Are targeted therapies for diabetic cardiomyopathy on the horizon?

Abstract

Diabetes increases the risk of heart failure approximately 2.5-fold, independent of coronary artery disease and other comorbidities. This process, termed diabetic cardiomyopathy, is characterized by initial impairment of left ventricular (LV) relaxation followed by LV contractile dysfunction. Post-mortem examination reveals that human diastolic dysfunction is closely associated with LV damage, including cardiomyocyte hypertrophy, apoptosis and fibrosis, with impaired coronary microvascular perfusion. The pathophysiological mechanisms underpinning the characteristic features of diabetic cardiomyopathy remain poorly understood, although multiple factors including altered lipid metabolism, mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress, inflammation, as well as epigenetic changes, are implicated. Despite a recent rise in research interrogating these mechanisms and an increased understanding of the clinical importance of diabetic cardiomyopathy, there remains a lack of specific treatment strategies. How the chronic metabolic disturbances observed in diabetes lead to structural and functional changes remains a pertinent question, and it is hoped that recent advances, particularly in the area of epigenetics, among others, may provide some answers. This review hence explores the temporal onset of the pathological features of diabetic cardiomyopathy, and their relative contribution to the resultant disease phenotype, as well as both current and potential therapeutic options. The emergence of glucose-optimizing agents, namely glucagon-like peptide-1 (GLP-1) agonists and sodium/glucose co-transporter (SGLT)2 inhibitors that confer benefits on cardiovascular outcomes, together with novel experimental approaches, highlight a new and exciting era in diabetes research, which is likely to result in major clinical impact.

Keywords: cardiac fibrosis; cardiomyocyte hypertrophy; diabetic cardiomyopathy; diastolic dysfunction; hyperglycaemia.