Large, long-term study shows Avandia has no increased overall cardiovascular risk compared to other commonly used diabetes medicines

RECORD trial also demonstrates durable blood sugar control over time with Avandia

Friday, 5^th June 2009 at 4:15 pm CDT, London UK, Research Triangle Park US and New Orleans US

Clinical trial results presented today at the American Diabetes Association annual meeting show that overall rates of cardiovascular hospitalization and cardiovascular death are similar in patients taking Avandia (rosiglitazone) compared to those receiving metformin and sulfonylurea.

Results from the 4,447-patient Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study, which was sponsored by GlaxoSmithKline, Avandia’s maker, were also published online today in the medical journal The Lancet. 

RECORD is a large, prospective, randomized, controlled study that was initiated in 2001, and designed to compare cardiovascular outcomes of patients on Avandia added to metformin or sulfonylurea to those on metformin and sulfonylurea. The study confirmed its primary hypothesis. It showed that cardiovascular hospitalization or cardiovascular death (which includes heart attack, congestive heart failure, and stroke) was not statistically different between the two groups after an average of 5.5 years of therapy.  This translates into 321 events (14.5 percent) among patients receiving Avandia compared to 323 events (also 14.5 percent) for patients receiving control medications (hazard ratio=0.99, 95% confidence interval=0.85 to 1.16) (Data on the individual components are provided below.)

“RECORD provides a robust assessment of rosiglitazone’s cardiovascular safety and achieving the study’s primary endpoint leads us to conclude that rosiglitazone carries no increased risk of overall cardiovascular death or hospitalization compared to the most commonly used diabetes medicines, metformin and sulfonylurea, which have been used for decades,” said Dr. Philip D. Home, chairman of the RECORD Steering Committee and a professor at Newcastle University.  “Millions of patients with diabetes do not achieve good blood sugar control, even with combination therapy, making a wide range of therapeutic options critical for the management of this growing and deadly disease.”

Glycaemic control, as measured by mean hemoglobin A1c, was statistically significantly better in the patient group randomized to  Avandia after the average of 5.5 years of treatment in the trial. RECORD’s glycaemic result is consistent with the superior long term glycaemic control (for nearly five years) previously demonstrated by Avandia versus metformin and sulfonylurea in the ADOPT study.

Although RECORD was not designed to study microvascular endpoints, previous studies such as the United Kingdom Prospective Diabetes Study, which studied other medicines, have found that improved glycemic control may reduce complications of diabetes that can lead to amputations, kidney failure and eye damage.

Congestive heart failure is a known effect of Avandia and other drugs in the thiazolidinedione (TZD) class and is prominently described in a boxed warning in current labels of both TZDs. As anticipated, rates of CHF in RECORD were higher in the group randomized to Avandia (61 events or 2.7 percent versus 29 events or 1.3 percent) (hazard ratio=2.10, 95 percent confidence interval=1.35 to 3.27). The difference was statistically significant.

Other adverse events in patients randomized to Avandia were consistent with those reported in the U.S. Prescribing Information for Avandia, including bone fractures, which were higher in the group randomized to Avandia and were seen mostly in the bones of the arm, hands, lower leg and feet, and predominantly in women.

Among patients randomized to Avandia, the results for the following prespecified secondary endpoints also showed:

• Fewer deaths from any cause (136 events or 6.1 percent versus 157 events or 7 percent for control) (hazard ratio=0.86, 95 percent confidence interval=0.68 to 1.08)
• Fewer deaths from cardiovascular disease (60 events or 2.7 percent versus 71 events or 3.2 percent) (hazard ratio=0.84, 95 percent confidence interval=0.59 to 1.18). Among these events, there were more CHF-related deaths (10 versus 2), though fewer deaths from heart attack (7 versus 10) and fewer from stroke (0 versus 5).
• Fewer events of a combination measure known as MACE, which includes cardiovascular death, heart attack or stroke (154 events or 6.9 percent versus 165 events or 7.4 percent) (hazard ratio=0.93, 95 percent confidence interval=0.74 to 1.15).
• More heart attacks (64 out of 2,220 patients or 2.9 percent versus 56 out of 2,227 patients or 2.5 percent) (hazard ratio=1.14, 95 percent confidence interval=0.80 to 1.63).
• Fewer strokes (46 events or 2.1 percent versus 63 events or 2.8 percent) (hazard ratio=0.72, 95 percent confidence interval=0.49 to 1.06)

None of the differences for these secondary endpoints (any cause death, cardiovascular death, MACE, heart attack and stroke) was statistically significant.

RECORD showed no evidence of an increase in malignancies. There were fewer events of pancreatic cancer in patients taking Avandia although the numbers were small.

“RECORD provides important and reassuring information about Avandia for physicians fighting diabetes,” said Dr. Ellen Strahlman, GSK’s Chief Medical Officer. “Clinical outcomes trials like this offer the highest standard of evidence when considering the benefits and risks of medicines.  RECORD clearly demonstrates that overall rates of cardiovascular hospitalization and death are similar in patients taking Avandia compared to those receiving metformin and sulfonylurea. We believe that Avandia remains an important diabetes medicine for the appropriate patients.”

Avandia, introduced on the market in 1999, is a member of the TZD class of oral anti-diabetic medications which improve blood sugar control by directly targeting insulin resistance, an underlying cause of type 2 diabetes. This helps the body respond better to its own natural insulin. Avandia is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. 

More than 18 million Americans have type 2 diabetes, making it the most common form of diabetes, which accounts for about 90 to 95 percent of diagnosed diabetes cases. Type 2 diabetes has been associated with a variety of serious health problems including heart disease, stroke, eye damage, kidney failure and foot problems that lead to amputations.

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For more information please visit: us.gsk.com. 

Important safety information for Avandia® (rosiglitazone maleate)

Prescription Avandia, along with diet and exercise, helps improve blood sugar control in adults with type 2 diabetes. Taking Avandia with insulin or nitrates is not recommended.

Avandia can cause or worsen heart failure.  If you have severe heart failure (very poor pumping ability of the heart) you cannot be started on Avandia. Avandia is also not recommended if you have heart failure with symptoms (such as shortness of breath or swelling) even if these symptoms are not severe.

Avandia may increase your risk of other heart problems that occur when there is reduced blood flow to the heart, such as chest pain (angina) or heart attack (myocardial infarction). This risk appeared higher in patients taking medicines called nitrates or insulin.

If you have chest pain or a feeling of chest pressure, you should seek immediate medical attention, regardless of what diabetes medicines you are taking. If you take Avandia, tell your doctor right away if you: have swollen legs or ankles, a rapid increase in weight or difficulty breathing, or unusual tiredness; experience changes in vision; become pregnant.

Before taking Avandia, review your medical history and tell your doctor if you:

• Have heart failure or other heart problems, or are on any medicines for high blood pressure, high cholesterol or heart failure, or for prevention of heart disease or stroke.
• Take insulin or nitrate medicines.
• Have a type of diabetic eye disease called macular edema.
• Have liver problems or had liver problems while taking REZULIN® (troglitazone).
• Are pregnant or planning to become pregnant.
• Are breastfeeding or planning to breastfeed.

Women taking Avandia should know that Avandia may increase the risk of pregnancy. More fractures have been observed in women taking Avandia. Other possible side effects of Avandia include anemia and hypoglycaemia. Your doctor should do blood tests to check your liver before you start Avandia and during treatment as needed.

For more information about Avandia, please see Medication Guide or full Prescribing Information at www.AVANDIA.com.

You are encouraged to report negative side effects of prescription drugs to the FDA.

Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

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Cautionary statement regarding forward-looking statements
Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK' s operations are described under 'Risk Factors' in the 'Business Review' in the company' s Annual Report on Form 20-F for 2008.