Weight Gain with Glitazone Therapy

Tommy Johnson, Pharm D, CDE

Actos (pioglitazone) and Avandia (rosiglitazone) are the commercially available thiazolidinediones, or for short “glitazones,” for lowering blood glucose levels. These agents are insulin sensitizers that decrease insulin resistance by acting as agonists of the peroxisome proliferator-activated receptors-gamma or PPARgamma. The gamma subtype can be found in vascular smooth muscle, the heart, liver, skeletal muscle and others. By decreasing insulin resistance, a decrease in serum insulin levels, improved endothelial function, decreased vascular inflammation and insulin-mediated vasorelaxation occurs. Insulin resistance also leads to an increased risk of hypertension, cardiac remodeling. With so many beneficial cardiovascular effects, why are these agents contraindicated in patients with New York Heart Association (NYHA) class III and IV heart failure?

                When used for patients with type 2 diabetes in combination with insulin, weight gain due to adipogenesis and fluid retention has been observed. The exact mechanism is unknown. It is estimated that 12% of patients with type 2 diabetes have heart failure. An estimated 5-15% of patients receiving insulin and a glitazone and 2-5% of patients receiving either glitazone as monotherapy have experienced peripheral edema. In patients that already have conditions such as heart failure or renal dysfunction, this may be serious. In an article published in Mayo Clin Proc. 2003;78:1076-1077, the question *Do Thiazolinediones Cause Congestive Heart Failure* was raised. It was found that these agents cause fluid overload, which may cause or worsen heart failure in compromised patients. But these agents also have shown positive effects on cardiac function such as increasing natriuretic peptide production and causing coronary vasodilation.

                Some of the proposed mechanisms for fluid retention and increasing the risk of or worsening of heart failure are interference with renal hemodynamics, which lead to increased sodium and water retention. Fluid retention may cause dilutional anemia due to the fact that glitazones at maximal doses may decrease hemoglobin by 2g/dl.  Increased intravascular volume of 6-7% can be seen possibly through a vascular leak mechanism caused by endothelial mediated vasodilation or increased levels of vascular endothelial growth factors. One general explanation may be that with improved blood glucose control, decreased glycosuria occurs. The fluid retention and edema are dose dependent with more problems with higher doses. In a 52-week study comparing weight gain using either a sulfonylurea (7.5 mg/d) or rosiglitazone (4 mg/d), a mean weight gain of 1.9 kg was observed with both agents. When the rosiglitazone dose was increased to 8 mg/d, a weight gain of 2.9 kg was observed. When 4 and 8 mg of rosiglitazone was added to a mean dose of 70 units/day of insulin, a 4.1 kg and 5.4 kg weight increase was seen. In a prospective, randomized study published in Diabetes Care 2003;25:708-711, as you increase the pioglitazone dose with or without insulin, weight increased. The fluid retention does not respond well to diuretics, but does respond  to lowering the dose or discontinuing the drug. This fluid retention may occur within days of starting therapy, or it may occur months afterward.

                In two articles, one in Diabetes Care 1999;22:288-293 and the other in Diabetes Res Clin Pract. 2001;181-190, the association of an increase in subcutaneous fat and a decrease in visceral fat are explored. In these articles, a shift in fat distribution and a decrease in leptin levels and increase in appetite are discussed as possible causes of weight gain when troglitazone, which has been removed from the market, was used.

                In summary, it is known that the glitazones as a class, can cause fluid retention and weight gain. The amount of weight gain is dose dependent and increases in cardiac-compromised patients. The decision to use the agents in patients with ischemic cardiomyopathy of NYHA class III or IV heart failure should be used with caution. In patients that have not previously been diagnosed with these conditions, a safe way to utilize these agents, since they have shown beneficial cardiovascular effects is to start with low doses and have the patient monitor for sudden increases in weight, shortness of breath or edema. If these signs and symptoms are noticed, the dosage should be decreased or stopped. At each visit with a diabetes educator or the clinic, evaluation of adverse effects in patients taking these agents, especially when combined with insulin, should be performed.

Tommy Johnson is an Assistant Professor of Pharmacy at the University of Georgia.