Tirzepatide Reduces Heart Failure Events in HFpEF With Obesity

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

The SUMMIT trial found that tirzepatide, a long-acting agonist of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, reduced the risk of the co-primary outcome — a composite of death from cardiovascular causes or a worsening heart failure event — by 38% versus placebo. The effect was driven by a reduction in worsening heart failure events defined as those requiring hospitalization or urgent intravenous drug therapy.

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

“SUMMIT is the first trial in patients with HFpEF and obesity that had major heart failure outcomes as the primary prespecified endpoint, and is therefore the first trial to demonstrate that a medication can change the clinical trajectory of the disease in patients with HFpEF and obesity,” said lead investigator Milton Packer, MD.

Packer, a distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas, Texas, and visiting professor at Imperial College, London, UK, presented the SUMMIT results on November 16 at the American Heart Association (AHA) Scientific Sessions 2024.

The trial 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 with overweight or obesity, and previous studies have shown weight loss of 12%-21% with the drug.

However, there are significant issues with access to GLP-1 agonist drugs because of their expense, and it is hoped that these data now showing a benefit in heart failure outcomes will somewhat improve that situation.

“Practice Changing”

Discussing the trial during an AHA press conference, Jennifer Ho, MD, associate professor of medicine at Harvard Medical School, Boston, Massachusetts, said: “This really is a practice-changing trial and cements this type of therapy as one of the cornerstones of obesity and HFpEF treatment.”

Ho explained that the prevalence of heart failure continues to increase, and although most patients with heart failure are thought to 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 “struggles every day in clinic with how to make our patients with HFpEF feel better.” 

She pointed out that obesity is a known key factor that leads to HFpEF, and in some studies, over 80% of patients with HFpEF have overweight or obesity.

“So this is an enormous problem, and this study is going to affect how 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 — enrolled patients with HFpEF and obesity, and both showed improvements in quality of life, physical limitations, and weight loss, but they were not powered for a reduction in major clinical outcomes.

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

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

The SUMMIT 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/m² were randomized to receive tirzepatide up to 15 mg subcutaneously once per week or placebo for at least 52 weeks. The mean duration of follow-up was 104 weeks.

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

Results showed that death from cardiovascular causes or a worsening heart failure event occurred in 9.9% of the tirzepatide group versus 15.3% with placebo (hazard ratio [HR], 0.62; 95% CI, 0.41 – 0.95; P = .026).

The benefit was driven by a reduction in worsening 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).

Death from cardiovascular causes 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 small to be meaningful and attributed the increase in the tirzepatide group to chance. 

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

Secondary endpoints showed an improvement in 6-minute walk distance of 18 m, 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 of which were highly statistically significant findings, Packer reported.

The benefit with tirzepatide was consistent across all major subgroups.

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

Cost a Big Issue

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

“There are many, many barriers that our patients and our providers face, including access, costs, health inequities, and provider expertise to really guide and initiate these therapies successfully.”

She said she prescribes these drugs routinely for patients with obesity and cardiovascular risk, but “we often come up against financial and insurance barriers, and this is highly variable across patients in being successful in getting these medications filled.”

Packer is hopeful that the SUMMIT data will improve access to these drugs.

“The concept that a lot of payers face is the sheer number of people who qualify as having obesity is enormous. They look at that number multiplied by the cost of the drugs and they are in pain,” he said.

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

Ho pointed out that another problem with these drugs is the high discontinuation rate: around 10% of patients who start therapy with one of these medications stop by 6 weeks, and up to 50% discontinue by 1 year.

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

“Angry Adipocytes”

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

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

He explained that the process is driven by visceral adiposity: “There is fat around the major organs of the body, particularly fat around the heart. When it becomes expanded, it changes its biology and starts secreting molecules that cause fluid retention and inflammation systemically and within 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. The GLP-1 agonist drugs work to reduce this inflammatory response, and the reduction in inflammation in this trial was really striking,” he explained.

Packer said it is not known whether the dual action of tirzepatide as a GIP agonist as well as a GLP-1 agonist would have further anti-inflammatory effects. “There are suggestions that this may be the case from laboratory studies, but we really don’t know how that translates into the clinical setting. We don’t really know whether these drugs (tirzepatide and semaglutide) are meaningfully different.”

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

“Prior studies have shown that GLP-1 drugs can improve quality of life, but now we have evidence that tirzepatide can improve major heart failure outcomes. There are key learnings here supporting cardiovascular benefits of tirzepatide and the availability of meaningful treatment for patients with HFpEF and obesity. But we must acknowledge that these medications are expensive. The real challenge will be to try to ensure equitable access to all who can benefit from them,” he said.