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.

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.