Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RA) increase glucose-stimulated insulin secretion, suppress glucagon production, increase satiety, reduce food intake, improve insulin sensitivity, and reduce visceral fat. This study aims to compare the GLP-1RA and insulin combination or GLP-1RA added to background insulin therapy with other injectable therapies in patients with type-2 diabetes mellitus (T2DM). We searched for studies that compared GLP-1RA and insulin combination with other injectable therapies in T2DM patients for HbA1c (%) change, achieving HbA1c <7% at study end, hypoglycemia incidence, and weight change. The following intervention groups were analyzed: the combination of basal insulin and GLP-1RA, basal-plus/basal-bolus, and placebo/insulin intensification (insulin uptitration)/GLP-1RA. A total of 48 studies were included. Insulin and GLP-1RA combination therapy reduced HbA1c more than placebo/insulin intensification (insulin up-titration)/GLP-1RA (WMD -0.693, p <0.001) and basal-plus/basal-bolus (WMD -0.105, p =0.027). Insulin and GLP-1RA combination therapy significantly reduced body weight more than placebo/insulin intensification (insulin up-titration)/GLP-1RA (WMD -1.894, p <0.001) and basal-plus/basal-bolus (WMD -3.6, p =0.001). Patients on insulin and GLP-1RA combination therapy had a higher chance of achieving the HbA1c target than placebo/insulin intensification (insulin up-titration)/GLP-1RA arm (RR 1.964, p <0.001), but not than basal-plus/basal-bolus arm (RR 1.037, 95% CI 0.971 to 1.103). Hypoglycemia rates were comparable between combination therapy and placebo/insulin intensification (insulin up-titration)/GLP-1RA (RR 0.94, 95% 0.84 - 1.04), but statistically significant when compared to combination therapy and basal-plus/basal-bolus (RR 0.63, p <0.001). Our findings support using GLP-1RA in combination with insulin as a useful intensification approach for producing therapeutic improvement in T2DM therapy for individuals who have not reached their HbA1c goal.

Key words: Basal insulin, Glucagon-like peptide-1 receptor agonists, Type 2 diabetes mellitus, Glycaemic control, Meta-analysis.