Metformin and pioglitazone: Effectively treating insulin resistance.

BACKGROUND: Insulin resistance has a complex etiology, with multiple manifestations across the organ systems involved in glucose homeostasis. Glucose-lowering drug therapies that target insulin resistance can therefore utilize different mechanistic approaches. Two key classes of insulin-sensitizing agents--the biguanides (principally metformin) and thiazolidinediones (pioglitazone and rosiglitazone)--have distinct molecular mechanisms of action and differing effects on metabolic dysfunction. This provides an opportunity for complementary beneficial effects in the treatment of type 2 diabetes and on the potential consequences of insulin resistance, such as dyslipidemia and atherosclerosis. SCOPE: This review (based upon EMBASE and MEDLINE searches from January 1990 to April 2006) highlights the mechanistic distinctions and clinical data that support the rationale for thiazolidinedione/metformin combination therapy in patients with type 2 diabetes.
FINDINGS: The different insulin-sensitizing mechanisms of metformin and the thiazolidinediones are manifest in partially distinct effects on hepatic and peripheral glucose homeostasis, and clinical studies show improved glucose control with combination therapy. Both metformin and thiazolidinediones may also have pancreatic beta-cell preserving properties. Furthermore, they have different beneficial effects on several other metabolic risk markers and risk factors for cardiovascular disease. Whereas the thiazolidinediones (particularly pioglitazone) have greater effects on multiple aspects of dyslipidemia, metformin has anorexigenic properties. They also have distinct effects on levels of mediators involved in inflammation and endothelial dysfunction, and outcome studies suggest that either pioglitazone or metformin may reduce the risk of macrovascular events.
CONCLUSION: The distinct, but complementary, mechanisms of action of the thiazolidinediones and metformin provide the opportunity for effective combination therapy with two insulin-sensitizing agents. Such an approach has consequences, not only for improved glucose control, but also for reducing metabolic risk and potentially improving major cardiovascular disease outcomes.