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Ertugliflozin, An SGLT-2, Meets Goals in Two Phase 3 Trials

The investigational sodium/glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin (Merck), being developed to improve glycemic control in adults with type 2 diabetes, met the primary outcomes in two yearlong phase 3 trials, VERTIS SU and VERTIS SITA2.

VERTIS MET, a 26-week study, evaluated the efficacy and safety of ertugliflozin in combination with metformin, compared with placebo and metformin, in adults with type 2 diabetes uncontrolled on metformin monotherapy. The study showed patients taking ertugliflozin 5 mg or 15 mg and metformin experienced greater reductions in A1C compared to placebo (0.7 percent and 0.9 percent, respectively, compared with 0.0 percent for placebo, p<0.001, for both comparisons). Ertugliflozin in combination with metformin also met a secondary endpoint in the study, as significantly more patients taking either ertugliflozin 5 mg or 15 mg achieved the ADA’s recommended A1C treatment goal of less than 7.0 percent compared with placebo and metformin. As add-on therapy to metformin, treatment with ertugliflozin also resulted in significant reductions in fasting plasma glucose (FPG), body weight, systolic blood pressure (SBP) and diastolic blood pressure (DBP), compared with placebo.

At 52 weeks, in patients with type 2 diabetes inadequately controlled with metformin, ertugliflozin 15 mg was noninferior to glimepiride in lowering HbA1c, provided greater body-weight reduction relative to glimepiride, and was associated with less hypoglycemia compared with glimepiride.  On average, with glimepiride, patients had gained 0.9 kg, whereas with the two ertugliflozin doses combined they had lost 3.0 or 3.4 kg, at 1 year (P < .001).  The rate of symptomatic hypoglycemia (requiring help) was 19% in the glimepiride group but only 5.2% in the group that received 15-mg/day ertugliflozin and 4.0% in the group that received 5-mg/day ertugliflozin (P < .001).

Men and women who received either dose of ertugliflozin had higher rates of genital mycotic infection than those who received glimepiride.

The 26-week VERTIS SITA study compared the efficacy and safety of initial combination therapy with ertugliflozin and Merck’s DPP-4 inhibitor JANUVIA® (sitagliptin) with placebo. In this study, patients taking ertugliflozin 5 mg or 15 mg, in combination with sitagliptin 100 mg, experienced greater reductions in A1C compared with patients taking placebo alone (1.6 percent and 1.7 percent, respectively, compared with 0.4 percent in patients taking placebo, p<0.001 for both comparisons). Additionally, the co-administration of ertugliflozin and sitagliptin met a secondary endpoint in the study, as significantly more patients taking ertugliflozin 5 mg or 15 mg, in combination with sitagliptin 100 mg, achieved the A1C treatment goal of less than 7.0 percent. Treatment with the initial combination of ertugliflozin and sitagliptin also resulted in significant reductions in FPG, body weight and SBP, compared with placebo.

The VERTIS SITA 2 trial randomized patients who had stable HbA1c > 7% but < 10.5% while taking > 1500 mg/day metformin and 100 mg/day of the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck) to also receive 5-mg/day ertugliflozin (156 patients), 15-mg/day ertugliflozin (153 patients), or placebo (153 patients).  The efficacy end points at 52 weeks included proportion of patients with HbA1c < 7%.

At 52 weeks, a greater proportion of patients receiving either dose of ertugliflozin vs placebo attained an HbA1c <7% (33% vs 13.7%).  Patients in the ertugliflozin groups lost more weight than patients in the placebo group (3.5 kg and 2.8 kg vs 1.0 kg), and their systolic blood pressure dropped by 4.1 mm Hg vs 0.8 mm Hg.

Patients in all three groups had similar rates of symptomatic hypoglycemia and urinary-tract infections, but those in the ertugliflozin groups had higher rates of genital mycotic infections.

New drug applications (NDAs) for ertugliflozin and for two fixed-dose combination products — ertugliflozin and sitagliptin and ertugliflozin and metformin — are under review with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

The company also notes that VERTIS CV, a cardiovascular-outcomes trial with ertugliflozin, recently completed enrollment with about 8000 patients with type 2 diabetes and established vascular disease and final data for this outcome are expected by the end of 2019.

Practice Pearls:

  • Ertugliflozin 5 mg or 15 mg and metformin experienced greater reductions in A1C compared to placebo.
  • Ertugliflozin in combination with sitagliptin 100 mg, experienced greater reductions in A1C compared with patients taking placebo alone.
  • In patients with type 2 diabetes inadequately controlled with metformin, ertugliflozin 15 mg was noninferior to glimepiride in lowering HbA1c, provided greater body-weight reduction relative to glimepiride, and was associated with less hypoglycemia compared with glimepiride.

Reference:

European Association for the Study of Diabetes 2017 Annual Meeting; September 12, 2017; Lisbon, Portugal. Abstract 38, Abstract 41  The two trials, which are part of the nine-trial VERTIS program, were presented in an oral session at the recent European Association for the Study of Diabetes (EASD) 2017 Annual Meeting