AT-001, a potent aldose reductase inhibitor, did not improve exercise capacity in diabetic cardiomyopathy with impaired exercise capacity

By Christina Lalani on

Key Points: 

  • The ARISE-HF trial evaluates the use of AT-001, a potent aldose reductase inhibitor, to reduce the risk of diabetic cardiomyopathy among patients with Type II diabetes.
  • The trial did not find a significant difference in its primary outcome, change in a patient’s peak VO2 consumption, or secondary outcomes, including risk of progression to overt heart failure, between patients who received the higher dose of AT-001 (1500 mg) compared to placebo.
  • In a pre-specified secondary analysis of patients who were not receiving either a GLP1 agonist or an SGLT2 inhibitor, there was a statistically significant difference in VO2 consumption after 15 months between patients receiving AT-001 1500 mg and those receiving placebo.

Diabetic cardiomyopathy is a potential complication of long-standing Type II diabetes with an estimated prevalence of 1 in 5 among patients with diabetes and no pathophysiology-specific treatments. Patients with diabetes continue to have an increased risk of heart failure even after adjustment for other comorbidities. The development of diabetic cardiomyopathy is thought to involve increased activity of the polyol pathway, which is catalyzed by aldose reductase, and plays a role in the development of myocardial injury. In the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial, the authors evaluate the use of a selective and potent aldose reductase inhibitor, AT-001, in patients with early asymptomatic diabetic cardiomyopathy. AT-001 acts by inhibiting aldose reductase from breaking down glucose into sorbitol, a type of sugar that can cause myocardial damage by causing myocardial stiffening and decreasing myocardial function. 

ARISE-HF enrolled 691 patients across 62 international sites between September 2019 and October 2022. To be eligible for enrollment, patients had to have a history of type 2 diabetes with evidence of myocardial dysfunction via elevated biomarkers or structural abnormalities as well as decreased exercise capacity. Patients could not have a known history of clinical heart failure, severe coronary artery disease, severe valvular disease, prior stroke or clinically significant arrhythmias. The primary endpoint for the trial was change in a patient’s peak oxygen consumption (VO2) from baseline to 15 months. The secondary outcomes included risk of progression to overt heart failure, NT-proBNP level, and patient-reported metrics including the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Physical Activity Scale of the Elderly (PASE). 

Of the 691 patients enrolled in the trial, 50% were female. The mean participant age was 67.4 years old and the mean duration of diabetes was 14.5 years with a mean hemoglobin A1c of 7.0%. Patients had reasonably well-controlled hypertension (mean blood pressure of 130/76 mmHg) and hyperlipidemia (mean LDL-cholesterol of 77 mg/dL). At baseline, the median NT-proBNP was 71 ng/L and the average peak VO2 was depressed at 15.7 3.8 mL/Kg/minute. 25.3% of patients had a depressed global longitudinal strain on TTE. At the time of enrollment 38% of patients were taking SGLT-2 inhibitors or GLP-1 agonists.

After enrollment, patients were randomized to receive one of the following: AT-001 1000 mg, AT-001 1500 mg, or placebo. After 15 months, there was no statistically significant difference in peak VO2 max between patients who received AT-001 1500 mg and those who received placebo. There was also no significant difference between the two groups in the predetermined secondary outcomes. 

However, in the predesignated subgroup analysis of patients not receiving SGLT2 inhibitors or GLP1 agonists, there was a statistically significant difference between the two groups with a least squares difference of means of 0.62 (p =0.04) after 15 months. Within this subgroup, there was a ≥ 6% decline in peak VO2 among 46.0% of patients who received the placebo and among 32.7% of patients who received the high dose AT-001 (OR = 0.56, 95% CI: 0.33, 0.96, p = 0.04).  Future studies are needed regarding the potential role of AT-001 to improve CV outcomes in this high-risk patient population.