Selective aldose reductase inhibitor for DCM disappoints in trial

Treatment with AT-001, a highly selective aldose reductase inhibitor, for 15 months seems no better than placebo in improving exercise capacity among individuals with diabetic cardiomyopathy (DCM) and impaired exercise capacity, a study has shown.

A team of investigators randomly assigned a total of 691 individuals with DCM who met the eligibility criteria to receive either ascending doses of AT-001 or placebo twice daily. The inclusion criteria were as follows: region of enrolment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists.

The proportional change in peak Vo₂ from baseline to 15 months was the primary endpoint. In subgroup analyses, the investigators assessed disease severity and stratification variables.

Of the participants (mean age 67.5 years), half (50.4 percent) were women.  Peak Vo₂ at 15 months dropped by ‒0.31 mL/kg/min in the placebo group (p=0.005 compared to baseline) compared with ‒0.01 mL/kg/min in high-dose AT-001 group (p=0.21). The between-group difference was 0.30 (p=0.19).

Prespecified subgroup analyses among individuals not receiving SGLT2 inhibitors or GLP-1 receptor agonists at baseline revealed a difference in peak Vo₂ of 0.62 mL/kg/min at 15 months in the placebo versus high-dose AT-001 groups (p=0.04; p_interaction=0.10).

“Progression to symptomatic heart failure is a complication of type 2 diabetes,” the investigators said. “[H]eart failure onset in this setting is commonly preceded by deterioration in exercise capacity.”