Safety of Ertugliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Seven Phase 3 Randomized Controlled Trials

Abstract

Introduction: The sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin is approved for the treatment of adults with type 2 diabetes mellitus (T2DM). This analysis was conducted on safety data pooled from phase 3 studies using ertugliflozin 5 mg or 15 mg versus placebo or an active comparator.

Methods: The placebo pool (n = 1544) comprised data from three similarly designed 26-week placebo-controlled studies. The broad pool (n = 4849) comprised these three placebo-controlled studies plus four placebo- or active-controlled studies with treatment durations of up to 104 weeks.

Results: In the placebo pool, there were no notable differences across groups in the incidence of adverse events (AEs), serious AEs, or AEs resulting in discontinuation from study medication, while associations were observed with genital mycotic infection in both females (3.0%, 9.1%, and 12.2% in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively) and males (0.4%, 3.7%, 4.2%), thirst (0.2%, 1.3%, 1.0%), and increased urination (1.0%, 2.7%, 2.4%). In the broad pool, volume depletion was increased with ertugliflozin in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m2, aged ≥ 65 years, or who were taking diuretics. Ertugliflozin was not associated with increased urinary tract infection, fracture, hypoglycemia, pancreatitis, renal or hepatic injury, hypersensitivity, malignancy, or venous thromboembolism. Small numbers of patients were reported with lower limb amputation [0.1% (non-ertugliflozin group), 0.2% (ertugliflozin 5 mg), 0.5% (ertugliflozin 15 mg)]. There were three cases of ketoacidosis (all ertugliflozin 15 mg) and no cases of Fournier's gangrene.

Conclusion: This pooled analysis showed that ertugliflozin was generally well tolerated in a large population of patients with T2DM with and without moderate renal impairment who were taking a range of background diabetes medications including insulin and insulin secretagogs, with results that are generally consistent with those for other SGLT2 inhibitors.

Trial registration: Clinicaltrials.gov indentifier, NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218.

Keywords: Ertugliflozin; Genital mycotic infection; Sodium-glucose cotransporter 2 inhibitor; Type 2 diabetes mellitus; Urinary tract infection; Volume depletion.

Figures

Fig. 1

Phase 3 studies included in the pooled analyses. HbA1C glycated hemoglobin Source: Adapted from Liu et al. [45]

Fig. 2

Proportion of patients in the placebo pool meeting the PDLC criterion for orthostatic blood pressure upon standing from the supine position for a SBP and b DBP. PDLC criterion for orthostatic change in SBP was defined as a reduction ≥ 20 mmHg after 1 and/or 3 min in the standing position from the supine position (relative to the mean value from measurements taken in the supine position). Orthostatic change in DBP was defined as a reduction ≥ 10 mmHg after 1 and/or 3 min in the standing position from the supine position (relative to the mean value for measurements taken in the supine position). DBP diastolic blood pressure, PDLC predefined limit of change, SBP systolic blood pressure

Fig. 3

Cumulative percentage of patients in the broad pool with AEs associated with a volume depletion AEs; b GMI in females; c GMI in males; d UTI AEs. AE adverse event, GMI genital mycotic infection, UTI urinary tract infection

Fig. 4

Mean change from baseline in eGFR over time in a the placebo poola; b VERTIS RENALa; c VERTIS RENAL 54-week reversibility data.b Reproduced from Grunberger, G., Camp, S., Johnson, J. et al. Ertugliflozin in Patients with Stage 3 Chronic Kidney Disease and Type 2 Diabetes Mellitus: The VERTIS RENAL Randomized Study. Diabetes Ther 9, 49–66 (2018). 10.1007/s13300-017-0337-5 [19], which is licensed under Creative Commons Attribution-Non Commercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/). aSample size indicates patients with a baseline measurement. bPatients included in this analysis were receiving study medication at week 52 and had baseline, week 52 (last on-treatment visit), and week 54 (2 weeks post-treatment visit) data. eGFR estimated glomerular filtration rate, SE standard error

Fig. 5

Proportion of patients meeting PDLC criterion for decrease in eGFR from baseline in a the placebo pool; b the VERTIS RENAL study. PDLC criterion for eGFR: > 30% or > 50% decline from baseline. eGFR estimated glomerular filtration rate, PDLC predefined limit of change