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CHICAGO -- A long-acting GIP/GLP-1 receptor agonist conferred significant clinical benefit for people with obesity and accompanying heart failure with preserved ejection fraction (HFpEF), according to the SUMMIT trial.

Incident cardiovascular death or worsening heart failure (HF) events were down over a median 104 weeks of follow-up in people who had been randomized to tirzepatide (Zepbound, Mounjaro) instead of placebo (9.9% vs 15.3%, HR 0.62, 95% CI 0.41-0.95), reported Milton Packer, MD, of Baylor University Medical Center in Dallas and Imperial College London.

These event rates translated to 5.5 vs 8.8 events per 100 patient-years on time-to-first-event analysis -- the difference driven by a decreased risk of worsening HF events requiring hospitalization or urgent intravenous drug therapy, Packer told the audience here at the American Heart Association (AHA) annual meeting. The SUMMIT manuscript was simultaneously published in the .

"In my mind, this really is a practice-changing trial and cements incretin-based therapies as one of the cornerstones of obesity-HFpEF treatment," commented Jennifer Ho, MD, of Harvard Medical School, during an AHA press conference.

Packer stressed that SUMMIT is the first GLP-1 receptor agonist trial powered to assess major HF outcomes in HFpEF with obesity. Previously, the STEP-HFpEF and STEP-HFpEF-DM trials were able to link semaglutide (Wegovy) to Kansas City Cardiomyopathy Questionnaire (KCCQ) improvements alone in those with obesity-related HFpEF.

He reported other endpoints that favored tirzepatide over placebo in SUMMIT:

• Quality of life per the KCCQ-Clinical Summary Score: between-group difference from baseline to 52 weeks +6.9 points (P<0.001)
• Functional capacity as measured by change in 6-minute walk distance: +18.3 m between-group difference (P<0.001)
• Change in weight: between-group reduction of 11.6% (P<0.001)
• Change in systemic inflammation: between-group difference -34.9% (P<0.001)

In SUMMIT, 4.1% of the tirzepatide group discontinued treatment for gastrointestinal side effects, consistent with the known safety profile of tirzepatide and other GLP-1 receptor agonists. There were also small, non-significant excesses in cardiovascular death (2.2% vs 1.4%) and any death (5.2% vs 4.1%) in the tirzepatide group, which Packer attributed to chance.

HFpEF is now the most prevalent phenotype of HF, affecting disproportionately more women in particular. Obesity is a major known driver of HFpEF disease.

Ho cited challenges ahead in understanding how tirzepatide and other GLP-1 receptor agonists fit into the landscape of therapies for HFpEF.

In 2021, FDA approved sacubitril/valsartan (Entresto) for a broad HF indication that includes some HFpEF patients. In 2022, empagliflozin (Jardiance) was approved for a broader indication in heart failure across the spectrum of ejection fraction (EF). In 2023, another SGLT2 inhibitor, dapagliflozin (Farxiga), also had its label extended for HF across the spectrum of EF.

Meanwhile, tirzepatide injections are currently FDA approved for type 2 diabetes and chronic weight management.

Ho suggested a lot of work ahead regarding implementation of the GLP-1 receptor agonists at large. She said she prescribes this class of medication routinely in her practice, but patients have variable success getting the scripts filled. "There are many, many barriers that our patients and our providers face, including access, including health inequities, including provider expertise to really guide and initiate these therapies successfully," she shared from personal experience.

It may not be surprising that payers are unwilling to pay for GLP-1 receptor agonists for all patients. "The sheer number of people who qualify as having obesity is enormous," Packer explained during the press conference. "[The payers] take that number and multiply by cost, and they look at their annual budget, and they're in pain."

After SUMMIT, he reasoned, "one would think [with] one prescribed drug for a targeted group of patients with obesity, a group that's suffering enormously with a high event rate, that the equation would make a lot more sense."

The double-blind trial had 731 people with HFpEF and obesity (defined as BMI at least 30) assigned either weekly tirzepatide or placebo treatment for up to 3 years. The cohort had enriched for high risk during screening to accrue the number of events needed to detect a significant clinical benefit.

SUMMIT participants were around age 65 years on average, over 50% women, and about 30% non-white. Baseline EF was around 61%, eGFR around 64.4 ml/min/1.73 m², and KCCQ-Clinical Summary Score just under 54. An estimated 47% of the cohort had had a heart failure decompensation event within 12 months.

The observed clinical benefit in the trial was driven by fewer instances of worsening heart failure requiring hospitalization or IV drugs (HR 0.41, 95% CI 0.22-0.75) and hospitalizations for heart failure (HR 0.44, 95% CI 0.22-0.87).

Benefits were consistent in all predefined subgroups, according to Packer's group.

The investigators acknowledged that their trial criteria did not account for different definitions of obesity, including by waist-to-height ratio.

Ho also noted that the mechanism of benefit remains unknown for GLP-1 receptor agonists; it is unclear if the HF benefit is simply due to weight loss or other mechanisms.

"The effects of tirzepatide are probably related to its ability to reduce fat mass, thus diminishing the resulting expansion of plasma volume and inflammatory response that appear to underlie the pathogenesis of [HFpEF]," Packer's group surmised.

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