Molidustat: A Potential Treatment for Heart Function in Diabetics

A drug, molidustat, has been identified by researchers at the University of Oxford that may help improve heart function in diabetics who have heart attacks. It has been found in clinical trials that the drug may be a potential treatment for a form of anaemia and could help reduce the risk of developing heart failure in diabetes patients.

In earlier research, it was found that people with diabetes have lower levels of HIF in their heart cells. Oral Molidustat works by increasing levels of a protein called Hypoxia-Inducible Factor 1 (HIF). Molidustat is currently in phase III clinical trials for treating anaemia in chronic kidney disease.

This study was conducted by Maria da Luz Sousa Fialho and team, and the findings were published in the Journal of the American Diabetes Association on 15th September, 2021.

The pharmaceutical stabilization of Hypoxia-Inducible Factor (HIF)1 can overcome the decreased hypoxic response caused by insulin resistance. T2D affects the activation of Hypoxia-Inducible Factor (HIF)1a, a master transcription factor that promotes cellular adaptation to hypoxia. HIF1 activation is reduced in T2D, which contributes to the poor post-ischemic remodeling found after myocardial infarction.

Molidustat, an orally administered drug, is now in phase III clinical studies for the treatment of anemia in chronic renal disease. It acts by raising the concentration of a protein known as Hypoxia-Inducible Factor 1 (HIF). When oxygen levels drop, HIF levels rise, enabling it to activate its 'target' genes, which aid in cell adaptation and survival. Previous studies, however, have discovered that patients with diabetes had decreased amounts of HIF in their heart cells.

Oral molidustat therapy restored the heart metabolic dysfunction induced by T2D in T2D rats, increasing glucose metabolism and mitochondrial activity while inhibiting fatty acid oxidation and lipid accumulation. This had a positive effect on post-ischemic cardiac performance, with molidustat therapy reversing the decreased contractile recovery in T2D hearts. Molidustat stabilized HIF1 and downstream HIF target genes in human cardiomyocytes, increasing anaerobic glucose metabolism. Insulin resistance inhibited HIF1 activation and downstream signaling in hypoxia, whereas molidustat restored this.

HIF is also involved in post-heart-attack repair processes, such as the formation of new blood vessels, a process known as angiogenesis. New blood arteries form to bypass the dead tissue and guarantee a healthy blood supply to the heart's surrounding regions that have survived. Diabetic hearts have decreased angiogenesis, which is thought to be a crucial stage in the development of heart failure. Molidustat treatment of rats with type 2 diabetes resulted in higher levels of the signals involved in the formation of new blood vessels, according to the researchers.

The researchers concluded by pointing out that the encouraging findings imply that medicines that stabilize HIF might become a novel therapy to minimize the risk of heart failure following a heart attack in diabetics. More study is now required to translate these preliminary findings into therapeutic benefit.

Reference

da Luz Sousa Fialho, M., Purnama, U., Dennis, K. M., Montes Aparicio, C. N., Castro-Guarda, M., Massourides, E., Tyler, D. J., Carr, C. A., & Heather, L. C. (2021). Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart. In Diabetes (p. db210398). American Diabetes Association. https://doi.org/10.2337/db21-0398