Empagliflozin Monotherapy Trial Extension Highlights Advantages of SGLT2 Inhibitors for Treatment of Type 2 Diabetes

June 17, 2014
Dennis Bittner, PhD

Study results show long-term treatment with empagliflozin was well tolerated and associated with reductions in HbA1c, bodyweight, and systolic blood pressure compared with placebo and sitagliptin.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are an important emerging class of medications for the treatment of type 2 diabetes. SGLT2 is a low-affinity, high-capacity glucose transporter that exerts its influence in the proximal tubule of the kidney. As SGLT2 is responsible for 90% of glucose reabsorption, inhibition of SGLT2 leads to a decrease in blood glucose due to increased renal glucose excretion.

During a session focused on SGLT2 inhibitors Monday at the American Diabetes Association’s 74th Scientific Sessions, Michael Roden, MD, director of the Institute for Clinical Diabetology of the German Diabetes Center in Düsseldorf, presented results from a phase 3 clinical trial that assessed the long-term safety and efficacy of monotherapy with the SGLT2 inhibitor empagliflozin compared with either placebo or the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin in patients with type 2 diabetes.

In discussing the purpose of the trial, Roden said, “Metformin is recommended as first-line drug treatment for type 2 diabetes, but several other drugs may be used. Empagliflozin is an SGLT2 inhibitor in development for treatment of type 2 diabetes that reduces HbA1C, bodyweight, and blood pressure. The objective of the study was to evaluate the long-term safety, tolerability, and efficacy of empagliflozin compared with sitagliptin or placebo as monotherapy in drug-naïve patients with type 2 diabetes.”

In a double-blind trial previously reported as EMPA-REG MONO, 899 patients were randomized to empagliflozin 10 mg, empagliflozin 25 mg, placebo, or sitagliptin 100 mg for 24 weeks. Inclusion criteria at the start of the initial study were HbA1c levels ≥7.0% and ≤10.0%. Patients also had to be drug-naïve with no glucose-lowering treatment for ≥12 weeks prior to randomization. Roden reported results from EMPA-REG EXTEND, in which 615 (68.4%) of the original patients continued for ≥52 weeks in a double-blind extension of the original study. Characteristics of these patients were comparable with the population in EMPA-REG MONO.

Exploratory efficacy endpoints were changes from baseline in HbA1c, bodyweight, and systolic and diastolic blood pressure (SBP and DBP) at week 76. At week 76, empagliflozin at both the 10 mg and 25 mg doses had significantly reduced HbA1c and bodyweight versus placebo and also led to clinically meaningful and sustained reductions in SBP. Empagliflozin 25 mg reduced HbA1c levels compared with sitagliptin.

Safety was also assessed for ≥76 weeks. Adverse events (AEs) were reported in similar proportions in patients on empagliflozin, placebo, and sitagliptin. Hypoglycemic AEs (ie, those with glucose ≤70 mg/dL and/or requiring assistance) were reported in 2 patients (0.9%) in each treatment group; 1 patient on empagliflozin 10 mg required assistance.

Vaginal yeast infections and urinary tract infections are the most common side effects associated with SGLT2 inhibitors, with female patients and uncircumcised male patients facing the greatest risk. Adverse events consistent with urinary tract infection were reported in similar proportions for patients on empagliflozin, placebo, and sitagliptin. Adverse events consistent with genital infection were reported in more patients on empagliflozin than placebo or sitagliptin.

In conclusion, Roden said, “In drug-naïve patients with type 2 diabetes, 76 weeks of empagliflozin monotherapy at either the 10 mg or 25 mg dose was well tolerated. The 25 mg dose of empagliflozin reduced HbA1c compared with sitagliptin or placebo at week 76, and treatment with empagliflozin 10 mg or 25 mg for 76 weeks led to reduced bodyweight and systolic blood pressure compared with sitagliptin or placebo.”

This study was funded by Boehringer Ingelheim and Eli Lilly & Company.