Oral Combination Therapy for Type 2 Diabetes

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Insulin resistance in the liver and peripheral tissue and dysfunction of the pancreatic beta cells are the two processes that result in type 2 diabetes mellitus. In the management of type 2 diabetes, the goal is to achieve glycemic control. Unfortunately, the longer patients have type 2 diabetes, the less likely they will be able to achieve and maintain glycemic goals with monotherapy. The combination of an insulin secretagogue and an insulin sensitizer addresses both processes. A tablet combining glyburide and metformin provides better glycemic control and contains agents that can correct both underlying processes.

Some patients with type 2 diabetes progress to the point where dual therapy does not provide adequate control. In these patients, the addition of a thiazolidinedione can provide better glycemic control. Dailey and colleagues evaluated the safety and efficacy of a thiazolidinedione, rosiglitazone, in the combination treatment of type 2 diabetes mellitus.

The study was a randomized, double-blind, placebo-controlled multicenter trial of patients with poorly controlled type 2 diabetes. Poor glycemic control was defined as an A1C level between 7.1 and 10 percent. In addition, patients had to have a body mass index of 23 to 40 kg per m2. The first portion of the study was an open-label lead-in to the optimal dosage of combined glyburide/metformin. At the end of that phase, patients were randomized to receive 4 mg of rosiglit-azone once daily or placebo for a 24-week period. If glycemic control was not achieved, the dosage of rosiglitazone was increased to 4 mg twice daily. If the participants developed hypoglycemia, the dosage of glyburide/metformin was reduced by 2.5/500 mg. The main outcome measure was the A1C level at the end of the trial period. Other end points included A1C levels of less than 7 percent, a fasting plasma glucose level of less than 126 mg per dL (7 mmol per L), and lipid levels. In addition, investigators recorded and graded any adverse drug events.

There were 365 patients enrolled in the study. The combination therapy of glyburide/metformin plus rosiglitazone provided patients with a significant reduction in A1C levels (-1 percent) compared with patients receiving glyburide/metformin plus placebo. In addition, a significantly larger portion of patients taking triple active medications had A1C levels of less than 7 percent compared with those in the glyburide/metformin plus placebo group. The patients who received three active medications had a statisically significant reduction of 48 mg per dL (1.25 mmol per L) in fasting blood glucose levels compared with the glyburide/metformin plus placebo group. The most common adverse events reported during the study period in the glyburide/metformin and rosiglitazone group included mild to moderate edema, hypoglycemia, and a weight gain of 3 kg (6.6 lb). At no time during the study did patients need third-party assistance because of a hypoglycemic episode.

The authors conclude that in patients with type 2 diabetes mellitus who are not achieving glycemic control with a combination of glyburide/metformin, the addition of rosiglitazone can result in improved control. They add that the triple combination improves patients' chances of attaining A1C levels of less than 7 percent, which could lead to a delay in the necessity for insulin therapy. This benefit occurred with minimal adverse events.

karl e. miller, m.d.