Diabetes and Heart Failure: A Literature Review, Reflection and Outlook

Abstract

Heart failure (HF) is a complex clinical syndrome caused by structural or functional dysfunction of the ventricular filling or blood supply. Diabetes mellitus (DM) is an independent predictor of mortality for HF. The increase in prevalence, co-morbidity and hospitalization rates of both DM and HF has further fueled the possibility of overlapping disease pathology between the two. For decades, antidiabetic drugs that are known to definitively increase the risk of HF are the thiazolidinediones (TZDs) and saxagliptin in the dipeptidyl peptidase-4 (DPP-4) inhibitor, and insulin, which causes sodium and water retention, and whether metformin is effective or safe for HF is not clear. Notably, sodium-glucose transporter 2 (SGLT2) inhibitors and partial glucagon-like peptide-1 receptor agonists (GLP-1 RA) all achieved positive results for HF endpoints, with SGLT2 inhibitors in particular significantly reducing the composite endpoint of cardiovascular mortality and hospitalization for heart failure (HHF). Further understanding of the mutual pathophysiological mechanisms between HF and DM may facilitate the detection of novel therapeutic targets to improve the clinical outcome. This review focuses on the association between HF and DM, emphasizing the efficacy and safety of antidiabetic drugs and HF treatment. In addition, recent therapeutic advances in HF and the important mechanisms by which SGLT2 inhibitors/mineralocorticoid receptor antagonist (MRA)/vericiguat contribute to the benefits of HF are summarized.

Keywords: SGLT2 inhibitor; antidiabetic drugs; diabetes; heart failure; left ventricular ejection fraction; randomized controlled trial.

Figure 1

Pathophysiological mechanism of diabetic heart failure. Diabetic patients with hyperglycemia, insulin resistance, and hyperinsulinemia trigger vascular lesions, metabolic abnormalities, cellular dysfunction, and abnormal activation of the endocrine and nervous systems of the body, leading to ischemic heart disease, hypertensive heart disease, diabetic cardiomyopathy, and ultimately heart failure. ASVD, atherosclerotic vascular disease; FFAs, free fatty acids; AGEs, advanced glycosylation products; RAAS, renin–angiotensin–aldosterone system.

Figure 2

The pathological mechanism of interaction between heart failure and diabetes. Diabetes mellitus leads to hyperglycemia and insulin resistance, and the chronic hyperglycemic leads to chronic inflammation, endothelial and cardiomyocyte damage, promoting cardiac fibrosis, myocardial ischemia, cardiac remodeling, and further worsening heart failure. Heart failure leads to decreased cardiac output, sodium and water retention, activation of sympathetic nerves and the RASS system, which further reduces insulin secretion and exacerbates hyperglycemia, creating a vicious cycle. By Figdraw. RAAS, renin–angiotensin–aldosterone system; AGEs, advanced glycosylation products; ROS, reactive oxygen species; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction.

Figure 3

Potential mechanisms of clinical benefit of SGLT2 inhibitors. SGLT2 inhibitors exert beneficial effects on the cardiovascular system through a variety of mechanisms, including hypoglycemia, antihypertension, diuresis, weight loss, improvement of myocardial energy metabolism, reduction of oxidative stress and inflammation, protection of renal function, body weight reduction, and metabolic improvement. Recently, SGLT2 inhibitors have been found to have novel mechanisms of increased heme oxygenase expression, increased ketone bodies as a better fuel for the myocardium, and decreased epicardial fat, which together reduced risk of cardiovascular death or heart failure hospitalization. SGLT2, sodium-glucose transporter 2; EPO, erythropoietin; AGEs, advanced glycosylation products; FFAs, free fatty acids.

Figure 4

Mechanism of cardiorenal benefits of vericiguat. Vericiguat is the first sGC agonist that can directly stimulate sGC or synergize with endogenous NO to jointly increase intracellular levels of cGMP, leading to smooth muscle relaxation and vasodilation. By repairing damage to NO-sGC-cGMP, a cellular signaling pathway, the three major target organs, heart, blood vessels, and kidneys, are benefited. By Figdraw. SCG, soluble guanylate cyclase; NO, nitric oxide; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate.