Source: Neuron  |  Posted 9 years ago

Adding Avandia? Increased Insulin Sensitivity, Improved Certain Lipid Parameters Without Hypoglycemia

PHILADELPHIA, PA -- April 30, 2002 -- Results from a study published recently in Diabetes/Metabolism: Research and Reviews showed that adding the insulin sensitizing agent Avandia? (rosiglitazone maleate) to metformin significantly helped improve blood sugar levels in Mexican patients whose type 2 diabetes was inadequately controlled by metformin alone. Type 2 diabetes is the third leading cause of death in Mexico and is also a serious and growing problem among Mexican immigrants to the United States. Indeed, in the United States, diabetes currently affects more than one million Mexican- Americans, resulting in an increased incidence of diabetes-related complications compared to non-Hispanic Caucasians. This is largely attributed to a higher incidence of insulin resistance, an underlying cause of the disease.

In this controlled trial, researchers found that adding Avandia to metformin therapy had a positive effect on several metabolic deficiencies of type 2 diabetes, including insulin resistance and certain lipid parameters. Specifically, Avandia increased high density lipoprotein (HDL or "good") cholesterol, reduced triglycerides and significantly decreased free fatty acid levels. Elevated levels of free fatty acids have been associated with insulin resistance, and with possible damage to the insulin-producing beta cells in the pancreas. In addition, this study reported a low incidence of hypoglycemia (or low blood sugar) in all treatment groups.

"GlaxoSmithKline is committed to type 2 diabetes research in high risk ethnic groups. We are encouraged by the results of this study, which was undertaken to evaluate the safety and efficacy of the Avandia plus metformin combination in Mexican patients. This study holds promise for Mexican- Americans, Hispanics, Latinos and other minorities who are adversely affected by type 2 diabetes," said Martin Freed, M.D., Global Vice President, Metabolism Therapeutic Area, Clinical Development and Medical Affairs, GlaxoSmithKline. "With complementary mechanisms of action, Avandia and metformin seem to be working in an additive fashion to achieve improved blood sugar levels, with a low risk of hypoglycemia."

Type 2 diabetes, characterized by high blood sugar levels, is caused by defects in the body's ability to produce enough insulin and/or use effectively the insulin it already makes - a condition called "insulin resistance." Hispanics, Latinos and other ethnic groups are more likely to be insulin resistant than Caucasians, which puts them at greater risk for type 2 diabetes. Avandia directly targets insulin resistance by increasing insulin sensitivity in the muscle and adipose tissue, while metformin primarily works by decreasing the output of glucose (or sugar) by the liver. Due to the limitations of traditional monotherapy, most patients require combination treatment in the long term. In fact, the United Kingdom Prospective Diabetes Study (UKPDS) showed that the majority of patients on metformin alone required combination therapy after three years.

Importance of Aggressive Diabetes Management
In the long term, untreated or poorly managed type 2 diabetes can lead to serious and life-threatening complications, including heart disease, heart attack, stroke, kidney disease, nerve damage and blindness. Importantly, this study in Mexican patients showed that A1C levels -- the most effective measure of long-term diabetes control -- were reduced significantly in more patients who received Avandia therapy added to metformin than in patients taking the highest dose of metformin alone. In contrast, A1C levels actually increased in the metformin treatment group.

Increases in A1C levels are directly linked to increases in a patient's risk for cardiovascular disease, a serious diabetes-related complication. To help minimize complications, American Diabetes Association guidelines advocate A1C levels of less than seven percent as the target for diabetes control.

"It is clear from the results of our study, that adding Avandia to metformin significantly lowers A1C levels, improving blood sugar levels while minimizing the risk of hypoglycemia," said Francisco Gomez-Perez, M.D., Head, Endocrinology and Metabolism Department, Instituto Nacional de Ciencias Medicas y Nutricion "Salvador Zubiran" Mexico City, Mexico. "It is crucial that we continue to research and find new therapeutic approaches for type 2 diabetes, including safe and effective combination therapies, to improve the lifetime management of the disease."

Avandia Added to Metformin in Mexican Diabetes Patients
This multi-center, double-blind, placebo-controlled study was conducted to determine the efficacy and safety of Avandia in combination with a maintenance dose of metformin (2.5 g/day) in Mexican patients whose type 2 diabetes was inadequately controlled with metformin alone. A total of 116 type 2 diabetes patients was randomly assigned to receive metformin plus placebo, metformin plus Avandia (2 mg twice daily), or metformin plus Avandia (4 mg twice daily) for 26 weeks.

Investigators found that compared with baseline levels and with metformin therapy alone, combination treatment significantly reduced levels of fasting plasma glucose and A1C in a dose-dependent manner. In addition, results of the study showed a decrease in insulin resistance as measured by the reduction of immunoreactive insulin and C-peptide levels in the Avandia groups.

The addition of Avandia improved other non-glycemic (or non-blood sugar-related) metabolic factors as well. Although there was no clinically meaningful change in any of the treatment groups in the ratio of total cholesterol to HDL cholesterol and HDL to low density lipoprotein (LDL or "bad") cholesterol, Avandia-treated patients experienced increases in HDL cholesterol, reductions in triglyceride levels, and statistically significant reductions in concentrations of free fatty acids. Elevated levels of free fatty acids have been linked to insulin resistance; toxic effects on pancreatic beta cells; and possibly vascular abnormalities.

Overall, the Avandia regimens were well tolerated. The incidence of adverse events was similar in all three treatment groups, and patients in the Avandia treatment groups generally experienced minimal weight gain (<3 kg). There were no reports of significant hypoglycemia across treatment groups.

Avandia for Type 2 Diabetes
Avandia is an insulin sensitizer that works by making the cells in the body more sensitive to its own natural insulin. Since the approval of Avandia (May 25, 1999), more than 16 million prescriptions have been written, with over 2.7 million patients on therapy in the United States.

Avandia, along with diet and exercise, helps improve blood sugar control. It may be prescribed alone, with Glucophage (metformin HCl tablets), or with sulfonylureas. When taking Avandia with a sulfonylurea, patients may be at risk for low blood sugar. Patients should ask their doctor whether they need to lower their sulfonylurea dosage.

Some people may experience tiredness, weight gain or swelling with Avandia.

Avandia in combination with insulin may increase the risk of serious heart problems. Because of this, patients should talk to their doctor before using Avandia and insulin together. Avandia may cause fluid retention or swelling which could lead to or worsen heart failure, so patients should tell their doctor if they have a history of these conditions. If patients experience an unusually rapid increase in weight, swelling or shortness of breath while taking Avandia, they should talk to their doctor immediately. Avandia is not for everyone. If patients have severe heart failure or active liver disease, Avandia is not recommended.

Also, blood tests to check for serious liver problems should be conducted before and during Avandia therapy. Patients should tell their doctor if they have liver disease, or if they experience unexplained tiredness, stomach problems, dark urine or yellowing of skin while taking Avandia.

If patients are nursing, pregnant or thinking about becoming pregnant, or are a premenopausal woman who is not ovulating, they should talk to their doctor before taking Avandia.

GlaxoSmithKline (NYSE: GSK), one of the world's leading research-based pharmaceutical and health care companies, is committed to improving the quality of human life by enabling people to do more, feel better and live longer.

SOURCE: GlaxoSmithKline