Efficacy and Safety of Ertugliflozin in Patients with Type 2 Diabetes Inadequately Controlled by Metformin and Sulfonylurea: A Sub-Study of VERTIS CV

Abstract

Introduction: VERTIS CV is the cardiovascular outcome trial for the sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin. A sub-study was conducted to assess the efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus (T2DM) inadequately glycemic-controlled on metformin and a sulfonylurea (SU).

Methods: Patients with T2DM, established atherosclerotic cardiovascular disease (ASCVD), and an HbA1c of 7.0-10.5% on stable metformin (≥ 1500 mg/day) and moderate to high SU doses were randomly assigned to once-daily ertugliflozin (5 or 15 mg) or placebo. The primary sub-study objectives were to assess the effect of ertugliflozin on HbA1c compared with placebo and to evaluate safety following 18 weeks of treatment. Key secondary endpoints included changes in fasting plasma glucose (FPG), body weight (BW), blood pressure (BP), and the proportion of patients achieving HbA1c < 7%.

Results: Of the 8246 patients enrolled in VERTIS CV, 330 were eligible for this sub-study (ertugliflozin 5 mg, n = 100; ertugliflozin 15 mg, n = 113; placebo, n = 117). This subgroup had a mean (SD) age of 63.2 (8.4) years and T2DM duration of 11.4 (7.4) years. At week 18, ertugliflozin 5 mg and 15 mg were each associated with significantly greater least squares (LS) mean reductions from baseline in HbA1c relative to placebo (placebo-adjusted LS mean [95% CI] - 0.66% [- 0.89, - 0.43] and - 0.75% [- 0.98, - 0.53], respectively, p < 0.001 for each dose vs placebo). Ertugliflozin significantly reduced FPG and BW compared with placebo (p < 0.001), but not systolic BP. Adverse events were reported in 48.0%, 54.9%, and 47.0% of patients in the ertugliflozin 5 mg and 15 mg, and placebo groups. The incidences of symptomatic hypoglycemia were 11.0% (5 mg), 12.4% (15 mg), and 7.7% (placebo), and of severe hypoglycemia 2.0% (5 mg), 1.8% (15 mg), and 0.9% (placebo).

Conclusions: In patients with T2DM and ASCVD, ertugliflozin added to metformin and SU improved glycemic control, reduced BW, and was generally well tolerated.

Trial registration: VERTIS CV ClinicalTrials.gov identifier, NCT01986881.

Keywords: Ertugliflozin; Glycemic control; HbA1c; Metformin; SGLT2 inhibitor; Sulfonylurea; Type 2 diabetes mellitus.

Figures

Fig. 1

Study flow diagram

Fig. 2

LS mean change from baseline in HbA1c over time. HbA1c glycated hemoglobin, LS least squares, SE standard error of the mean

Fig. 3

Primary and secondary efficacy outcomes. a LS mean change from baseline in HbA1c at week 18; b Proportion of patients with HbA1c < 7% at week 18; c LS mean change from baseline in FPG at week 18; d LS mean change from baseline in body weight at week 18; e LS mean change from baseline in systolic BP at week 18; f LS mean change from baseline in diastolic BP at week 18. BP blood pressure, CI confidence interval, FPG fasting plasma glucose, HbA1c glycated hemoglobin, LS least squares

Fig. 4

Estimate of placebo-adjusted change from baseline in HbA1c at week 18 by subgroup category (FAS population, excluding rescue approach). Point estimate and 95% CIs are shown. The median age (65 years) and median HbA1c (8.1%) were derived from the overall patient population of the main study. Values in parentheses are n’s for placebo, ertugliflozin 5 mg and 15 mg groups, respectively. CI confidence interval, FAS full analysis set, HbA1c glycated hemoglobin, LS least squares