‘A Turning Point’ in Heart Failure

For decades, physicians had little to offer patients who have heart failure with preserved ejection fraction (HFpEF), which is a growing global health problem with a grim death rate in the 5 years after diagnosis. But that started to change in 2021, when a drug trial showed benefits in preventing hospitalization and death.

And each year since, has brought a new clinical trial that shows the value of yet another drug for HFpEF.

“It’s so wonderful,” said Michelle Kittleson, MD, PhD, professor of cardiology at the Smidt Heart Institute at Cedars-Sinai in Los Angeles and chair of the writing committee for the latest American College of Cardiology (ACC) update to the HFpEF management pathway.

Talking to patients with HFpEF used to be “very hard because there was nothing you could do but manage expectations. You had to say, ‘I’m sorry, but we have no medications that affect the natural history of your disease,’” she said.

“It’s comforting as a clinician that we’ve reached an era of HFpEF where we can say, ‘I have tools that will improve your quality of life,’” she added.

Five New Drugs in 4 Years

“It’s a turning point in the history of treatment of HFpEF,” said Marco Metra, MD, director of the Institute of Cardiology at ASST Spedali Civili and professor at the University of Brescia, both in Brescia, Italy. He cochaired a heart failure task force of the European Society of Cardiology (ESC) that updated its guidelines in 2023. “We didn’t have anything before except exercise and diet, which are difficult to put into clinical practice.”

The rapidly changing landscape means an increased emphasis on diagnosis and treatment decisions for cardiologists and primary care clinicians navigating the new terrain, according to experts.

Diagnosing HFpEF is even more important because there are now evidence-based treatments that can substantially alter the course of the disease. This has forced committees looking at heart failure to update their guidelines.

The ESC heart failure guidelines, previously issued in 2021, contained no recommendations for HFpEF.

“Half an hour after we presented the ESC guidelines in 2021, we saw the presentation of EMPEROR-Preserved” — the first trial of a sodium-glucose cotransporter 2 (SGLT2) inhibitor, empagliflozin, in HFpEF, said Metra.

Enter SGLT2 inhibitors

This was followed, in 2022, by the DELIVER trial of dapagliflozin, another SGLT2 inhibitor, in HFpEF. Both trials showed significant improvements in their primary outcome: Cardiovascular death or hospitalization for heart failure. The DELIVER trial’s outcome also included urgent medical visits.

Most of the benefit in these trials was in reduced hospitalization, said Metra, but a meta-analysis later showed that cardiovascular death was also reduced. The effect on death was likely difficult to show because there were few deaths in these trials, he explained.

SGLT2 inhibitors represent “the hugest advance in HFpEF in the last decade,” said Kittleson.

In 2023, updates to the ESC guidelines and the ACC management pathway were published, both of which included SGLT2 inhibitors. But there have been more developments since then.

Glucagon-Like Peptide 1s (GLP-1s) and Heart Failure

The 2023 STEP-HFpEF trial showed the value of semaglutide, the well-known GLP-1 agonist used for patients with diabetes and obesity. In the trial, patients with HFpEF and obesity who received semaglutide had larger reductions in symptoms and physical limitations and greater improvements in exercise function than those who received placebo.

In 2024, the SUMMIT trial showed that another GLP-1 agonist, tirzepatide, led to a lower risk for cardiovascular death or worsening heart failure and a better health status in patients with HFpEF and obesity.

These two trials were limited by the small number of cardiovascular events and deaths in each, said Metra. Although clear conclusions about cardiovascular events may be premature, “we can say for sure that GLP-1 agonists improve quality of life and are likely to reduce major events” in patients with HFpEF and obesity.

It is unclear how the GLP-1 agonists work in HFpEF, said Kittleson. “There’s some special sauce, we think, to these medications. They have an intrinsic cardiac benefit in the natural progression of HFpEF.” However, they are not yet indicated for HFpEF by any regulatory authorities.

Also in 2024, the FINEARTS trial showed that a drug recently approved for chronic kidney disease, finerenone, lowered rates of worsening heart failure or cardiovascular death compared with placebo in patients who have heart failure with mildly reduced or preserved ejection fraction. Finerenone is a steroidal mineralocorticoid receptor antagonist, as is spironolactone, which has long been used in heart failure.

An international study of spironolactone in HFpEF 10 years earlier showed no improvement in cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure. However, there were large differences in outcomes among different regions of the world in that trial, leading to concern about how it was implemented, said Kittleson.

And there are now treatments for specific causes of HFpEF, said Metra, including cardiac myosin inhibitors for hypertrophic cardiomyopathy. And drugs are in the pipeline for cardiac amyloidosis.

Although effective drugs are good news, they lead to clinical questions.

Clinical Practice Catches Up

The various drugs “work through different mechanisms,” said Neil Skolnik, MD, professor of family and community medicine at the Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia. The challenge is identifying people who can benefit from these treatments that have emerged in the last 5 years, he explained, and deciding which medicine to use for which person and who would benefit from more than one medication.

The current standard of care should include a mineralocorticoid antagonist and an SGLT2 inhibitor. A GLP-1 inhibitor can be added for patients with obesity or diabetes. Although these drugs are not yet indicated for HFpEF, “if your patient has another indication for these drugs, your patient is safe if they have HFpEF” and, in fact, may benefit, said Kittleson.

Angiotensin receptor–neprilysin inhibitors and angiotensin receptor blockers may be added if indicated. The treatment of comorbidities is also important.

The increasing prevalence of HFpEF is tied to the aging of the population. And with “aging being the largest risk factor, HFpEF will be increasing as patients live longer,” said Kittleson.

Added to age are the “many comorbidities that contribute to HFpEF, and these will be more common with age,” as well, she explained. The management pathway describes a complex interplay, with hypertension, diabetes, and obesity resulting in coronary artery disease, atrial fibrillation, sleep apnea, and chronic kidney disease. The latter two conditions worsen hypertension, and all comorbidities affect outcomes in patients with HFpEF.

“It’s a perfect storm,” said Kittleson.

The growing prevalence means that primary care physicians must be alert to the possibility of HFpEF, said Skolnik.

For example, HFpEF is found in 20%-25% of people with diabetes, he pointed out, and the American Diabetes Association recommends annual screening for heart failure in these patients.

Without screening, HFpEF can be missed. “The presentation can be very subtle in comparison with heart failure with reduced ejection fraction, where people have a high burden of illness,” he explained. “In HFpEF, symptoms often overlap with the experience of people over 50-60 years of age who don’t actively exercise — fatigue, shortness of breath with exertion, peripheral edema — particularly if they are also overweight.”

The number one critical thing in primary care is a high index of suspicion and a low threshold for screening, Skolnik said.

“Primary care physicians must be aware of these drugs, which are well tolerated,” Metra added.

“I hope that the heroes of our healthcare system — primary care physicians — feel empowered to prescribe these therapies,” Kittleson said.