Changes in Insulin Sensitivity and Insulin Secretion with the Sodium Glucose Cotransporter 2 Inhibitor Dapagliflozin

Aim: This randomized, double-blind, placebo-controlled parallel-group study assessed the effects of sodium glucose cotransporter 2 inhibition by dapagliflozin on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM), who had inadequate glycemic control with metformin (with or without an insulin secretagogue). Subjects and Methods: Forty-four subjects were randomized to receive dapagliflozin 5 mg or matching placebo once daily for 12 weeks. Subjects continued stable doses of background antidiabetes medication throughout the study. Insulin sensitivity was assessed by measuring the glucose disappearance rate (G(DR)) during the last 40 min of a 5-h hyperinsulinemic, euglycemic clamp. Insulin secretion was determined as the acute insulin response to glucose (AIR(g)) during the first 10 min of a frequently sampled intravenous glucose tolerance test. Where noted, data were adjusted for baseline values and background antidiabetes medication. Results: An adjusted mean increase from baseline in G(DR) (last observation carried forward), at Week 12, was observed with dapagliflozin (7.98%) versus a decrease with placebo (-9.99%). The 19.97% (95% confidence interval 5.75-36.10) difference in G(DR) versus placebo was statistically significant (P=0.0059). A change from baseline in adjusted mean AIR(g) of 15.39 mU/L min was observed with dapagliflozin at Week 12, versus -12.73 mU/L min with placebo (P=0.0598). Over 12 weeks, numerical reductions from baseline in glycosylated hemoglobin (HbA(1c)), fasting plasma glucose, and body weight were observed with dapagliflozin (-0.38%, -0.39 mmol/L, and -1.58%, respectively) versus slight numerical increases with placebo (0.03%, 0.26 mmol/L, and 0.62%, respectively). Conclusions: In patients with T2DM and inadequate glycemic control, dapagliflozin treatment improved insulin sensitivity in the setting of reductions in HbA(1c) and weight.