Tirzepatide reduces heart failure events in HFpEF with obesity

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

The SUMMIT trial revealed that Tirzepatidea long-acting agonist of glucagonPeptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors reduce the risk of the composite secondary outcome of cardiovascular death or worsening heart failure events compared to placebo. 38% reduction. . This effect was driven by fewer worsening heart failure events requiring hospitalization or emergency 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 to have a significant heart failure outcome as a pre-specified primary endpoint, and therefore demonstrates that drug therapy may improve the clinical course of the disease in patients with HFpEF and obesity. “This is the first study to demonstrate that we can make a difference,” said lead researcher Dr. Milton Packer.

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

The test results came out at the same time. Published online in New England Medical Journal.

Tirzepatide is already approved in the United States to treat: type 2 diabetes Used for weight management in overweight or obese people, previous studies have shown this drug to reduce weight by 12% to 21%.

However, the availability of GLP-1 agonist drugs is a significant problem due to their cost, and it is hoped that these data showing benefit in heart failure outcomes will improve the situation somewhat.

“Practice to change”

Jennifer Ho, M.D., associate professor of medicine at Harvard Medical School in Boston, Massachusetts, spoke about the trial at an AHA press conference and said, “This is truly a game-changing trial, making this type of therapy one of the cornerstones of medical practice.” We will firmly establish this as one of the Obesity and HFpEF treatment. ”

Dr. Ho said that while the prevalence of heart failure continues to increase and most patients with heart failure are thought to have preserved ejection fraction rather than reduced ejection fraction, there are no treatments available for HFpEF. He explained that there were few options.

As a cardiologist who treats patients with advanced heart failure, Dr. Ho said, “I struggle every day in the clinic to think of ways to help patients with HFpEF feel better.”

He noted that obesity is known to be an important factor in causing HFpEF, with some studies showing that more than 80% of HFpEF patients are overweight or obese.

“This is a huge problem, and this study will impact the way we think about the vast majority of people with HFpEF,” she said.

Dr. Ho said that in two previous trials using different GLP-1 agonists, Semaglutide — Step HFpEF and STEP HFpEF Diabetes — Enrolled patients with HFpEF and obesity, both of whom showed improvements in quality of life, physical limitations, and weight loss, but no effect on reductions in primary clinical outcomes.

A combined analysis of data from these two trials and HFpEF patients from two other semaglutide trials showed a 31% reduction in the risk of worsening heart failure or cardiovascular death. “However, this combined 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 will really expand our knowledge base, as the first trial to evaluate the clinical outcomes of HFpEF with obesity, and the clinical implications in my mind are that these drugs are the mainstay of pharmacotherapy for obesity and HFpEF,” she said.

summit trial

The SUMMIT trial enrolled 731 heart failure patients with obesity, defined as an ejection fraction of at least 50% and a BMI of at least 30 kg/m3.² Participants were randomly assigned to receive up to 15 mg of tirzepatide subcutaneously once a week or a placebo for at least 52 weeks. The mean duration of follow-up was 104 weeks.

The two primary endpoints were death from cardiovascular disease or worsening heart failure events and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; scores range from 0 to 100, with higher scores decreasing (changes up to week 52) were composite values. (indicating an improved quality of life).

Results showed that death from cardiovascular disease or worsening heart failure occurred in 15.3% of patients in the tirzepatide group compared to 9.9% in the tirzepatide group (hazard ratio). [HR]0.62; 95% CI, 0.41 to 0.95. P = .026).

This effect was driven by a reduction in heart failure worsening events that occurred in 8.0% and 14.2% of the tirzepatide and placebo groups, respectively (HR, 0.54; 95% CI, 0.34 to 0.85).

Cardiovascular death occurred in 8 (2.2%) and 5 (1.4%) patients, respectively (HR, 1.58; 95% CI, 0.52 to 4.83). Professor Packer said these numbers were too small to be meaningful and thought the increase in tirzepatide was due to chance.

For the second primary endpoint, the mean improvement in KCCQ-CSS scores was 19.5 for the tirzepatide group compared to 12.7 for the placebo group, a difference of 6.9 points, which Packer described as “a very substantial improvement.'' The difference was statistically significant.”

Secondary endpoints showed that tirzepatide improved 6-minute walking distance by 18 meters, reduced body weight by 12%, and “most significantly” reduced C-reactive protein (a measure of systemic inflammation) by 34.9%. Packer reported that the results were highly statistically significant.

The benefit with tirzepatide was consistent across all major subgroups.

Adverse events (primarily gastrointestinal) that led to study drug discontinuation occurred in 6.3% of patients in the tirzepatide group and 1.4% in the placebo group, which Packer said is consistent with previous trials of tirzepatide in obese patients. said.

Cost is a big issue

Ho said the biggest challenge ahead is to put the results into practice and expand the use of GLP-1 agonists.

“There are many barriers that patients and health care providers face, including access, cost, health inequities, and the expertise of health care providers to actually guide and initiate these treatments. ”

She said she regularly prescribes these drugs to patients who are overweight or obese. cardiovascular riskHowever, “financial and insurance barriers are often encountered, and the success of filling these medications varies widely from patient to patient.”

Packer hopes the data from the summit will improve access to these medicines.

“What many payers are facing is the sheer number of people who are identified as obese. They look at that number multiplied by the cost of their medications, and they're suffering.” he said.

“If these drugs were prescribed to a targeted group of obese patients (HFpEF patients) who suffer greatly from high incidence, this equation would make more sense for patients and physicians alike. But I think this data is also very useful for payers.”

Professor Ho pointed out that another problem with these drugs is the high discontinuation rate. Approximately 10% of patients who start treatment with any of these drugs will discontinue by 6 weeks, and up to 50% will discontinue by 1 year.

“We know that discontinuing these drugs causes weight gain and that most of their effects are likely to be reversed,” she said.

“Angry fat cells”

Packer discussed the mechanisms behind the benefits and pointed out that obesity is one of the main factors in HFpEF.

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

He explained that this process is caused by visceral fat accumulation. “There is fat around the body's major organs, especially around the heart. As fat expands, its biological properties change and it secretes molecules that cause fluid retention and inflammation throughout the body. ” causes fibrosis and HFpEF within the heart. ”

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

“These are very angry cells, going into full-blown endocrine rebellion. GLP-1 agonist drugs work to reduce this inflammatory response. And the reduction in inflammation in this trial really “It was remarkable,” he explained.

Professor Packer said it was unclear whether tirzepatide's dual action as a GIP agonist and GLP-1 agonist resulted in additional anti-inflammatory effects. “There are suggestions from laboratory studies that this may be the case, but we don't really know how that translates to clinical practice. I don't really know if there's any difference.”

Amit Khera, MD, chair of the AHA 2024 Scientific Sessions Program Council and chief of preventive cardiology at UT Southwestern Medical Center in Dallas, Texas, also commented on the SUMMIT trial, saying: Increase in obesity, diabetes, high blood pressure. ”

“Previous studies have shown that GLP-1 drugs can improve quality of life, but now we have evidence that tirzepatide can improve key heart failure outcomes. There are important findings supporting the cardiovascular benefits of HFpEF and the availability of meaningful treatments for patients with HFpEF.However, it must be recognized that these drugs are expensive. “It's about ensuring fair access for all who benefit from it,” he said.