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Aldose Reductase Inhibitor Treatment in Diabetic Cardiomyopathy
Quick Takes
- Among individuals with well-controlled T2DM with stage B HF and impaired exercise capacity, 15 months of an aldose reductase inhibitor (AT-001) did not result in higher peak VO2 vs. placebo.
- Future studies should evaluate longer treatment with AT-001 in a more generalizable population of patients with T2DM and also assess the incremental benefit of AT-001 (if any) with SGLT2 inhibitors or GLP-1 receptor agonists (GLP-1RA).
- At this time, it seems prudent to focus on strategies to improve access to guideline-directed medical therapies for diabetes, which include SGLT2 inhibitors and possibly GLP-1RA to prevent progression of diabetic cardiomyopathy.
Study Questions:
What is the effect of AT-001, an aldose reductase inhibitor, on exercise capacity among individuals with diabetic cardiomyopathy (DbCM) with reduced exercise capacity and at high risk for progression to overt heart failure (HF)?
Methods:
The trial investigators randomized a total of 691 individuals with DbCM meeting inclusion and exclusion criteria to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonists (GLP-1RA). The primary endpoint was proportional change in peak oxygen uptake (VO2) from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables. The primary endpoint of the change in VO2 from baseline to 15 months was analyzed using a mixed model for repeat measures analysis of covariance model with an unstructured covariance matrix using α/2; least-square mean changes (with SE) in peak VO2 were examined.
Results:
The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak VO2 fell in the placebo-treated patients by –0.31 mL/kg/min (p = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak VO2 fell by –0.01 mL/kg/min (p = 0.21); the difference in peak VO2 between placebo and high-dose AT-001 was 0.30 (p = 0.19). In prespecified subgroup analyses among those not receiving SGLT2i or GLP-1RA at baseline, the difference between peak VO2 in placebo versus high-dose AT-001 at 15 months was 0.62 mL/kg/min (p = 0.04; interaction p = 0.10).
Conclusions:
The authors report that among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo.
Perspective:
This randomized controlled trial of individuals with well-controlled type 2 diabetes mellitus (T2DM) with stage B HF and impaired exercise capacity reports that 15 months of an aldose reductase inhibitor (AT-001) did not result in higher peak VO2 versus placebo. Of note, in a prespecified subgroup of individuals not prescribed an SGLT2i or GLP-1RA at baseline, AT-001 treatment was associated with better exercise capacity at 15 months. These results, however, should be considered exploratory at best. Future studies should evaluate longer treatment with AT-001 in a more generalizable population of patients with T2DM and also assess the incremental benefit of AT-001 (if any) with SGLT2i or GLP-1RA. At this time, it seems prudent to focus on strategies to improve the access to guideline-directed medical therapies for diabetes, which include SGLT2i and possibly GLP-1RA to prevent progression of DbCM.
Clinical Topics: Heart Failure and Cardiomyopathies, Prevention
Keywords: Cardiomyopathies, Diabetes Mellitus, Type 2
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