In adults with type 2 diabetes (T2DM) and obesity, abnormalities in myocardial energetics are observed both in the absence of heart failure (HF) and in those with heart failure with preserved ejection fraction (HFpEF), prompting evaluation of therapies targeting cardiac energy metabolism. In Circulation, results are reported from the open-label, phase 2a IMPROVE-DiCE (Improve Diabetic Cardiac Energetics) trial evaluating ninerafaxstat in this population.

The study enrolled 42 participants who received ninerafaxstat 200 mg twice daily. Part 1 included 21 patients with T2DM and obesity without HFpEF who were treated for 4 to 8 weeks. Part 2 included 21 patients with T2DM, obesity, and symptomatic HFpEF who were treated for 12 weeks. The primary outcome was myocardial energetics assessed by the phosphocreatine-to-adenosine triphosphate ratio (PCr/ATP), measured using magnetic resonance imaging (MRI) and magnetic resonance spectroscopy.

In part 1, treatment was associated with an increase in PCr/ATP of +0.39±0.49 (95% CI, 0.16–0.62; Cohen’s d, 0.79; P=0.002) and a reduction in myocardial triglyceride content by 34% (P=0.03). In part 2, PCr/ATP increased by +0.15±0.25 (95% CI, 0.03–0.26; Cohen’s d, 0.60; P=0.02).

Among participants with HFpEF, treatment was associated with improved systolic augmentation to exercise (+1.4 L/min; P=0.04), increased 6-minute walk distance (+16 m; P=0.02), and improvement in New York Heart Association (NYHA) functional class symptom burden. Across both study parts, ninerafaxstat was reported to be safely tolerated.