Diabetes Treatment (cont.)

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Medications that increase the sensitivity of cells to insulin (Actos and Avandia)

The class of drugs known as thiazolidinediones lowers blood glucose by improving target cell response to insulin (that is, increasing the sensitivity of the cells to insulin). Troglitazone (Rezulin) was the first of this class in the U.S. Because of severe toxic liver effects, troglitazone has been taken off the market. Sister compounds are now available with a better safety profile. These drugs include pioglitazone (Actos) and rosiglitazone (Avandia).

Pioglitazone (Actos) and rosiglitazone (Avandia) are thiazolidinediones approved for use in the U.S. While they are sister compounds to Rezulin, extensive studies have failed to show that they are associated with any liver problems. Both Avandia and Actos act by increasing the sensitivity (responsiveness) of cells to insulin. They improve the sensitivity of muscle and fat cells to insulin. These drugs have been effective in lowering blood sugars in patients with type 2 diabetes, Actos and Avandia act within one hour of administration and are taken once daily. It is important to note that it takes up to six weeks to see a drop in blood glucose levels with these drugs and up to 12 weeks to see a maximum benefit. Actos and Avandia have been approved as first line therapy in diabetes and for use in combination with other drugs. Both drugs may be used in patients taking other oral drugs as well as those using insulin.

Rosiglitazone (Avandia), however, has been associated with an increased risk of heart attack and stroke, and experts have debated the severity of these concerns. On September 23, 2010, the U.S. Food and Drug Administration (FDA) announced that it will significantly restrict the use of the diabetes drug Avandia to patients with type 2 diabetes who cannot control their diabetes on other medications such as Actos. These new restrictions are in response to data that suggest an elevated risk of cardiovascular events, such as heart attack and stroke, in patients treated with Avandia. Also, GlaxoSmithKline (the manufacturer of Avandia) will be required to establish a Risk Evaluation and Mitigation Strategy (REMS) program in which patients, their doctors, and their pharmacists must participate in order to receive, prescribe, or sell Avandia.

While reported liver problems with these agents are mild (and reversible with discontinuation of the drug), most physicians choose to follow an earlier recommendation to do blood tests to detect liver injury every two months or so during the first year of therapy. Recently this recommendation has been removed. If at any point the liver tests increase to three times the normal upper limit, the drug should be stopped.

The most important contraindications to these medications include any type of liver disease, and heart failure. Fluid retention can be of particular concern in patients with signs or symptoms of heart failure and in those with ejection fractions of less than 40% which indicates poor function of the heart. While the reports are three to eight pounds, clinical experience shows up to 12-15 pounds of weight gain can occur. Usually the majority of this is fluid, but an absolute body weight gain can also occur. This is likely to be dose-dependent and, therefore, the increases in weight may be greater with higher doses of drug. Weight gain is more pronounced in patients who are also taking insulin.

In general, the ankle swelling and puffiness due to the accumulation of fluid can be controlled with the addition of a diuretic such as spironolactone (Aldactone) - (furosemide (Lasix) does not work as well) - or by reducing the dose. On occasion, patients may be symptomatic enough from fluid retention to warrant withdrawal of the drug. Some recent studies have suggested an association between pioglitazone and rosiglitazone and untoward cardiac events, for example, heart attacks, though this association is controversial. Regardless of the controversy, it is well established that pioglitazone and rosiglitazone should be avoided in patients with symptomatic heart failure or heart failure.

Another newer concern is an association of treatment with a small increase in the frequency of fractures of the distal long bones of the arms and legs. At present, this does not translate into fractures of the hip and spine, which would be clinically more worrisome. More data is needed to make a definitive statement about cause and effect at this time.

As an aside, Actos and Avandia have an added benefit of changing cholesterol patterns in diabetes. HDL (or good cholesterol) increases with these medications, and triglycerides often decrease. While there is some controversy regarding what happens to bad cholesterol (LDL) levels, there is a suggestion that Actos may be superior in changing lipid profiles than Avandia. In this population of diabetics that is already at an increased risk for heart disease, an improvement in cholesterol profile is beneficial. As more and more data becomes available, there is mounting evidence that this class of drugs may provide direct benefits to the heart and large blood vessels and may actually be valuable in preventing the progression of diabetes in high-risk individuals by reducing inflammation and by decreasing clotting factors.

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