Balancing efficacy and safety: glucokinase activators in glycemic and metabolic management of type 2 diabetes mellitus-a meta-analysis.

Abstract

Type 2 diabetes mellitus (T2DM) is a persistent condition typically defined by prolonged hyperglycemia resulting from beta-cell impairment and insulin resistance. Glucokinase activators (GKAs) are new medications that target glucokinase (GK) to increase glucose utilization in both the pancreas and liver. Its effectiveness and safety are inconsistent across various doses and types. The meta-analysis assessed the effectiveness and safety of GKAs in T2DM on glycemic control (hemoglobin A1c [HbA1c], fasting plasma glucose [FPG], postprandial plasma glucose [PPG]) as well as metabolic parameters (lipids, body weight, safety outcomes) stratified by dosage, type, and intervention time. The study involved a comprehensive analysis of 3,854 participants drawn from 11 randomized controlled trials (RCTs). Standardized mean differences (SMDs) and risk ratios (RRs) were computed employing random-effects models, alongside conducting sensitivity and subgroup analyses. GKAs effectively lowered HbA1c and PPG, especially high-dose (HbA1c: SMD = -0.43, 95% CI: -0.62 to -0.24) and dual-acting GKAs. Medium and high-dose GKAs were associated with increased risk of hypoglycemia (RR = 1.50; 1.63). At 24 weeks, GKAs led to increases in triglycerides, body weight, and liver enzymes, with the majority of these effects subsiding by 52 weeks. GKAs provide favorable glycemic control but carry dose-dependent concerns. While dual-acting GKAs demonstrate impressive efficacy, hepatoselective GKAs reveal improved safety. There exists a pressing need for further longitudinal studies and customized treatment approaches concerning the utilization of GKAs.PROSPERO registration: CRD42020188517.