Several categories of glucose-lowering agents are available for patients with type 2 diabetes: (1) agents that bind to the sulfonylurea receptor and stimulate insulin secretion (sulfonylureas, meglitinides, d-phenylalanine derivatives); (2) agents that lower glucose levels by their actions on liver, muscle, and adipose tissue (biguanides, thiazolidinediones); (3) agents that principally slow the intestinal absorption of glucose (α-glucosidase inhibitors); agents that mimic incretin effect or prolong incretin action (GLP-1 receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors), (5) agents that inhibit the reabsorption of glucose in the kidney (sodium-glucose co-transporter inhibitors [SGLTs]), and agents that act by other or ill-defined mechanisms (pramlintide, bromocriptine, colesevelam).
Mechanism of Action
The major action of sulfonylureas is to increase insulin release from the pancreas (Table 41–7). They bind to a 140-kDa high-affinity sulfonylurea receptor that is associated with a beta-cell inward rectifier ATP-sensitive potassium channel (Figure 41–2). Binding of a sulfonylurea inhibits the efflux of potassium ions through the channel and results in depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin.
TABLE 41–7 Regulation of insulin release in humans.
Stimulants of insulin release
Humoral: Glucose, mannose, leucine, arginine, other amino acids, fatty acids (high concentrations)
Hormonal: Glucagon, glucagon-like peptide 1 (7–37), glucose-dependent insulinotropic polypeptide, cholecystokinin, gastrin
Neural: β-Adrenergic stimulation, vagal stimulation
Drugs: Sulfonylureas, meglitinide, nateglinide, isoproterenol, acetylcholine
Inhibitors of insulin release
Hormonal: Somatostatin, insulin, leptin
Neural: α-Sympathomimetic effect of catecholamines
Drugs: Diazoxide, phenytoin, vinblastine, colchicine
Adapted, with permission, from Greenspan FS, Gardner DG [editors]: Basic & Clinical Endocrinology, 6th ed. McGraw-Hill, 2001. Copyright © The McGraw-Hill Companies, Inc.
Efficacy & Safety of the Sulfonylureas
Sulfonylureas are metabolized by the liver and, with the exception of acetohexamide, the metabolites are either weakly active or inactive. The metabolites are excreted by the kidney and, in the case of the second-generation sulfonylureas, partly excreted in the bile. Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia, thrombocytopenia) occurring in less than 0.1% of cases. The second-generation sulfonylureas have greater affinity for their receptor compared with the first-generation agents. The correspondingly lower effective doses and plasma levels of the second-generation drugs therefore lower the risk of drug-drug interactions based on competition for plasma binding sites or hepatic enzyme action.