Evaluating the Overall Safety of Glucokinase Activators in Patients with Type 2 Diabetes Mellitus.

Abstract

Purpose: This study aimed to assess the overall clinical adverse events (AEs) associated with glucokinase activators (GKAs) in patients with type 2 diabetes mellitus (T2DM).

Methods: We searched MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov databases from their dates of inception to June 6, 2023, for randomized controlled trials (RCTs) that reported safety data for GKAs in patients with T2DM. A random-effects model was used to obtain a summary odds ratio (OR) with associated 95% Confidence Intervals (CIs). Pre-specified subgroup analyses were conducted according to individual GKAs (dorzagliatin and all other GKAs), various controls, follow-up duration, mean duration of diabetes, and the location of clinical research.

Results: 17 RCTs enrolling 4,918 patients (3,196 patients received GKAs and 1,722 patients received placebo or other hypoglycemic drugs) were identified. Among the 17 RCTs, dorzagliatin, AZD1656 and MK-0941 in three trials (1,541 patients), five trials (885 patients), and three trials (798 patients), respectively. GKA treatment was associated with a higher risk of any AEs (OR 1.220, 95% CI 1.072-1.389), mild AEs (OR 1.373, 95% CI 1.085-1.738), hyperlipidemia (OR 1.532, 95% CI 1.071-2.189), and hyperuricemia (OR 2.768, 95% CI 1.562-4.903) compared to patients in the control groups. The higher risks of any AEs were mainly attributed to dorzagliatin and MK-0941 and mild AEs mainly attributed to dorzagliatin. Notably, dorzagliatin had significant effects on the occurrence of hyperlipidemia (OR 1.476, 95% CI 1.025-2.126) and hyperuricemia (OR 2.727, 95% CI 1.523-4.883) in the subgroup analyses. No significant effects were detected from other GKAs when regarding hyperlipidemia and hyperuricemia.

Conclusion: The results of our meta-analysis indicated that GKAs were associated with a higher risk of any AEs, mild AEs, hyperlipidemia, and hyperuricemia. Further subgroup analyses revealed that the increased occurrence of hyperlipidemia, and hyperuricemia mainly originated from dorzagliatin treatment.