Regional heterogeneity of the results of glucagon-like peptide-1 receptor agonists trials in type 2 diabetes: a reanalysis of individual participant data

Objective. Multiregional trials are designed under the assumption that treatment effect applies to the entire target population. Yet, several factors may introduce geographic heterogeneity in treatment effect. We explored whether such variations exist in trials assessing the efficacy of glucagon-like peptide-1 receptor agonists (GLP-1Ra) on major cardiovascular events (MACE) in type 2 diabetes.

Research Design and Methods. A systematic search was conducted on MEDLINE® and the Cochrane database, until June 30th 2020. We included international, randomized controlled trials comparing any GLP-1Ra versus placebo with MACE as a primary endpoint. Individual participant data (IPD) were subsequently requested to the sponsor or through data sharing platforms. For each trial, we calculated hazard ratios (HR) and their 95% confidence intervals (95%CI) for MACE, sub-grouped by region. We then performed a random effects meta-analysis, and conducted meta-regressions to assess the influence of predetermined variables of interest on treatment effect.

Results. We included 6 trials including 45,426 patients. Baseline risk of MACE ranged from 2.9 in Southern Asia to 7.4 per 100 patient.years in Sub-Saharan Africa. HR (95% CI) for MACE ranged between 0.25 (0.05 to 1.12) in Northern Africa to 0.98 (0.79 to 1.22) in Western Europe. There was no significant subgroup difference across regions (p=0.70). Baseline risk of MACE and indexes of the development status were independently associated with GLP-1Ra efficacy.

Conclusions. This study does not suggest any regional heterogeneity of GLP-1Ra efficacy on MACE. However, a higher baseline risk and lower development status were associated with a greater benefit of these drugs.