A systematic review and mixed-treatment comparison of dapagliflozin with existing anti-diabetes treatments for those with type 2 diabetes mellitus inadequately controlled by sulfonylurea monotherapy

Abstract

Background: To compare the first-in-class sodium glucose co-transporter 2 (SGLT2) inhibitor, dapagliflozin, with existing type 2 diabetes mellitus (T2DM) treatment options available within the European Union (EU) for add-on therapy to sulfonylureas (SUs).

Methods: A systematic review was conducted to identify randomised controlled trials (RCTs) in T2DM patients inadequately controlled by SU monotherapy. Direct meta-analysis, Bucher indirect comparisons and Bayesian network meta-analysis (NMA) were conducted on studies meeting predefined inclusion criteria. Sufficient data were available to assess three clinical endpoints at 24 (+/- 6) weeks follow-up: mean change in HbA1c from baseline, mean change in weight from baseline, and the proportion of patients experiencing at least one episode of hypoglycaemia. The effect of confounding baseline factors was explored through covariate analyses.

Results: The search identified 1,901 unique citations, with 1,870 excluded based on title/abstract. From reviewing full-texts of the remaining 31 articles, 5 studies were considered eligible for analysis. All studies were comparable in terms of baseline characteristics, including: HbA1c, age and body mass index (BMI). In addition to dapagliflozin, sufficient data for meta-analysis was available for three dipeptidyl peptidase-4 (DPP-4) inhibitors and one glucagon-like peptide-1 (GLP-1) analogue. Based on fixed-effect NMA, all treatment classes resulted in statistically significant decreases in HbA1c at follow-up compared to placebo. Dapagliflozin treatment resulted in significantly decreased weight at follow-up compared to placebo (-1.54 kg; 95% CrI -2.16, -0.92), in contrast to treatment with GLP-1 analogues (-0.65 kg; 95% CrI -1.37, 0.07) and DPP-4 inhibitors (0.57 kg; 95% CrI 0.09, 1.06). The odds of hypoglycaemia were similar to placebo for dapagliflozin and DPP-4 inhibitor add-on treatment, but significantly greater than placebo for GLP-1 analogue add-on treatment (10.89; 95% CrI 4.24, 38.28). Assessment of NMA model heterogeneity was hindered by the small size of the network.

Conclusions: Dapagliflozin, DPP-4 inhibitors and GLP-1 analogues, in combination with SU, all provided better short-term glycaemic control compared to SU monotherapy. Dapagliflozin was the only add-on therapy that had both a favourable weight and hypoglycaemia profile compared to the other classes of treatment evaluated.

Keywords: Dapagliflozin; Diabetes; Mixed treatment comparison; Network meta-analysis; Systematic review.

Figure 1

Flow diagram of study selection (systematic review).

Figure 2

Network diagram for studies meeting criteria for inclusion in the meta-analysis.

Figure 3

Direct meta-analysis forest plots versus placebo-control. A) HbA1c weighted mean difference, B) weight (kg) weighted mean difference, C) hypoglycaemia odds ratio; CI, confidence interval; DPP-4, dipeptidyl peptidase-4 inhibitors; GLP-1, glucagon-like peptide-1 analogues; N, number of patients; OR, odds ratio; SD, standard deviation; SGLT2, sodium glucose co-transporter 2 inhibitors; WMD, weighted mean difference.

Figure 4

Sensitivity analysis across different meta-analysis models. A) HbA1c, weighted mean difference, B) weight (kg), weighted mean difference, C) hypoglycaemia odds ratio; DPP-4, dipeptidyl peptidase-4 inhibitors; direct, direct meta-analysis; FE, fixed-effect; GLP-1, glucagon-like peptide-1 analogues; NMA, network meta-analysis; OR, odds ratio; RE, random-effects; SGLT2, sodium glucose co-transporter 2 inhibitors; WMD, weighted mean difference.