Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy

James L Januzzi Jr; Javed Butler; Stefano Del Prato; Justin A Ezekowitz; Nasrien E Ibrahim; Carolyn S P Lam; Gregory D Lewis; Thomas H Marwick; Riccardo Perfetti; Julio Rosenstock; Scott D Solomon; W H Wilson Tang; Faiez Zannad

doi:10.1016/j.jacc.2024.03.380

Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy

J Am Coll Cardiol. 2024 Apr 3:S0735-1097(24)06613-0. doi: 10.1016/j.jacc.2024.03.380. Online ahead of print.

Authors

Affiliations

¹ Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; Baim Institute for Clinical Research, Boston, Massachusetts, USA. Electronic address: JJanuzzi@mgb.org.
² University of Mississippi Medical Center, Jackson, Mississippi, USA; Baylor Scott and White Institute, Dallas, Texas, USA.
³ Interdisciplinary Center "Health Sciences," Sant'Anna School of Advanced Studies, Pisa, Italy.
⁴ Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
⁵ Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁶ Baim Institute for Clinical Research, Boston, Massachusetts, USA; National Heart Centre Singapore and Duke-National University of Singapore, Singapore.
⁷ Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁸ Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.
⁹ Applied Therapeutics, New York, New York, USA.
¹⁰ Velocity Clinical Research Center at Medical City, Dallas, Texas, USA.
¹¹ Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, Ohio, USA.
¹² Université de Lorraine, Inserm CIC and CHRU, Nancy, France.

PMID: 38597864
DOI: 10.1016/j.jacc.2024.03.380

Abstract

Background: Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity.

Objectives: The study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo₂).

Methods: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo₂ from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables.

Results: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo₂ fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo₂ fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo₂ between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo₂ in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10).

Conclusions: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).

Keywords: aldose reductase inhibitor; diabetes; heart failure.

Associated data

ClinicalTrials.gov/NCT04083339