In 2021, a landmark trial conducted at Northwestern Medicine found that the antidiabetic drug semaglutide was twice as effective in helping individuals lose weight than other weight-loss drugs on the market. Soon after the publication of these results, the drug — currently sold under the brand names Ozempic, Rybelsus and Wegovy — received the FDA’s approval for chronic weight management.
Two years later, Northwestern Medicine scientists remain at the forefront of investigating the drug’s potential in helping patients who are overweight or have obesity who also have other preexisting health conditions.
Reducing Risk of Secondary Cardiovascular Events
Semaglutide may help reduce the risk of cardiovascular-related mortality in patients with cardiovascular disease who are overweight or have obesity but do not have diabetes, according to results from a recent clinical trial published in The New England Journal of Medicine.
“This drug has a lifesaving quality. It has an increased likelihood of reducing another cardiovascular event, including death,” said Robert Kushner, MD, ’80 ’82 GME, professor of Medicine in the Division of Endocrinology and a co-author of the study.
In the international, multicenter trial, more than 17,000 patients who were 45 years or older, had cardiovascular disease, and were overweight or had obesity but who had no history of diabetes were randomized to receive either a once-weekly dose of semaglutide (2.4 milligrams) or a placebo.
Patients received semaglutide or the placebo for an average of 33 months and were observed for an average of 40 months.
Overall, semaglutide reduced patients’ risk of mortality from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke by 20 percent. Any one of those events occurred in 6.5 percent of patients in the semaglutide group and 8 percent of patients in the placebo group, respectively. Serious adverse events, including death and revascularization, also occurred more often in the placebo group.
“A 20 percent reduction was statistically significant between the two groups, semaglutide versus placebo. That’s the first time we’ve ever seen this,” said Kushner, who is also a professor of Medical Education.
While this reduction was significant, Kushner said the trial also included a number of caveats. For example, all patients enrolled had been receiving standard of care for cardiovascular disease prior to the start of the trial and the reduction in secondary cardiovascular events occurred within the first few months of the trial, suggesting weight loss wasn’t the only cause in the observed reduction, according to Kushner.
“It’s likely due to the drug itself having what we call ‘weight-independent effects’ on cardiovascular events, things like reduced inflammation and improved vasculature and kidney health, all these other beneficial effects that have to do with reducing the development another cardiovascular event,” Kushner said.
Next steps for the trial will involve producing a detailed secondary analysis of the semaglutide group to determine non-weight related benefits of the drug, according to Kushner.
“The challenge will be who’s going to prescribe the medication? With cardiologists, for example, is their practice set up for taking over management of a drug that typically is used for either diabetes or obesity and not traditionally cardiovascular disease?” Kushner said.
This work was supported by Novo Nordisk.
Improving Quality of Life for Patients with HFpEF and Obesity
Once-weekly semaglutide was also found to improve health outcomes and quality of life, regardless of baseline health status, in patients with heart failure with preserved ejection fraction (HFpEF) and obesity compared to placebo, according to a clinical trial published in Circulation.
The findings expand on an original clinical trial, which found semaglutide can help patients with both obesity and HFpEF — when the heart muscle stiffens, causing fluid to build up in the lungs and the body — lose weight while also improving symptoms and increasing exercise capacity.
“These findings extend the primary results paper by demonstrating that patients with HFpEF and obesity benefit from semaglutide across the range of health status, showing that patients with very poor quality of life and those with only mildly reduced quality of life and all those in between benefit in terms of improvements in weight loss, quality of life, symptoms, exercise capacity, and reduction in inflammation,” said Sanjiv Shah, ’00 MD, the Neil J. Stone, MD, Professor of Medicine in the Division of Cardiology and a co-author of the study.
In the study, 529 patients with obesity and HFpEF were randomly assigned to receive once-weekly semaglutide (2.4 milligrams) or placebo for a year.
The investigators found that regardless of baseline health status, which included overall symptoms and quality of life, patients on semaglutide experienced greater weight loss and larger improvements in heart failure-related symptoms, physical limitations, exercise function (performing a 6-minute walking test), NTproBNP (a marker of congestion and severity of heart failure) and inflammation compared to patients on placebo.
Semaglutide was also associated with improvements in all domains of the Kansas City Cardiomyopathy Questionnaire, a measure of health status that combines patient quality of life and symptoms.
“No medication previously tested in clinical trials has achieved this level of benefit in symptoms and quality of life in patients with heart failure of any type. These results demonstrate that in HFpEF and obesity, semaglutide is beneficial across a wide spectrum of patients,” Shah said.
Shah said his team is currently awaiting results for a companion trial with similar inclusion criteria but which includes patients with HFpEF and obesity who also have diabetes.
This work was supported by Novo Nordisk and National Institutes of Health grants U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731 and R01 HL149423.