Biguanides
History
Metformin (GLUCOPHAGE) and phenformin were introduced in 1957, and buformin was introduced in 1958. The latter was of limited use, but metformin and phenformin were widely used. Phenformin was withdrawn in many countries during the 1970s because of an association with lactic acidosis. Metformin has been associated only rarely with that complication, and has been widely used in Europe and Canada; it became available in the United States in 1995. Metformin given alone or in combination with a sulfonyl-urea improves glycemic control and lipid concentrations in patients who respond poorly to diet or to a sulfonylurea alone (DeFronzo et al., 1995).
ADME
Metformin is absorbed mainly from the small intestine. The drug is stable, does not bind to plasma proteins, and is excreted unchanged in the urine. It has a half-life of 1.3 to 4.5 hours (see Bailey, 1992). The maximum recommended daily dose of metformin is 3 g, taken in three doses with meals.
Mechanism of action
The main causes of reduced glucose levels during metformin therapy appear to be an increase in insulin action in peripheral tissues (see Bailey, 1992) and reduced hepatic glucose output due to inhibition of gluconeogenesis (Stumvoll et al., 1995). Metformin also may decrease plasma glucose by reducing the absorption of glucose from the intestine, but this action has not been shown to have clinical relevance.
Therapeutic uses
Metformin hydrochloride has been most often prescribed for patients with refractory obesity whose hypoglycemia is due to ineffective insulin action, i.e., “insulin resistance syndrome”. Because metformin is an insulin-sparing agent and does not increase weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such patients. Another indication for its use is in combination with sulfonylureas in non-insulin-dependent diabetics in whom sulfonylurea therapy alone is inadequate.
Contraindications
Patients with renal impairment should not receive metformin. Hepatic disease, a past history of lactic acidosis (of any cause), cardiac failure, or chronic hypoxic lung disease also are contraindications to the use of the drug. These conditions all predispose to increased lactate production and hence to the fatal complications of lactic acidosis. The reported incidence of lactic acidosis during metformin treatment is lower than 0.1 case per 1000 patient years, and the mortality risk is even lower.
Side effects
Acute side effects of metformin, which occur in up to 20% of patients, include diarrhea, abdominal discomfort, nausea, metallic taste, and anorexia. These are usually minimized by increasing the dosage of the drug slowly and taking it with meals. Intestinal absorption of vitamin B12 and folate often is decreased during chronic metformin therapy.
Consideration should be given to stopping treatment with metformin if the plasma lactate level exceeds 3 mM. Similarly, decreased renal or hepatic function also may be a strong indication for withholding treatment. It also would be prudent to stop metformin if a patient is undergoing a prolonged fast or is treated with a very low calorie diet. Myocardial infarction or septicemia mandate stopping the drug immediately. Metformin often is given in combination with sulfonylureas (Hermann et al., 1994).
History
Metformin (GLUCOPHAGE) and phenformin were introduced in 1957, and buformin was introduced in 1958. The latter was of limited use, but metformin and phenformin were widely used. Phenformin was withdrawn in many countries during the 1970s because of an association with lactic acidosis. Metformin has been associated only rarely with that complication, and has been widely used in Europe and Canada; it became available in the United States in 1995. Metformin given alone or in combination with a sulfonyl-urea improves glycemic control and lipid concentrations in patients who respond poorly to diet or to a sulfonylurea alone (DeFronzo et al., 1995).
ADME
Metformin is absorbed mainly from the small intestine. The drug is stable, does not bind to plasma proteins, and is excreted unchanged in the urine. It has a half-life of 1.3 to 4.5 hours (see Bailey, 1992). The maximum recommended daily dose of metformin is 3 g, taken in three doses with meals.
Mechanism of action
The main causes of reduced glucose levels during metformin therapy appear to be an increase in insulin action in peripheral tissues (see Bailey, 1992) and reduced hepatic glucose output due to inhibition of gluconeogenesis (Stumvoll et al., 1995). Metformin also may decrease plasma glucose by reducing the absorption of glucose from the intestine, but this action has not been shown to have clinical relevance.
Therapeutic uses
Metformin hydrochloride has been most often prescribed for patients with refractory obesity whose hypoglycemia is due to ineffective insulin action, i.e., “insulin resistance syndrome”. Because metformin is an insulin-sparing agent and does not increase weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia in such patients. Another indication for its use is in combination with sulfonylureas in non-insulin-dependent diabetics in whom sulfonylurea therapy alone is inadequate.
Contraindications
Patients with renal impairment should not receive metformin. Hepatic disease, a past history of lactic acidosis (of any cause), cardiac failure, or chronic hypoxic lung disease also are contraindications to the use of the drug. These conditions all predispose to increased lactate production and hence to the fatal complications of lactic acidosis. The reported incidence of lactic acidosis during metformin treatment is lower than 0.1 case per 1000 patient years, and the mortality risk is even lower.
Side effects
Acute side effects of metformin, which occur in up to 20% of patients, include diarrhea, abdominal discomfort, nausea, metallic taste, and anorexia. These are usually minimized by increasing the dosage of the drug slowly and taking it with meals. Intestinal absorption of vitamin B12 and folate often is decreased during chronic metformin therapy.
Consideration should be given to stopping treatment with metformin if the plasma lactate level exceeds 3 mM. Similarly, decreased renal or hepatic function also may be a strong indication for withholding treatment. It also would be prudent to stop metformin if a patient is undergoing a prolonged fast or is treated with a very low calorie diet. Myocardial infarction or septicemia mandate stopping the drug immediately. Metformin often is given in combination with sulfonylureas (Hermann et al., 1994).
Other Oral Hypoglycemic Agents
Thiazolidinediones
Ciglitazone, Pioglitazone are thiazolidinediones. They are antihyperglycemic in a variety of insulin-resistant and diabetic animal models. Like biguanides, they do not cause hypoglycemia in diabetic or normal persons. Ciglitazone reduces plasma glucose, insulin, and lipid concentrations after oral administration in several insulin-resistant animal models. The reduction in plasma insulin levels follows a fall in plasma glucose concentration, which is thought to be due to an effect of the drug to decrease insulin resistance in liver, skeletal muscle, and adipose tissue. The administration of these agents to normal animals does not potentiate insulin effects. Thiazolidinediones appear to augment insulin action in insulin-resistant animals by increasing the number of glucose transporters. These compounds, along with several other newer analogs, are currently undergoing phase I or II clinical trials.
Thiazolidinediones
Ciglitazone, Pioglitazone are thiazolidinediones. They are antihyperglycemic in a variety of insulin-resistant and diabetic animal models. Like biguanides, they do not cause hypoglycemia in diabetic or normal persons. Ciglitazone reduces plasma glucose, insulin, and lipid concentrations after oral administration in several insulin-resistant animal models. The reduction in plasma insulin levels follows a fall in plasma glucose concentration, which is thought to be due to an effect of the drug to decrease insulin resistance in liver, skeletal muscle, and adipose tissue. The administration of these agents to normal animals does not potentiate insulin effects. Thiazolidinediones appear to augment insulin action in insulin-resistant animals by increasing the number of glucose transporters. These compounds, along with several other newer analogs, are currently undergoing phase I or II clinical trials.
α-Glucosidase Inhibitors
α-Glucosidase inhibitors such as acarbose reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of intestinal brush border α-glucosidase. Inhibition of this enzyme slows the absorption of carbohydrates; the postprandial rise in plasma glucose is blunted in both normal and diabetic subjects.
Acarbose also competitively inhibits glucoamylase and sucrase but has weak effects on pancreatic α-amylase. It reduces postprandial plasma glucose levels in IDDM and NIDDM subjects. However, only small improvements in hemoglobin A1C values have been reported. The drug is poorly absorbed.
Acarbose results in dose-related malabsorption, flatulence, and abdominal bloating. Doses of 50 to 100 mg given with each meal are usually well tolerated. Smaller doses are given with snacks. Acarbose is most effective when given with a starchy, high-fiber diet with restricted amounts of glucose and sucrose (Bressler and Johnson, 1992).
α-Glucosidase inhibitors such as acarbose reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of intestinal brush border α-glucosidase. Inhibition of this enzyme slows the absorption of carbohydrates; the postprandial rise in plasma glucose is blunted in both normal and diabetic subjects.
Acarbose also competitively inhibits glucoamylase and sucrase but has weak effects on pancreatic α-amylase. It reduces postprandial plasma glucose levels in IDDM and NIDDM subjects. However, only small improvements in hemoglobin A1C values have been reported. The drug is poorly absorbed.
Acarbose results in dose-related malabsorption, flatulence, and abdominal bloating. Doses of 50 to 100 mg given with each meal are usually well tolerated. Smaller doses are given with snacks. Acarbose is most effective when given with a starchy, high-fiber diet with restricted amounts of glucose and sucrose (Bressler and Johnson, 1992).
