OBJECTIVE: To discuss a rational approach to improvement of glycemic control in 
patients with type 2 diabetes mellitus with use of combination therapy.
METHODS: We review the mechanisms of action and clinical applications for the 
various antidiabetic agents alone and in various combinations. Relevant studies 
in the literature are reviewed.
RESULTS: Although diet and exercise remain the cornerstones of treatment, in 
most patients with type 2 diabetes, pharmacologic agents are needed to achieve 
optimal glycemic control and likely reduce the incidence of microvascular and 
possibly macrovascular complications as well. Sulfonylureas have long been the 
foundation of oral pharmacologic therapy and provide adequate glycemic control 
for most patients for 5 to 10 years or longer. In the past, when treatment with 
sulfonylureas was no longer effective, insulin therapy was inevitable. With the 
approval of several new pharmacologic agents for the treatment of type 2 
diabetes, however, the addition of one or more orally administered agents to 
sulfonylurea therapy or use of other oral combination therapy is rapidly 
evolving as a means of optimizing glycemic control. In many patients, 
combination therapy can delay the need to add or switch to insulin, or it can 
enhance glycemic control in patients already receiving insulin. In selected 
patients treated solely with insulin, discontinuation of insulin treatment and 
reinitiation of oral therapy may even be possible.
CONCLUSION: Currently, four classes of orally administered antidiabetic agents 
are available for use in patients with type 2 diabetes: insulin secretagogues, 
biguanides, a-glucosidase inhibitors, and thiazolidinediones. By taking 
advantage of differing mechanisms of action, combination therapy is evolving as 
a means of optimizing glycemic control in patients in whom a single agent or 
insulin is inadequate. Combinations of orally administered agents can often 
delay the need for insulin or in combination with insulin aid in achieving 
glycemic goals. Continuing research will help optimize combination therapies 
even further.