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

Diabetes Care. 2017 Apr;40(4):614-624. doi: 10.2337/dc16-1957.


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.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Blood Glucose / metabolism
  • Databases, Factual
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Therapy, Combination
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glycated Hemoglobin / metabolism
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Insulin / therapeutic use*
  • Non-Randomized Controlled Trials as Topic
  • Observational Studies as Topic
  • Randomized Controlled Trials as Topic


  • Blood Glucose
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin