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



We conducted an electronic search until November 2016 on many electronic databases to identify RCTs assessing changes in HbA1c, proportion of patients at HbA1ctarget ≤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.



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 HbA1ctarget (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 (HbA1cWMD = -0.56%, 95% CI -0.72 to -0.40).



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.
Diabetes Unit, Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, University of Campania "Luigi Vanvitelli," Naples, Italy.
Maria Ida
MI
Maiorino
Medical Statistics Unit, University of Campania "Luigi Vanvitelli," Naples, Italy.
Paolo
P
Chiodini
Division of Endocrinology and Metabolic Diseases, Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, University of Campania "Luigi Vanvitelli," Naples, Italy.
Giuseppe
G
Bellastella
Section of Pharmacology, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli," Naples, Italy.
Annalisa
A
Capuano
Diabetes Unit, Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, University of Campania "Luigi Vanvitelli," Naples, Italy.
Katherine
K
Esposito
Division of Endocrinology and Metabolic Diseases, Department of Medical, Surgical, Neurological, Metabolic Sciences and Aging, University of Campania "Luigi Vanvitelli," Naples, Italy dario.giugliano@unina2.it.
Dario
D
Giugliano
D001786:Blood Glucose / Q000378:metabolism; D016208:Databases, Factual; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use*; D065228:Non-Randomized Controlled Trials as Topic; D064887:Observational Studies as Topic; D016032:Randomized Controlled Trials as Topic; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067757:Glucagon-Like Peptide-1 Receptor
D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor