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Landmark Study Shows Rosiglitazone Maleate More Effective Than Metformin or a Sulfonylurea in Long-Term Blood Sugar Control in Type 2 Diabetes

Avandia Reduces Risk of Monotherapy Failure at Five Years

CAPE TOWN, SOUTH AFRICA -- December 4, 2006 -- Results from ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial treatment with Avandia(R) (rosiglitazone maleate) reduced the risk of monotherapy failure in people with type 2 diabetes by 32% compared to metformin (P <.001), and 63% compared to glyburide (P <.001) at five years.

The results of this international study involving 4,360 people recently diagnosed with type 2 diabetes were today published in the New England Journal of Medicine and presented at the 19th World Diabetes Congress of the International Diabetes Federation (IDF).

Rosiglitazone was more effective than metformin or glyburide in delaying the progressive loss of blood sugar control, as measured in the study by fasting plasma glucose (FPG) and Hemoglobin A1c levels (HbA1c). The primary reasons for loss of blood sugar control are increasing insulin resistance and declining beta-cell function. ADOPT demonstrated that rosiglitazone significantly improved insulin sensitivity (P <.001 versus metformin or glyburide) and reduced the rate of loss of beta-cell function (P =.02 versus metformin; P <.001 versus glyburide).

"ADOPT provides evidence supporting earlier treatment with rosiglitazone in the management of type 2 diabetes. This is the first long-term study to demonstrate that the progressive loss of blood sugar control can be delayed and target blood sugar levels can be maintained for a longer period with rosiglitazone than with metformin and glyburide -- the two most frequently prescribed oral antidiabetic agents," said Dr. Steven Kahn, professor of medicine, VA Puget Sound Healthcare System and University of Washington School of Medicine, Seattle, Wa. and Dr. Giancarlo Viberti, professor of diabetes and metabolic medicine, King's College School of Medicine, UK. "The more durable effect on blood sugar with rosiglitazone was also consistent with greater improvements in core defects of the disease, including significant effects on insulin resistance and beta-cell function."

ADOPT provides an important update to findings from the United Kingdom Prospective Diabetes Study (UKPDS) released in 1998, which preceded availability of thiazolidinediones (TZDs) and included only two of the three oral agents evaluated in ADOPT -- metformin and sulfonylurea.

Initial therapy with rosiglitazone delayed progressive loss of blood sugar control more effectively than metformin or glyburide using different blood sugar thresholds -- from FPG >180 mg/dl (>10 mmol/l) to a lower blood sugar level more consistent with current therapeutic approaches, FPG >140 mg/dl (>7.8 mmol/l). Long-term blood glucose control as measured by a mean HbA1c of <7.0% was maintained for longer with rosiglitazone -- 60 months versus 45 months with metformin and 33 months with glyburide.

"With ADOPT, we now have clear evidence from a large international study that the initial use of rosiglitazone is more effective than standard therapies for type 2 diabetes in maintaining blood sugar control," said Dr. Lawson Macartney, senior vice president, Cardiovascular and Metabolic Medicine Development Centre, GlaxoSmtihKline. "ADOPT adds to the growing body of evidence released this year supporting the rationale for incorporating rosiglitazone as a cornerstone of treatment of type 2 diabetes by demonstrating patient benefits in terms of long-term glucose control."

In ADOPT, rosiglitazone was reported to be generally well-tolerated among the large cohort of people with type 2 diabetes who were followed for up to six years. There was no significant difference between the rosiglitazone and metformin groups in treatment discontinuation, but the rate was higher for the glyburide group (44% in the glyburide group; 38% in the metformin group; 37% in the rosiglitazone group). This difference was driven largely by a higher level of withdrawals due to hypoglycemia for people in the glyburide group.

The same number of congestive heart failure (CHF) serious adverse events was reported with rosiglitazone (0.8%) as for metformin (0.8%); however, people given glyburide experienced a lower rate of CHF events (0.2%).

After the five-year period of study, commonly reported adverse events across the treatment groups were edema (rosiglitazone 14.1%; glyburide 8.5%; metformin 7.2%); weight gain (rosiglitazone 6.9%; glyburide 3.3%; metformin 1.2%); gastrointestinal side effects (metformin 38.3%; rosiglitazone 23.0%; glyburide 21.9%); and hypoglycemia (glyburide 38.7%; metformin 11.6%; rosiglitazone 9.8%).

Recent further analysis showed a lower rate of fractures reported as adverse events in women taking glyburide or metformin versus rosiglitazone (glyburide 3.5%; metformin 5.1%; rosiglitazone 9.3%), most commonly involving fractures of the foot and upper limb bones. There was no observed difference among treatment groups in the number of fractures reported in men. These observed fracture rates appear to be within the range seen in a literature-based review of observational studies in women with diabetes, and analysis of large managed care databases. This evidence suggests that older women with type 2 diabetes are at increased risk of fractures.

About ADOPT
ADOPT is an international, multi-center, randomized, double-blind study involving 4,360 drug-naive people who had been recently diagnosed with type 2 diabetes (less than or equal to 3 years) at over 400 sites throughout North America and Europe. People included in the study were randomized to rosiglitazone, a sulfonylurea (glyburide), or metformin and titrated to the maximum daily effective doses (rosiglitazone 4 mg twice daily; metformin 1 g twice daily; glyburide 7.5 mg twice daily). These people were followed for four to six years to examine the long-term efficacy of each drug used as initial monotherapy on blood sugar control, insulin resistance and beta-cell function. At the time of monotherapy failure, 99.3%, 98.6% and 99.0% of participants were receiving maximal doses of rosiglitazone, metformin and glyburide, respectively.

When ADOPT was designed, HbA1c was not chosen as the primary outcome because the guidelines at the time focused largely on FPG. Nevertheless, HbA1c data collected in the study as a secondary endpoint provided results, which are consistent with those for FPG and are applicable to current clinical practice.

ADOPT was funded by GlaxoSmithKline.

About Rosiglitazone
Rosiglitazone belongs to the thiazolidinedione (TZD) class of drugs and is an approved treatment for type 2 diabetes that improves blood sugar control, enabling people to reach recommended blood sugar levels. The addition of rosiglitazone to metformin and/or a sulfonylurea has been shown to help people with type 2 diabetes reach and maintain treatment goal, and findings from ADOPT support the long-term durability of rosiglitazone monotherapy.

About Type 2 Diabetes
Type 2 diabetes is a chronic, progressive illness often linked to premature death, and affects approximately 18 million people in the U.S. and approximately 230 million people worldwide. The IDF estimates that by 2025, more than 350 million people worldwide will suffer from this disease.

Type 2 diabetes occurs when the body does not respond properly to, or produce enough, insulin. Over time, the chronic, progressive nature of type 2 diabetes makes it more difficult to maintain blood sugar levels and therefore, more than one medication may be required to reach recommended goals. Keeping blood sugar levels in control is important in preventing diabetes-related conditions such as eye disease (blindness), kidney disease (kidney failure/dialysis), nerve damage, amputation, heart disease, stroke and peripheral vascular disease. Such complications can decrease a person's quality of life and result in increased health care costs. Untreated diabetes can lead to death. Every ten seconds, a person dies from diabetes-related causes.

Avandia (rosiglitazone maleate) Indication & Important Safety Information

Avandia, along with diet and exercise, helps improve blood sugar control. It may be taken alone or with other diabetes medicine.

Tell your doctor if you have heart problems or heart failure. Avandia can cause your body to keep extra fluid which leads to swelling and weight gain. Extra body fluid can make some heart problems worse or lead to heart failure. If you have swelling or fluid retention, shortness of breath or trouble breathing, an unusually rapid increase in weight, or unusual tiredness while taking Avandia, call your doctor right away. You should not take Avandia if you have liver problems. Blood tests should be used to check for liver problems before starting and while taking Avandia. Tell your doctor if you have liver disease, or if you experience unexplained tiredness, stomach problems, dark urine or yellowing of skin while taking Avandia.

Tell your doctor about all of the medicines you are taking. If you are taking Avandia with another diabetes medicine that lowers blood sugar, you may be at increased risk for low blood sugar. Ask your doctor whether you need to lower the dose of your other diabetes medicine. Avandia may increase your risk of pregnancy. Talk to your doctor before taking Avandia if you could become pregnant or if you are pregnant. If you are nursing, you should not take Avandia. Your doctor should check your eyes regularly. Very rarely, some individuals have experienced vision changes due to swelling in the back of the eye while taking Avandia.


SOURCE: GlaxoSmithKline

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