Abstract

Type 2 diabetes mellitus (T2DM) was characterized by impaired glucose homeostasis and insulin resistance, 
necessitating pharmacologic interventions to maintain glycemic control. Sulfonylureas (SUs) had been widely used 
to stimulate insulin secretion but were associated with a significant risk of hypoglycemia. Hepatic glucokinase 
activators (GKAs) are emerging agents that enhance hepatic glucose uptake and metabolism, potentially reducing 
hypoglycemia risk by acting insulin-independently. This review critically examined the comparative hypoglycemia 
risk profiles of hepatic glucokinase activators versus sulfonylureas in T2DM management. A comprehensive 
literature search was conducted using major scientific databases to identify preclinical and clinical studies evaluating 
hypoglycemia incidence associated with GKAs and SUs, focusing on randomized controlled trials, mechanistic 
studies, and meta-analyses. Sulfonylureas induce hypoglycemia predominantly by stimulating pancreatic β-cell 
insulin secretion regardless of ambient glucose levels. In contrast, hepatic GKAs amplify glucose phosphorylation 
in hepatocytes, enhancing glycogen synthesis and glucose clearance without direct insulin stimulation. Clinical 
evidence indicated that GKAs reduced fasting and postprandial glucose effectively with a lower incidence of 
hypoglycemia compared to SUs. Nevertheless, hepatic GKAs’ efficacy varied depending on their isoform selectivity 
and pharmacokinetic profiles. Limitations included the relatively recent clinical trial data on GKAs and the long
term safety concerns related to liver metabolism modulation. Hepatic glucokinase activators represented a promising 
therapeutic alternative to sulfonylureas, with a more favorable hypoglycemia risk profile in the management of 
T2DM. However, further longitudinal studies were required to establish sustained efficacy, safety, and optimal 
dosing.