This story was published in the March 2024 issue of the Breakthroughs newsletter.
This is part of a two-part series covering anti-obesity medications and the research Feinberg faculty are leading. In the second part, we are covering anti-obesity medications that are being tested to treat heart disease and how scientists and physicians are addressing health equity challenges around these drugs.
As GLP-1 receptor agonist medications like semaglutide have been shown to be effective at helping patients lose weight, scientists are now asking, whether they can treat other conditions where obesity is a risk factor. Most recently, initial studies have shown that they can reduce the risk of cardiovascular disease by reducing overall body weight.
A study published in the New England Journal of Medicine showed that semaglutide can reduce the risk of cardiovascular-related disease for people who have obesity but who do not have diabetes.
“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 of another cardiovascular event,” said Robert Kushner, MD, 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. Participants received semaglutide or the placebo for an average of 33 months and were observed for an average of 40 months.
Overall, semaglutide reduced participants’ 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 participants in the semaglutide group and in 8 percent of participants in the placebo group, respectively. Serious adverse events, including death and revascularization, also occurred more often in the placebo group.
“This new era of medicine has the capability of changing our society,” said Clyde Yancy, MD, MSc, vice dean for Diversity and Inclusion, and the Magerstadt Professor and chief of Cardiology in the Department of Medicine.
Because more than half of the world’s population is projected to be obese or overweight by 2035, these drugs could improve health, reduce healthcare costs and improve quality of life for people living with obesity and subsequent medical complications like heart failure.
Honing in on HFpEF
Sanjiv Shah, MD, the Neil J. Stone, MD, Professor of Medicine in the Division of Cardiology, has been involved in clinical trials that look at a specific type of heart failure called heart failure with preserved ejection fraction (HFpEF). He was co-author on a study published in Circulation that found once weekly semaglutide improved health outcomes and quality of life in patients living with obesity and HFpEF.
Imaging of the heart has shown that people with HFpEF experience a heart muscle that stiffens, causing fluid to build up in the lungs and the body. In the study, more than 500 participants living with obesity and HFpEF were randomly assigned to receive once-weekly semaglutide (2.4 milligrams) or placebo for a year.
“We know that obesity is tied to the HPpEF epidemic,” Shah said.
Of the estimated five million patients in the U.S. diagnosed with heart failure annually, nearly half will develop HFpEF.
In the study, investigators found that regardless of baseline health status, which included overall symptoms and quality of life, participants on semaglutide experienced greater weight loss and larger improvements in heart failure-related symptoms, physical limitations, exercise function and more. 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.
Another study published in the New England Journal of Medicine, for which Shah was a co-author, showed that participants on semaglutide lost more weight, with a mean percent reduction in body weight of 13.3 percent compared to 2.6 percent for patients taking a placebo, according to the trial.
At the end of the trial, patients receiving semaglutide could also walk farther than those on placebo and had lower levels of C-reactive protein, a biomarker for inflammation known to drive heart failure. Importantly, compared to placebo, patients on semaglutide also had greater reductions in B-type natriuretic peptide, a biomarker that correlates to severity of heart failure.
“It was really remarkable to see how effective a weight loss drug it was, even in the setting of heart failure,” Shah said. “However, we were most interested in whether the drug could reduce symptoms and signs of heart failure itself. We found that patients treated with semaglutide (compared to placebo) had much greater improvements in their health status (which includes quality of life, symptoms and physical limitations). In fact, health status improved with semaglutide more than any other heart failure medical therapy tested to date. [All of this] is hopefully convincing the scientific community that obesity drives this syndrome,” Shah said.
According to Shah, there are combination therapies and other drugs being tested that could also make a big difference for these patients.
“Semaglutide is just the tip of the iceberg,” Shah said.
Identifying Health Equity Challenges
With any new therapy, a lot of questions swirl about implementation and access: Who can get access to the drug and who can’t? What are the financial costs and what are the lifestyle costs?
Clyde Yancy, MD, MSc, professor of Medicine in the Division of Cardiology, said these new drugs that treat obesity allow us to think differently about obesity. “[Obesity] should be treated as a disease, and these drugs allows us to destigmatize. Obesity should not be a pejorative descriptor, it’s a medical condition, just like high blood pressure or diabetes.”
Still, the cohorts for these clinical trials lack racial diversity in their participant cohorts, according to Yancy. The lack of diversity can make it hard to compellingly prove that semaglutide and other GLP-1 receptor agonists will work for a variety of people and even more so to introduce this therapy to populations with sparse representation in the pivotal studies.
Veronica Johnson, MD, assistant professor of Medicine, treats patients in the Center for Lifestyle Medicine. She got into obesity medicine because she noticed that there were few Black female physicians in the field treating obesity.
Johnson said it’s important to raise awareness about the barriers of access to these drugs, whether it’s insurance, a provider’s lack of education around obesity treatment, stigma, race or other issues.
In the media, there has been a lot of talk about using these drugs for cosmetic purposes, but Johnson said that’s not safe. “We don’t have data that shows that it’s safe for people to use for cosmetic purposes.”
Johnson contributed to a commentary published in Nature Medicine, which outlines inequalities facing patients and providers around GLP-1 receptor agonists. Lack of insurance coverage, costs, stigma and regulations are some of the key factors she discussed.
There is a lot of potential for semaglutide and similar drugs to make an impact, but the barriers to access make them hard to see realized, according to Johnson and colleagues. More research is still needed to understand long-term use and how “weight stigma and biases experienced in society all impair the acceptance of these therapies,” according to Johnson.
“We know from bariatric surgery research that Black and Latino patients don’t do as well for a variety of reasons after that surgery. We need more clinical trials that have diverse populations and samples.”
Melissa Rohman and Olivia Dimmer contributed to this story.
This is part of a two-part series. Last month we covered the anti-obesity medications being used to treat obesity and advocacy that is happening to improve access for patients. Read that story here.