Tirzepatide Shows Powerful Diabetes Prevention Effect in Three Year Trial

Tirzepatide, a new injectable weight-loss drug with the trade name Zepbound, reduced the risk of diabetes in patients with obesity and prediabetes by more than 90% over a three-year period, compared with placebo, according to the results of a new study led by investigators at Weill Cornell Medicine, NewYork-Presbyterian, Yale School of Medicine and other institutions.

The study, published Nov. 13 in the New England Journal of Medicine, was a continuation of one of the first Eli Lilly-sponsored tirzepatide trials, the 72-week SURMOUNT-1 trial, which supported the FDA approval of the injectable drug for diabetes, and later, obesity. The new results show that after 176 weeks of treatment, only 1.3% of patients who were both obese and prediabetic, and who took the drug in any of three doses, progressed to type 2 diabetes, compared with 13.3% of patients taking a placebo.

"These results show that type 2 diabetes may be prevented, even in people who are on the verge of it, by using a medicine that causes weight loss," said study co-author Dr. Louis Aronne, the Sanford I. Weill Professor of Metabolic Research and director of the Comprehensive Weight Control Center, which is part of the Division of Endocrinology, Diabetes, and Metabolism at Weill Cornell Medicine.

A subset of the study's patients were treated at Weill Cornell Medicine, where Dr. Aronne and colleagues have worked for decades to advance the concept of obesity-the major cause of type 2 diabetes-as a treatable disease.

Tirzepatide belongs to a broad new class of drugs that simulate nutrient-stimulated hormones, helping patients lose significant weight and improve their blood sugar control. The drugs work, at least in part, by activating one or multiple receptors throughout the body, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors on cells in the brain, pancreas and elsewhere. Tirzepatide activates both GLP-1 and GIP, leading to greater weight loss and fewer side effects than older GLP-1 alone compounds. The drug's overall effect is to promote a feeling of fullness or "satiety," which reduces the desire for food and to boost insulin secretion, which reduces glucose levels in the blood.

The SURMOUNT-1 trial initially found that patients with obesity taking tirzepatide for 72 weeks lost 15% to 22.5% of their initial weight, on average, depending on the dose, and also saw a significant average reduction in their levels of glycated hemoglobin, known as A1c levels, a standard measure of blood sugar control. The new study focused on 1,032 of these patients who initially had obesity and prediabetes-a diabetes precursor condition in which A1c levels are above normal but below the threshold for diabetes.

The study found that after 176 weeks, only 10 tirzepatide-treated patients progressed to diabetes, representing a roughly 93% reduction in risk compared to the placebo group. More than 90% of the patients on tirzepatide had normal A1c levels at 176 weeks, versus 59% of placebo-treated patients.

The trial uncovered no new safety issues; the most common gastrointestinal side effects such as nausea and vomiting decreased as the trial went on, suggesting that long-term use of tirzepatide is relatively tolerable. A follow-up analysis, 17 weeks after stopping treatment, found modest gains in weight and A1c levels, bringing some patients back into the prediabetes and diabetes ranges, and underscoring the likely need for chronic treatment.

The results point to the possibility that the drug someday could become the first approved treatment for prediabetes, said Dr. Aronne, who is also an internist specializing in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Center.

"Think about the impact these types of weight-loss drugs can have in preventing not only diabetes but also many other common diabetes-related complications such as heart disease, liver and kidney disease, sleep apnea, arthritis, and more," he said. Over time, the treatment of obesity may become a first line treatment, and more common than treating high blood pressure or cholesterol.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. Dr. Louis J. Aronne serves as a paid advisor for Eli Lilly and Company. For further information, see the profile for Dr. Louis Aronne.

- Courtesy of Weill Cornell Medicine's newsroom

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