Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus

Abstract

Hyperglycemia is the primary factor responsible for the microvascular, and to a lesser extent macrovascular, complications of diabetes. Despite this well-established relationship, approximately half of all type 2 diabetic patients in the US have a hemoglobin A1c (HbA1c) ≥7.0%. This is associated in part with the side effects, i.e., weight gain and hypoglycemia, of currently available antidiabetic agents and in part with the failure to utilize medications that reverse the basic pathophysiological defects present in patients with type 2 diabetes. The kidney has been shown to play a central role in the development of hyperglycemia by excessive production of glucose throughout the sleeping hours and enhanced reabsorption of filtered glucose by the renal tubules secondary to an increase in the threshold at which glucose spills into the urine. Recently, a new class of antidiabetic agents, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, has been developed and approved for the treatment of patients with type 2 diabetes. In this review, we examine their mechanism of action, efficacy, safety, and place in the therapeutic armamentarium. Since the SGLT2 inhibitors have a unique mode of action that differs from all other oral and injectable antidiabetic agents, they can be used at all stages of the disease and in combination with all other antidiabetic medications.

Keywords: SGLT2 inhibition; kidney; sodium-glucose cotransport; type 2 diabetes.

Copyright © 2015 the American Physiological Society.

Figures

Fig. 1.

Kinetics of renal glucose handling.

Fig. 2.

Effect of background therapy on hemoglobin A1c (HbA1c) reduction in type 2 diabetic patients treated with canagliflozin (Cana), dapagliflozin (Dapa), and empagliflozin (Empa). SU, sulfonylurea. Drawn from data in Refs. , , , , , , , , , and .

Fig. 3.

A: time course of effect of dapagliflozin (n = 400) vs. glipizide on the decrement in A1c (ΔA1c) in metformin-treated type 2 diabetic patients. Drawn from data in Refs. and . B: time course of effect of canagliflozin (CANA; n = 377) vs. sitagliptin (SITA; n = 378) in poorly controlled type 2 diabetic patients treated with metformin + sulfonylurea. Redrawn from Ref. with permission.

Fig. 4.

Effect of dapagliflozin on the renal maximum glucose transport capacity (Tmglu; A), threshold (B), and splay (C) for glucose in healthy normal-glucose-tolerant (NGT) and type 2 diabetic (T2DM) subjects. From Ref. with permission.

Fig. 5.

Renal tubular reabsorption of glucose in healthy NGT subjects with a glomerular filtration rate (GFR) of 180 liters/day and a mean day-long plasma glucose concentration of 100 mg/dl. Impact of complete SGLT2 inhibition on glucose reabsorption by SGLT1 and glucose excretion. Adapted from Ref. with permission.

Fig. 6.

Left: renal tubular glucose reabsorption in wild-type, SGLT1 knockout (KO), and SGLT2 KO mice. Right: renal tubular reabsorption in WT mice and SGLT1 KO mice treated with empagliflozin. From Ref. with permission.

Fig. 7.

Influence of baseline HbA1c on the efficacy of dapagliflozin (DAPA) and saxagliptin (SAXA). From Ref. with permission.

Fig. 8.

Impact of reduced renal function on the glucose-lowering efficacy (A1c) of dapagliflozin [adapted from Bristol Myers Squibb NDA (Ref. 15)].

Fig. 9.

Effect of dapagliflozin on endogenous (primarily reflects hepatic) glucose production (EGP) in type 2 diabetic subjects. First 2 symbols on the curves represent the basal rate of EGP. Dapagliflozin or placebo was administered at 9 AM on day 1. From Ref. with permission.