A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications

Abstract

The rising incidence of obesity and insulin resistance to epidemic proportions has closely paralleled the surge in the prevalence of diabetes and outpaced therapeutic advances in diabetes prevention and treatment. Current evidence points to obesity induced oxidative stress and chronic inflammation as the common denominators in the evolution of insulin resistance and diabetes. Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes. In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population. The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes. Finally, this review will address the currently available evidence on diabetic cardiomyopathy and the potential role of combination therapy with pioglitazone and metformin.

Figure 1

Diabetes is characterized by decompensated insulin secretion for insulin resistance at target organs including adipose tissue, liver and muscle. Insulin resistance is associated with increased proinflammatory cytokines. Inflammatory pathways in insulin resistance can be initiated by extracellular mediators such as cytokines and free fatty acid (FFA) or by intracellular stresses such as ER stress, excess ROS production by mitochondria or lipotoxicity. Activation of NF-κB pathway leads to induction of chemokines that recruit inflammatory cells, such as macrophages. (FFA Free fatty acid, ER Endoplasmic reticulum, DAG diacylglycerol, LCFA long chain fatty acid, IR insulin receptor).