opinions were compiled in an article that appeared in the December edition of JAMA Network.

Discussions centered on semaglutide, the GLP-1 receptor agonist for chronic weight management marketed as Wegovy, and tirzepatide, a glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist.  Tirzepatide, whose brand name is Zepbound, was approved by the US Food and Drug Administration (FDA) on November 8.

Semaglutide and tirzepatide are drugs that mimic hormones that were originally approved as diabetes therapies under the names Ozempic and Mounjaro, respectively.

John Michael Taormina, MD, assistant professor at the University of Colorado School of Medicine, stressed one of the most critical aspects of this discussion: “ In the era of highly effective drugs for weight management, the role for intensive diet and exercise changes and frequent behavioral counseling may be less clear.”

In this vein, researchers presented the results of the SURMOUNT-3 trial, which was designed to look at the efficacy of adding tirzepatide after intensive lifestyle intervention that included a low-calorie diet, 2.5 or more hours of physical activity per week, and regular behavioral therapy.

According to the study authors, although intensive lifestyle intervention is a “cornerstone of obesity management,” its general efficacy is limited because only a minority of people achieve significant weight loss, and regaining weight is common. In the SURMOUNT-3 trial, 600 participants who had already lost an average of 5% of their body weight as part of a 3-month intensive lifestyle intervention were randomized to two groups, with one receiving tirzepatide and the other placebo.  Their baseline body mass index (BMI) before the lifestyle intervention was 30 or greater, or 27 or greater with at least one obesity-related complication besides diabetes.

After 72 weeks, people who received tirzepatide in doses of 10 mg or 15 mg lost an additional 18% of their body weight on average, whereas people who received a placebo regained 2.5% of their body weight.

Tirzepatide’s efficacy was clear, but questions remain about how much exercise or calorie restriction is necessary with new anti-obesity medications, said Taormina, who treats patients with obesity at the University of Colorado Anschutz Weight Management and Wellness Clinic.

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In the trial that followed, SURMOUNT-4, people who received tirzepatide for 88 weeks lost 26% of their body weight without any intensive lifestyle intervention. These results were presented this October at the European Association for the Study of Diabetes meeting. 

Although trials continue to analyze how these new medications interact with other interventions, there are still other questions to be answered, such as: do patients who take these medications lose healthy lean body mass? Do they develop nutritional deficiencies? What are the results of these new drugs based on the person’s age and whether they have preexisting conditions?

Another concern is weight cycling with the drugs, said Taormina. In this scenario, people who have lost significant weight stop taking the medications, regain weight primarily as fat (increasing their total fat percentage), and “subsequently may have greater challenges losing weight with future attempts,” he explained.

Another ObesityWeek talk, led by Dr. Jacinda Nicklas, was on the use of these medications by sex. In-depth analysis of data from the semaglutide STEP trials revealed that women had greater weight reduction than men. This was also seen in a phase 2 retatrutide trial on the treatment of obesity without type 2 diabetes. Participants who received the highest dose lost an average of 24% of their body weight, but women lost much more—around 29%—than men, who lost approximately 20%.

Doctors said that the conference, instead of providing definitive answers, demonstrated that specialists are anxious for more data on the new generation of anti-obesity medications and from current weight assessment tools beyond BMI, a controversial stand-alone obesity measurement. 

Taormina said that body composition measurements such as waist circumference or dual-energy x-ray absorptiometry (DXA) scans, should be included in clinical trials of new drugs, but also should be available and affordable for people currently undergoing obesity treatment.

This story was produced using content from original studies or reports, as well as other medical research and health and public health sources cited in links throughout the article.