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Ertugliflozin Compared to Other Anti-Hyperglycemic Agents As Diabetes Ther https://doi.org/10.1007/s13300-019-0566-x ORIGINAL RESEARCH 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 Ann M. McNeill . Glenn Davies . Eliza Kruger . Stacey Kowal . Tim Reason . Flavia Ejzykowicz . Hakima Hannachi . Nilo Cater . Euan McLeod Received: September 19, 2018 Ó The Author(s) 2019 ABSTRACT Methods: A systematic literature review (SLR) identified randomized controlled trials (RCTs) Introduction: Ertugliflozin is a new sodium- reporting outcomes at 24–26 weeks of treat- glucose co-transporter-2 inhibitor (SGLT2i) for ment. Comparators to ertugliflozin were the the treatment of type 2 diabetes mellitus. As SGLT2is canagliflozin, dapagliflozin and empa- there are no head-to-head trials comparing the gliflozin, with non-SGLT2i comparators also efficacy of SGLT2is, the primary objective of this evaluated third-line [insulin and glucagon-like analysis was to indirectly compare ertugliflozin peptide-1 receptor agonists (GLP-1 RAs)]. Out- to other SGLT2i in patient populations with comes were change from baseline in HbA1c, inadequately controlled glycated hemoglobin weight and systolic blood pressure (SBP) as well \ (HbA1c [ 7.0%) and previously treated with as HbA1c 7% and key safety events. Bayesian either diet/exercise, metformin alone or met- network meta-analysis was used to synthesize formin plus a dipeptidyl peptidase-4 inhibitor evidence. Results are presented as the median of (DPP4i). the mean difference (MD) or as odds ratios with 95% credible intervals (CrI). Results: In patients uncontrolled on diet/exer- Enhanced Digital Features To view enhanced digital cise, the efficacy of ertugliflozin 5 mg features for this article go to https://doi.org/10.6084/ m9.figshare.7565786. monotherapy was not significantly different from that of other low-dose SGLT2is in terms of Electronic supplementary material The online HbA1c reduction, while ertugliflozin 15 mg was version of this article (https://doi.org/10.1007/s13300- 019-0566-x) contains supplementary material, which is more effective than dapagliflozin 10 mg (MD available to authorized users. - 0.36%, CrI - 0.65, - 0.08) and empagliflozin 25 mg (MD - 0.31%, CrI - 0.58, - 0.04). As A. M. McNeill (&) Á G. Davies Á F. Ejzykowicz Á add-on therapy to metformin, ertugliflozin H. Hannachi 5 mg was more effective in lowering HbA1c Merck & Co., Inc., Kenilworth, NJ, USA than dapagliflozin 5 mg (MD - 0.22%, CrI e-mail: [email protected] - 0.42, - 0.02), and ertugliflozin 15 mg was E. Kruger Á S. Kowal Á T. Reason more effective than dapagliflozin 10 mg (MD IQVIA, Parsippany, NJ, USA - 0.26%, CrI - 0.46, - 0.06) and empagliflozin N. Cater 25 mg (MD - 0.23%, CrI - 0.44, - 0.03). Pfizer, New York, NY, USA Among patients uncontrolled on combination therapy metformin plus a DPP4i, no relevant E. McLeod RCTs with insulin were identified from the SLR. Pfizer, Tadworth, UK Diabetes Ther One study with a GLP-1 RA was included in a phase III trials that found ertugliflozin lowered sensitivity analysis due to limited data. There HbA1c, weight and blood pressure [4–8]. were no differences between ertugliflozin 5 or The clinical and safety profile of individual 15 mg and other SGLT2is, with the exception of SGLT2is has been investigated in clinical trials dapagliflozin 10 mg, which was significantly in comparison to placebo and other oral anti- less effective when added to sitagliptin and diabetic drug classes, as mono-therapy and add- metformin. Overall, there were no other signif- on therapy among patients with T2DM. The icant differences for remaining efficacy and SGLT2i drug class as a whole has been also safety outcomes except for a lower SBP for compared to other anti-diabetic drug classes in canagliflozin 300 mg compared to ertugliflozin research using indirect comparison methodol- 15 mg in the diet/exercise population. ogy [9]. However, comparisons within a class of Conclusions: Indirect comparisons for HbA1c medicines are also of interest to clinical practi- reduction found that ertugliflozin 5 mg was tioners and health policy decision-makers. more effective than dapagliflozin 5 mg when Because no head-to-head randomized clinical added to metformin monotherapy, whereas trials (RCTs) assessing efficacy have been con- ertugliflozin 15 mg was more effective than ducted among SGLT2is, indirect comparisons dapagliflozin 10 mg and empagliflozin 25 mg synthesized from network-meta analysis (NMA) when added to diet/exercise and to metformin can provide alternative evidence of comparative monotherapy. The HbA1c reduction associated efficacy. NMAs are an extension of pairwise with ertugliflozin was no different than that meta-analysis that bring together evidence from associated with canagliflozin across all RCTs and use common comparators to indi- populations. rectly make comparisons across multiple treat- Funding: Merck Sharp & Dohme Corp., a sub- ments either within or outside of a drug class. sidiary of Merck & Co., Inc., Kenilworth, NJ, Although this approach allows for an observa- USA, and Pfizer Inc., New York, NY, USA. tional synthesis of prior evidence, careful con- sideration of RCTs included in an NMA is Keywords: Canagliflozin; Dapagliflozin; required to minimize potential bias in observed Empagliflozin; Ertugliflozin; Network meta- results due to differences in study characteristics analysis; SGLT2; Systematic literature review; (e.g. quality, baseline patient characteristics, Type 2 diabetes disease severity) that can influence the treat- ment effects of the interventions [10]. Several indirect comparisons within the INTRODUCTION SGLT2i class have been published comparing canagliflozin, dapagliflozin and empagliflozin. Sodium-glucose co-transporter 2 inhibitors These have either compared these drugs across (SGLT2is) are effective in lowering glycated all trial populations or focused on patients hemoglobin (HbA1c) levels and also have ben- inadequately controlled on either diet and eficial effects on weight and blood pressure exercise or metformin [11, 12]. These compar- [1, 2]. These potential benefits have been rec- isons have not included ertugliflozin as data ognized, as evidenced by the increasing promi- from trials with ertugliflozin were not yet nence of this class of prescription medicine in available at the time of the studies. the latest clinical practice guidelines [3]. Ertu- Thus, the primary objective of the research gliflozin is the newest SGLT2i to become avail- reported here was to conduct a systemic litera- able, approved as an adjunct to diet and exercise ture review (SLR) and NMA to assess the efficacy to improve glycemic control in adult patients and safety of ertugliflozin relative to other with type 2 diabetes mellitus (T2DM), with SGLT2is for the treatment of T2DM in three recent regulatory approvals in the United States patient populations defined by inadequate (USA) (December 2017), European Union (EU) control of HbA1c during prior treatments with (March 2018) and elsewhere. Regulatory (1) diet and exercise alone, (2) metformin alone approval of ertugliflozin was based on multiple and (3) metformin plus a dipeptidyl peptidase-4 Diabetes Ther inhibitor (DPP4i). Given the established role of all relevant trials were identified via the search. insulin and glucagon-like peptide-1 receptor See ESM Table 1 for search terms. agonists (GLP-1 RAs) as options for third-line therapy, a secondary objective was to include Study Selection these as comparators in the population uncon- trolled on combination therapy with met- The patient populations, interventions, com- formin and a DPP4i. parators, outcomes and study design (PICOS) NMAs require that heterogeneity between statement are presented in Table 1. In brief, studies be minimized; therefore, the present patients were adults with T2DM, uncontrolled analyses focused on each population separately. HbA1c (all patients with HbA1c C 7.0%) and As there is no published evidence synthesis either managed with diet and exercise, on specifically evaluating SGLT2i performance in metformin alone; or on metformin plus a DPP4i those inadequately controlled on combination prior to intervention. Studies evaluating treat- therapy with metformin plus a DPP4i, a sec- ments in special populations, such as those with ondary objective was to compare the effective- renal impairment, were excluded. ness and safety of ertugliflozin added to dual Comparators to ertugliflozin 5 mg and 15 mg ? therapy with metformin sitagliptin (a com- were other commercially available SGLT2i bination regimen consisting of three oral anti- products in the USA and the EU, including hyperglycemic therapies) to the addition of canagliflozin 100 mg and 300 mg, dapagliflozin insulin or dual therapy (metformin plus a GLP-1 5 mg and 10 mg and empagliflozin 10 mg and RA) in this population. 25 mg, and placebo for all populations. For those inadequately controlled on combination METHODS therapy with metformin plus a DPP4i, GLP-1 RAs and insulins were also included in the scope This article is based on previously conducted of the SLR. studies and does not contain any new studies with human participants or animals performed Data Extraction and Quality Assessment by any of the authors. Two researchers performed the literature search Data Sources and Searches and conducted an initial abstract review. Uncertainty regarding whether to include This study was conducted according to a pre- studies was resolved either through reconcilia- specified protocol and followed the standard tion or via consultation
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