Search

Aims To identify and synthesize phase 3 and phase 4 randomized controlled trials (RCTs) of sodium-glucose co-transporter (SGLT) inhibitors and metformin as adjuncts to insulin in type 1 diabetes (T1DM) using network meta-analysis (NMA). Materials and methods A systematic literature review (SLR) identified relevant RCTs of ≥12 Weeks duration. MEDLINE, Embase, the Cochrane Library and grey literature were searched through October 2018. NMAs indirectly compared SGLT inhibitors and metformin for change from baseline in HbA1c, weight, total daily insulin dose and systolic blood pressure at Week 24 to 26 and Week 52. Safety outcomes were also explored. Results Nine trials (N = 6780) were included in the SLR. NMAs indicated that all therapies performed better than placebo for the efficacy outcomes at both time points. Compared with metformin at Week 24 to 26, the SGLT inhibitors dapagliflozin (5 mg), sotagliflozin (200 mg) and empagliflozin (10 mg) had larger reductions in HbA1c (mean difference [MD] = -0.24, 95% credible interval [CrI], -0.41 to -0.07, MD = -0.23, 95% CrI, -0.39 to -0.08 and MD = -0.35, 95% CrI, -0.51 to -0.19, respectively) and in weight, which were sustained in sensitivity analyses. There were few differences observed in the results of safety outcomes, such as risk of diabetic ketoacidosis (DKA), which should be interpreted cautiously because of wide CrIs. Conclusions Adjunctive use of SGLT inhibitors in T1DM can improve glycaemic control compared with metformin while enabling weight loss, with consistent efficacy across the class. However, these results are based on indirect evidence so confirmation in a head-to-head study would be valuable.

T1DM is characterized by deficient insulin production, requiring multiple daily insulin doses. However, glycemic control is often suboptimal, and insulin-associated weight gain and hypoglycemia are concerns. Therefore, adjunctive therapy may be beneficial. A SLR with searches conducted to 16 Oct 2018 identified phase III/IV RCTs of MET or SGLT1/2 inhibitors as add-on to insulin in T1DM. MEDLINE, Embase and the Cochrane Library were searched, as well as congresses, reference lists and grey literature. Bayesian NMAs were performed at Week 24/26 (Week 24) and Week 52 (Week 52) for change from baseline in HbA1c and weight, and the proportion of participants experiencing hypoglycemic events and hypoglycemic severe adverse events. Nine placebo (PBO) controlled RCTs of dapagliflozin (DAPA), MET, sotagliflozin (SOTA) or empagliflozin (EMPA) reporting results were included. There was some evidence of heterogeneity in study design and outcomes. Results of the NMAs for MET vs. comparator (Table) found that the SGLT2 and SGLT1/2 inhibitors generally performed better than MET for HbA1c and weight, but there were few significant differences for hypoglycemia at Week 52. Results suggest that adjunctive use of SGLT2 and SGLT1/2 inhibitors including DAPA can improve glycemic control compared to MET while enabling weight loss in T1DM, and demonstrate consistent efficacy for the class. Disclosure B.E. Langford: Employee; Self; Costello Medical. Research Support; Self; AstraZeneca. M. Evans: Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sunovion Pharmaceuticals Inc. T. Haskins-Coulter: Employee; Self; Costello Medical. M. O'Connor: Employee; Self; Costello Medical. H.E. Cant: Employee; Self; Costello Medical. L.A. Eddowes: Employee; Self; Costello Medical. C. Edmonds: Employee; Self; AstraZeneca. A. Tank: Employee; Self; AstraZeneca. Funding AstraZeneca; Cambridge University