Ting-Ting Liang,1,* Min-Jia Cao,2,* Qian Wang,1 Jia-Shuang Zou,1 Xiao-Ming Yang,1 Li-Fang Gu,1 Fang-Hong Shi2 

1Department of Pharmacy, Changshu Affiliated Hospital of Nanjing University of Chinese Medicine, Suzhou, Jiangsu, People’s Republic of China; 2Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Li-Fang Gu, Department of Pharmacy, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu, People’s Republic of China, Email fsyy01000@njucm.edu.cn Fang-Hong Shi, Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China, Email shifanghong@hotmail.com

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.
Plain Language Summary: Glucokinase activators (GKAs) reduce blood glucose by increasing the activity of glucokinase (GK) and are being developed for the treatment of diabetes. Here, we aimed to assess the safety of GKAs in patients with type 2 diabetes. The results showed that GKAs were associated with a higher risk of any AEs, mild AE, hyperlipidemia, and hyperuricemia compared to controls.

Keywords: type 2 diabetes mellitus, safety, randomized controlled trials, systematic review, meta-analysis