The emerging role of novel antihyperglycemic agents in the treatment of heart failure and diabetes: A focus on cardiorenal outcomes

Abstract

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are two global pandemics, affecting over 25 and 420 million people, respectively. The prevalence of comorbid HF and T2DM is rising, and the prognosis remains poor. One central area of overlap of these two disease processes is renal dysfunction, which contributes to poor cardiovascular outcomes and mortality. As such, there is a growing need for antihyperglycemic agents with cardio- and renoprotective effects. Three classes of novel antihyperglycemic agents, sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RA), and dipeptidyl peptidase-4 (DPP4) inhibitors have demonstrated varied cardiorenal outcomes in recent cardiovascular outcomes trials. Understanding the differential effects of these agents, together with their proposed mechanisms, is crucial for the development of safe and effective treatment regimens and future pharmacologic targets for HF and T2DM. In this review, we discuss the overlapping pathophysiology of HF and T2DM, summarize outcomes data for the novel antihyperglycemic agents and proposed mechanisms of action, and review how the current evidence informs future management of comorbid HF and T2DM.

Keywords: diabetes; heart failure; kidney disease.

Figure 1

The figure exhibits how both a decrease in cardiac output in the setting of HF, as well as metabolic abnormalities in T2DM, such as increased adiposity and hyperinsulinemia, contribute to neurohumoral activation, alterations in sodium handling and renal hemodynamics, and ultimately congestion and renal dysfunction. RAAS activation causes increased systemic vascular resistance and intrarenal vascular resistance, predominately at the efferent arteriole, as well as increased sodium reabsorption in the proximal convoluted tubule by the sodium‐glucose cotransporter 2 (SGLT2) and the sodium‐hydrogen exchanger 3 (NHE3). Decreased solute delivery to the distal tubule is sensed by the macula densa, and through tubuloglomerular feedback, causes afferent arteriole dilation and further RAAS activation. SGLT2 is upregulated in T2DM, so this effect is magnified. Afferent arteriole dilation and efferent constriction lead to a maladaptive state of renal hyperfiltration, the hallmark of diabetic nephropathy. In HF, GFR further falls due to venous hypertension, intravascular under filling, and sympathetic activation. Other consequences of increased proximal absorption include decreased delivery of natriuretic peptides to the distal tubule, and the inability to escape aldosterone's effect of increased sodium reabsorption in the distal tubule, leading to significant edema formation. Finally, hyperglycemia induced production of intrarenal AngII and aldosterone contributes to podocyte injury and fibrosis and subsequent proteinuria. Abbreviations: Aldo, aldosterone; CO, cardiac output; GFR, glomerular filtration rate; Glu, glucose; H, hydrogen; K+, potassium; Na, sodium; NKCC2, Na‐K‐2Cl cotransporter; SNS, sympathetic nervous system; RBF, renal blood flow