ATLANTA, GA — A multicenter controlled trial testing the ability of an aldose reductase inhibitor to stabilize early-stage asymptomatic diabetic cardiomyopathy missed its primary endpoint, researchers reported.
But several signals of benefit support a hypothesis that heart failure might be preventable if the polyol pathway, which features upregulation of aldose reductase, is inhibited at an early stage.
In the randomized trial, ARISE-HF, the experimental agent called AT-001 did not perform significantly better than placebo on preventing deterioration in peak oxygen uptake (peak VO2), the primary endpoint, but the benefit was significant in a prespecified subgroup, said James L. Januzzi, Jr, MD, a professor of medicine at Harvard University and an investigator at the Baim Institute for Clinical Research, Boston, Massachusetts.
In addition, the primary endpoint moved in the right direction numerically overall, and there were several factors likely to have been obstacles to a positive result, particularly relatively tight glycemic control in the study population at baseline. It is chronic hyperglycemia, which activates the polyol pathway and the upregulation of aldose reductase, Januzzi explained.
Aldose Reductase Target Is Supported
"There is abundant evidence to support upregulation of aldose reductase and activation of the polyol pathway as pivotal events in diabetic cardiomyopathy," Januzzi said. "Had we evaluated a more representative population with less control of blood glucose, the result might have been different."
Diabetic cardiomyopathy is a heart muscle disease related to chronic hyperglycemia. When the polyol pathway is activated, upregulated aldose reductase prompts release of sorbitol, a source of osmotic stress and cell death, and release of fructose, which activates neurohormones, reactive oxygen species, and other noxious stimuli leading to myocyte damage, Januzzi explained.
The hypothesis of the trial was that the aldose reductase inhibitor AT-001 could abort this process in patients with type 2 diabetes mellitus. By interfering with this key pathogenic process, heart damage could be prevented, preserving exercise tolerance as reflected in stabilization of peak VO2 over time.
The results of the ARISE-HF study were presented on April 8 by Januzzi in a late-breaking clinical trials session at the annual meeting of the American College of Cardiology and published online simultaneously in the Journal of the American College of Cardiology.
Global Study Included 62 Sites
In the global ARISE-HF trial, 691 individuals with type 2 diabetes and reduced exercise capacity but otherwise asymptomatic for heart failure and without any known history of atherosclerotic cardiovascular disease were randomized at 62 sites to one of two doses of AT-001 (1000 mg or 1500 mg daily) or placebo. Blood pressure control and an A1c < 8.5% were also entry criteria.
The change in peak VO2 from baseline was compared after 15 months of therapy.
At month 15, peak VO2 fell a mean of −0.34 mL/kg/min from baseline in placebo patients, a decline that was highly statistically significant (P = .005). In contrast, there was essentially no change from baseline among those on the higher dose of AT-001 (−0.03; P = .21). However, the difference in the between-arm values did not reach statistical significance (P = .19).
There were no differences in secondary endpoints, such as change in the Kansas City Cardiomyopathy Questionnaire or in N-terminal pro-b-type natriuretic peptide, but patients who were not taking a sodium-glucose cotransport-2 inhibitor or a glucagon-like peptide-1 receptor agonist were evaluated as a prespecified subgroup.
Representing slightly more than 60% of the population, the fall in peak VO2 was greater among placebo patients who were not taking one of these antidiabetic agents (−0.54 mL/kg/min), while there was a slight gain (+0.8 mL/kg/min) among those randomized to ATT-001. The mean between-group change (0.62 mL/kg/min) did reach statistical significance (P = .04).
The relative preservation of peak VO2, a surrogate for the functional capacity of the heart, is modest, but the ACC-invited discussant, Anuradha Lala-Trindade, MD, an expert in heart failure and an associate professor at the Icahn School of Medicine at Mount Sinai, New York City, was intrigued. She noted that patients who report no heart failure symptoms yet have diminished functional capacity on testing are common.
If these patients could be identified through screening and then offered a therapy that preserves VO2, the goal would be to prevent rather than treat the cardiomyopathy, she said.
For a common complication and major source of morbidity and mortality in patients with diabetes, "this might be the best way to move forward from here," Lala-Trindade said.
Himabindu Vidula, MD, director of the ventricular assist device program at the University of Pennsylvania, Philadelphia, Pennsylvania, agreed that the underlying pathophysiology that Januzzi described is supported by evidence.
She suggested the signal of benefit in ARISE-HF encourages further evaluation of intervention in advance of diabetic cardiomyopathy if further work can establish that aldose reductase or another strategy prevents rather than treats the underlying pathophysiology.
Januzzi reported financial relationships with more than 15 pharmaceutical companies, including Applied Therapeutics, which provided funding for this trial. Lala-Trindade reported financial relationships with AstraZeneca, Cytokinetics, Merck, and Novartis. Vidula reported a financial relationship with Abbott.
Ted Bosworth is a medical journalist based in New York City.