Year in Review: Tirzepatide, Finerenone, and Digitoxin Score Big in Heart Failure

As in years past, heart failure (HF) continues to be one of cardiology’s most exciting areas when it comes to the development of new therapies and innovations for patient care.

The year saw the emergence of a new version of an old drug that proved beneficial in patients who have heart failure with reduced ejection fraction (HFrEF) and the approval of a new nonsteroidal mineralocorticoid receptor antagonist (MRA). Physicians, not to mention patients, also received good news when it came to eliminating the need for tight fluid restriction in chronic HF and the possibility of a polypill that combines several elements of guideline-directed medical therapy (GDMT).

And while the presentation and publication of the SUMMIT trial happened in late 2024, the trial’s results continued to reverberate in 2025.

In SUMMIT, tirzepatide (Zepbound; Eli Lilly) cut the risk of major cardiovascular events in patients who had heart failure with preserved ejection fraction (HFpEF) and obesity, with both Amanda Vest, MBBS (Cleveland Clinic, OH), and Carlos Santos-Gallego, MD, PhD (Icahn School of Medicine at Mount Sinai, New York, NY), citing the trial as pivotal given the limited number of treatments for this patient population.

“Right now, we have two effective therapies for HFpEF patients with obesity,” Santos-Gallego told TCTMD. “One is SGLT2 inhibitors, and now we have a second therapy [with tirzepatide].” In the SUMMIT trial, the benefit of treatment was driven by the 46% reduction in the risk of worsening HF events resulting in hospitalization, intravenous drug therapy in an urgent care setting, or intensification of oral diuretic therapy, a benefit Santos-Gallego called “incredible.”

To TCTMD, Vest said the metabolic treatment of obesity-related HFpEF is “very hot and germane.” Since the main SUMMIT publication in the New England Journal of Medicine, several different subanalyses have emerged this year, including one that showed tirzepatide reduced LV mass as well as pericardial and epicardial adipose tissue at 52 weeks.

DIGIT-HF, a trial that surprised some, also caught the attention of the experts. In that study, adding it to contemporary GDMT significantly cut the risk of all-cause mortality or hospital admissions for worsening HF in patients with advanced HFrEF.

“It’s a very interesting trial, almost resurrecting a previous drug from the dead,” said Santos-Gallego. “In this case, it's not exactly digoxin, it's like a version of digoxin. [DIGIT-HF] is important because of safety. In the past we were not using digoxin, not because of lack of efficacy, but because it was very easy for the patients to develop digitalis toxicity.”

While both digoxin and digitoxin are cardiac glycosides, digitoxin is cleared by the liver and not the kidney, so a comorbidity like chronic kidney disease is not a barrier to using the drug, he said. Vest added that DIGIT-HF was exciting given the positive results, particularly since it may fill a gap for patients with advanced HF who continue to be at risk despite GDMT.

“We’re still all sort of figuring out what this means in terms of the clinical application,” she added.

At the moment, digitoxin is not available in the US, but Santos-Gallego expects it will be soon given its effectiveness in DIGIT-HF. He stressed that the four pillars of HF therapy—angiotensin receptor-neprilysin inhibitor (ARNI) or ACE inhibitor/ARB, beta-blocker, SGLT2 inhibitor, and MRA—come first, but said digitoxin may be a useful adjunct in those who continue to be symptomatic despite treatment.

New MRA Approved and FRESH-UP

Another big HF story in 2025 was the approval of the MRA finerenone (Kerendia; Bayer) for patients who have HF with mildly reduced or preserved ejection fraction. The approval was based on the FINEARTS-HF study, but this year saw the publication of a noteworthy secondary analysis from the trial, said Vest.

“There was an analysis in JAMA Cardiology about the stabilization of outpatient worsening heart failure,” she said, noting that finerenone significantly reduced the number of events requiring oral diuretic intensification.

Vest also highlighted FOOD-HF, a small, randomized trial that showed access to healthy foods could improve quality of life in patients with HF, as another that generated buzz in 2025. At the Cleveland Clinic, patients with HF are connected with registered dieticians who focus on cardiovascular medicine, but there are continued challenges with outpatient consults, said Vest.

The US Centers for Medicare & Medicaid Services “only covers a dietician consultation in specific circumstances, and simply having heart failure, unfortunately, isn't one of them,” said Vest. “Patients with commercial insurance may have an out-of-pocket copay. We really see registered dieticians as an integral part of our inpatient and outpatient heart failure care team, and myself and others are involved in various initiatives to provide more guidance around this, and to increase opportunities for patients.”

With FRESH-UP, another big one in 2025, investigators showed that tight fluid restriction isn’t necessary in patients with chronic HF.

“It was just 504 patients, but I think it was really interesting and practical,” said Vest. “There was no difference in their primary outcome of health status with the more liberal versus restricted fluid approaches, but they did find that thirst distress was higher in the restricted group.”

“This is a trial that I love,” added Santos-Gallego. “One of my pet peeves is restricting fluids to patients. Imagine, 30 years ago when we did not have any types of treatment, restricting fluid was important, but right now we are basically making our patients thirst for nothing. We’re not achieving any benefit.”

For Santos-Gallego, POLY-HF was another key study this year. In that trial, a polypill containing three of the four pillars of GDMT in HFrEF—beta-blocker, SGLT2 inhibitor, and MRA—led to greater improvements in LVEF, quality of life, and adherence, as well as a lower risk of a composite of HF events or death by 6 months, when compared with usual care.

“Everything was improved, and there were no safety issues,” he said. “This is a very good therapy that is not necessarily for everybody. If you're in an academic institution, then you're going to be discharged, and you’re going to have an appointment at the transition clinic in 2 weeks and another appointment in 2 weeks and another appointment in 1 month. You’re not going to need [a polypill], but if you’re in an area where access to healthcare is limited, this is a great strategy.”

Other Key Studies

When it comes to interventions, follow-up data from TRILUMINATE also caught his attention. At 2 years, transcatheter edge-to-edge repair (TEER) for severe tricuspid regurgitation (TR) significantly reduced HF hospitalizations when compared with medical therapy alone. While TEER is approved for patients with severe TR who aren’t candidates for surgery, the approval was based largely on subjective endpoints, such as quality of life.

“We are getting more solid data now,” said Santos-Gallego. The 2-year results are important as many HF doctors questioned whether they should refer patients for the procedure. “Now we have a hard endpoint, a clinically relevant endpoint, with less heart failure hospitalizations.”

In terms of other studies, BAX-HTN stood out in 2025, said Santos-Gallego. The aldosterone synthase inhibitor baxdrostat (AstraZeneca) is a new medication for reducing blood pressure, which in turn reduces the risk of HF, stroke, progression to dialysis, and other adverse outcomes. A large meta-analysis also found no benefit of beta-blockers in post-MI patients with preserved EF, which is another critical publication this year.

Finally, he highlighted a study from his group: SOTA-P-CARDIA. Here, the dual SGLT1 and SGLT2 inhibitor sotagliflozin (Zynquista; Sanofi Aventis/Lexicon) induced remodeling in HFpEF patients without type 2 diabetes, with researchers showing improved LV mass, diastolic function, functional capacity, and quality of life.