Ertugliflozin Compared to Other Anti-hyperglycemic Agents as Monotherapy and Add-on Therapy in Type 2 Diabetes: A Systematic Literature Review and Network Meta-Analysis

Abstract

Introduction: Ertugliflozin is a new sodium-glucose co-transporter-2 inhibitor (SGLT2i) for the treatment of type 2 diabetes mellitus. As there are no head-to-head trials comparing the efficacy of SGLT2is, the primary objective of this analysis was to indirectly compare ertugliflozin to other SGLT2i in patient populations with inadequately controlled glycated hemoglobin (HbA1c > 7.0%) and previously treated with either diet/exercise, metformin alone or metformin plus a dipeptidyl peptidase-4 inhibitor (DPP4i).

Methods: A systematic literature review (SLR) identified randomized controlled trials (RCTs) reporting outcomes at 24-26 weeks of treatment. Comparators to ertugliflozin were the SGLT2is canagliflozin, dapagliflozin and empagliflozin, with non-SGLT2i comparators also evaluated third-line [insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)]. Outcomes were change from baseline in HbA1c, weight and systolic blood pressure (SBP) as well as HbA1c < 7% and key safety events. Bayesian network meta-analysis was used to synthesize evidence. Results are presented as the median of the mean difference (MD) or as odds ratios with 95% credible intervals (CrI).

Results: In patients uncontrolled on diet/exercise, the efficacy of ertugliflozin 5 mg monotherapy was not significantly different from that of other low-dose SGLT2is in terms of HbA1c reduction, while ertugliflozin 15 mg was more effective than dapagliflozin 10 mg (MD - 0.36%, CrI - 0.65, - 0.08) and empagliflozin 25 mg (MD - 0.31%, CrI - 0.58, - 0.04). As add-on therapy to metformin, ertugliflozin 5 mg was more effective in lowering HbA1c than dapagliflozin 5 mg (MD - 0.22%, CrI - 0.42, - 0.02), and ertugliflozin 15 mg was more effective than dapagliflozin 10 mg (MD - 0.26%, CrI - 0.46, - 0.06) and empagliflozin 25 mg (MD - 0.23%, CrI - 0.44, - 0.03). Among patients uncontrolled on combination therapy metformin plus a DPP4i, no relevant RCTs with insulin were identified from the SLR. One study with a GLP-1 RA was included in a sensitivity analysis due to limited data. There were no differences between ertugliflozin 5 or 15 mg and other SGLT2is, with the exception of dapagliflozin 10 mg, which was significantly less effective when added to sitagliptin and metformin. Overall, there were no other significant differences for remaining efficacy and safety outcomes except for a lower SBP for canagliflozin 300 mg compared to ertugliflozin 15 mg in the diet/exercise population.

Conclusions: Indirect comparisons for HbA1c reduction found that ertugliflozin 5 mg was more effective than dapagliflozin 5 mg when added to metformin monotherapy, whereas ertugliflozin 15 mg was more effective than dapagliflozin 10 mg and empagliflozin 25 mg when added to diet/exercise and to metformin monotherapy. The HbA1c reduction associated with ertugliflozin was no different than that associated with canagliflozin across all populations.

Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

Keywords: Canagliflozin; Dapagliflozin; Empagliflozin; Ertugliflozin; Network meta-analysis; SGLT2; Systematic literature review; Type 2 diabetes.

Figures

Fig. 1

PRISMA diagram. BC Base case, CSR clinical study report, DPP4i dipeptidyl peptidase-4 inhibitor, SA sensitivity analysis, Diet and Exercise inadequately controlled on diet and exercise, Metformin Alone inadequately controlled on metformin alone, Metformin plus DPP4i inadequately controlled on metformin plus a DPP4i

Fig. 2

Network diagrams for type 2 diabetes mellitus (T2DM) patients inadequately controlled on diet and exercise (a), inadequately controlled on metformin alone (b) and inadequately controlled on combination therapy with metformin (MET) plus a dipeptidyl peptidase-4 inhibitor (DPP4i; name listed where relevant) (c). Superscripts: 1 Study added for sensitivity analysis only, 2 study dropped from sensitivity analysis (no connection via placebo), 3 study does not report systolic blood pressure, 4 data from VERTIS MONO, subsequently published by Terra et al. 2017 [8], 5 study does not report non-severe hypoglycemic events, genital mycotic infections (GMIs), severe hypoglycemic events, 6 data from the VERTIS MET trial, subsequently published in Rosenstock et al. 2018 [7], 7 data from the VERTIS FACTORIAL trial, subsequently published in Pratley et al. 2018 [6], 8 data from VERTIS SITA2 trial, subsequently published in Dagogo-Jack et al. 2018 [4], 9 study does not report target glycated hemoglobin, GMIs, urinary tract infections, hypoglycemic events, adverse events. Circles represent sodium-glucose co-transporter-2 inhibitor treatments, hexagons represent glucagon-like peptide-1 receptor agonists. Dark gray shapes are on a background of MET, light grey shapes are on a background combination therapy of MET plus a DPP4i (specific DPP4i stated for clarity). CANA Canagliflozin, DAPA dapagliflozin, EMPA empagliflozin, ERTU ertugliflozin, LINA linagliptin, LIRA liraglutide, PBO placebo, SAXA saxagliptin, SITA sitagliptin

Fig. 3

Forest plots for T2DM patients inadequately controlled on diet and exercise, inadequately controlled on metformin alone and inadequately controlled on combination therapy of metformin plus a DPP4i. CrI Credible interval, HbA1c glycated hemoglobin, MD mean difference. DPP4i in parentheses for clarity, single asterisk indicates results from sensitivity analysis (switch from SITA), double asterisk indicates titrated CANA