CHICAGO – A new study has shown for the first time that drug treatment can improve clinical outcomes of major heart failure in patients with heart failure with preserved ejection fraction (HF to EF) and obesity.
Significant positive effects
The test SUMMIT found that tirzepatide, a long-acting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, reduced the risk of co-primary endpoint, a composite endpoint combining death from cardiovascular causes or worsening of a heart failure event, 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 effects on health status, exercise tolerance and systemic inflammation.
“SUMMIT is the first trial in patients with HF with preserved EF and obesity to have major outcomes of heart failure as a prespecified primary endpoint. Therefore, this is the first trial to demonstrate that a drug can modify the clinical trajectory of the disease in patients with HF with preserved EF and obesity,” said principal investigator Dr. Pr Milton Packer.
The Pr Packera leading cardiovascular scientist at Baylor University Medical Center in Dallas, Texas, and visiting professor at Imperial College London, United Kingdom, presented results from the SUMMIT trial on November 16 at of the 2024 American Heart Association (AHA) Scientific Sessions.
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 who are overweight or obese, and previous studies have shown weight loss of 12 to 21 percent with the drug.
However, access to GLP-1 agonists poses significant challenges due to cost, and it is hoped that these data now showing a benefit in heart failure outcomes will improve this situation somewhat.
“Change of practice”
At an AHA press conference, the Dre Jennifer Holecturer in medicine at Harvard Medical School (Boston, USA), said: “This is truly a practice-changing trial that cements this type of treatment as one of the Basics of obesity and treatment of HF with preserved EF. »
Dr. Ho explains that the prevalence of heart failure continues to increase, and although most patients with heart failure are considered to have preserved ejection fraction, rather than reduced ejection fraction, Few therapeutic options are available for HF with preserved EF.
As a cardiologist who treats patients with advanced heart failure, Dr. Ho said she “fights every day in the hospital to make our HF patients with preserved EF feel better.”
She pointed out that obesity is a known key factor that leads to HF with preserved EF, according to some studies, more than 80% of patients with HF with preserved EF are overweight or obese.
“So this is a huge problem, and this study is going to influence how we look at the majority of HF patients with preserved EF,” she said.
Dr. Ho noted that two previous trials of another GLP-1 agonist, semaglutide, STEP HFpEF and STEP HFpEF Diabetes, included patients with HF with preserved EF and obesity, and that the two showed improvements in quality of life, physical limitations and weight loss, but lacked the statistical power to reduce major clinical outcomes.
A combined analysis with data from these two trials as well as HF patients with preserved EF from two other semaglutide trials showed a 31% reduction in the risk of worsening heart failure or death. cardiovascular origin. “However, this pooled analysis should be taken with a grain of salt, as these trials did not have the primary aim of examining clinical outcomes,” Jennifer Ho said.
“This is where SUMMIT really expands our knowledge base, as the first trial with the power to evaluate clinical outcomes in preserved HR with obesity. In clinical terms, I believe these drugs are central in the pharmacotherapy of obesity and HF with preserved EF,” she said.
The SUMMIT test
In the SUMMIT study, 731 patients with heart failure with an ejection fraction of at least 50% and obesity defined by a body mass index of at least 30 kg/m2 were randomized to receive tirzepatide 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 progression from baseline to 52e week, clinical summary score Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life).
The results showed that death of cardiovascular origin or worsening of a heart failure event occurred in 9.9% of patients in the tirzepatide group compared to 15.3% of patients in the placebo group (relative risk [RR] : 0,62 ; IC à 95 % : 0,41-0,95 ; p = 0,026).
The benefit was due to a reduction in worsening heart failure events, which occurred in 8.0% and 14.2% of the tirzepatide and placebo groups, respectively (RR: 0.54; 95% CI: 0.34-0.85).
Deaths from cardiovascular causes occurred in eight patients (2.2%) and five patients (1.4%), respectively (RR: 1.58; 95% CI: 0.52-4.83). Prof Packer said these figures are too low to be significant and attributed the increase in the tirzepatide group to luck.
Substantial improvement in quality of life
The second primary endpoint showed a mean improvement in KCCQ-CSS score of 19.5 in the tirzepatide group versus 12.7 in the placebo group, a difference of 6.9 points, which Prof. Packer described as “a very substantial, highly statistically significant difference”.
Secondary endpoints showed an 18m improvement in 6-minute walking distance, 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 results, Prof. Packer reported.
The benefit associated with tirzepatide was consistent across all major subgroups.
Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 6.3% of patients in the tirzepatide group and in 1.4% of patients in the placebo group, which corresponds according to Pr Packer to previous trials of tirzepatide in obesity.
Cost, a major issue
Dr. Ho said the biggest challenge was implementing the findings and expanding the use of GLP-1 agonists.
“Patients and healthcare professionals face many barriers, including access, costs, health inequities and healthcare professional expertise, to successfully guide and initiate these treatments. »
She says these drugs are routinely prescribed to patients who are obese and at cardiovascular risk, but “we often face financial and insurance barriers, and it varies greatly from patient to patient in terms of get these medications prescribed.”
Professor Packer hopes that SUMMIT data will improve access to these drugs.
“The fact is that payers are faced with a very large number of people considered obese. When they multiply that number by the cost of drugs, it scares them,” he said.
Dr. Ho noted that another problem with these drugs is the high rate of discontinuation: about 10% of patients who start treatment with one of these drugs stop after 6 weeks, and up to 50% stop after a year.
“We know that after stopping these medications weight gain occurs and most of the benefits are likely to be reversed,” she noted.
“Angry Adipocytes”
To explain the mechanism behind the benefits, Professor Packer recalled that obesity is one of the main factors in HF with preserved EF.
“We have an obesity epidemic in the United States and around the world, and the most serious and common cardiovascular complication in obesity is HF with preserved EF,” said Professor Packer.
He explains that the process is due to visceral adiposity: “There is fat around the main organs of the body and particularly around the heart. As fat expands, it changes its biology and begins to secrete molecules that cause fluid retention and systemic and cardiac inflammation, leading to fibrosis and preserved EF. »
He described heart failure with preserved ejection fraction as “an obesity-related disease of angry adipocytes.”
Dual action of tirzepatide
“These are particularly aggressive cells. They are in full endocrine rebellion. GLP-1 agonists work by reducing this inflammatory response, and the reduction seen in this trial was really striking,” he explained.
According to Professor Packer, it is not known whether tirzepatide’s dual action as a GIP agonist as well as a GLP-1 agonist would have other anti-inflammatory effects. “Laboratory studies suggest that this might be the case, but we don’t really know how this translates into the clinical setting. We do not have enough information to know whether these medicines (tirzepatide and semaglutide) are significantly different. »
The Dr Amit Kherachair of the AHA 2024 Council on Scientific Session Scheduling and director of preventive cardiology at UT Southwestern Medical Center in Dallas, Texas, USA, also commented on the SUMMIT trial: “Patients with HF with preserved EF have become all too common due to the increase in obesity, diabetes and hypertension. »
“Previous studies have shown that GLP-1-based treatments can improve quality of life, but we now have evidence that tirzepatide can improve outcomes in major heart failure. There are key lessons here supporting the cardiovascular benefits of tirzepatide and the availability of meaningful treatment for patients with HF with preserved EF and obesity. However, we must recognize that these drugs are expensive. The real challenge will be trying to ensure equitable access to all who can benefit,” he said.
This article was translated from Medscape.com part of the Medscape professional network, using several editorial tools, including AI, in the process. The content was reviewed by the editorial staff before publication.
