Sulfonylureas

Sulfonylureas are insulin secretagogues that stimulate pancreatic beta cells to release insulin.

They lower blood glucose by increasing endogenous insulin secretion.

They carry a significant risk of hypoglycemia.

→ Diabetes Pharmacology

Sulfonylureas act on pancreatic beta cells.

They bind to:

• The sulfonylurea receptor (SUR1)
• Part of the ATP-sensitive potassium (KATP) channel

Mechanism sequence:

• KATP channel closure
• Membrane depolarization
• Opening of voltage-gated calcium channels
• Increased intracellular calcium
• Insulin exocytosis

Important:

• Insulin release is NOT glucose-dependent.
• Hypoglycemia can occur even at low glucose levels.

First Generation:

• Chlorpropamide
• Tolbutamide

Second Generation (more commonly used):

• Glipizide
• Glyburide
• Glimepiride

Second-generation agents are more potent and have fewer side effects.

• Moderate HbA1c reduction
• Rapid onset
• Weight gain
• High hypoglycemia risk

They require functioning pancreatic beta cells.

Common:

• Hypoglycemia
• Weight gain

Serious:

• Severe hypoglycemia (especially in elderly)
• Rare hyponatremia (chlorpropamide)
• Rare hematologic reactions

Risk factors for hypoglycemia:

• Elderly patients
• Renal impairment
• Irregular meals
• Alcohol use

• Type 1 Diabetes
• History of severe hypoglycemia
• Advanced renal failure (dose caution)

Use caution in:

• Elderly patients
• CKD

Compared to:

• Metformin → more hypoglycemia, more weight gain
• GLP-1 Receptor Agonists → less weight loss, no ASCVD benefit
• SGLT2 Inhibitors → no heart failure benefit
• Thiazolidinediones → faster onset, more hypoglycemia

Sulfonylureas are inexpensive but lack cardioprotective benefit.

• Close KATP channels in beta cells
• Insulin release is NOT glucose-dependent
• High hypoglycemia risk
• Cause weight gain
• Require functional beta cells
• Often avoided in elderly when safer options available

• Diabetes Pharmacology
• Metformin
• Thiazolidinediones
• GLP-1 Receptor Agonists
• SGLT2 Inhibitors