Pathophysiological basis of the cardiological benefits of SGLT-2 inhibitors: a narrative review

Abstract

In recent years, GLP-1 receptor agonists (GLP-1RA), and SGLT-2 inhibitors (SGLT-2i) have become available, which have become valuable additions to therapy for type 2 diabetes as they are associated with low risk for hypoglycemia and cardiovascular benefits. Indeed, SGLT-2i have emerged as a promising class of agents to treat heart failure (HF). By inhibiting SGLT-2, these agents lead to excretion of glucose in urine with subsequent lowering of plasma glucose, although it is becoming clear that the observed benefits in HF cannot be explained by glucose-lowering alone. In fact, multiple mechanisms have been proposed to explain the cardiovascular and renal benefits of SGLT-2i, including hemodynamic, anti-inflammatory, anti-fibrotic, antioxidant, and metabolic effects. Herein, we review the available evidence on the pathophysiology of the cardiological benefits of SGLT-2i. In diabetic heart disease, in both clinical and animal models, the effect of SGLT-2i have been shown to improve diastolic function, which is even more evident in HF with preserved ejection fraction. The probable pathogenic mechanisms likely involve damage from free radicals, apoptosis, and inflammation, and therefore fibrosis, many of which have been shown to be improved by SGLT-2i. While the effects on systolic function in models of diabetic heart disease and HF with preserved ejection fraction is limited and contrasting, it is a key element in patients with HF and reduced ejection fraction both with and without diabetes. The significant improvement in systolic function appears to lead to subsequent structural remodeling of the heart with a reduction in left ventricle volume and a consequent reduction in pulmonary pressure. While the effects on cardiac metabolism and inflammation appear to be consolidated, greater efforts are still warranted to further define the entity to which these mechanisms contribute to the cardiovascular benefits of SGLT-2i.

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Acute Coronary Syndrome

“…Fourth, SGLT2i normalize nutrient transport and oxidative phosphorylation . In addition, the cardioprotective mechanisms of SGLT2i include hemodynamic, antifibrotic, antioxidant, and anti-inflammatory effects . The effect of SGLT2i on an ischemic stroke is controversial.…”

Long-term glycemic variability predicts compromised development of heart failure with improved ejection fraction: a cohort study

“…Noteworthy, although only a small proportion of patients were on SGLT2 inhibitors (n=32, 6.2%) since the medication has not been introduced to our center until the second half of 2019, the univariate analysis exhibited a positive association between the use of SGLT2 inhibitors and HFimpEF. SGLT2 inhibitors have pleiotropic cardio-protective effects through modulating renin-angiotensin-aldosterone system, shifting energy substrate, and attenuating systemic inflammatory status ( 54 , 55 ). Given the promising results from DAPA-HF ( 56 ) and EMPEROR-Reduced trials ( 57 ), SGLT2 inhibitors have become a cornerstone of HFrEF treatment.…”

Beyond Blood Sugar: Investigating the Cardiovascular Effects of Antidiabetic Drugs

“…Numerous theories have been suggested to explain the positive impacts of SGLT-2 inhibitors on cardiovascular and renal well-being. These include enhancements in hemodynamics, decreased inflammation and fibrosis, antioxidative characteristics, as well as metabolic effects [ 71 ].…”