Treatment with selective aldose reductase inhibitor effective against diabetic cardiomyopathy? Study provides insights

The researchers found that among individuals with diabetic cardiomyopathy (DbCM) and impaired exercise capacity, treatment with AT-001, a highly selective aldose reductase inhibitor, for 15 months did not significantly better exercise capacity compared with a placebo. However, several signals of benefit support a hypothesis that heart failure might be preventable if the polyol pathway, which features aldose reductase upregulation, is inhibited early.

The findings were published online in the Journal of the American College of Cardiology on April 8, 2024.

Progression to symptomatic heart failure is a complication of type 2 diabetes (T2D); heart failure onset in this setting is commonly preceded by deterioration in exercise capacity.

Diabetic cardiomyopathy, a condition characterized by structural and functional changes in the heart muscle, is a leading cause of morbidity and mortality among diabetic patients. Despite advancements in diabetes management, therapeutic options for diabetic cardiomyopathy remain limited, highlighting the urgent need for innovative treatments.

Against the above background, James L. Januzzi, Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA, and colleagues sought to determine whether AT-001 can stabilize exercise capacity among individuals with diabetic cardiomyopathy and reduced peak oxygen uptake (Vo2).

Six hundred and ninety-one individuals with DbCM meeting inclusion and exclusion criteria were randomized to twice daily placebo or ascending doses of AT-001. The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. Stratification at inclusion included region of enrollment, use of glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter 2 inhibitors, and cardiopulmonary exercise test results.

The primary endpoint was a proportional change from baseline to 15 months in peak Vo2. Subgroup analyses included measures of disease severity and stratification variables.

The study led to the following findings:

• By 15 months, peak Vo2 fell in the placebo-treated patients by –0.31 mL/kg/min, whereas in those receiving high-dose AT-001, peak Vo2 fell by –0.01 mL/kg/min; the difference in peak Vo2 between placebo and high-dose AT-001 was 0.30.
• In prespecified subgroup analyses among those not receiving glucagon-like peptide-1 receptor agonists or sodium-glucose cotransporter 2 inhibitors at baseline, the difference between peak Vo2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min.

While further research is warranted to validate these findings and explore long-term outcomes, the results of this randomized trial offer a beacon of hope for individuals living with diabetic cardiomyopathy. As researchers continue to unravel the complexities of this condition, the pursuit of innovative treatments remains paramount in improving the quality of life and prognosis for diabetic patients worldwide.

Reference:

Januzzi JL Jr, Butler J, Del Prato S, Ezekowitz JA, Ibrahim NE, Lam CSP, Lewis GD, Marwick TH, Perfetti R, Rosenstock J, Solomon SD, Tang WHW, Zannad F. 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. Epub ahead of print. PMID: 38597864.