Key result
Ninerafaxstat significantly improved myocardial energetics (PCr/ATP median by 32%, p<0.01) and reduced myocardial triglyceride content (by 34%, p=0.03) in patients with T2D and obesity.
Why the study?
Type 2 diabetes drives heart failure through energetic, metabolic, and functional changes, prompting investigation into whether the novel cardiac mitotrope ninerafaxstat can shift substrate utilisation to glucose and restore myocardial energy homeostasis.
Does ninerafaxstat improve myocardial energetics and diastolic function in patients with type 2 diabetes and obesity?
Does ninerafaxstat improve myocardial energetics and diastolic function in patients with type 2 diabetes and obesity?
p-value: p=<0.01
In a phase 2a trial, the novel cardiac mitotrope ninerafaxstat improved myocardial energetics, reduced steatosis, and enhanced diastolic function in patients with type 2 diabetes and obesity.
May enhance myocardial energetics in T2D-HF; leaves open clinical benefit pending larger trials.
Background Type 2 diabetes (T2D) is a significant, independent contributor to the development of heart failure (HF), driven by energetic, metabolic, structural and functional myocardial changes. The T2D heart is characterised by over-reliance on fatty acid utilisation, shows reduced glucose oxidation and inhibition of pyruvate dehydrogenase (PDH). This results in a diminished myocardial energy reserve and blunted adenosine triphosphate (ATP) generation as well as cardiac steatosis, contributing to lipotoxicity, and diastolic dysfunction. Purpose We assessed the effects of ninerafaxstat – a novel cardiac mitotrope designed to shift myocardial substrate utilisation in favour of glucose and thus, restore myocardial energy homeostasis – on cardiac metabolism & diastolic function in patients with T2D and obesity. Methods In this open-label, mechanistic phase 2a trial, we enrolled 21 patients with T2D & obesity (HbA1c median 7.0% (IQR 6.6, 7.8), weight 97kg (90, 102)) and subsequently treated them with 200mg ninerafaxstat twice daily for 4 or 8 weeks; (Fig. 1). Cardiac metabolism and function were assessed pre- & post-treatment using magnetic resonance imaging (MRI), 31P-, 1H- and, in a subset of n=9, hyperpolarized [1-13C]pyruvate MR spectroscopy. Results T2D patients at baseline presented with impaired myocardial energetics with a markedly reduced PCr/ATP (1.6 [1.4, 2.1]), myocardial steatosis (myocardial triglycerides 2.2% [1.5, 3.2]) left ventricular (LV) hypertrophy (LV mass 130g [98, 152]), and diastolic dysfunction (peak diastolic strain rate 0.86 1/s [0.82, 1.06]). Ninerafaxstat significantly improved myocardial energetics (PCr/ATP median by 32%, p<0.01), reduced myocardial triglyceride content (by 34%, p=0.03) and improved LV diastolic function (peak circumferential diastolic strain rate by 10%, peak LV filling rate by 11%, both p<0.05) (Fig. 2). PDH flux was increased in 7/9 subjects (mean 45%, p=0.08), consistent with improved glucose utilisation. Left ventricular volumes and mass, heart rate and blood pressure remained unchanged. Conclusions Treatment with ninerafaxstat significantly improves myocardial energetics, reduces myocardial steatosis and improves diastolic function in patients with T2D and obesity. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Imbria Pharmaaceuticals
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Hundertmark et al. (2022) studied Type 2 diabetes and obesity (n=21). Ninerafaxstat was evaluated on Myocardial energetics (PCr/ATP) (p=<0.01). Ninerafaxstat significantly improved myocardial energetics (PCr/ATP median by 32%, p<0.01) and reduced myocardial triglyceride content (by 34%, p=0.03) in patients with T2D and obesity.