Oral Agents for Type 2 Diabetes

Sulphonylureas
With the labeling of tolbutamide by the U.S. Food and Drug Administration in 1962, the sulfonylurea class of drugs quickly became the mainstay of treatment for type 2 diabetes. Although newer agents have recently entered the marketplace, sulfonylureas still play a primary role in pharmacologic management of type 2 diabetes. Patients who respond best to treatment with sulfonylureas include those with a diagnosis of type 2 diabetes before 40 years of age, duration of disease less than five years before initiation of drug therapy and a fasting blood glucose level of less than 300 mg per dL (16.7 mmol per L) Approximately two thirds of patients who begin therapy with a sulfonylurea respond, although up to 20 percent of them eventually require additional medication. Few patients with uncontrolled diabetes receive clinical benefit when switched from one sulfonylurea agent to another. (Mooradian AD. 1996). The use of agents with a longer half-life e.g., chlorpropamide in the elderly and in patients with renal impairment is discouraged because the risk of hypoglycemia is increased.
Metformin
Metformin is a biguanide agent that lowers blood glucose primarily by decreasing hepatic glucose output and reducing insulin resistance. Metformin is used as monotherapy or in combination with sulfonylureas for management of type 2 diabetes. When used as monotherapy, metformin does not cause hypoglycemia and is thus termed an "antihyperglycemic." The use of metformin is contraindicated in patients with renal insufficiency (i.e., a serum creatinine level of 1.5 mg per dL [130 µmol per L] in men and 1.4 mg per dL [120 µmol] in women, or abnormal creatinine clearance) or acute or chronic metabolic acidosis. Metformin should be temporarily withheld before any procedure involving intravascular administration of iodinated contrast media. Normal renal function should be confirmed 48 hours after the procedure before restarting metformin therapy. There is no known reason to discontinue metformin therapy during other parenteral contrast studies. Extreme caution should be used in patients with severe hepatic dysfunction, hypoxemic states (e.g., severe chronic obstructive pulmonary disease, congestive heart failure), moderate to severe illness and excessive alcohol intake. In these patients, the use of metformin may contribute to the development of lactic acidosis, a condition that is fatal in about 50 percent of patients who develop it (one episode per 100,000 patient-years). Cimetidine decreases the renal clearance of metformin and may potentiate its effects. Patients receiving oral anticoagulant therapy and metformin may require a higher dosage of warfarin to achieve a therapeutic antithrombotic effect. (Melchior WR, Jaber LA. 1996) Hemogloblin, hematocrit, red blood cell indexes and renal function should be monitored at least annually in patients taking metformin.
Alpha-Glucosidase Inhibitors
Alpha-glucosidase inhibitors, such as acarbose and miglitol are indicated as monotherapy or in combination with sulfonylureas for management of type 2 diabetes. These agents inhibit the breakdown of complex carbohydrates and delay the absorption of monosaccharide from the gastrointestinal tract. Acarbose and miglitol should be titrated over two to three weeks to minimize flatulence and other gastrointestinal side effects that commonly lead to discontinuation of these agents. Alpha-glucosidase inhibitors are contraindicated in patients with inflammatory bowel disease, partial intestinal obstruction, a predisposition to intestinal obstruction, colonic ulceration and other gastrointestinal disorders. (Campbell LK, White JR, 1996). Dose-dependent hepatotoxicity is associated with this drug class, so liver function tests should be carefully monitored in patients receiving higher dosages of these medications (e.g., more than 50 mg three times daily). Transaminase elevations are reversible with discontinuation of the drug and are often asymptomatic. Serum transaminase levels should be checked every three months for the first year patients take the medication and periodically thereafter. Drugs that are susceptible to binding with other agents (e.g., cholestyramine [Questran]) should be taken two to four hours apart from alpha-glucosidase inhibitors to avoid drug interactions. Intestinal absorbents and digestive enzyme preparations should not be administered with acarbose. Near-normal or improved glycemic control has been shown to significantly diminish the risk of microvascular complications in patients with type 2 diabetes mellitus.
Troglitazone
The thiazolidinediones are a unique drug class of "insulin sensitizers" that promote skeletal muscle glucose uptake Troglitazone is the first agent of this drug class to be introduced in the U.S. market and, like metformin, it reduces insulin resistance. Troglitazone is beneficial in patients requiring large daily amounts of insulin (more than 30 units per day) whose diabetes is still uncontrolled. A reduction of up to 50 percent in total daily insulin dosage is possible with drug titration. Troglitazone is also effective when used in combination with other oral agents thereby potentially delaying the need to start insulin therapy. The U.S. Food and Drug Administration recently ruled that troglitazone should only be used in combination with other diabetic therapies. The effectiveness of oral contraceptives may be decreased with troglitazone administration. Over 150 case reports of hepatotoxicity have been reported with troglitazone, so liver function must be monitored every month for the first eight months of treatment and every other month for four months thereafter. (Sparano N, Seaton TL. 1998). Periodic transaminase measurements should be obtained as long as the patient is taking troglitazone.
Repaglinide
Repaglinide is a benzoic acid derivative and the first of the non-sulfonylurea meglitinides introduced in early 1998. The mechanism of action and side effect profile of repaglinide are similar to those of the sulfonylureas. (Scheen AJ. 1997) This agent has a rapid onset of action and should be taken with meals two to four times daily. Repaglinide is a suitable option for patients with severe sulfa allergy who are not candidates for sulfonylurea therapy. The drug is used as monotherapy or in combination with metformin. It should be titrated cautiously in elderly patients and in those with renal or hepatic dysfunction.