Sulfonylureas

In the normal β cell, plasma glucose is the main regulator of insulin secretion. Glucose is taken up through glucose transporters, and glucokinase lets the β cell respond to the glucose level. Metabolism of glucose raises cellular ATP, which closes ATP-dependent potassium channels in the β-cell membrane; the membrane depolarizes, calcium flows in, and the rise in intracellular calcium increases insulin secretion. Sulfonylureas enter this pathway at the channel itself, so they bypass the glucose step.

The ATP-sensitive potassium (K-ATP) channel is made of two proteins: Kir6.2, which forms the pore, and a sulfonylurea receptor (SUR). Sulfonylureas bind to SUR1 on the β-cell membrane and inhibit the channel. Potassium efflux decreases, the membrane depolarizes, voltage-gated calcium channels open, and the rise in intracellular calcium triggers insulin exocytosis. Mutations in the genes for the channel subunits (KCNJ11, ABCC8) cause neonatal diabetes, and glyburide has been studied off-label for it.

Sulfonylureas cause insulin release regardless of blood glucose levels, and they are effective only in patients with residual β-cell activity — which is why type 1 diabetes and diabetic ketoacidosis are contraindications (treated with insulin). They may also lower glucose outside the pancreas: decreased hepatic insulin clearance, decreased glucagon secretion and increased peripheral insulin sensitivity. Meglitinides (repaglinide, nateglinide) also stimulate β cells to secrete insulin, and sulfonylureas are not combined with them.

SUR1 is found mostly in the brain and on pancreatic β cells; SUR2 is found in cardiac muscle (SUR2A) and smooth muscle (SUR2B). Sulfonylureas differ in their affinity for these subtypes. Glimepiride has a lower affinity for cardiac muscle and is not associated with cardiovascular safety concerns, and unlike other sulfonylureas it does not affect ischemic preconditioning of cardiac myocytes.

All three labels, glimepiride’s included, carry a warning on increased cardiovascular mortality (a “special warning” on the glipizide and glyburide labels), based on the University Group Diabetes Program (UGDP), in which tolbutamide was associated with about 2½ times the cardiovascular mortality of diet alone; the warning is extended to the class because of the drugs’ similar mode of action and structure.

Because insulin is released whatever the glucose, hypoglycemia is the most common adverse effect, together with weight gain. It may be severe after a missed meal or exercise, and all sulfonylureas can cause severe hypoglycemia. Renal or hepatic insufficiency can raise drug levels — and liver disease also diminishes gluconeogenic capacity — so hypoglycemia becomes more likely and, when it occurs, prolonged. Elderly, debilitated or malnourished patients and those with adrenal or pituitary insufficiency are particularly susceptible, and hypoglycemia may be hard to recognize in older adults and in people taking β-blockers.

Sulfonylureas bind plasma proteins with high affinity, so drugs that displace them — sulfonamides, gemfibrozil, warfarin — increase the risk. Glipizide and glimepiride cause less hypoglycemia than glyburide. Because of severe, prolonged hypoglycemia with long-acting sulfonylureas, glyburide is on the AGS Beers Criteria as potentially inappropriate after age 65, and geriatric guidance recommends short-acting sulfonylureas such as glipizide.

Sulfonylureas have a narrow therapeutic index; hypoglycemia is the main toxicity of an overdose and may take up to 12 hours to appear. Severe cases can cause seizures, coma or death. In hospital, IV dextrose is first-line, often as a continuous infusion with long-acting agents — but dextrose itself can trigger more insulin secretion from the drug-primed β cells and a recurrence of hypoglycemia.

Octreotide, a somatostatin analog, binds somatostatin-2 receptors on β cells and inhibits calcium influx, blocking the insulin secretion that dextrose provokes; it reduces dextrose requirements and helps maintain euglycemia. Glucagon raises glucose by glycogenolysis and gluconeogenesis but can itself trigger insulin release, so it is not used routinely. Dialysis is unlikely to help because glipizide is highly protein bound, and patients are monitored for 12 hours after treatment for recurrence.