April 9, 2024 — One of the first studies to try to treat early heart failure in people with type 2 diabetes did not meet its primary endpoint, but a pre-planned subgroup analysis found that We found a statistically significant treatment effect in patients without. SGLT2 inhibitors or GLP-1 RAs are antidiabetic drugs that also have effects on the heart. The study was presented at the American College of Cardiology’s Annual Scientific Sessions.

Decline in exercise capacity is a hallmark of progression to overt heart failure. The international ARISE-HF trial was designed to test the efficacy of investigational drug AT-001 in stabilizing exercise capacity in patients with diabetic cardiomyopathy. The study’s primary endpoint was that each patient between the placebo group and the group receiving high-dose AT-001 had a The difference was in the maximum amount of oxygen that could be produced (peak VO2). Months later.

James Januzzi, MD

“Although the primary endpoint did not reach statistical significance, these results provide an encouraging signal that increases enthusiasm for further evaluating the effects of AT-001 on diabetic cardiomyopathy,” said Harvard Medical School. said Dr. James Januzzi, Hatter Family Professor of Medicine. is a cardiologist at Massachusetts General Hospital, a heart failure investigator at the Baim Institute for Clinical Research, and the study’s lead author. “These results also highlight the importance of recognizing heart failure risk early in patients with diabetes and continuing to focus on initiating treatment before symptoms progress to overt heart failure.”

Diabetic cardiomyopathy is a disease in which chronically high levels of blood sugar (hyperglycemia) damage the heart muscle, leading to heart failure over time. The difference between diabetic cardiomyopathy and other heart diseases is that people with the condition typically do not have coronary artery disease, heart valve disease or other causes of heart failure, Januzzi said. It is estimated that approximately 1 in 5 people with diabetes has diabetic cardiomyopathy, but it may go unnoticed at first as there are no symptoms.

AT-001 works by preventing the enzyme aldose reductase from breaking down glucose into another type of sugar called sorbitol. Sorbitol can damage heart tissue by causing stiffening of the heart muscle and decreased heart function over time. Yanuzzi said there are currently no approved treatments that target diabetic cardiomyopathy and the underlying changes that lead to its progression to overt heart failure.

The ARISE-HF trial enrolled 691 patients (median age 67 years) at 62 centers around the world, half of whom were women. Patients had type 2 diabetes for an average of 14 years. Although they had no symptoms of heart failure or blockages in the arteries that carry blood to the heart, all had structural heart disease or abnormal cardiac biomarkers that put them at risk for heart failure. , had a higher risk of developing overt heart failure symptoms. diagnosis. At the time of study entry, 38% of patients received sodium glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which have been shown to have beneficial effects on heart disease. He was taking diabetes medication. These include reductions in heart failure, heart attacks, and strokes.

Patients were randomly assigned to receive 1,000 mg or 1,500 mg of AT-001 or placebo twice daily. All patients underwent a cardiopulmonary exercise test at the start of the study and again 15 months later to measure oxygen and carbon dioxide levels in their blood and the amount of air their lungs could take in. Patients’ median peak VO2 – maximum amount of oxygen at the time they entered the study, Januzzi said, was 15.7, which is higher than the average of about 27 for men over 65 and about 23 for women in the same age group. It is said to be below.

“Their dramatic decline in peak VO2 indicates a highly impaired population who are more likely to progress to symptomatic heart failure,” Januzzi said.

Secondary endpoints include changes in patients’ overall physical activity level, changes in symptoms and perception of quality of life. The researchers also conducted a preplanned subgroup analysis comparing outcomes for patients who were receiving an SGLT2 inhibitor or GLP-1 RA at baseline with those who were not.

At 15 months, a primary comparison of patients treated with high-dose AT-001 and patients in the placebo group showed no worsening in peak VO2 in the AT-001 group, but a statistically significant decrease in peak VO2 in the placebo group. A significant decrease was observed. reduction. The mean difference in peak VO2 between the two groups was 0.3, which was not statistically significant, Januzzi said. Results for secondary endpoints also did not reach statistical significance.

However, in a pre-planned subgroup analysis that included only patients taking and not taking SGLT2 inhibitors or GLP-1RAs, the mean peak VO2 between the AT-001 and placebo groups The difference was 0.64 and was statistically and clinically significant. said Januzzi.

“Although this is an exploratory finding, differences in levels of peak VO2 may lead to an improved ability to perform daily activities with less effort,” he said.

The study’s original plan included the option to treat patients for an additional 12 months and follow them for a total of 27 months, Januzzi said. However, the study began just before the start of the COVID-19 pandemic, leading to recruitment delays. As a result, the sponsor decided that he would end the study at the 15-month mark.

“We will never know whether a longer treatment period would have helped more patients achieve peak VO2 improvements, perhaps including those on heart-effective drugs,” Januzzi said. .

Another possible study limitation was that all enrolled patients had well-controlled blood sugar levels, which was a requirement for study approval by the U.S. Food and Drug Administration, Yannuzzi said. Stated.

“Our patient had early-stage diabetic cardiomyopathy, but his blood sugar levels were very well controlled, which may be why the condition progressed so slowly,” he says. .

Overall, the study “demonstrated the tolerability and safety of a very potent drug with potential applications in a wide range of complications of diabetes,” Dr. Januzzi said.

The research was funded by Applied Therapeutics, which manufactures AT-100. The study was published online in the Journal of the American College of Cardiology upon publication.

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