What is the class and mechanism of action (MOA) of gliclazide, a second-generation sulfonylurea, in the management of type 2 diabetes mellitus?

Gliclazide: Drug Class and Mechanism of Action

Gliclazide is a second-generation sulfonylurea that stimulates insulin secretion from pancreatic β-cells by binding to the sulfonylurea receptor, and it specifically restores the abnormal first-phase insulin release characteristic of type 2 diabetes. 1

Drug Class

• Gliclazide belongs to the second-generation sulfonylurea class of oral antidiabetic agents 2, 3
• Second-generation sulfonylureas, including gliclazide, glipizide, and glimepiride, have a substantially lower risk of severe hypoglycemia compared to first-generation agents 2
• The American Diabetes Association recognizes sulfonylureas as effective glucose-lowering agents with the capacity to reduce HbA1c by approximately 1.5 percentage points 2

Mechanism of Action

Primary Pancreatic Effects

• Gliclazide stimulates insulin secretion through binding to the β-cell sulfonylurea receptor, which is the primary mechanism of glucose lowering 1
• The drug may also have a direct effect on intracellular calcium transport within pancreatic β-cells 1
• Gliclazide specifically improves the abnormal first-phase insulin release in type 2 diabetes, which is characteristically impaired in this condition 1
• The drug also enhances second-phase insulin secretion, providing sustained glucose control 1

Extrapancreatic Effects

• Gliclazide reduces hepatic glucose production and improves glucose clearance without changes in insulin receptors, suggesting a post-receptor effect on insulin action 1
• The drug may stimulate hepatic fructose-2,6-bisphosphatase and muscle glycogen synthase, contributing to improved glucose metabolism 1
• At lower doses, gliclazide appears to have an incretin-enhancing effect, which distinguishes it from other sulfonylureas 3

Unique Cardiovascular and Hematologic Properties

• Gliclazide contains an azabicyclo-octyl group that confers special properties beyond the basic sulfonylurea structure 1
• The drug reduces platelet adhesion, aggregation, and hyperactivity, and increases fibrinolysis 1
• These antiplatelet and fibrinolytic actions are thought to be independent of its hypoglycemic activity and may help halt the progression of diabetic microangiopathy 1

Pharmacokinetic Profile

• Gliclazide has an intermediate half-life of approximately 11 hours 1
• The drug is extensively metabolized, with renal clearance accounting for only 4% of total drug clearance 1
• The modified release (MR) formulation provides good 24-hour glycemic efficacy when given once daily 3

Clinical Safety Advantages

• The pattern of insulin release produced by gliclazide explains the lower incidence of hypoglycemic episodes and weight gain compared with some other sulfonylureas 1
• Meta-analysis demonstrates that gliclazide has a significantly lower risk of hypoglycemia compared to other sulfonylureas (RR 0.47; 95% CI 0.27 to 0.79) 4
• Cardiovascular outcome studies have shown no evidence of increased cardiovascular events with gliclazide 3
• The American Diabetes Association and American Geriatrics Society recommend newer-generation sulfonylureas like gliclazide over older agents due to their lower hypoglycemia risk 2, 5