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| |  ADA MEETING: Avandia Shows Promising Results In Combination Therapy SAN DIEGO, CA -- June 21, 1999 -- Avandia® (rosiglitazone maleate, SmithKline Beecham) improves blood sugar control in combination with other diabetes medications, according to studies presented at the annual scientific sessions of the American Diabetes Association (ADA). These new research shows that Avandia -- a new insulin-sensitizer recently approved by the FDA as monotherapy or in combination with metformin -- also improves blood sugar levels when used in combination with sulfonylureas or insulin, providing better control than can be achieved with these treatments alone. "Based upon the Avandia data presented at the ADA meeting, it is now clear that we are entering a new era of diabetes management for a spectrum of type 2 diabetes patients," said Alan J. Garber, M.D., Ph.D., Chief, Endocrinology, Diabetes and Metabolism, Methodist Hospital, Houston. “Avandia can be used alone or with metformin to produce good glucose control and may ultimately prove beneficial in combination with other standard antidiabetic therapies such as sulfonylureas or insulin, helping patients at various stages of their disease reach treatment goals."
Avandia Mechanism of Action Type 2 diabetes affects an estimated 15 million Americans and can lead to devastating complications such as heart disease, blindness, kidney failure and limb amputation. Avandia is a new thiazolidinedione (TZD), a class of novel, oral antidiabetic agents that treat the symptoms of type 2 diabetes and directly target insulin resistance -- or the failure of the body to respond adequately to its own insulin. By contrast, most older therapies for type 2 diabetes exert their effects primarily through different mechanisms. Metformin works by reducing glucose output from the liver, sulfonylureas by stimulating the pancreas to produce more insulin and insulin injections by taking the place of the natural insulin that the pancreas can no longer produce. Although all of these therapies offer benefits, they may dwindle with time. Sulfonylureas, for example, through their stimulation of the pancreas, may hasten the exhaustion of insulin-producing beta cells, with the result that many patients must ultimately receive insulin injections. Given such limitations, and given the varying mechanisms of drug action, the Avandia clinical program has investigated several combinations of Avandia with other therapies for type 2 diabetes, as shown in the studies presented at the ADA meeting.
Avandia: Combination With Sulfonylurea The maximum dose of Avandia used in sulfonylurea combination studies was 4 mg/day. These studies were designed to evaluate both the efficacy of this combination and the potential for hypoglycemia. In the patients that received sulfonylurea alone, there was little change in hemoglobin A(1c), a measure of glucose levels over time, or fasting plasma glucose. The addition of 4 mg/day of Avandia to therapy in patients inadequately controlled on sulfonylurea produced significant improvements in both hemoglobin A(lc) and fasting plasma glucose. Proportions of patients with symptoms of hypoglycemia were similar in all treatment groups.
Avandia: Combination With Insulin Many patients on traditional oral medications fail on their therapy and must eventually receive insulin injections, frequently at high doses, to manage their blood sugar, according to the United Kingdom Prospective Diabetes Study. This is due to a progressive loss of insulin secretion capacity from the beta-cells of the pancreas. New data presented at the ADA meeting suggest that Avandia’s insulin-sensitizing effects make it an appropriate candidate for combination therapy in patients taking insulin. Among 319 patients who required insulin injections but whose blood sugar was not well controlled despite two insulin shots a day, the addition of 8 mg/day of Avandia to insulin produced mean decreases in fasting blood sugar levels of 55 mg/dL and in hemoglobin A(lc) levels of 1.3 percentage points compared to insulin alone. The addition of Avandia to twice-daily insulin therapy was associated with an increased frequency of hypoglycemic events; adjustments in insulin dose appeared to reduce the risk of such events without compromising efficacy. Reduction in insulin doses was recommended in patients whose fasting plasma glucose dropped below 100 mg/dL.
Avandia: Combination With Metformin Avandia combination therapy not only reduced levels of hemoglobin A(lc) and fasting plasma glucose, but also decreased insulin resistance and improved estimates of beta-cell function, according to data presented at the meeting. Calculation of these improvements was made with HOMA (Homeostasis Model Assessment), a mathematical model that permits estimates of beta-cell function and insulin sensitivity from fasting plasma insulin and glucose values. In a study of 348 patients inadequately controlled on the maximum daily dose of metformin, the addition of 8 mg/day of Avandia produced a drop in hemoglobin A(lc) of 1.2 percentage points versus metformin alone. The estimate of beta-cell function in the 8 mg/day Avandia plus metformin group increased by 94.2 percent and insulin resistance decreased by 20.4 percent versus no change in the metformin only group. "The body of evidence is rapidly growing to support the use of Avandia in a wide variety of patients with diabetes at various stages of their disease," said Dr. Garber. "The HOMA data presented at the meeting are exciting because of Avandia’s ability to decrease insulin resistance and apparent improvement in estimates of beta-cell function. Therapies that preserve pancreatic function should slow the progression of disease; however, clinical studies are required to validate these early findings with Avandia." Avandia is approved by the FDA for use as monotherapy and in combination with metformin; however, it is not currently approved for use in combination with sulfonylureas or insulin.
No Evidence Of Drug-Related Liver Damage No evidence of drug-related liver damage was seen in more than 4,500 patients treated with Avandia as monotherapy, in combination with sulfonylureas and in combination with metformin. According to data presented at the ADA meeting in San Diego, CA, patients being treated for more than six months and many for more than one year have shown no signs of liver damage. In the new studies, Avandia in combination with insulin, no patient has shown signs of drug-related liver toxicity. Hepatic effects were the subject of an in vitro study presented at the meeting during the ADA’s Presidential Poster Session. In vitro, troglitazone -- another member of the TZD class -- affected all endpoints of liver cell toxicity at low concentrations, indicating marked toxicity to rat liver cells. In contrast, Avandia affected only one endpoint, indicating virtually no toxicity to rat liver cells. The data suggest that liver toxicity may not be a TZD class effect. "The recent availability of Avandia provides renewed hope from the TZD class for diabetes patients," said Dr. Garber. "Avandia is a safe and effective new treatment option for targeting insulin resistance and improving glycemic control."
Favorable Tolerability Avandia was well-tolerated in clinical trials. Commonly reported adverse events for both placebo and Avandia were upper respiratory tract infections and headaches. As observed with other members of this class of drugs, improvements in glycemic control were associated with weight gain. Additionally, a low incidence of anemia and edema was reported.
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