ACC.24 – In patients with diabetic cardiomyopathy and reduced exercise tolerance, the aldose reductase inhibitor AT-001 did not improve exercise tolerance as measured by change in peak VO₂ compared with placebo

p>This summary is based on the presentation of James Januzzi Jr., MD (Boston, MA, US) at the ACC.24 Scientific Session – A Selective Aldose Reductase Inhibitor for the Treatment of Diabetic Cardiomyopathy – Primary Results of the Phase 3 Randomized Controlled ARISE-HF Study

Introduction and methods

Heart failure (HF) is a major CV complication among individuals with diabetes (DM). Patients with DM have a 2-fold increased risk for HF development. This increased risk for HF persists even when adjusting for the presence of classical HF risk factors. DM may result in heart muscle disease known as diabetic cardiomyopathy (DbCM) which is related to the severity and chronicity of hyperglycermia. It is thought to occur in around one in five patients with diabetes. Aldose reductase plays a role in the pathway in the myocardium responsible for myocardial injury associated with elevated blood glucose.

In ARISE-HF, 691 DbCM patients with reduced exercise tolerance (likely to transition to over HF in a short period of time) were randomized to 1000 mg of the aldose reductase inhibitor AT-001, 1500 mg AT-001 or placebo, all in a dosing of twice daily. Follow-up was 15 months.

Main results

• At 15 months, the LS-mean difference of change in peak VO₂ between the AT-001 1500 mg group vs. placebo was 0.30 (02.23) (P=0.19).
• In a prespecified subgroup of patients not receiving SGLT2 inhibitors or GLP-1RA, the LS-mean difference of change in peak VO₂ between the AT-001 1500 mg group vs. the placebo group was 0.62 (0.30) (P=0.04).
• The drug was well tolerated without off-target side effects.

Conclusion

In the ARISE-HF trial, treatment with AT-001 did not results in improved exercise tolerance compared with placebo in patients with DbCM and reduced exercise capacity. The drug was well tolerated and appeared to be safe.

Januzzi speculated that the study participants in ARISE-HF had very well-controlled DM which may not reflect persons with DbCM more generally. He ended his presentation by saying that more investigation (for a longer time period in a more generalizable population of DbCM) is needed regarding the potential role of AT-001 to improve CV outcomes in this high-risk population.

- Our reporting is based on the information provided at the ACC.24 Scientific Session -

The findings of this study were simultaneously published in J Am Coll Cardiol