Comparative efficacy and safety of antidiabetic drug regimens added to metformin monotherapy in patients with type 2 diabetes: a network meta-analysis

Abstract

Introduction: When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone.

Materials and methods: A search of MEDLINE and CENTRAL, clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3-12 months duration, evaluating Food and Drug Administration or European Union approved agents (noninsulin and long acting, once daily basal insulins) in patients experiencing inadequate glycemic control with metformin monotherapy (≥ 1500 mg daily or maximally tolerated dose for ≥ 4 weeks). Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI).

Results: Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent (range, 0.43% for miglitol to 1.29% for glibenclamide). Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo (range, 4.00-11.67). Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW (range, 1.15-2.26 kg) whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain (range, 1.19-2.44 kg). SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP (range, 1.88-5.43 mmHg). No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI (range, 2.16-8.03).

Conclusions: Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy.

Fig 1. Results of the Literature Search.

CCTR = Cochrane controlled trials register; EU = European Union; FDA = Food and Drug Administration; HbA1c = hemoglobin A1c.

Fig 2. Network Diagram of Randomized Controlled Trials Evaluating Antidiabetic Therapies in Addition to Optimized Metformin in Type 2 Diabetes.

All agents are in combination with optimized metformin and include oral and subcutaneous agents and long-acting, once daily basal insulins. Lines represent the presence of direct comparison trial(s). The width of the line is proportional to the number of trials with direct comparisons. ACA, acarbose; ALO, alogliptin; ALO/PIO, alogliptin/pioglitazone; CANA, canagliflozin; COL, colesevelam; DAPA, dapagliflozin; EMPA, empagliflozin; EMPA/LINA, empagliflozin/linagliptin; EXEN, exenatide; GLAR, insulin glargine; GLIB, glibenclamide; GLIC, gliclazide; GLIM, glimeperide; GLIP, glipizide; LINA, linagliptin; LIRA, liraglutide; LIX, lixisenatide; MIG, miglitol; NAT, nateglinide; PIO, pioglitizone; PLC, placebo; REP, repaglinide; ROSI, rosiglitizone; SAX, saxagliptin; SITA, sitagliptin; VILDA, vildagliptin