Metformin hydrochloride 

 

There was no evidence of a mutagenic potential of metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus test were also negative.

Impairment of Fertility 

Ertugliflozin 

 

In the rat fertility and embryonic development study, male and female rats were administered ertugliflozin at 5, 25, and 250 mg/kg/day. No effects on fertility were observed at 250 mg/kg/day (approximately 480 and 570 times male and female human exposures, respectively, at the MRHD of 15 mg/day based on AUC comparison).

Metformin hydrochloride 

 

Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

 

14 CLINICAL STUDIES 

 

14.1 Overview of Clinical Studies in Patients with Type 2 Diabetes Mellitus

 

The efficacy and safety of ertugliflozin in combination with metformin have been studied in 4 multicenter, randomized, double-blind, placebo- and active comparator-controlled, clinical studies involving 3,643 patients with type 2 diabetes mellitus. These studies included White, Hispanic, Black, Asian, and other racial and ethnic groups, and patients with an age range of 21 to 86 years.

 

In patients with type 2 diabetes mellitus, treatment with ertugliflozin in combination with metformin reduced hemoglobin A1c (HbA1c) compared to placebo.

 

In patients with type 2 diabetes mellitus treated with ertugliflozin in combination with metformin, the reduction in HbA1c was generally similar across subgroups defined by age, sex, race, geographic region, baseline body mass index (BMI), and duration of type 2 diabetes mellitus. 

14.2 Ertugliflozin as Add-on Combination Therapy with Metformin

 

A total of 621 patients with type 2 diabetes mellitus inadequately controlled (HbA1c between 7% and 10.5%) on metformin monotherapy (≥1,500 mg/day for ≥8 weeks) participated in a randomized, double-blind, multi-center, 26-week, placebo-controlled study (NCT02033889) to eva luate the efficacy and safety of ertugliflozin in combination with metformin. Patients entered a 2-week, single-blind, placebo run-in, and were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg administered once daily in addition to continuation of background metformin therapy.

 

At Week 26, statistically significant reductions in HbA1c were observed in the ertugliflozin 5 mg and 15 mg groups compared to placebo. Ertugliflozin also resulted in a greater proportion of patients achieving an HbA1c <7% compared to placebo (see Table 6 and Figure 3).

 

Table 6: Results at Week 26 from a Placebo-Controlled Study for Ertugliflozin Used in Combination with Metformin in Patients with Type 2 Diabetes Mellitus* 

Placebo

 

Ertugliflozin 5 mg

 

Ertugliflozin 15 mg