Do the SGLT-2 Inhibitors Offer More than Hypoglycemic Activity?

Abstract

Type 2 diabetes mellitus (T2DM) is one of the most common chronic health conditions in the USA; it affects approximately 10% of adults with up to one-quarter being undiagnosed. T2DM is associated with substantial cardiovascular (CV) morbidity and mortality. T2DM is a pathological condition characterized by elevated levels of glucose and associated with high CV risk. Traditional hypoglycemic drugs have demonstrated their capability for effective and maintained management of high glucose levels, but they have not significantly impacted on the incidence of CV events. Recently, a new class of hypoglycemic agents, SGLT-2 receptor inhibitors, has been developed. The EMPA-OUTCOME trial involving empagliflozin (a SGLT-2 receptor inhibitor) has shown significant reductions in major adverse cardiac events (MACEs), cardiovascular mortality, and hospitalization for heart failure (HF) when administered on top of standard-of-care therapy for T2DM patients at high CV risk. The dramatic change driving the superiority of the primary composite outcome (major adverse CV events) was a significantly lower CV death rate (38% relative risk reduction). In addition, there were also an impressive 35 and 32% relative risk reductions in hospitalization for heart failure (HF) and death from any cause, respectively. These effects are even more important given the difficulties for treating concomitant HF in T2DM patients. These surprising results have been also corroborated by another agent of this class, canagliflozin, and the CANVAS trial. The magnitude of these somehow surprising cardiac benefits attained in the absence of major differences in glycemic, lipid, or blood pressure (BP) control has led to several groups to suggest that these benefits may be independent of its hypoglycemic activity and whether this new class could be considered a "cardiac" drug. The objective of this review has been to review the different hypotheses proposed to explain the cardiac benefits of this new class of antidiabetic drugs.

The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats

“…The current antidiabetic drugs are less effective and even harmful to patients with DM with HF. However, sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors are new class of antidiabetic drugs that shows beneficial to cardiovascular patients with DM (Flores, Santos‐Gallego, Diaz‐Mejia, & Badimon, ). These drugs cause more glucose excreted in the urine; therefore, there is higher chance of infections in genital and urinary tract.…”

“…The current antidiabetic drugs are less effective and even harmful to patients with DM with HF. However, sodium-glucose co-transporter-2 (SGLT2) inhibitors are new class of antidiabetic drugs that shows beneficial to cardiovascular patients with DM (Flores, Santos-Gallego, Diaz-Mejia, & Badimon, 2018).…”

Effect of low carbohydrate high fat diet on LDL cholesterol and gene expression in normal-weight, young adults: A randomized controlled study

“…The authors discuss that the loss of glucose in urine may increase the secretion of glucagon, which subsequently induce the ketosis. Further, SGLT2 inhibitors may slightly increase LDL-C (0.1 mmol/l or less) [41]. Taken together, further research is needed on how this class of drugs affects lipid metabolism.…”

Effects of Sodium–Glucose Co-transporter 2 Inhibition with Empaglifozin on Renal Structure and Function in Non-diabetic Rats with Left Ventricular Dysfunction After Myocardial Infarction

“…SGLT2i have potent diuretic properties, which may partially explain their beneficial effects on HF hospitalisations [13,14]. Nevertheless, the diuretic effects of SGLT2i could also limit the use of SGLT2i in HF patients without T2D.…”