Control of type 2 diabetes (formerly known as non–insulin-dependent diabetes) is an important health issue in the United States. The American Diabetes Association recommends patients reach a glycolylated hemoglobin (HbA1c) level of less than 7.0 percent; however, helping patients achieve this has always been challenging. Few patients are able to achieve tight control with diet and exercise alone. Options for obtaining better control include oral hypoglycemic agents and insulin. Although criticisms of oral agents exist, there is general support for the idea that insulin therapy should be reserved to treat diabetes when oral agents have failed. Oral agents have been developed to address each of the three metabolic disorders characteristic of type 2 diabetes: decreased pancreatic beta-cell function, elevated hepatic glucose output and insulin resistance. The choice of a particular oral agent may be suggested by specific conditions, such as obesity, or dictated by problems such as renal insufficiency. The characteristics of each class of drugs must be carefully weighed before initiating therapy. Feinglos and Bethel present a comprehensive summary of oral agents for patients with type 2 diabetes.
Sulfonylureas. These drugs act by enhancing insulin release from beta cells and may decrease peripheral insulin resistance. On average, sulfonylureas reduce fasting glucose levels by 50 to 70 mg per dL (2.8 to 3.9 mmol per L) and reduce HbA1c levels by 0.8 to 1.7 percent. Failure to respond to a sulfonylurea occurs in approximately 30 percent of patients. However, patients with the following characteristics are more likely to have a response: age over 40, duration of diabetes more than five years, body weight 110 to 160 percent of ideal and no previous insulin therapy.
Biguanides. Metformin is currently the only drug in this class available in the United States. The mechanism of action is a reduction in hepatic glucose output. Metformin has been shown to reduce the fasting glucose level by 50 to 70 mg per dL and the HbA1c by 1.4 to 1.8 percent. Metformin is not associated with the weight gain and hypoglycemia that occur with the use of sulfonylureas. It may also produce a more favorable lipid response. Lactic acidosis is the greatest concern and is more likely to occur in patients with renal insufficiency; its use is therefore not recommended in patients with a creatinine level above 1.5 mg per dL (130 μmol per L).
Alpha-Glucosidase Inhibitors. Acarbose is the only drug in this class available in the United States. This drug works by inhibiting absorption of complex carbohydrate from the gut. The drug has no effect on glucose or lactose. Treatment typically reduces fasting glucose levels by 35 to 40 mg per dL (1.9 to 2.2 mmol per L) and HbA1c levels by 0.4 to 0.7 percent. The most bothersome adverse effects are flatulence, abdominal pain and diarrhea. These effects may be mitigated by beginning therapy at a low dosage and slowly increasing it.
Thiazolidinediones. Troglidazone is the only medication in this class available in the United States. This class of drug works by directly enhancing insulin sensitivity without having an effect on insulin secretion. Troglidazone is associated with a reduction of HbA1c levels of 0.5 to 1.5 percent. Although treatment has been associated with weight gain, hypoglycemia has not been reported. There are recent concerns about its effect on the liver; specifically, an association with liver failure. All patients using this drug should be monitored monthly for six months and then bimonthly for another six months. Troglidazone is currently undergoing review by the U.S. Food and Drug Administration to determine whether it will remain available as a treatment option.
A number of studies on combination therapy have investigated whether adding a second agent improves glucose control. It is clear that a second agent can improve treatment. The choice of a particular agent should be based on patient characteristics described above. Among the combinations studied, the most potent has been a sulfonylurea with metformin. No studies have assessed the benefits of three-drug combinations.
The recommendations provided by Feinglos and Bethel give a rational approach to the treatment of a common and very challenging disease. Management recommendations consist of six components: (1) All new patients with type 2 diabetes should have an initial trial of diet and exercise therapy, except patients with severe hyperglycemia (fasting glucose level greater than 250 mg per dL [13.9 mmol per L] or random glucose levels greater than 400 mg per dL [22.2 mmol per L]). (2) If ADA guidelines are not met within four weeks, patients should be started on an oral agent. (3) The choice of an oral agent is dictated by patient characteristics. In patients with abnormal liver function tests, all oral agents are contraindicated, and insulin therapy should be started. Patients with impaired renal function manifested by a serum creatinine level greater than 1.5 mg per dL may use any agent except metformin. (4) In obese patients, metformin should be considered as the initial agent. (5) In patients for whom monotherapy fails, combination therapy should be considered. (6) Those for whom combination therapy fails should start insulin therapy, either alone or together with an oral agent.