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

• Published in: Diabetes care Vol. 40; no. 4; pp. 614 - 624
• Main Authors: Maiorino, Maria Ida, Chiodini, Paolo, Bellastella, Giuseppe, Capuano, Annalisa, Esposito, Katherine, Giugliano, Dario
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.04.2017
• Subjects: Blood Glucose - metabolism; Clinical trials; Databases, Factual; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Drug Therapy, Combination; Glucagon-Like Peptide-1 Receptor - agonists; Glycated Hemoglobin A - metabolism; Humans; Hypoglycemia; Hypoglycemic Agents - therapeutic use; Insulin; Insulin - therapeutic use; Medical treatment; Non-Randomized Controlled Trials as Topic; Observational Studies as Topic; Peptides; Randomized Controlled Trials as Topic
• ISSN: 0149-5992; 1935-5548
• DOI: 10.2337/dc16-1957

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 HbA , proportion of patients at HbA 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. 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 HbA (WMD = -0.47%, 95% CI -0.59 to -0.35), more patients at HbA 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 ( > 89%, < 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 (HbA WMD = -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.