GLP-1 Drugs and Heart Failure: The HFpEF Story | Philadelphia

TL;DR30-second take

GLP-1 drugs like semaglutide and tirzepatide help one particular kind of heart failure: the obesity-driven form of heart failure with preserved ejection fraction, or HFpEF, where the heart pumps normally but is stiff and does not relax well. In the STEP-HFpEF trial, semaglutide improved heart-failure symptoms, walking distance, and inflammation in people with obesity and HFpEF. In the SUMMIT trial, tirzepatide went further and reduced heart-failure events, though not deaths. This benefit is specific to HFpEF with obesity. In the other main kind, heart failure with reduced ejection fraction, older GLP-1 studies showed no benefit and some signs of harm, so these drugs are not a general heart-failure treatment. They are not yet FDA-approved for HFpEF, and they work differently from SGLT2 inhibitors, another drug class used in heart failure.

TL;DR: GLP-1 drugs have become a treatment for one specific kind of heart failure, and understanding which kind is the whole point. They help the obesity-driven form of heart failure with preserved ejection fraction, called HFpEF, where the heart squeezes with a normal strength but is stiff and fills poorly. In the STEP-HFpEF trial, semaglutide improved symptoms, walking distance, and inflammation in people with obesity and HFpEF. In the SUMMIT trial, tirzepatide went a step further and cut the rate of heart-failure events, though it did not reduce deaths. The benefit is tied to this obese-HFpEF phenotype, and much of it appears to come from the weight loss itself. The key caution is that this does not extend to the other main kind of heart failure, the reduced-ejection-fraction form, where older GLP-1 trials found no benefit and some signals of harm. These drugs are not yet FDA-approved for HFpEF specifically, and they are a different class from SGLT2 inhibitors, which are also used in heart failure but work in their own way.

Can GLP-1 drugs treat heart failure?

For one kind, yes, and this is one of the more important developments in metabolic and heart medicine of the last few years. But heart failure is not a single disease, and the answer depends on which kind is meant, so the distinction has to come first.

Doctors divide heart failure broadly into two types by how well the heart's main pumping chamber squeezes, a measure called the ejection fraction. In heart failure with reduced ejection fraction, the heart muscle is weak and pumps out too little blood. In heart failure with preserved ejection fraction, or HFpEF, the heart squeezes with normal force but has become stiff, so it cannot relax and fill properly between beats. The two look similar to a patient, with breathlessness and swelling, but they are different problems with different treatments. The GLP-1 story is about HFpEF, and specifically the version driven by obesity.

What is HFpEF, and what does obesity have to do with it?

HFpEF is heart failure of the stiff, poorly-relaxing heart. Because the ejection fraction looks normal on an ultrasound, it was long underrecognized, but it is now understood to be about half of all heart failure, and it is closely tied to obesity, high blood pressure, diabetes, and aging.

There is a recognized obesity phenotype of HFpEF, a version in which excess weight is the central driver.¹ Carrying a large amount of fat raises the heart's workload in several ways at once: it expands the volume of blood the heart must move, it fuels body-wide inflammation, and it deposits fat around and even within the heart, including the pericardium, the sac around the heart, which can physically restrain it. The result is a heart that is squeezed from the outside and overloaded from within. This is the group in whom GLP-1 drugs, which remove the excess weight, would be expected to help, and the trials were designed around this phenotype.

What did the trials show? STEP-HFpEF and SUMMIT

Two major trials built the evidence, and they showed different, complementary things.

The first was STEP-HFpEF, which tested semaglutide at the 2.4 mg weight-loss dose in people who had obesity and HFpEF but did not have diabetes.² Over about a year, semaglutide clearly improved how people felt and functioned: their heart-failure symptom scores rose substantially, they could walk noticeably farther in a timed test, their inflammation marker CRP fell sharply, and they lost about 10% of their body weight relative to placebo. A companion trial in people who also had diabetes found the same kind of benefit.³ It is important to hold this clearly, though: STEP-HFpEF was built to measure symptoms, function, and weight rather than hard events like hospitalizations or death, so it proved people felt and moved better rather than that fewer of them ended up in the hospital.

That next step came from SUMMIT, which tested tirzepatide in obesity-related HFpEF.⁴ SUMMIT was designed to capture events, and it did: tirzepatide reduced a combined measure of cardiovascular death or worsening heart-failure events by about 38%, alongside the expected gains in symptoms. This is meaningful, because it moved the story from feeling better to fewer heart-failure crises. One honest point of precision: that benefit was driven mostly by fewer worsening-heart-failure events rather than by fewer deaths; deaths were too few to show a difference and did not fall. So the fair summary is that tirzepatide reduced heart-failure events, which is a meaningful clinical win, without yet being shown to extend life.

Why HFpEF but not the other kind of heart failure?

This is the most important safety point in the whole topic, and it is easy to miss. The benefit is specific to HFpEF with obesity. In heart failure with reduced ejection fraction, the weak-pump kind, GLP-1 drugs have not helped, and there are signals they could hurt.

The evidence comes from older trials of liraglutide, an earlier GLP-1 drug, in people with reduced ejection fraction. In the FIGHT trial, in people with advanced weak-pump heart failure, liraglutide did not improve their stability and showed a trend toward more heart-failure hospitalizations and deaths.⁵ In the LIVE trial, in more stable weak-pump patients, liraglutide did not improve heart function and caused more serious heart-related problems, including a rise in heart rate and more heart-rhythm disturbances.⁶ These were small, shorter trials with an older drug, so they should not be read as proof that GLP-1 drugs are dangerous across the board. But the direction is consistent and cautionary, and it is why the reduced-ejection-fraction setting is treated very differently from the obese-HFpEF one.

The practical takeaway is that the kind of heart failure matters enormously here. A GLP-1 drug that is a genuine help for a stiff, obesity-loaded heart is not a proven help, and may be a risk, for a weak, dilated one. This is a decision that belongs with a physician who knows which type a patient has.

How do these drugs help the heart?

The leading explanation is that the benefit flows largely from the weight loss itself, working on the very drivers that make obese HFpEF what it is. Losing a large amount of weight lowers the volume of blood the heart has to move, quiets the body-wide inflammation that stiffens tissues, and shrinks the fat deposited around the heart that was restraining it, all of which ease the overloaded, squeezed heart. The sharp drop in the inflammation marker CRP in the semaglutide trial fits this picture.

That said, it is described as the leading explanation rather than a settled fact. Some analyses hint that the heart benefit may be partly independent of how much weight is lost, which would suggest the drugs have effects on the heart and blood vessels beyond the pounds shed. The trials establish that these drugs help and that these changes happen together; untangling how much is weight loss versus direct drug effect is still being worked out.

How is this different from SGLT2 inhibitors?

This is worth keeping straight, because both drug classes are now used in HFpEF but they are not the same and were proven in different ways.

SGLT2 inhibitors, a separate class originally developed for diabetes, were shown in large trials to reduce heart-failure hospitalizations across HFpEF broadly, beyond the obesity phenotype alone.⁷^,⁸ Their main proven benefit is fewer hospitalizations. GLP-1 drugs, by contrast, were proven in the obese-HFpEF group specifically, improving symptoms and function and, with tirzepatide, reducing heart-failure events. So the two classes are complementary rather than interchangeable: an SGLT2 inhibitor is a broad HFpEF tool with a hospitalization benefit, while a GLP-1 drug is aimed at the obesity that drives one large subset. For many patients with obese HFpEF, both may have a role, decided with a cardiologist.

Is it approved for heart failure?

Not specifically, and this is worth stating plainly. As of 2026, neither semaglutide nor tirzepatide is FDA-approved for a HFpEF indication. Their approvals are for weight management, type 2 diabetes, and related uses, so using them for HFpEF rests on the trial evidence rather than on a formal heart-failure label. That does not make the evidence weak; STEP-HFpEF and SUMMIT are strong randomized trials, and a 2025 American College of Cardiology scientific statement on managing obesity in heart failure recognizes the benefit in obese HFpEF.⁹ Guidelines are beginning to incorporate it. But it is honest to say this is an emerging, trial-supported use that the formal indications have not yet caught up to, and one that should be guided by a cardiologist rather than assumed.

Guidance from the Clinic

"This is an important advance, and it is also one where the details decide everything. For a patient carrying significant weight with the stiff-heart kind of heart failure, a GLP-1 drug can improve how they feel, how far they can walk, and, with tirzepatide, how often their heart failure flares. That is a lot to offer. The line I never blur is the type of heart failure. These drugs earned their place in the obesity-driven, preserved-ejection-fraction group, and the older data in the weak-pump group point the other way, toward no benefit and some risk. So the first question is always which kind of heart failure a person has, which takes an echocardiogram and a careful look rather than an assumption. Used in the right patient, this is metabolic medicine and heart medicine pulling in the same direction."

Key Takeaways

GLP-1 drugs help one specific kind of heart failure: the obesity-driven form of heart failure with preserved ejection fraction (HFpEF), where the heart is stiff rather than weak.
In STEP-HFpEF, semaglutide improved symptoms, walking distance, inflammation, and weight; in SUMMIT, tirzepatide went further and reduced heart-failure events by about 38%, though not deaths.
The benefit does not extend to heart failure with reduced ejection fraction, the weak-pump kind, where older GLP-1 trials showed no benefit and some signals of harm; the type of heart failure is the decisive factor.
The benefit is thought to come largely from the weight loss easing the burdens of obese HFpEF, with a possibility of additional direct effects still being studied.
Neither drug is FDA-approved for HFpEF, though a 2025 ACC scientific statement recognizes the benefit; and GLP-1 drugs are a different class from SGLT2 inhibitors, which reduce hospitalizations across HFpEF more broadly.

Tirzepatide (Zepbound, Mounjaro) - the drug behind the SUMMIT heart-failure result, in depth
SGLT2 Inhibitors: Heart, Kidney, and Longevity - the other drug class used in HFpEF, and how it differs
Ozempic, Wegovy, and Mounjaro: The GLP-1 Strategy - how these drugs are prescribed and managed
What Is a Preventive Cardiologist? - the approach that connects weight, metabolism, and the heart
High Troponin and NT-proBNP: Reading Cardiac Markers - what a falling NT-proBNP on these drugs reflects, and how to read the marker
Semaglutide for Kidney Disease (FLOW) - another organ-protection story for the same drug

Scientific References

Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. "Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure with Preserved Ejection Fraction." Circulation. 2017;136(1):6-19.
Kosiborod MN, Abildstrom SZ, Borlaug BA, et al. "Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity." New England Journal of Medicine. 2023;389(12):1069-1084.
Kosiborod MN, Petrie MC, Borlaug BA, et al. "Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes." New England Journal of Medicine. 2024;390(15):1394-1407.
Packer M, Zile MR, Kramer CM, et al. "Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity." New England Journal of Medicine. 2025;392(5):427-437.
Margulies KB, Hernandez AF, Redfield MM, et al. "Effects of Liraglutide on Clinical Stability Among Patients with Advanced Heart Failure and Reduced Ejection Fraction: A Randomized Clinical Trial." JAMA. 2016;316(5):500-508.
Jorsal A, Kistorp C, Holmager P, et al. "Effect of Liraglutide, a Glucagon-Like Peptide-1 Analogue, on Left Ventricular Function in Stable Chronic Heart Failure Patients With and Without Diabetes (LIVE)." European Journal of Heart Failure. 2017;19(1):69-77.
Anker SD, Butler J, Filippatos G, et al. "Empagliflozin in Heart Failure with a Preserved Ejection Fraction." New England Journal of Medicine. 2021;385(16):1451-1461.
Solomon SD, McMurray JJV, Claggett B, et al. "Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction." New England Journal of Medicine. 2022;387(12):1089-1098.
Kittleson MM, et al. "2025 ACC Scientific Statement on the Management of Obesity in Adults With Heart Failure: A Report of the American College of Cardiology." Journal of the American College of Cardiology. 2025;86(20):1953-1975.

Medical Disclaimer: This resource provides clinical context for educational purposes and is not medical advice. Do not start, stop, or change any medication based on this article, and never assume a heart-failure treatment applies to you without knowing which type of heart failure you have. In Precision Medicine there is no one-size-fits-all; the right plan must be matched to your heart, your metabolism, and your history. Consult Dr. Ash, your cardiologist, or your own physician about your care.

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Frequently Asked Questions

Common Questions

They help one specific kind: the obesity-driven form of heart failure with preserved ejection fraction, HFpEF, where the heart is stiff rather than weak. In trials, semaglutide improved symptoms and walking distance in people with obesity and HFpEF, and tirzepatide reduced heart-failure events. They are not a treatment for all heart failure, and in the weak-pump kind, heart failure with reduced ejection fraction, older GLP-1 data showed no benefit and some signs of harm. The kind of heart failure decides whether these drugs help.

Both are heart failure, but they are opposite mechanical problems. In heart failure with reduced ejection fraction, the heart muscle is weak and cannot pump out enough blood. In heart failure with preserved ejection fraction, HFpEF, the heart pumps with normal strength but has become stiff and cannot relax and fill properly. They can feel similar, with breathlessness and swelling, but the treatments differ, and GLP-1 drugs have been shown to help the HFpEF kind, particularly when obesity is driving it.

Not yet. In STEP-HFpEF, semaglutide improved symptoms, function, and weight, but that trial was not built to measure deaths or hospitalizations. In SUMMIT, tirzepatide reduced a combined measure of cardiovascular death or worsening heart-failure events by about 38%, but that was driven by fewer heart-failure events rather than by fewer deaths, which did not fall. So the proven benefit is feeling better and having fewer heart-failure crises, not, so far, living longer.

Not for a heart-failure indication as of 2026. These drugs are approved for weight management, diabetes, and related uses, and their use in HFpEF rests on the trial evidence rather than a formal heart-failure label. A 2025 American College of Cardiology scientific statement recognizes their benefit in obesity-related HFpEF, and guidelines are starting to incorporate it, but it remains an emerging, trial-supported use that should be guided by a cardiologist.

This is a decision for your cardiologist, and caution is warranted. The trials that showed heart benefit were in the stiff-heart HFpEF group with obesity. In heart failure with reduced ejection fraction, older GLP-1 trials found no benefit and some signals of harm, including more heart-rhythm problems. That does not automatically rule these drugs out if there is another strong reason to use one, but it means the decision has to be made carefully and individually, not assumed from the HFpEF results.

Deep-Dive Questions

Because the two kinds of heart failure fail for opposite reasons, so the same intervention plays out differently. Obese HFpEF is, in large part, a problem of the heart being overloaded and physically crowded by excess weight: too much circulating volume, too much inflammation, too much fat pressing on the heart. Removing the weight relieves those very burdens, so the stiff heart has less to fight against. A weak, reduced-ejection-fraction heart is failing because the muscle itself cannot generate enough force, a problem weight loss does not fix, and the strain, rapid heart-rate changes, or fluid shifts that can accompany these drugs may be less well tolerated by an already-failing pump. So the mismatch is not surprising once you see that HFpEF and the reduced-fraction kind are nearly opposite mechanical problems.

This is the live scientific question. The simplest reading is that most of the benefit comes from the weight loss, because obese HFpEF is so directly a disease of excess weight, and the improvements in symptoms, function, and inflammation track the weight lost. But a few analyses have found that the heart benefit does not line up perfectly with the amount of weight a person lost, which hints that the drugs may also act on the heart and blood vessels through other routes, such as reducing inflammation or improving how blood vessels behave, somewhat apart from the scale. The most accurate statement today is that weight loss is the main engine, with a strong possibility of additional direct effects that researchers are still measuring.

Because of what each trial was built to measure. STEP-HFpEF measured how people felt and functioned, their symptom scores, their walking distance, their weight, and it showed clear improvement, which matters a great deal to daily life. But feeling better is a softer endpoint than staying out of the hospital, and a treatment can improve symptoms without changing the course of the disease. SUMMIT was designed to capture the harder outcome of heart-failure events, and by showing that tirzepatide reduced those events, it provided the stronger kind of proof that the drug changes what happens to the disease, beyond how it feels. The honest limit is that even SUMMIT did not show fewer deaths, so the proof reaches to fewer heart-failure crises but not yet to longer life.

That is a decision for a cardiologist, but the logic is worth understanding. SGLT2 inhibitors have the broadest HFpEF evidence, reducing hospitalizations across the condition, and they are generally well tolerated, so they are often a foundation. A GLP-1 drug adds a different benefit aimed squarely at the obesity that is driving your particular heart failure, improving symptoms and function and, with tirzepatide, reducing events. Because the two classes work through different routes and were proven in different ways, they are not redundant, and for many people with obese HFpEF there is a reasonable case for both, layered thoughtfully. The right combination depends on your other conditions, your kidney function, your tolerance, and your goals, which is the kind of individual judgment this calls for.

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