Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function

Abstract

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose–dependent and –independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone. Expected final online publication date for the Annual Review of Physiology, Volume 83 is February 10, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial

“…Our findings are therefore consistent with the hypothesis that acute SGLT2 inhibition improves renal cortical oxygenation by reducing energy expenditure by inhibition of the oxygen demanding glucose-and sodium cotransport in the renal proximal tubule. Improved oxygenation in the kidneys can result from a reduced oxygen demand or an increased supply of oxygen as discussed by Vallon and Verma [5]. As we found no difference between dapagliflozin and placebo in the changes in renal perfusion, renal blood flow, blood pressure, heart rate, or baroreflex sensitivity, an increased supply of blood does not explain the improved renal cortical oxygenation.…”

Effective cholesterol lowering after myocardial infarction in patients with nephrotic syndrome may require a multi-pharmacological approach: a case report

“…The success in reaching recommended LDL-C target for this patient can be attributed to the multi-pharmacological approach with SGLT2 and PCSK9 inhibitors on top of conventional lipid-lowering therapy. The recognized protein-sparing effect of SGLT2 inhibitors 9 could in this case (plasma albumin +41% after start of empagliflozin) contribute to increased oncotic pressure and thereby help to reduce hepatic LDL overproduction. Speculatively, SGLT2 inhibition could also assist in reducing urinary loss of the PCSK9 antibody.…”

Managing diabetes in diabetic patients with COVID: where do we start from?

“…SGLT2i rapidly inhibits renal glucose reabsorption by 30–50%, reducing blood glucose, body weight, and blood pressure. Cardiovascular outcome trials, both in patients with and without diabetes, have provided evidence that SGLT2i treatment is associated with remarkably positive cardiovascular outcomes [ 50 ]. Interestingly, both experimental and human data indicate that SGLT2i blunts inflammation with a specific protective effect exerted in the kidney and the liver [ 51 ]: these drugs may reverse molecular processes related to inflammation by decreasing interleukin-1, interleukin-6, and tumor necrosis factor 1 receptor.…”