Phase-3 study to evaluate efficacy and safety of ertugliflozin monotherapy.
This was a 52-week, double-blind, multi-center, randomized, parallel-group study with a 26-week, placebo-controlled treatment period (Phase A) followed by a 26-week active-controlled treatment period (Phase B) in 461 men and women, at least 18 years of age and inadequate glycemic control (HbA1c 7.0-10.5% [53-91 mmol/mol], inclusive) despite diet and exercise.
Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the most recent class of oral anti-hyperglycemic agents approved for the treatment of type 2 diabetes mellitus (T2DM). Glucose is filtered in the glomerulus and with normoglycemia almost all the filtered glucose is reabsorbed into the circulation in the early and late portion of the proximal tubule via SGLT2 and sodium-glucose co-transporter 1 (SGLT1), respectively. With hyperglycemia, when the transporters reach their maximum reabsorptive capacity, glucosuria ensues. SGLT2 inhibitors reduce renal glucose reabsorption and lower renal threshold for glucose excretion thereby increasing urinary glucose excretion and reducing plasma glucose and HbA1c in patients with T2DM [1-2].
Ertugliflozin is an SGLT2 inhibitor with greater than 2000-fold higher selectivity for SGLT2 compared to SGLT1. In Phase 2 studies, ertugliflozin significantly reduced plasma glucose and HbA1c in patients with T2DM and also reduced 24-hour ambulatory blood pressure to a similar extent as hydrochlorothiazide. The purpose of this study (VERTIS MONO) was to evaluate the efficacy and safety of ertugliflozin monotherapy in patients with T2DM and inadequate glycemic control despite diet and exercise.
At Week 26, the placebo-adjusted mean HbA1c changes from baseline were -0.99% and -1.16% for the ertugliflozin 5 mg and 15 mg doses, respectively (p<0.001 for both doses). The odds of having HbA1c <7.0% (53 mmol/mol) were significantly greater in the ertugliflozin 5 mg and 15 mg groups compared to the placebo group. Both doses of ertugliflozin significantly lowered fasting plasma glucose, 2-hour post-prandial glucose and body weight. The placebo-adjusted differences in changes from baseline in systolic blood pressure were not statistically significant. A higher incidence of genital mycotic infections occurred in men and women treated with ertugliflozin compared to placebo. There was no significant difference between treatments in the proportion of subjects with symptomatic hypoglycemia or adverse events associated with urinary tract infection or hypovolemia.
The primary efficacy endpoint was the change from baseline in HbA1c at Week 26. Pre-specified secondary efficacy endpoints were changes from baseline at Week 26 in FPG, body weight, 2-hour post-prandial glucose (PPG), systolic blood pressure (SBP), diastolic blood pressure (DBP) and the proportion of patients with HbA1c <7.0% (53 mmol/mol) at Week 26.
For patients with baseline HbA1c ≥8%, the placebo-adjusted LS mean changes in HbA1c at Week 26 were -1.11% (-1.46, -0.77) and -1.52% (-1.86, -1.17) for ertugliflozin 5 mg and 15 mg, respectively. For patients with baseline HbA1c <8%, the placebo-adjusted mean changes in HbA1c at Week 26 were -0.96% (-1.28, -0.64) and -1.01% (-1.34, -0.69), for ertugliflozin 5 mg and 15 mg, respectively. In this Phase 3 study of patients with T2DM who had inadequate glycemic control on diet and exercise alone, treatment with ertugliflozin 5 mg and 15 mg provided statistically significant and clinically relevant improvements in glycemic control and body weight. The reduction from baseline in HbA1c at Week 26 was significantly greater in the ertugliflozin 5 mg and 15 mg groups compared to placebo. The SGLT2 inhibitors, canagliflozin, emapagliflozin and dapagliflozin have also been evaluated as monotherapy in T2DM patients. While there are no head-to-head trials comparing HbA1c changes between SGLT2 inhibitors, the results from this study suggest that ertugliflozin also provides meaningful improvements in glycemic control.
Adverse Effects were similar to other SGLT2’s.
In conclusion, in patients with T2DM inadequately controlled on diet and exercise, ertugliflozin 5 mg and 15 mg provides effective glycemic control, reduces body weight and is generally well tolerated, when used as monotherapy.
- Analyses of lipid parameters showed an increase in LDL-C and HDL-C as also shown in other SGLT2 inhibitors.
- Ertugliflozin also reduced body weight and was well tolerated as a monotherapy.
- Ertugliflozin, an SGLT-2 inhibitor at 5 and 15mg for 26 weeks was well tolerated as a monotherapy.
Published online in Diabetes, Obesity and Metabolism, Jan 2017.