Long-Term Safety and Efficacy of Empagliflozin,Sitagliptin, and Metformin: An active-controlled,parallel-group,randomized, 78-week open-label extension study in patients with type 2 diabetes

OBJECTIVE

To investigate the long-term safety and efficacy of empagliflozin, a sodium glucose cotransporter 2 inhibitor; sitagliptin; and metformin in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

In this randomized, open-label, 78-week extension study of two 12-week, blinded, dose-finding studies of empagliflozin (monotherapy and add-on to metformin) with open-label comparators, 272 patients received 10 mg empagliflozin (166 as add-on to metformin), 275 received 25 mg empagliflozin (166 as add-on to metformin), 56 patients received metformin, and 56 patients received sitagliptin as add-on to metformin.

RESULTS

Changes from baseline in HbA_1c at week 90 were −0.34 to −0.63% (−3.7 to −6.9 mmol/mol) with empagliflozin, −0.56% (−6.1 mmol/mol) with metformin, and −0.40% (−4.4 mmol/mol) with sitagliptin. Changes from baseline in weight at week 90 were −2.2 to −4.0 kg with empagliflozin, −1.3 kg with metformin, and −0.4 kg with sitagliptin. Adverse events (AEs) were reported in 63.2–74.1% of patients on empagliflozin and 69.6% on metformin or sitagliptin; most AEs were mild or moderate in intensity. Hypoglycemic events were rare in all treatment groups, and none required assistance. AEs consistent with genital infections were reported in 3.0–5.5% of patients on empagliflozin, 1.8% on metformin, and none on sitagliptin. AEs consistent with urinary tract infections were reported in 3.8–12.7% of patients on empagliflozin, 3.6% on metformin, and 12.5% on sitagliptin.

CONCLUSIONS

Long-term empagliflozin treatment provided sustained glycemic and weight control and was well tolerated with a low risk of hypoglycemia in patients with type 2 diabetes.Type 2 diabetes is characterized by insulin resistance and progressive deterioration of β-cell function (1). Metformin is the recommended first-line antidiabetes agent for patients with type 2 diabetes (2). However, in order to achieve and maintain glycemic control as the disease progresses, patients often require therapies in addition to metformin (2,3).Despite the availability of a number of antihyperglycemic agents, the side effects associated with existing treatments and their gradual loss of efficacy over time (2,3) mean that many patients with type 2 diabetes do not reach therapeutic goals (3,4). In addition, treatment is often complicated by common comorbidities of type 2 diabetes such as obesity and hypertension, which are not addressed by existing oral antidiabetes agents (5–7).Inhibition of sodium glucose cotransporter 2 (SGLT2), located in the proximal tubule of the kidney, represents an approach for the treatment of type 2 diabetes that is independent of β-cell function and insulin resistance (8,9). SGLT2 mediates most of renal glucose reabsorption, and inhibition of this transporter leads to reduced reabsorption of filtered glucose and increased urinary glucose excretion (8,10), resulting in reduced plasma glucose levels in patients with type 2 diabetes (8–10). In addition, this mechanism leads to weight loss owing to the loss of calories via urinary glucose excretion (8,11).Empagliflozin is a potent and selective inhibitor of SGLT2 (12), which in patients with type 2 diabetes causes urinary glucose excretion of up to 90 g/day (13). In two placebo- and active-controlled, dose-finding trials, treatment with empagliflozin for 12 weeks in patients with type 2 diabetes was generally well tolerated and resulted in placebo-corrected reductions in HbA_1c of up to 0.72% (7.9 mmol/mol) and placebo-corrected reductions in weight of up to 1.7 kg (14,15). In these studies, reductions in HbA_1c were comparable to those of the active comparators metformin and sitagliptin (14,15). The objective of this study was to assess the long-term safety and efficacy of empagliflozin, sitagliptin, and metformin in a 78-week, open-label extension study of two dose-finding trials.