Actos and Avandia (Glitazones)

Thiazolidinediones or glitazones are the first class of medication designed to reverse the basic problem in Type 2 diabetes of resistance to insulin. Insulin resistance appears to be associated with high blood pressure and the high triglycerides/low HDL cholesterol problem that puts many people with Type 2 diabetes at risk for heart disease.

Target Organ: muscle, fat, and liver
Action: improve receptivity of insulin receptors, reduce glucose production by liver
Lowers HbA1c by 0.5% to 1.5%
Time to reach maximum effect: 6 – 8 weeks
Taken: with or without food
Drug Dose Range Doses/Day
15 – 45 mg 1
2 – 8 mg 1 – 2
Side Effects: swelling of legs, fluid retention, weights gain(upper respiratory tract infections, headaches, muscle aches, toothaches, sore throat in less than 1%)
Contraindications: kidney or liver disease, enlarged heart, congestive heart failure, edema, pregnancy

The drugs currently available in this group, Avandia and Actos, reverse insulin resistance by improving the sensitivity of insulin receptors in muscle, liver, and fat cells. This helps the body use insulin better. They improve sensitivity partly by reducing levels of inflammatory cytokines like tumor necrosis factor alpha, while increasing activity of the PPAR gamma receptor. They also help keep the liver from overproducing glucose. They have been shown to lower blood sugar levels about 15% while at the same time lowering insulin levels by 20%. In Type 2, insulin levels are raised as the body produces more insulin than normal to try to overcome insulin resistance. Lower insulin levels indicate that these drugs are decreasing insulin resistance.

In addition to improving insulin sensitivity, glitazones may decrease cardiac risks. They raise the LDL level slightly, but increase the size of the LDL molecule. This may make LDL less harmful, because small, dense LDL is the type most likely to clog blood vessels. Glitazones also lower alpha tumor necrosis factor, an inflammatory particle that is associated with an increased risk of heart disease. Blood pressure and triglyceride levels are somewhat reduced, while HDL levels are slightly raised. Newer glitazones, which work on other PPAR receptors and are currently in clinical trials, also seem to lower high triglycerides and raise the low levels of protective HDL cholesterol commonly seen with insulin resistance.

Glitazones decrease insulin resistance and improve cholesterol, lipid and glucose levels around the clock. Their greatest effect on the blood glucose occurs after eating. They do not cause hypoglycemia when used alone, but can cause lows if used with a sulfonylurea or insulin.

Less insulin is required to control blood sugars when glitazones are used. This means that doses of other drugs that increase insulin production, like sulfonylureas and Prandin, or insulin itself may need to be reduced when a glitazone is started.

Avandia and Actos may produce side effects, such as water retention and swelling of the ankles, especially in older people. Other possible side effects include weight gain, muscle weakness, and fatigue. Because they lower insulin resistance, they also increase fertility in younger women who have polycystic ovary disease, called PCOS. If pregnancy is not desired, a premenopausal woman using one of these drugs should be careful to use birth control. Although they have been shown to rarely cause liver damage, the FDA requires that liver tests be done before treatment starts, every two months for the first year and periodically thereafter. If the liver enzyme ALT shows a value more than three times the upper limit of normal, the drug must be stopped.

The glitazones work well in Type 2 diabetes only when insulin resistance is present. People with Type 1.5 diabetes, caused by a lower production of insulin rather than resistance to insulin, are unlikely to benefit from a glitazone. The presence of excess abdominal weight, a low HDL level, high triglycerides, or high blood pressure, all associated with insulin resistance, are good indicators that glitazones may be worth trying.