Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial

Abstract

Background: Management of type 2 diabetes with metformin often does not provide adequate glycemic control, thereby necessitating add-on treatment. In a 24-week clinical trial, dapagliflozin, an investigational sodium glucose cotransporter 2 inhibitor, improved glycemic control in patients inadequately controlled with metformin. The present study is an extension that was undertaken to evaluate dapagliflozin as long-term therapy in this population.

Methods: This was a long-term extension (total 102 weeks) of a 24-week phase 3, multicenter, randomized, placebo-controlled, double-blind, parallel-group trial. Patients were randomly assigned (1:1:1:1) to blinded daily treatment (placebo, or dapagliflozin 2.5 to 5, or 10 mg) plus open-label metformin (≥1,500 mg). The previously published primary endpoint was change from baseline in glycated hemoglobin (HbA1c) at 24 weeks. This paper reports the follow-up to week 102, with analysis of covariance model performed at 24 weeks with last observation carried forward; a repeated measures analysis was utilized to evaluate changes from baseline in HbA1c, fasting plasma glucose (FPG), and weight.

Results: A total of 546 patients were randomized to 1 of the 4 treatments. The completion rate for the 78-week double-blind extension period was lower for the placebo group (63.5%) than for the dapagliflozin groups (68.3% to 79.8%). At week 102, mean changes from baseline HbA1c (8.06%) were +0.02% for placebo compared with -0.48% (P = 0.0008), -0.58% (P <0.0001), and -0.78% (P <0.0001) for dapagliflozin 2.5 to 5, and 10 mg, respectively. In addition, all dapagliflozin groups had sustained reductions from baseline in FPG (-1.07 to -1.47 mmol/l) and body weight (-1.10 to -1.74 kg) at 102 weeks, whereas increases were noted in placebo-treated patients for both of these outcomes. Events of hypoglycemia were rare and were not severe. Evidence suggestive of genital infection was reported in 11.7% to 14.6% of dapagliflozin patients and 5.1% of placebo patients, with one related discontinuation (dapagliflozin 5 mg). Evidence suggestive of urinary tract infection was reported in 8.0% to 13.3% of dapagliflozin patients and 8.0% of placebo patients, with one related discontinuation (dapagliflozin 2.5 mg).

Conclusions: Dapagliflozin added to metformin for 102 weeks enabled sustained reductions in HbA1c, FPG, and weight without increased risk of hypoglycemia in patients with type 2 diabetes who were inadequately controlled on metformin alone.

Trial registration: ClinicalTrials.gov: NCT00528879.

Figure 1

Trial profile over 102 weeks.

Figure 2

Change from baseline in (A) glycated hemoglobin (HbA1c), (B) urinary glucose:creatinine ratio, and (C) body weight for placebo (circles), dapagliflozin 2.5 mg (squares), dapagliflozin 5 mg (triangles), and dapagliflozin 10 mg (diamonds) groups all plus metformin up to 102 weeks. Data are means (95% CI) obtained from longitudinal repeated measures analyses. Data for HbA1c exclude patients who received rescue therapy to achieve the strict HbA1c requirements to remain in the trial. The urinary glucose:creatinine ratios also exclude patients who received rescue therapy. Data for weight, however, include patients who received rescue therapy (pioglitazone), demonstrating the ability of dapagliflozin to attenuate weight gain by this antidiabetes medication. Mean change from baseline in HbA1c after adjustment for baseline value (A), mean change from baseline in urinary glucose:creatinine ratio (g/g) after adjustment for baseline value (B) and mean change from baseline in body weight after adjustment for baseline value (C) are shown.