Semaglutide, also known by its brand names Ozempic and Wegovy, marks a new era in anti-obesity therapeutics. The unprecedented drug offers a safe and effective option for patients that addresses the root of obesity. But this is only the beginning. More novel medications are coming down the pipeline that will further revolutionize obesity medicine, with much of the cutting-edge work being led at Yale with three simultaneous publications in the New England Journal of Medicine and Lancet in June.
We are truly transforming the way we can care for our patients with obesity now and going forward with these emerging new pharmacotherapeutics.
Ania Jastreboff, MD, PhD
The United States and countries around the world are facing a skyrocketing obesity epidemic, but until recently, clinicians had few effective therapies to offer patients. Now, numerous clinical trials are exploring new pharmacotherapies that target the mechanisms underlying the disease. Among the drugs researchers are evaluating are retatrutide and tirzepatide [Mounjaro] (the latter, FDA-approved for type 2 diabetes), which are weekly injectable medications that clinical trials are showing to be highly effective in treating obesity and type 2 diabetes. While not yet FDA-approved for chronic weight management, they show promise to eventually outshine the current drugs dominating the market.
“It’s an exciting time to lead research in the rapidly evolving landscape of anti-obesity pharmacotherapeutics,” says Ania Jastreboff, MD, PhD, associate professor of medicine (endocrinology) and of pediatrics (pediatric endocrinology), director of the Yale Obesity Research Center (Y-Weight) and co-director of the Yale Center for Weight Management, and a leader in studying this new class of therapeutics. “We are truly transforming the way we can care for our patients with obesity now and going forward with these emerging new pharmacotherapeutics.”
Obesity is a chronic neurometabolic disease that impacts nearly half of Americans. And by 2035, researchers estimate that the disease will affect nearly a quarter of the world’s population. Because obesity is associated with as many as 200 weight-related diseases, developing highly effective and safe interventions that address the underlying causes of disease is critical.
The body has evolved a beautiful, intricate system in which hormones send signals to the brain about the body’s energy state. However, drivers of obesity—including highly processed foods, increased stress, lack of physical activity, and decreased sleep—can pathologically alter this system and make it extremely difficult to lose weight. The goal of the new nutrient-stimulated hormone-based medications, such as semaglutide and tirzepatide, that Jastreboff and colleagues are evaluating is to safely and effectively treat obesity by reregulating this system.
Retatrutide Is Highly Effective in Treating Obesity
Retatrutide is a novel triple-hormone-receptor agonist that targets three nutrient-stimulated hormone receptors—glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon (GCG). The recent phase 2 clinical trial led by Jastreboff and published in the New England Journal of Medicine on June 26 evaluated the efficacy and safety of this molecule. The trial enrolled 338 patients who were randomized to receive a weekly injection of retatrutide or a placebo for 48 weeks. Of those in the experimental group, participants received varying dosages ranging from 1 mg to 12 mg.
The results were substantial. Participants who received the highest dose of retatrutide on average lost nearly a quarter of their baseline body weight (24.2%) over the 11 months of the trial—on average, 58 pounds. Furthermore, all participants receiving an 8 mg or 12 mg dose met their weight reduction target of greater than or equal to 5% of body weight. This number matters because the U.S. Food and Drug Administration (FDA) has deemed the 5% threshold to be clinically significant—in other words, this degree of weight reduction is linked to metabolic and other health benefits.
The trial also explored how baseline characteristics of patients may predict how well they will respond to the medication. The team studied baseline body mass index (BMI) and sex. They found that participants who had a baseline BMI greater than or equal to 35 lost more weight than participants with a lower BMI. “We found that individuals with more severe obesity lost a greater percent of their body weight than those with less severe obesity,” says Jastreboff.
The team also found that on average, women lost a greater percent of their body weight than men. “These findings need to be explored further to understand why this is occurring, to elucidate the underlying mechanisms,” says Jastreboff.
In terms of safety and tolerability, the study identified the most common side effects as gastrointestinal. They were mild to moderate in severity and occurred mostly during dose escalation.
Overall, Jastreboff says the results support moving retatrutide to phase 3 trials, which are the clinical trials required by the FDA to determine safety and efficacy and regularly enable decisions about drug approvals.
Retatrutide Is Effective for Type 2 Diabetes Management
Jastreboff also co-authored a clinical trial published in the Lancet on June 26 studying retatrutide for type 2 diabetes management. The trial was conducted over 36 weeks and included 281 participants. One way researchers can evaluate a patient’s glycemic control is through a hemoglobin A1C (HbA1C) test, which provides an average of the individual’s blood sugar levels over three months.
After 36 weeks, the average HbA1C reduction across patients receiving the highest dose of the drug was 2.16%. Furthermore, patients receiving the highest dose saw an average weight reduction of 16.9%.
On average, participants with type 2 diabetes in this trial lost less weight on retatrutide than participants in the obesity clinical trial. There are several reasons for this, Jastreboff explains. First, prior research has shown that individuals with type 2 diabetes generally lose less weight than those with obesity alone. Furthermore, the length of the trial was shorter than the obesity trial. But for both of the trials, the weight reduction curve had yet to plateau. “Participants were still losing weight at the time the study drug was stopped,” says Jastreboff. “Had the study drug been continued, we would anticipate that the participants would have continued losing weight in both trials.”
Tirzepatide Trials Show Promise for Obesity and Type 2 Diabetes Management
In 2022, Jastreboff was lead author of a phase 3 clinical trial published in the New England Journal of Medicine called SURMOUNT-1, a 72 week-long study that included over 2,000 participants with obesity investigating the efficacy and safety of tirzepatide, a novel GIP/GLP-1 receptor agonist. The team found that individuals treated with 15 mg of tirzepatide lost 22.5% of their body weight.
A year later, Jastreboff co-authored the SURMOUNT-2 phase 3 trial, which included 938 patients with type 2 diabetes and was published in the Lancet on June 26 of this year. In this randomized study, participants either received 15 mg of tirzepatide, 10 mg of tirzepatide, or a placebo. Over 72 weeks, the researchers saw an average weight loss of 15.7% and an average HbA1C reduction of about 2%. Approximately half of the participants lost more than 15% of their total body weight.
Looking to the Future of Obesity Management
Retatrutide is now moving into phase 3 clinical trials. Tirzepatide is further along; with the completion of the phase 3 SURMOUNT-2 trial, it is now undergoing FDA regulatory review for a chronic weight management (obesity) indication.
Retatrutide and tirzepatide are just two of the many agents in development for the treatment of obesity. Researchers are investigating numerous combinations of nutrient-stimulated hormone-based injectable medications. They are also testing oral formulations of this class of drugs, including higher doses of oral semaglutide, an oral formulation of the peptide which recently completed phase 3 obesity trials, as well as small molecule (non-peptide) GLP-1 receptor agonists such as orforglipron, which recently completed phase 2 and is moving into phase 3 trials. Oral formulations of these medications may provide options for patients who prefer pills to injections, which could improve accessibility.
Because obesity is a complex disease with different pathophysiological mechanisms, having numerous tools in the arsenal will be essential for overcoming the epidemic. “For various chronic diseases, such as type 2 diabetes, we have many different classes of medications, and several medications within each class,” says Jastreboff. “That’s what we need for our patients with obesity. We need a diverse set of tools to enable us to individualize and optimize obesity care and provide our patients with treatment options which best meet their health goals.”