Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial

Abstract

Objective: Although initially effective, sulfonylureas are associated with poor glycemic durability, weight gain, and hypoglycemia. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia by increasing urinary glucose excretion independent of insulin and may cause fewer of these adverse effects. We compared the efficacy, safety, and tolerability of dapagliflozin with the sulfonylurea glipizide in patients with type 2 diabetes inadequately controlled with metformin monotherapy.

Research design and methods: This 52-week, double-blind, multicenter, active-controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA(1c), 7.7%), who were receiving metformin monotherapy, to add-on dapagliflozin (n = 406) or glipizide (n = 408) up-titrated over 18 weeks, based on glycemic response and tolerability, to ≤10 or ≤20 mg/day, respectively.

Results: The primary end point, adjusted mean HbA(1c) reduction with dapagliflozin (-0.52%) compared with glipizide (-0.52%), was statistically noninferior at 52 weeks. Key secondary end points: dapagliflozin produced significant adjusted mean weight loss (-3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide, significantly increased the proportion of patients achieving ≥5% body weight reduction (33.3%) versus glipizide (2.5%; P < 0.0001), and significantly decreased the proportion experiencing hypoglycemia (3.5%) versus glipizide (40.8%; P < 0.0001). Events suggestive of genital infections and lower urinary tract infections were reported more frequently with dapagliflozin compared with glipizide but responded to standard treatment and rarely led to study discontinuation.

Conclusions: Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors.

Figures

Figure 1

Change in HbA1c (%) (A) and TBW (kg) (B) during the 52-week double-blind treatment period. Data are adjusted mean change from baseline and 95% CI derived from ANCOVA using the full analysis set and LOCF values. *Dapagliflozin noninferior to glipizide; difference 0.00 (95% CI of difference −0.11 to 0.11). †Difference from glipizide −4.65 kg (95% CI of difference −5.14 to −4.17; P < 0.0001).

Figure 2

Effect of treatments with dapagliflozin (DAPA) and glipizide (GLIP) with metformin (MET) on hypoglycemia, reduction in body weight, and time to study discontinuation due to lack of glycemic control at 52 weeks. A: Proportion of patients with at least one episode of hypoglycemia at 52 weeks. *Difference vs. GLIP + MET, −37.2% (95% CI of difference −42.3 to −21.2; P < 0.0001). B: Proportion of patients with ≥5% reduction in body weight at 52 weeks. †Difference vs. GLIP + MET, 30.8% (95% CI of difference 26.0–35.7; P < 0.0001). Data are adjusted proportions and 95% CI according to the methodology of Zhang et al. (15) using the full analysis set and LOCF values. C: Time to study discontinuation due to lack of glycemic control. Symbols represent censored observations. Week is not the scheduled visit week but the actual number of days from the first dose of double-blind study medication divided by 7. Number of patients at risk is the number of patients at risk at the beginning of the period.