CHICAGO — A new study has shown for the first time that drug treatment can reduce the major clinical consequences of heart failure in patients with heart failure and preserved ejection fraction (HFpEF) and obesity.

The SUMMIT trial found that tirzepatida long-acting agonist glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, reduced the risk of the co-primary outcome – a composite of cardiovascular death or worsening of an event heart failure – 38% compared to placebo. The effect was due to a reduction in the worsening of heart failure events defined as those requiring hospitalization or urgent intravenous drug treatment.

Tirzepatide also had significant and meaningful effects on health status, exercise tolerance, and systemic inflammation.

“SUMMIT is the first trial in patients with HFpEF and obesity that had a pre-specified primary endpoint of major consequences for heart failure, and is therefore the first trial to demonstrate that a drug can modify the clinical trajectory of disease in patients with ICFpEF and obesity,” said principal investigator Milton Packer, MD.

Packer, a leading researcher in cardiovascular sciences at Baylor University Medical Center in Dallas, Texas, and visiting professor at Imperial College London, United Kingdom, presented the SUMMIT results Nov. 16 at the occasion of American Heart Association (AHA) 2024 Scientific Sessions.

The test results were simultaneously published online in the New England Journal of Medicine.

Tirzepatide is already approved in the United States for the treatment of type 2 diabetes and for weight management in people who are overweight or obese, and previous studies have shown 12 to 21 percent weight loss with the drug.

However, access to GLP-1 agonist drugs poses significant problems due to their cost, and it is hoped that these data now showing a benefit in the progression of heart failure will improve this situation somewhat.

“Change of practice”

Discussing the trial at an AHA press conference, Jennifer Ho, MD, associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said, “This is truly a trial that changes practice and cements this type of therapy as one of the cornerstones of the study. obesity and HFpEF treatment.

Ho explained that the prevalence of heart failure continues to increase and although it is believed that most patients with heart failure have preserved ejection fraction, rather than reduced ejection fraction , few treatment options are available for HFpEF.

As a cardiologist who treats patients with advanced heart failure, Ho said she “fights every day in the clinic to make our HFpEF patients feel better.”

She highlighted that obesity is a known key factor leading to ICFpEF and that in some studies more than 80% of patients with ICFpEF are overweight or obese.

“So this is a huge problem, and this study is going to affect the way we think about the majority of patients with HFpEF,” she said.

Ho pointed out that two previous trials with another GLP-1 agonist, semaglutide — STEP HFpEF And STEP HFpEF Diabetes – recruited patients with HFpEF and obesity, and both showed improvements in quality of life, physical limitations, and weight loss, but they were not powered enough to reduce the primary outcomes clinics.

A pooled analysis of data from these two trials as well as HFpEF patients from two other semaglutide trials showed a 31% reduction in the risk of worsening heart failure or cardiovascular death. “But this pooled analysis should be taken with a grain of salt, as these trials were not primarily intended to examine clinical outcomes,” Ho said.

“This is where SUMMIT really expands our knowledge base, as the first trial to evaluate the clinical outcomes of HFpEF associated with obesity, and the clinical implications in my mind are that these drugs are essential in the pharmacotherapy for obesity and HFpEF,” she said.

The SOMMET trial

For the SUMMIT trial, 731 patients with heart failure and an ejection fraction of at least 50%, who also had obesity defined as a body mass index of at least 30 kg/m.² were randomized to receive tirzepatide up to 15 mg subcutaneously once weekly or placebo for at least 52 weeks. The average follow-up duration was 104 weeks.

The two primary endpoints were a composite of death from cardiovascular causes or worsening of a heart failure event and a change from baseline to 52 weeks in the clinical summary score of the Kansas City Cardiomyopathy Questionnaire (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life).

The results showed that deaths due to cardiovascular causes or worsening heart failure occurred in 9.9% of the tirzepatide group compared to 15.3% in the placebo group (relative risk (HR), 0.62 95% CI, 0.41 – 0.95; P. = 0.026).

The benefit was due to a reduction in the worsening of heart failure events, which occurred in 8.0% and 14.2% of the tirzepatide and placebo groups, respectively (HR: 0.54; 95% CI, 0.34 – 0.85).

Cardiovascular deaths occurred in eight patients (2.2%) and five patients (1.4%), respectively (HR: 1.58; 95% CI, 0.52 – 4.83). Packer said these numbers are too low to be significant and attributed the increase in the tirzepatide group to chance.

The second primary endpoint showed a mean KCCQ-CSS score improvement of 19.5 in the tirzepatide group compared to 12.7 with placebo, a difference of 6.9 points, which Packer described as ” a very substantial, highly statistically significant difference.”

Secondary endpoints showed an improvement in walking distance of 18 m in 6 minutes, a 12% reduction in body weight and a “most remarkable” 34.9% reduction in C-reactive protein ( a measure of systemic inflammation) with tirzepatide, all combined with tirzepatide. were highly statistically significant results, Packer reported.

The benefit with tirzepatide was consistent across all major subgroups.

Adverse events (primarily gastrointestinal) leading to discontinuation of the trial drug occurred in 6.3% of the tirzepatide group and 1.4% of the placebo group, which Packer said was consistent with previous trials of tirzepatide in obesity.

It costs a big problem

Ho said the biggest challenge ahead was implementing the findings and expanding the use of GLP-1 agonist drugs.

“Our patients and providers face so many barriers, including access, cost, health inequities, and provider expertise to truly guide and launch these therapies successfully.”

She said she regularly prescribed these drugs to patients suffering from obesity and cardiovascular riskbut “we often face financial and insurance barriers, and it varies greatly among patients in successfully obtaining these medications.”

Packer hopes the SUMMIT data will improve access to these medications.

“The idea that many payers are faced with is that the number of people considered to have obesity is enormous. They look at that number multiplied by the cost of medications and they are suffering,” he said.

“One would like to think that if these drugs are prescribed to a targeted group of obese patients (those with HFpEF) who are in tremendous pain with a high event rate, the equation would make much more sense, not just for the patients and physicians”, but also to payers, I think this data will be very useful in this discussion.

Ho pointed out that another problem with these drugs is the high discontinuation rate: about 10% of patients who start treatment with one of these drugs stop it after 6 weeks, and up to 50% stop it after a year.

“We know that after stopping these medications, weight gain occurs and most of the benefits may then be reversed,” she noted.

“Angry fat cells”

Discussing the mechanism behind the benefits, Packer highlighted that obesity is one of the main drivers of HFpEF.

“We have an obesity epidemic in the United States and around the world, and the most serious and common cardiovascular complication of obesity is HFpEF,” Packer said.

He explained that the process is driven by visceral adiposity: “There is fat around the major organs of the body, particularly around the heart. When it expands, it changes its biology and begins to secrete molecules that cause fluid retention and inflammation systemically and in the heart, causing fibrosis and HFpEF.

He described HFpEF as “an obesity-related disease of angry adipocytes.”

“These are very angry cells. They are in full-scale endocrine rebellion. GLP-1 agonist drugs work to reduce this inflammatory response, and the reduction in inflammation in this trial was really striking,” he said. -he explained.

Packer said it is unclear whether tirzepatide’s dual action as a GIP agonist and GLP-1 agonist would have other anti-inflammatory effects. “Laboratory studies suggest that might be the case, but we don’t really know how that translates to the clinical setting. We don’t really know if these drugs (tirzepatide and semaglutide) are significantly different.”

Also commenting on the SUMMIT trial, Amit Khera, MD, chair of the AHA 2024 Scientific Sessions Programming Council and director of preventive cardiology at UT Southwestern Medical Center in Dallas, Texas, said: “Patients with HFpEF are become all too common due to the increase in obesity, diabetes and hypertension“.

“Previous studies have shown that GLP-1 drugs can improve quality of life, but we now have evidence that tirzepatide can improve major outcomes in heart failure. and obesity. But we must recognize that these drugs are expensive. The real challenge will be trying to ensure equitable access for all who can benefit from it,” he said.