Sodium Glucose Cotransporter 2 Inhibition in the Diabetic Kidney

An Update

Aleksandra Novikov; Volker Vallon

Disclosures

Curr Opin Nephrol Hypertens. 2016;25(1):50-58. 

In This Article

Sodium Glucose Cotransporter 2 Inhibition and Hypoglycemia, Gluconeogenesis, β Cell Preservation, and Ketogenesis

According to a meta-analysis of patients with T2DM, SGLT2 inhibitors decreased HbA1C levels by 0.5–0.7% at 12 weeks of treatment, and this effect persisted for up to 52 weeks. Hypoglycemia was noted only when SGLT2 inhibitors were used in combination with other drugs, but not as monotherapy.[23] The blood glucose lowering effects of SGLT2 inhibition depended on both serum glucose concentration and GFR. These two parameters determine how much glucose is delivered to SGLT2 in the early proximal tubule, and thus how much glucose can be excreted by SGLT2 inhibition. Therefore, lower values for each parameter are associated with lesser blood glucose lowering. Currently, SGLT2 inhibitors are approved for use only in type 2 diabetes, with dapagliflozin approved for GFR > 60 ml/min and canagliflozin and empagliflozin for GFR > 45 ml/min. Notably, SGLT2 inhibition in T2DM patients with stage 3 chronic kidney disease (CKD) (estimated GFR between 30 and 60 ml/min) was still able to reduce HbA1C by 0.42% at 24 weeks.[24] SGLT2 inhibitors lower blood glucose, and to some extent GFR (see below), and thereby their glucosuric potential, which is expected to help prevent and/or attenuate episodes of hypoglycemia.

Gluconeogenesis is another important mechanism that serves to maintain normal blood glucose levels and prevent hypoglycemia. As expected for blood glucose lowering agents, SGLT2 inhibition increased plasma glucagon concentrations and endogenous glucose production in T2DM db/db mice,[25] diabetic TALLYHO/JngJ mice,[25] insulin-resistant mice,[20] and in patients with T2DM.[26,27] Importantly, evidence was provided that SGLT2 itself is expressed on glucagon-secreting alfa cells in the pancreas, the expression is reduced in diabetic patients, and inhibition of SGLT2 on pancreatic alfa cells can induce glucagon release.[20] Thus, SGLT2 inhibition can induce glucagon release and, as a consequence, hepatic gluconeogenesis by lowering blood glucose levels, as well as direct effects on alfa cells (Fig. 1).

Although the central role of the liver in gluconeogenesis is well established and recognized, the kidneys also produce between 15–55 g glucose/day, and this process is upregulated in diabetes.[28] Phosphoenolpyruvate carboxykinase (PEPCK) is the main regulator of gluconeogenesis and is upregulated in the kidneys of diabetic rats and humans. Studies in T1DM Akita mice confirmed that renal PEPCK mRNA was upregulated; however, this effect was attenuated by SGLT2 inhibition.[14] Thus, SGLT2 inhibition may lower blood glucose levels in diabetes by inhibiting renal glucose reabsorption and renal gluconeogenesis (Fig. 1). In contrast to the liver, little is known about the regulation of gluconeogenesis in the kidney, and further studies are needed in this regard to further define the involved mechanisms and quantitative potential of SGLT2 inhibition.

Previous studies have shown that SGLT2 inhibition improved insulin sensitivity and increased β-cell mass in moderately hyperglycemic female Zucker diabetic fatty rats, that is, in an early-stage T2DM model.[29] Using male Zucker diabetic fatty rats, it was shown that SGLT2 inhibitors also evoked β-cell sparing effects in progressed T2DM with features of reduced β-cell mass.[30] Thus, SGLT2 inhibition, possibly by lowering glucose toxicity, may slow the loss of β cells in T2DM, and thereby the progression of the disease (Fig. 1).

In May 2015, the US Food and Drug Administration released a warning that SGLT2 inhibitors might increase the risk of ketoacidosis (http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm). Cases have been reported in both T1DM and T2DM diabetic patients. Potential mechanisms include lower insulin and higher glucagon levels in response to SGLT2 inhibition which can lead to increased lipolysis and ketogenesis, and potentially increased renal tubular reabsorption of ketones[31] (Fig. 1). The recently reported EMPA-REG OUTCOME study (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; see more details below) found no difference in rates of ketoacidosis in patients with T2DM treated with the SGLT2 inhibitor empagliflozin versus placebo over the course of 3 years.[32] Nevertheless, dedicated studies are needed to further define the clinical relevance and the involved mechanisms.

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