Mitiglinide (not available in the United States) is a benzylsuccinic acid derivative that binds to the sulfonylurea receptor and is similar to repaglinide in its clinical effects. It has been approved for use in Japan.
Nateglinide, a d-phenylalanine derivative, stimulates rapid and transient release of insulin from beta cells through closure of the ATP-sensitive K+ channel. It is absorbed within 20 minutes after oral administration with a time to peak concentration of less than 1 hour and is metabolized in the liver by CYP2C9 and CYP3A4 with a half-life of about 1 hour. The overall duration of action is about 4 hours. It is taken before the meal and reduces the postprandial rise in blood glucose levels. It is available as 60and 120-mg tablets. The lower dose is used in patients with mild elevations in HbA1c. Nateglinide is efficacious when given alone or in combination with non-secretagogue oral agents (such as metformin). Hypoglycemia is the main adverse effect. It can be used in patients with renal impairment and in the elderly.
DRUGS THAT PRIMARILY LOWER GLUCOSE LEVELS BY THEIR ACTIONS ON THE LIVER, MUSCLE, & ADIPOSE TISSUE
The structure of metformin is shown below. Phenformin (an older biguanide) was discontinued in the United States because of its association with lactic acidosis. Metformin is the only biguanide currently available in the United States.
Mechanisms of Action
A full explanation of the mechanism of action of the biguanides remains elusive, but their primary effect is to activate the enzyme AMP-activated protein kinase (AMPK) and reduce hepatic glucose production. Patients with type 2 diabetes have considerably less fasting hyperglycemia as well as lower postprandial hyperglycemia after administration of biguanides; however, hypoglycemia during biguanide therapy is rare. These agents are therefore more appropriately termed “euglycemic” agents.
Metformin has a half-life of 1.5–3 hours, is not bound to plasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. As a consequence of metformin’s blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, the biguanide accumulates and thereby increases the risk of lactic acidosis, which appears to be a dose-related complication. Metformin can be safely used in patients with estimated glomerular filtration rates (eGFR) between 60 and 45 mL/min per 1.73 m2. It can be used cautiously in patients with eGFR between 45 and 30 mL/min per 1.73 m2. It is contraindicated if the eGFR is less than 30 mL/min per 1.73 m2.