A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment

Abstract

Objective: To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).

Research design and methods: This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).

Results: At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated -0.70 and -0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C > or =0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and -9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were -1.9, -4.5, and -4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.

Conclusions: In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.

Figure 1

Patient disposition.

Figure 2

Mean A1C (A), mean FPG (B), and mean change from baseline in total body weight (C) over time. Data are for randomly assigned patients who took at least one dose of the double-blind study medication. Shown are mean values based on LOCF, excluding data after up-titration of insulin. Error bars represent 95% CIs. DAPA, dapagliflozin; INS, insulin; PLA, placebo.