New drug targets insulin-resistant diabetes
Rezulin called a breakthrough in diabetes care’
The U.S. Food and Drug Administration has cleared the way for the recently approved drug Rezulin (troglitazone) for use as either initial therapy or combination therapy with other commonly used agents such as sulfonylureas and insulin to treat patients with Type II diabetes. The announcement comes six months after the drug received initial FDA approval for treating patients with Type II diabetes.
The new drug is aimed at diabetics who take insulin injections but still have abnormally high blood sugar levels. The U.S. manufacturer, Parke-Davis, said the drug is the first designed to target insulin resistance, the underlying cause of Type II diabetes. Insulin resistance is a condition in which the tissues of the body fail to respond normally to insulin. Although people with Type II diabetes produce normal levels of insulin, they are unable to use their own insulin to metabolize glucose. As a result, the body begins to secrete abnormally high amounts of insulin to compensate for the defect. Eventually, however, the system no longer can stimulate glucose transport in muscle and fat and suppress hepatic glucose production. When glucose does not reach cells and remains in the blood stream, blood sugar levels rise, leading to Type II diabetes.
Over time, excessive blood sugar levels can severely damage the heart, blood vessels, kidneys, eyes, and nerves. A common outcome is skin breakdown and ulceration, particularly in the lower extremities.
Rezulin is the first drug to work at the cellular level to improve insulin resistance directly, thus enhancing the effects of circulating insulin without causing the body to increase insulin production. The drug achieves these effects through direct stimulation of peripheral glucose uptake and storage as well as through the inhibition of glucose production in the liver. Until now, other therapies lowered blood glucose by increasing insulin production or decreasing hepatic glucose output.
Rezulin was discovered by Sankyo Company Ltd. of Japan and co-developed in the United States by Parke-Davis, which states that the new indications for Rezulin come at a time when potentially millions of patients whose diabetes had previously gone undiagnosed will be screened and evaluated for treatment.
At its annual meeting last June, the American Diabetes Association (ADA) endorsed new guidelines that recommended diagnosing and treating diabetes at the earliest stages of the disease. Type II diabetes usually starts in adulthood and is by far the most common kind of diabetes in the United States, accounting for about 90% of the estimated 16 million cases. The disease and its complications are estimated to cost $100 billion annually.
In clinical studies, the use of Rezulin alone or in combination therapy with sulfonylureas or insulin resulted in blood glucose target levels recommended by the ADA. The ADA treatment guidelines recommend that physicians adjust therapy when hemoglobin A1c (HbA1c) levels exceed 8%. Sixty percent of patients on daily doses of 600 mg of Rezulin and 12 mg of micronized glyburide (a member of the sulfonylurea family) achieved HbA1c levels of 8% or less, while 41% of patients in that treatment group were able to achieve an HbA1c of 7% or less. Fifty-seven percent of patients taking a Rezulin-insulin combination achieved HbA1c levels of 8% or less, compared with only 11% of those who took insulin alone.
Patients who received sulfonylurea compounds alone had HbA1c levels of about 10%, and those who took insulin alone had HbA1c levels of about 11%. The average HbA1c reduction for combination Rezulin-sulfonylurea patients was 2.7% greater than reductions from micronized glyburide and 1.3% greater than reductions attributed to insulin alone.
May be combined with sulfonylurea
Patients who previously failed on dietary control alone and were treated with Rezulin monotherapy of 600 mg per day reduced their HbA1c levels by an average of 1.4% compared with placebo after 26 weeks. Rezulin should not be used as monotherapy in patients whose diabetes was previously well-controlled by sulfonylurea therapy, researchers say. For patients whose diabetes is inadequately controlled with sulfonylurea alone, Rezulin should be added to, not substituted for, the sulfonylurea.
"Rezulin is a remarkable treatment and a breakthrough in diabetes care," says Gerald Bernstein, MD, associate clinical professor of medicine at Albert Einstein College of Medicine in New York City. "It provides physicians with an effective option for those newly diagnosed as well as those unable to control their blood glucose with sulfonylureas or insulin."
Unlike sulfonylureas, Rezulin does not stimulate insulin secretion. The addition of Rezulin to a sulfonylurea has a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms. Rezulin reduces insulin resistance via a nuclear mechanism that allows the body to more efficiently use the insulin that it produces or that is injected, according to Parke-Davis.
"There is an impressive synergy between Rezulin and these older agents," says Bernstein. "This is important because the majority of patients currently receiving treatment are not able to reach the ADA targets for good glycemic control."
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