Emerging Roles of Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors in Diabetic Cardiovascular Diseases: Focusing on Immunity, Inflammation and Metabolism

Abstract

Diabetes mellitus (DM) is one of the most fast evolving global issues characterized by hyperglycemia. Patients with diabetes are considered to face with higher risks of adverse cardiovascular events. Those are the main cause of mortality and disability in diabetes patients. There are novel antidiabetic agents that selectively suppress sodium-glucose cotransporter-2 (SGLT-2). They work by reducing proximal tubule glucose reabsorption. Although increasing evidence has shown that SGLT-2 inhibitors can contribute to a series of cardiovascular benefits in diabetic patients, including a reduced incidence of major adverse cardiovascular events and protection of extracardiac organs, the potential mechanisms of SGLT2 inhibitors’ cardiovascular protective effects are still not fully elucidated. Given the important role of inflammation and metabolism in diabetic cardiovascular diseases, this review is intended to rationally compile the multifactorial mechanisms of SGLT-2 inhibitors from the point of immunity, inflammation and metabolism, depicting the fundamental cellular and molecular processing of SGLT-2 inhibitors exerting regulating immunity, inflammation and metabolism. Finally, future directions and perspectives to prevent or delay cardiovascular complications in DM by SGLT-2 inhibitors are presented.

Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Pneumonia and Septic Shock

“…Preliminary findings from “off-label” SGLT2i usage in subjects infected with severe or critical severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia suggest benefits in subjects with diabetes ( 20 ), and no effects in subjects without diabetes ( 21 ). These may be attributed to the more pronounced anti-inflammatory effects in the context of hyperglycemia, where inflammation is more severe (evidenced by the higher levels of interleukin-6, C-reactive protein, and erythrocyte sedimentation rate) than in the normoglycemic state ( 22–24 ). We performed a systematic review and meta-analysis of randomized controlled trials to comprehensively evaluate whether SGLT2is reduce the risk of pneumonia and septic shock in patients with DM.…”

An update on chronic complications of diabetes mellitus: from molecular mechanisms to therapeutic strategies with a focus on metabolic memory

“…Diabetic cardiovascular disorders, including diabetic cardiomyopathy (DCM) and arterial vasculopathy, are the leading causes of death among patients with diabetes (Fang et al 2004 ). Elevated blood glucose stimulates inflammation, regulates immune cells, and promotes the production of cytotoxic free radicals, thereby attacking myocardial cells and vascular endothelial cells (Johnson et al 2022 ; Xie et al 2022 ). Under the action of these mechanisms triggered by high glucose, damaged cells further secrete harmful irritants, which promote the transdifferentiation of other cell types into cardiac fibroblasts (Cheng et al 2023 ).…”

TorS ‐ Reframing a rational for type 2 diabetes treatment

“…Similarly, hypothalamic mTORC1 controls sympathetic tone, 116 implying a decrease in vascular tone, blood pressure and cardiac output by SGLT2i. Also, ASCVD combined with endothelial/eNOS dysfunction may be reversed by suppressing mTORC1 activity by SGLT2i 117 . Most importantly, the suppression of hyperactive mTORC1 by SGLT2i may result in activation of cardio‐renal autophagy and mitophagy, resulting in delaying/reverting diabetic and ageing cardiomyopathy and nephropathy, 118,119 independently of SGLT2 cotransporters.…”