'Game Changer' Semaglutide Halves Diabetes Risk From Obesity

Mitchel L. Zoler, PhD

September 19, 2022

Treatment of people with obesity but without diabetes with the glucagon-like peptide-1 (GLP-1) agonist semaglutide (Wegovy) — hailed at its approval in 2021 as a "game changer" for the treatment of obesity — led to beneficial changes in body mass index (BMI), glycemic control, and other clinical measures.

This collectively cut the calculated risk for possible future development of type 2 diabetes in study participants by more than half, based on post-hoc analysis of data from two pivotal trials that compared semaglutide with placebo.

The findings "suggest that semaglutide could help prevent type 2 diabetes in people with overweight or obesity," said W. Timothy Garvey, MD, in a presentation at the European Association for the Study of Diabetes 2022 Annual Meeting.

Asked to comment, Rodolfo J. Galindo, MD, said: "We devote a significant amount of effort to treating people with diabetes, but very little effort for diabetes prevention. We hope that further scientific findings showing the benefits of weight loss, as illustrated by Garvey [and colleagues] for diabetes prevention, will change the pandemic of adiposity-based chronic disease."

GLP-1 Agonists as Complication-Reducing Agents

Finding a link between treatment with semaglutide and a reduced future risk of developing type 2 diabetes is important because it shows that this regimen is not just a body mass index (BMI)-centric approach to treating people with obesity, but is also a way to potentially reduce complications of obesity such as diabetes onset, explained Garvey, a professor and director of the Diabetes Research Center at the University of Alabama at Birmingham.

Recent obesity-management recommendations have focused on interventions aimed at avoiding complications, as in 2016 guidelines from the American Association of Clinical Endocrinologists and the American College of Endocrinology, he noted.

Having evidence that treatment with a GLP-1 agonist such as semaglutide can reduce the incidence of diabetes in people with obesity might also help convince payers to more uniformly reimburse for this type of obesity intervention, which up to now has commonly faced coverage limitations, especially in the United States, he said in an interview.

Garvey added that evidence for a reduction in the incidence of cardiovascular disease complications such as myocardial infarction and stroke may need to join diabetes prevention as proven effects from obesity intervention before coverage decisions change.

He cited the SELECT trial that is testing the hypothesis that semaglutide treatment of people with overweight or obesity can reduce the incidence of cardiovascular events in about 17,500 participants and with expected completion toward the end of 2023.

"A complication-centric approach to management of people with obesity needs prediction tools that allow a focus on prevention strategies for people with obesity who are at increased risk of developing diabetes," commented Galindo, an endocrinologist at Emory University in Atlanta, Georgia, in an interview.

Combined Analysis of STEP 1 and STEP Data

The analysis conducted by Garvey and colleagues used data from the STEP 1 trial, which compared semaglutide 2.4 mg subcutaneous once weekly with placebo for weight loss in more than 1500 people predominantly with obesity (about 6% were overweight) and showed that after 68 weeks semaglutide cut the calculated risk of developing type 2 diabetes over the subsequent 10 years from 18% at baseline to 7%, compared with a drop from 18% at baseline to 16% among those who received placebo.

A second, similar analysis of data from people predominantly with obesity in the STEP 4 trial — which treated around 800 people with semaglutide 2.4 mg for 20 weeks and then randomized them to placebo or continued semaglutide treatment — showed that semaglutide treatment cut their calculated 10-year risk for incident type 2 diabetes from 20% at baseline to about 11% after 20 weeks. The risk rebounded in the study participants who then switched from semaglutide to placebo. Among those randomized to remain on semaglutide for a total of 68 weeks, the 10-year risk fell further to 8%.

Garvey and associates used a validated prognostic formula, the cardiometabolic disease staging (CMDS) tool, they had previously developed and reported to calculate 10-year risk for development of type 2 diabetes based on three unmodifiable factors (age, sex, and race) and five modifiable factors (BMI, blood pressure, glucose level, high-density lipoprotein (HDL) cholesterol, and triglycerides). They applied the analysis to data from 1561 of the STEP 1 participants and 766 participants in the STEP 4 study.

"There is no better tool I know of to predict diabetes incidence," commented Michael A. Nauck, MD, professor and chief of clinical research, diabetes division, St. Josef Hospital in Bochum, Germany.

In his opinion, the CMDS tool is appropriate for estimating the risk of developing incident type 2 diabetes in populations but not in specific individuals.

The new analyses also showed that, in STEP 1, the impact of semaglutide on reducing future risk of developing type 2 diabetes was roughly the same regardless of whether participants entered the study with prediabetes or were normoglycemic at entry.

Blood Glucose Changes Confer the Biggest Effect

The biggest contributor among the five modifiable components of the CMDS tool for altering the predicted risk for incident diabetes was the reduction in blood glucose produced by semaglutide treatment, which influenced just under half of the change in predicted risk, Garvey said. The four other modifiable components had roughly similar individual effects on predicted risk, with change in BMI influencing about 15% of the observed effect.

"Our analysis shows that semaglutide treatment is preventing diabetes via several mechanisms. It's not just a reduction in glucose," Garvey said.

Nauck cautioned, however, that it is hard to judge the efficacy of an intervention like semaglutide for preventing incident diabetes when one of its effects is to dampen down hyperglycemia, the signal indicator of diabetes onset.

Indeed, semaglutide was first approved as a treatment for type 2 diabetes (known as Ozempic, Novo Nordisk) at slightly lower doses than it is approved for obesity. It is also available as an oral agent to treat diabetes (Rybelsus).  

Nauck also noted that the results from at least one previously reported study had already shown the same relationship between treatment with the GLP-1 agonist liraglutide as an anti-obesity agent (3.0 mg dose daily, known as Saxenda) and a reduced subsequent incidence of type 2 diabetes, but using actual clinical outcomes during 3 years of follow-up rather than a calculated projection of diabetes likelihood.

The SCALE Obesity and Prediabetes trial randomized 2254 people with prediabetes and overweight or obesity to weekly treatment with 3.0 mg of liraglutide or placebo. After 160 weeks on treatment, the cumulative incidence of type 2 diabetes was 2% in those who received liraglutide and 6% among those on placebo, with a significant hazard ratio reduction of 79% in the incidence of diabetes on liraglutide treatment.

The STEP 1 and STEP 4 trials were sponsored by Novo Nordisk, the company that markets semaglutide (Wegovy). Garvey has reported serving as an advisor without compensation to Novo Nordisk as well as Boehringer Ingelheim, Eli Lilly, Jazz, and Pfizer. He is also a site principal investigator for multicentered clinical trials sponsored by the University of Alabama at Birmingham and funded by Novo Nordisk, Eli Lilly, Epitomee, and Pfizer. Galindo has reported being a consultant or advisor for Boehringer Ingelheim, Eli Lilly, Pfizer, Sanofi, and Weight Watchers, and receiving research funding from Dexcom, Eli Lilly, and Novo Nordisk. Nauck has reported being an advisor or consultant to Novo Nordisk as well as to Boehringer Ingelheim, Eli Lilly, Menarini/Berlin Chemie, MSD, Regor, and ShouTi/Gasherbrum, receiving research funding from MSD, being a member of a data monitoring and safety board for Inventiva, and being a speaker on behalf of Novo Nordisk as well as for Eli Lilly, Menarini/Berlin Chemie, MSD, and Sun Pharmaceuticals.

EASD 2022. Abstract #562. Presented September 21, 2022.

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