Empagliflozin as Add-on to Metformin Plus Sulfonylurea in Patients With Type 2 Diabetes: A 24-week,randomized, double-blind,placebo-controlled trial

OBJECTIVE

To investigate the efficacy and tolerability of empagliflozin as add-on to metformin and sulfonylurea in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Patients inadequately controlled on metformin and sulfonylurea (HbA_1c ≥7 to ≤10%) were randomized and treated with once-daily empagliflozin 10 mg (n = 225), empagliflozin 25 mg (n = 216), or placebo (n = 225) for 24 weeks. The primary end point was change from baseline in HbA_1c at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24.

RESULTS

At week 24, adjusted mean (SE) changes from baseline in HbA_1c were −0.17% (0.05) for placebo vs. −0.82% (0.05) and −0.77% (0.05) for empagliflozin 10 and 25 mg, respectively (both P < 0.001). Empagliflozin significantly reduced MDG, weight, and systolic (but not diastolic) blood pressure versus placebo. Adverse events were reported in 62.7, 67.9, and 64.1% of patients on placebo and empagliflozin 10 and 25 mg, respectively. Events consistent with urinary tract infection were reported in 8.0, 10.3, and 8.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 13.3, 18.0, and 17.5%, respectively; males: 2.7, 2.7, and 0%, respectively). Events consistent with genital infection were reported in 0.9, 2.7, and 2.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 0.9, 4.5, and 3.9%, respectively; males: 0.9% in each group).

CONCLUSIONS

Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin plus sulfonylurea improved glycemic control, weight, and systolic blood pressure and were well tolerated.Metformin is the standard first-line pharmacotherapy to achieve glycemic control in patients with type 2 diabetes (1). However, metformin alone frequently fails to maintain glycemic control in the long term (2), and most patients with type 2 diabetes will require additional therapies (1). Although initially effective, sulfonylureas are associated with low durability (2), and common side effects are hypoglycemia and weight gain (3–5). Furthermore, as type 2 diabetes progresses, with deterioration of β-cell function and increased insulin resistance (6), the use of agents utilizing pathways dependent on insulin becomes increasingly difficult. In addition, steady increases in weight are observed in patients with type 2 diabetes (7), which may be associated with worsening markers of insulin resistance (1). Thus, there is still a great unmet need for effective and well-tolerated antidiabetes agents that can be used in combination with existing treatments to improve glycemic control in patients with type 2 diabetes, in particular without the risk of hypoglycemia and weight gain.The sodium glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, represents a promising target for the treatment of type 2 diabetes. SGLT2 is responsible for tubular reabsorption of ∼90% of the glomerular filtrated glucose (8). In patients with type 2 diabetes, inhibition of SGLT2 leads to reduced renal glucose reabsorption and increased urinary glucose excretion, resulting in a reduction in hyperglycemia, irrespective of β-cell function or insulin resistance (9).Empagliflozin is a potent and selective inhibitor of SGLT2 (10). In phase II trials in patients with type 2 diabetes, a 12-week treatment with empagliflozin as monotherapy or as add-on to metformin resulted in reductions in HbA_1c, weight, and blood pressure and was well tolerated (11,12). These effects were shown to be sustained for up to 90 weeks (13).The aim of this study (EMPA-REG METSU) was to evaluate the efficacy, safety, and tolerability of empagliflozin (10 and 25 mg once daily) versus placebo over 24 weeks as add-on therapy to metformin plus sulfonylurea in patients with type 2 diabetes with inadequate glycemic control. In addition, the efficacy and safety of empagliflozin 25 mg was investigated in poorly controlled patients with HbA_1c >10% in an open-label treatment arm.