Treatment with AT-001, a highly selective aldose reductase inhibitor, had no significant effect on exercise capacity as measured by peak oxygen uptake (VO2) among individuals with diabetic cardiomyopathy (DbCM), according to results from a Late-Breaking Clinical Trial presented at ACC.24 and simultaneously published in JACC.

The global trial screened patients at 62 sites from Sept. 18, 2019, to Oct. 31, 2022, and randomized 691 participants with Stage B heart failure (HF) and reduced exercise capacity 1:1:1 to receive twice daily doses of either placebo, low-dose AT-001 (1,000 mg) or high-dose AT-001 (1,500 mg). The mean age of participants was 67.5 years, 50.4% were women and 82.5% were White. The average body mass index was 30.6 kg/m2, duration of diabetes 14.5 years, baseline HbA1c 6.98% and 76% had hypertension; about 38% were taking an SGLT2 inhibitor or GLP-1RA across study arms.

The baseline peak VO2 averaged 15.7 mL/kg/minute across treatment arms. The primary endpoint of proportional change in peak VO2 at 15 months was –0.03 mL/kg/minute (p=0.21) in the high-dose group compared with –0.34 mL/kg/minute (p=0.005) in the placebo group. The primary endpoint of LS-mean change difference between placebo and high-dose AT-001 was 0.30 and was not statistically significant (p=0.19).

A prespecified subgroup analysis looking at patients who were not taking an SGLT2 inhibitor or GLP-1RA found that peak VO2 declined by 0.54 mL/kg/minute at 15 months, while there was an improvement in peak VO2 of 0.08 mL/kg/minute with high-dose AT-001 (LS-mean difference, 0.62; p=0.04; interaction pvalue=0.10).

Results also showed there was a similar decline (–0.29 mL/kg/minute) in the secondary endpoint of peak VO2 between the low-dose AT-001 group and placebo group (p=0.84 for difference). Overall, a decline ≥6% in peak VO2 was observed in 41.8% of the placebo group and 36.2% of the high-dose AT-001 group (odds ratio [OR], 0.80; p=0.29); the difference was 46.0% vs. 32.7%, respectively, among patients who were not taking an SGLT2 inhibitor or GLP-1RA (OR, 0.56; p=0.04). No significant between-group differences were seen in relation to NT-proBNP.

"Although our primary endpoint fell short of statistical significance, there are encouraging signals in these results that increase enthusiasm to further evaluate effects of AT-001 on diabetic cardiomyopathy," said lead author James L. Januzzi Jr., MD, FACC. "These results also speak to the importance of continuing to focus on earlier recognition of [HF] risk in patients with diabetes and on initiating treatment before the condition has progressed to overt [HF]."

"AT-001 treatment was associated with better exercise capacity at 15 months," in the patients not taking an SGLT2 inhibitor or GLP-1RA at baseline (62% of the study population), wrote Januzzi, et al., according to the prespecified subgroup analysis. They noted that although this finding is exploratory, "such a finding is of note and suggests AT-001 may have an impact on a relevant outcome measure in certain patients with DbCM." Furthermore, "Given the urgency to reduce risk for HF in those with chronic DM, more investigation is needed regarding the potential role of AT-001 to reduce HF risk."