Towards single-tablet therapy for type 2 diabetes mellitus. Rationale and recent developments

Type 2 diabetes mellitus emerges as a result of multiple pathophysiologic changes. If the pharmacotherapy of type 2 diabetes should be tailored to the underlying pathophysiology, it would be necessary to use a combination of agents with complementary mechanisms of action. The two principal defects in type 2 diabetes are insulin deficiency and insulin resistance. Therefore, combining an insulin-providing agent with an insulin-sensitizing agent will augment the efficacy of current antihyperglycemic agents. This is the rationale for the development and marketing of sulfonylurea/metformin combination tablets.Randomized double-blind clinical trials have shown the safety and efficacy of these fixed combination tablets in both drug-naive individuals as well as in those individuals not achieving glycemic goals on sulfonylurea or metformin monotherapy. These studies have also shown that these tablets may be associated with better postprandial glycemic control compared with monotherapy. However, the risk of hypoglycemia is increased with the use of combination tablets, especially in drug-naive individuals with baseline glycosylated hemoglobins of <8.0%. Combining two insulin-sensitizing agents that have different mechanisms of action and that target different biochemical pathways, would also enhance efficacy. This can be accomplished by combining metformin with rosiglitazone or pioglitazone. The recently developed fixed formulation tablet of metformin/rosiglitazone is available for use as second-line therapy in individuals who have not reached their glycemic goals while on metformin. The advantages of combining several agents in one tablet include convenience and enhanced adherence to therapy. The main disadvantage is the loss of administration flexibility.