Comparison of Oral Antidiabetic Drugs as Add-On Treatments in Patients with Type 2 Diabetes Uncontrolled on Metformin: A Network Meta-Analysis

Abstract

We assessed the efficacy and safety of oral antidiabetic drugs (OADs) as an add-on treatment in patients with type 2 diabetes uncontrolled on metformin. PubMed, the Cochrane Library, and Embase were searched from inception to October 20, 2017. Pairwise and network meta-analyses were conducted using Stata 14.1 software. Odds ratios (ORs) and weighted mean differences (WMDs) were used to evaluate outcomes. Sixty-eight trials including 36,746 patients were analyzed. No significant differences in the risk of major adverse cardiovascular events (MACEs) and all-cause mortality were observed among any class of OADs when combined with metformin. All classes of OADs as add-ons to metformin improved glucose control, while sodium-glucose co-transporter-2 (SGLT-2) inhibitors showed greater fasting plasma glucose (FPG) reductions {WMD, - 1.49 [95% confidence interval (CI) - 1.69 to - 1.28] mmol/l} and 2 h postprandial glucose (2 h PPG) reductions [WMD, - 3.07 (95% CI - 4.12 to - 2.03) mmol/l]. Thiazolidinediones and sulfonylureas were associated with weight gain [WMD, 2.53 (95% CI 1.95-3.10) kg and 2.00 (95% CI 1.63-2.36) kg, respectively] when added to metformin. Sulfonylureas [WMD, 6.52 (95% CI 4.07-10.45)] were associated with the highest ORs of hypoglycemia. Our results suggest that the seven classes of OADs were not associated with any increased risk of MACEs or all-cause mortality when combined with metformin. Most OADs were associated with similarly large reductions in HbA1c levels when added to metformin, while SGLT-2 inhibitors might be the best option for reducing body weight, FPG, and 2-h PPG.

Keywords: Metformin; Network meta-analysis; Oral antidiabetic drug; Type 2 diabetes mellitus.

Fig. 1

Flow chart of the search for eligible studies

Fig. 2a–b

Clustered ranking plots of the network. a MACE (x-axis) and HbA1c (y-axis); b hypoglycemia (x-axis) and HbA1c (y-axis). MACE major adverse cardiovascular event, SGLT2 sodium-glucose co-transporter-2 inhibitor, DPP4 dipeptidyl peptidase-4 inhibitor, AGI alpha-glucosidase inhibitor, TZD thiazolidinedione, Met high-dose metformin, SU sulfonylurea