Efficacy and Acceptability of Glycemic Control of Glucagon-Like Peptide-1 Receptor Agonists among Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

Abstract

Objective: To synthesize current evidence of the impact of Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on hypoglycemia, treatment discontinuation and glycemic level in patients with type 2 diabetes.

Design: Systematic review and network meta-analysis.

Data sources: Literature search (Medline, Embase, the Cochrane library), website of clinical trial, bibliographies of published systematic reviews.

Eligibility criteria: Randomized controlled trials with available data comparing GLP-1 RAs with placebo or traditional anti-diabetic drugs in patients with type 2 diabetes.

Data synthesis: Traditional pairwise meta-analyses within DerSimonian-Laird random effects model and network meta-analysis within a Bayesian framework were performed to calculate odds ratios for the incidence of hypoglycemia, treatment discontinuation, HbA1c<7.0% and HbA1c<6.5%. Ranking probabilities for all treatments were estimated to obtain a treatment hierarchy using the surface under the cumulative ranking curve (SUCRA) and mean ranks.

Results: 78 trials with 13 treatments were included. Overall, all GLP-1 RAs except for albiglutide increased the risk of hypoglycemia when compared to placebo. Reduction in the incidence of hypoglycemia was found for all GLP-1 RAs versus insulin (except for dulaglutide) and sulphonylureas. For the incidence of treatment discontinuation, increase was found for exenatide, liraglutide, lixisenatide and taspoglutide versus placebo, insulin and sitagliptin. For glycemic level, decrease was found for all GLP-1 RAs versus placebo. Dulaglutide, exenatide long-acting release (exe_lar), liraglutide and taspoglutide had significant lowering effect when compared with sitagliptin (HbA1c<7.0%) and insulin (HbA1c<6.5%). Finally, according to SUCRAs, placebo, thiazolidinediones and albiglutide had the best decrease effect on hypoglycemia; sulphanylureas, sitagliptin and insulin decrease the incidence of treatment discontinuation most; exe_lar and dulaglutide had the highest impact on glycemic level among 13 treatments.

Conclusions: Among 13 treatments, GLP-1 RAs had a significant reduction with glycemic level but a slight increase effect on hypoglycemia and treatment discontinuation. While albiglutide had the best decrease effect on hypoglycemia and treatment discontinuation among all GLP-1 RAs. However, further evidence is necessary for more conclusive inferences on mechanisms underlying the rise in hypoglycemia.

Fig 1. Flow chart of studies considered for inclusion, RCT = randomized controlled trial.

This Flow chart is based on PRISMA 2009 Flow Diagram[30].

Fig 2. Evidence structure of eligible comparisons for network meta-analysis.

Fig 3. Impact of individual GLP-1 receptor agonists on hypoglycemia, treatment discontinuation, HbA1c <7.0%, HbA1c <6.5% of direct pairwise meta-analysis.

Fig 4. Results of network meta-analysis.

(A) Results of network meta-analysis for hypoglycemia (lower left quarter)and treatment discontinuation(upper right quarter). (B) Results of network meta-analysis for HbA1c<7.0% (lower left quarter) HbA1c and <6.5%(upper right quarter).