Functional and Clinical Importance of SGLT2-inhibitors in Frailty: From the Kidney to the Heart

Abstract

SGLT2 (sodium-glucose cotransporter 2) enables glucose and sodium reabsorption in the kidney. SGLT2-inhibitors (gliflozins, which include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) act by increasing glycosuria, thereby reducing glycemia. These drugs are critical to reach and keep glycemic control, a crucial feature, especially in patients with comorbidities, like frail individuals. Several studies evaluated the effects of SGLT2-inhibitors in different settings beyond diabetes, revealing that they are actually pleiotropic drugs. We recently evidenced the favorable effects of SGLT2-inhibition on physical and cognitive impairment in frail older adults with diabetes and hypertension. In the present overview, we summarize the latest clinical and preclinical studies exploring the main effects of SGLT2-inhibitors on kidney and heart, emphasizing their potential beneficial actions in frailty.

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

“…They decrease Na + reabsorption in the proximal tubule by decreasing Na + -coupled glucose transport and reducing sodium–hydrogen exchanger (NHE) 3 activity, thereby regulating the glomerular filtration rate and preventing harmful hyperfiltration. SGLT2i also regulate renal oxygen consumption and maintain renal mitochondrial homeostasis, thereby lowering the urinary albumin to creatinine ratio. − There are four main mechanisms that explain the cardioprotective effect of SGLT2i. First, SGLT2i inhibit NHE1 in cardiomyocytes, which lowers the intracellular sodium level and prevents calcium overload.…”

Association between glycosylated hemoglobin levels, diabetes duration, and left ventricular diastolic dysfunction in patients with type 2 diabetes and preserved ejection fraction: a cross-sectional study

“…Urgent attention is required for the development of treatment programs and antidiabetic drugs that can effectively reduce glucose levels and provide cardiac protection. Several studies have explored these areas ( 38 , 39 ), which will be a focus of our future research. Admittedly, this study has several limitations that should be acknowledged: Firstly, the study is constrained by a short follow-up period and a narrow window for the cross-sectional study, potential introducing observation bias.…”

SGLT2 inhibitor promotes mitochondrial dysfunction and ER-phagy in colorectal cancer cells

“…In this scenario, the SGLT2 inhibitors (iSGLT2), canagliflozin, dapagliflozin, tofogliflozin and empagliflozin, have been increasingly studied, given their strong anti-hyperglycemic activity as well as their emerging anticancer effects [ 8 , 10 ]. These drugs are used to treat patients with type 2 diabetes and chronic kidney disease, as well as to improve cardiac function and reduce the risk of cardiovascular events, including heart failure [ 11 – 13 ]. Treatment with iSGLT2 also results in weight loss, decreased high blood pressure, and ameliorated insulin resistance, lipid profiles, and visceral adiposity [ 14 , 15 ].…”

“…Treatment with iSGLT2 also results in weight loss, decreased high blood pressure, and ameliorated insulin resistance, lipid profiles, and visceral adiposity [ 14 , 15 ]. Overall, iSGLT2 are considered pleiotropic drugs exerting multiple beneficial effects, thus being considered as anti-frailty agents [ 13 ]. Canagliflozin is an antidiabetic drug acting on proximal renal tubules, able to reduce glucose reabsorption and promote its excretion through the urinary system, without affecting intestinal glucose uptake by SGLT1 [ 16 , 17 ].…”