SGLT2 Inhibition for Cardiovascular Diseases, Chronic Kidney Disease, and NAFLD

Abstract

Sodium glucose cotransporter 2 (SGLT-2) inhibitors are the latest class of antidiabetic medications. They prevent glucose reabsorption in the proximal convoluted tubule to decrease blood sugar. Several animal studies revealed that SGLT-2 is profoundly involved in the inflammatory response, fibrogenesis, and regulation of numerous intracellular signaling pathways. Likewise, SGLT-2 inhibitors markedly attenuated inflammation and fibrogenesis and improved the function of damaged organ in animal studies, observational studies, and clinical trials. SGLT-2 inhibitors can decrease blood pressure and ameliorate hypertriglyceridemia and obesity. Likewise, they improve the outcome of cardiovascular diseases such as heart failure, arrhythmias, and ischemic heart disease. SGLT-2 inhibitors are associated with lower cardiovascular and all-cause mortality as well. Meanwhile, they protect against nonalcoholic fatty liver disease (NAFLD), chronic kidney disease, acute kidney injury, and improve micro- and macroalbuminuria. SGLT-2 inhibitors can reprogram numerous signaling pathways to improve NAFLD, cardiovascular diseases, and renal diseases. For instance, they enhance lipolysis, ketogenesis, mitochondrial biogenesis, and autophagy while they attenuate the renin-angiotensin-aldosterone system, lipogenesis, endoplasmic reticulum stress, oxidative stress, apoptosis, and fibrogenesis. This review explains the beneficial effects of SGLT-2 inhibitors on NAFLD and cardiovascular and renal diseases and dissects the underlying molecular mechanisms in detail. This narrative review explains the beneficial effects of SGLT-2 inhibitors on NAFLD and cardiovascular and renal diseases using the results of latest observational studies, clinical trials, and meta-analyses. Thereafter, it dissects the underlying molecular mechanisms involved in the clinical effects of SGLT-2 inhibitors on these diseases.

Keywords: SGLT-2 inhibitors; autophagy; fibrosis; inflammation; ketogenesis; molecular mechanism.