Insulin and Glucagon-Like Peptide 1 Receptor Agonist Combination Therapy in Type 2 Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Abstract

OBJECTIVE The combination of basal insulin plus a glucagon-like peptide 1 receptor agonist (GLP-1RA) has been proposed as a treatment option to intensify insulin therapy in type 2 diabetes. We performed a meta-analysis of randomized controlled trials (RCTs) comparing this combination strategy to other injectable antidiabetes treatments on metabolic control in adult patients with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted an electronic search until November 2016 on many electronic databases to identify RCTs assessing changes in HbA1c, proportion of patients at HbA1c target ≤7% (53 mmol/mol), hypoglycemia, and weight change. We used a random-effect model to calculate the weighted mean difference (WMD) or relative risk (RR) with the 95% CI. RESULTS We identified 26 RCTs, lasting 12–52 weeks, and involving 11,425 patients. When the combination strategy was compared with other injectable treatments (overall data), there were reductions in HbA1c (WMD = −0.47%, 95% CI −0.59 to −0.35), more patients at HbA1c target (RR = 1.65, 95% CI 1.44–1.88), similar hypoglycemic events (RR = 1.14, 95% CI 0.93–1.39) and a reduction in weight (WMD = −2.5 kg, 95% CI −3.3 to −1.7), with high heterogeneity (I2 > 89%, P < 0.001) and a significant publication bias for three outcomes. In preplanned subgroup analyses, the combination treatment was similar to basal-bolus insulin regimens for glycemic control, with less hypoglycemia (RR = 0.66, 95% CI 0.46–0.93) and reduced weight (WMD = −4.7 kg, 95% CI −6.9 to −2.4). Fixed-ratio combinations yielded results similar to the overall analysis (HbA1c WMD = −0.56%, 95% CI −0.72 to −0.40). CONCLUSIONS GLP-1RAs alone or as titratable fixed-ratio combinations with basal insulin may represent a promising option to advance basal insulin therapy or to initiate injectable therapy in patients with type 2 diabetes inadequately controlled on oral agents. Longer studies are needed to assess durability and tolerability.