Comparative efficacy and safety of antidiabetic drug regimens added to stable and inadequate metformin and thiazolidinedione therapy in type 2 diabetes

Abstract

Aims: Determine the efficacy and safety of antidiabetic agents added-on to metformin and a thiazolidinedione (TZD) in patients with inadequately controlled type 2 diabetes (T2D). Methods: MEDLINE and CENTRAL were searched for randomised controlled trials (RCTs) evaluating the addition of an antidiabetic agent in patients with T2D inadequately controlled on stable, optimised metformin and TZD therapy (≥ 1500 mg metformin and ≥ 50% maximum TZD dose for ≥ 4 weeks). Frequentist network meta-analysis was performed on identified studies. Results: Eleven RCTs evaluating dipeptidyl peptidase-4 inhibitors (linagliptin, sitagliptin), sulfonylureas (SUs) (glibenclamide, glimepiride), glucagon-like peptide-1 (GLP-1) analogues (exenatide, liraglutide, dulaglutide, taspoglutide) and sodium-glucose cotransporter2 (SGLT2) inhibitors (canagliflozin, empagliflozin) were identified. The mean reduction in HbA1c from baseline was significant for all agents (range, 0.55-1.17%) vs. placebo. SUs were associated with weight gain (range, 3.31-7.29 kg), while weight loss was seen with all GLP-1 analogues (range, 1.53-2.20 kg) and SGLT2 inhibitors (range, 2.08-2.95 kg) vs. placebo. Relative risk of hypoglycaemia was increased with dulaglutide, exenatide and glimepiride vs. placebo (RR range, 2.65-6.17); and trended higher with all other agents except linagliptin. GLP-1 analogues and canagliflozin reduced systolic blood pressure vs. placebo (range, 2.39-5.05 mmHg). No agent with available data increased the risk of urinary or genital tract infection vs. placebo. Conclusion: When added to stable, optimised metformin and TZD, all evaluated antidiabetic agents reduced HbA1c; albeit not to the same degree. Moreover, agents differed in their effects on body weight, hypoglycaemia and systolic blood pressure. Review criteria• A systematic literature search was conducted in MEDLINE and Cochrane CENTRAL through 8 January 2015.• Randomised controlled trials (RCTs) evaluating adults with type 2 diabetes inadequately controlled on metformin plus a thiazolidinedione (TZD) were included if the trial compared a noninsulin drug or long-acting, once-daily basal insulin to another of these therapies or placebo and reported change in glycosylated haemoglobin A1c.• Frequentist network meta-analyses were performed on 11 identified RCTs. Message for the clinic• Ten therapies were evaluated in the following classes: dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas (SUs), glucagon-like peptide-1 (GLP-1) analogues and sodium-glucose cotransporter2 (SGLT2) inhibitors.• All individual agents reduced HbA1c when added to stable metformin plus TZD therapy, but not to the same degree.• SGLT2 inhibitors and GLP-1 agonists significantly reduced weight compared with DPP-4 inhibitors, SUs and placebo. No agent resulted in an increased risk of urinary or genital tract infection compared with placebo.

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