The actions of SGLT2 inhibitors on metabolism, renal function and blood pressure

Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT‐2i therapy. The observed improvements in CV and renal outcomes with SGLT‐2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add‐on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT‐2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti‐inflammatory and renal effects.

Section: Mechanism Of Glyaemic Control With Sglt‐2 Inhibitorsmentioning

confidence: 99%

Section: Mechanisms Of CV and Renal Protection With Sglt‐2 Inhibitorsmentioning

confidence: 99%

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Chilton

2019

“…Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors suppress glucose reabsorption in the kidney to increase urinary glucose excretion, resulting in reductions in fasting and postprandial glucose. These improvements are coupled with changes in adiposity, substrate utilization, lipolysis, hormone secretion and central regulation of appetite . SGLT2 inhibitors also appear to have beneficial effects with regard to renal function.…”

Section: Introductionmentioning

confidence: 99%

Identification of subgroups of patients with type 2 diabetes with differences in renal function preservation, comparing patients receiving sodium‐glucose co‐transporter‐2 inhibitors with those receiving dipeptidyl peptidase‐4 inhibitors, using a supervised machine‐learning algorithm (PROFILE study): A retrospective analysis of a Japanese commercial medical database

Zhou

Watada

Tajima

et al. 2019

Aims To investigate the effects of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors vs. dipeptidyl peptidase‐4 (DPP‐4) inhibitors on renal function preservation (RFP) using real‐world data of patients with type 2 diabetes in Japan, and to identify which subgroups of patients obtained greater RFP benefits with SGLT2 inhibitors vs. DPP‐4 inhibitors. Methods We retrospectively analysed claims data recorded in the Medical Data Vision database in Japan of patients with type 2 diabetes (aged ≥18 years) prescribed any SGLT2 inhibitor or any DPP‐4 inhibitor between May 2014 and September 2016 (identification period), in whom estimated glomerular filtration rate (eGFR) was measured at least twice (baseline, up to 6 months before the index date; follow‐up, 9 to 15 months after the index date) with continuous treatment until the follow‐up eGFR. The endpoint was the percentage of patients with RFP, defined as no change or an increase in eGFR from baseline to follow‐up. A proprietary supervised learning algorithm (Q‐Finder; Quinten, Paris, France) was used to identify the profiles of patients with an additional RFP benefit of SGLT2 inhibitors vs. DPP‐4 inhibitors. Results Data were available for 990 patients prescribed SGLT2 inhibitors and 4257 prescribed DPP‐4 inhibitors. The proportion of patients with RFP was significantly greater in the SGLT2 inhibitor group (odds ratio 1.27; P = 0.01). The Q‐Finder algorithm identified four clinically relevant subgroups showing superior RFP with SGLT2 inhibitors (P < 0.1): no hyperlipidaemia and eGFR ≥79 mL/min/1.73 m2; eGFR ≥79 mL/min/1.73 m2 and diabetes duration ≤1.2 years; eGFR ≥75 mL/min/1.73 m2 and use of antithrombotic agents; and haemoglobin ≤13.4 g/dL and LDL cholesterol ≥95.1 mg/dL. In each profile, glycaemic control was similar in the two groups. Conclusion SGLT2 inhibitors were associated with more favourable RFP vs. DPP‐4 inhibitors in patients with certain profiles in real‐world settings in Japan.

“…Treatment with SGLT2 inhibitors leads to a reduction in the insulin:glucagon ratio and increases hepatic glucose production by gluconeogenesis . In a recent study, administration of SGLT2 inhibitors alleviated glucose toxicity and improved peripheral insulin sensitivity, but increased glucose production in the liver by increasing glucagon levels . Recent studies also showed that NAD‐dependent deacetylase sirtuin‐1 (SIRT1) interacts with and deacetylates peroxisome proliferative activated receptor‐gamma co‐activator 1α (PGC‐1α or PPARGC1), leading to induction of gluconeogenic gene expression in the liver .…”

Section: Introductionmentioning

confidence: 99%

Effect of dapagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, on gluconeogenesis in proximal renal tubules

Kim

Wang

et al. 2019

Aims To investigate the effect of dapagliflozin, a sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor, on renal gluconeogenesis in vitro, ex vivo and in vivo. Materials and methods We treated HK‐2 cells (human renal proximal tubule cells) and mouse primary renal proximal tubule cells with dapagliflozin, and evaluated the process of renal gluconeogenesis. We also examined the effect of dapagliflozin on renal gluconeogenesis in normoglycaemic and hyperglycaemic mice. Results Dapagliflozin enhanced renal gluconeogenesis in vitro, ex vivo and in vivo. It increased phosphoenolpyruvate carboxykinase (PEPCK), glucose‐6‐phosphatase (G6Pase), peroxisome proliferative activated receptor‐gamma co‐activator 1α (PGC‐1α) and phosphorylated cyclic‐AMP response element binding protein (CREB) expression and decreased phosphorylated Forkhead Box O1 (FOXO1) expression in HK‐2 cells, mouse primary renal proximal tubule cells, and the mouse renal cortex. Glutamine enhanced the gluconeogenic effect of dapagliflozin in HK‐2 cells. Also, dapagliflozin increased 14C‐glutamine utilization in HK‐2 cells. Glucagon did not affect dapagliflozin‐induced enhancement in renal gluconeogenesis in HK‐2 cells. SGLT2 gene knockdown with siRNA resulted in an increase of gluconeogenic gene expression and associated transcription factors in HK‐2 cells. Dapagliflozin reduced fasting plasma glucose levels and improved oral glucose tolerance and insulin tolerance in high‐fat diet‐fed hyperglycaemic mice, although renal gluconeogenesis was enhanced. Conclusions Dapagliflozin increased levels of gluconeogenic enzyme in the renal cortex and consequently increased renal gluconeogenesis, which is mediated by SGLT2 inhibition.