Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones

Abstract

Insulin resistance underlies the pathogenesis of hyperglycaemia and cardiovascular disease in most people with type 2 diabetes. Metformin and thiazolidinediones (pioglitazone and rosiglitazone) counter insulin resistance by different cellular mechanisms and with complementary effects, making them suited for use in combination. Metformin exerts a stronger suppression of hepatic glucose output, while thiazolidinediones produce a greater increase in peripheral glucose uptake, enabling metformin-thiazolidinedione combinations to improve glycaemic control in type 2 diabetes with additive efficacy. Basal insulin concentrations are not raised by metformin or thiazolidinediones, so there is minimal risk of hypoglycaemia, and metformin can reduce the weight gain associated with thiazolidinediones. There are overlapping effects of metformin and thiazolidinediones against a range of athero-thrombotic factors and markers. These include decreased plasminogen activator inhibitor-1, reduced platelet aggregation, reductions of several vascular adhesion molecules, and reduced markers of low-grade inflammation such as C-reactive protein. Additionally, thiazolidinediones increase adiponectin and slightly reduce blood pressure. Both metformin and thiazolidinediones can improve components of the lipid profile: thiazolidinediones consistently reduce free fatty acid concentrations and decrease the proportion of small dense low-density-lipoprotein, and pioglitazone also decreases triglycerides. During co-administration, metformin and thiazolidinediones do not interfere with each other's pharmacokinetics, and lower doses of the two agents together can achieve efficacy with fewer side effects. Metformin-thiazolidinedione combinations require attention to the precautions for both agents, especially renal, cardiac and hepatic status. Thus, metformin and thiazolidinediones can be used in combination to address the hyperglycaemia and vascular risk in type 2 diabetes.