Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo‐controlled randomized study

Abstract

AimsTo assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin.Materials and MethodsIn this double‐blind randomized study (Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53‐91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2) were randomized to ertugliflozin 5 mg once‐daily, 15 mg once‐daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52.ResultsA total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m2). After 26 weeks, placebo‐adjusted least squares (LS) mean changes in HbA1c from baseline were −0.7% (−7.5 mmol/mol) and −0.8% (−8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%‐14.1%) vs placebo (0%‐1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups.ConclusionsErtugliflozin added to metformin and sitagliptin was well‐tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks.

Assessment of the Drug Interaction Potential of Ertugliflozin With Sitagliptin, Metformin, Glimepiride, or Simvastatin in Healthy Subjects

“…5,7 It is likely to be used in combination with a number of other antihyperglycemic and lipid-lowering agents (eg, statins) for comorbidities associated with diabetes. 5,7 It is likely to be used in combination with a number of other antihyperglycemic and lipid-lowering agents (eg, statins) for comorbidities associated with diabetes.…”

“…5,7,22,23 Coadministration of ertugliflozin with sitagliptin 100 mg provided greater glycemic control compared with each individual dose of ertugliflozin and sitagliptin with inadequate control on either metformin or diet and exercise. 5,7,22 Due to the linear and time-independent PK of ertugliflozin, single-dose PK are predictive of multiple-dose PK of ertugliflozin. 23 Ertugliflozin as an add-on to metformin, and metformin and sitagliptin, also provided clinically meaningful body weight and systolic blood pressure reductions.…”

Efficacy and Safety of Ertugliflozin in Patients with Overweight and Obesity with Type 2 Diabetes Mellitus

“…Data for this post hoc analysis were pooled from three randomized, double‐blind, multicenter, placebo‐controlled, Phase 3 studies (VERTIS SITA2, VERTIS MET, VERTIS MONO) of a total of 1,544 patients with T2DM treated with ertugliflozin or placebo. Studies had similar overall study populations, designs, and enrollment criteria (Supporting Information Table S1).…”

Novel Application of the Two‐Period Microtracer Approach to Determine Absolute Oral Bioavailability and Fraction Absorbed of Ertugliflozin

“…Recent phase III trials have demonstrated that ertugliflozin is associated with statistically significant reductions in hemoglobin A1c, fasting plasma glucose, and body weight when used as monotherapy (compared with placebo),3 and when added to sitagliptin4 or metformin plus sitagliptin 5. When dosed in the fasting state, ertugliflozin pharmacokinetics are characterized by rapid absorption following oral administration (with median time to maximum concentration (T max ) occurring at 0.5–1.5 h postdose), dose proportionality in exposure (area under the curve (AUC) and maximum concentration (C max )) over a dose range of 0.5–300 mg, and a terminal elimination half‐life (t 1/2 ) of 11–17 h 1.…”