Reference: N Engl J Med. 2023 Aug 25 early online
Practice Point: Semaglutide seems to improve signs and symptoms of HFpEF in non-diabetic patients with obesity.
EBM Pearl: When a drug is being evaluated to treat a disease affected by obesity, weight loss that occurs as a side effect is a potential confounder, making it difficult to know if benefits seen are from the drug, the weight loss, or both.
Neither heart failure with reduced ejection fraction (HFrEF) nor heart failure with preserved ejection fraction (HFpEF) has a great prognosis, but management of these two conditions is surprisingly disparate, considering both are “pump failure.” A few years ago, we figured out that sodium-glucose cotransport-2 (SGLT2) medications for diabetics helped out people with heart failure, which sort of made sense since they cause a diuresis through forcing people to excrete sugar. It also didn’t come as a shock that bariatric surgery reduced major cardiac events such as heart failure exacerbations in people with obesity and heart disease. After all, losing weight helps reduce the pumping we ask hearts to do, right? With a new study showing many substantial short term improvements in the health of people who have obesity and HFpEF without diabetes, we need to ask ourselves — are these benefits specific to the drug, the weight loss, or both?
The study, published in NEJM the last week of August, is a pharma-sponsored multi-site trial that enrolled nondiabetic patients with HFpEF, some with recent hospitalization, others defined by NYHA symptoms, and all with objective evidence of HFpEF. Five hundred twenty-nine patients were randomized to receive weekly semaglutide injections or placebo injections for one year. Participants were assessed at baseline and at 52 weeks for reported symptoms using the Kansas City Cardiomyopathy Questionnaire (KCCQ), BNP and CRP levels, and performance on a six minute walk test. It isn’t surprising that the people receiving semaglutide lost a lot more body weight (13.3% vs. 2.6%), but they also scored 8 additional points better on the 100-point KCCQ scale and did better on seemingly objective measurements such as the six-minute walk (+20m). One problem is that many of the questions on the KCCQ that ask about “heart failure” symptoms (fatigue, swelling in your legs, ability to do household chores and hobbies) might also apply to “obesity” symptoms. Similarly, it isn’t too much of a stretch to say that people with more obesity don’t walk quite as far in six minutes as people with less obesity, whether or not they have heart failure. Although some objective outcomes such as CRP and BNP also improved, these levels are also confounded by obesity, making interpretation difficult.
One intriguing aspect of this study was the use of the “estimand” framework with its accompanying terminology, which is a good thing. At first glance, this might seem like yet another tricky statistical thing that only statisticians understand. (If you watched Oppenheimer this summer, you may have learned that physicists don’t need math! So why should clinicians?) But in fact, the estimand framework is a standardizing method for RCTs promoted by the International Council for Harmonization (ICH). The framework considers the underlying condition in the patient and population studied, the outcomes for patients receiving treatment (treatment outcomes are termed the “estimand”) and the population, and “intercurrent events.” Intercurrent events are a fancy way of describing anything unexpected that happens to people between the time they are randomized and the completion of the trial, such as death, need for additional medicines, etc. The estimand framework is a new way of thinking of these old things, and although it’s only a few years old, is likely to be seen a lot more in randomized trials of interventions.
Overall, this study was worthwhile and advances our conversation about the role of obesity in heart failure. It is a far way from proving that semaglutide is a life-saving drug in these patients or even that it keeps people out of the hospital, but the improvements in quality of life metrics are hard to deny. It’s an appetizer, and the estimand framework can hopefully be used as a recipe to create a full meal demonstrating whether or not the weight loss from semaglutide translates into longer and happier lives for people with HFpEF and obesity.
For more information, see the topic Heart Failure With Preserved Ejection Fraction (HFpEF) in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, Deputy Editor at DynaMed. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral fellow at McMaster University; and Sarah Hill, MSc, Senior Associate Editor at DynaMed.