Overall Cardiovascular Safety Of Rosiglitazone Confirmed In 5 1/2-Year Study

Main Category: Diabetes
Also Included In: Cardiovascular / Cardiology
Article Date: 08 Jun 2009 - 7:00 PST

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Results of the long-awaited Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study were presented here in a symposium at the American Diabetes Association's 69th Scientific Sessions. The results are being simultaneously published online in The Lancet.

"The RECORD study was designed to evaluate the long-term impact of rosiglitazone on cardiovascular outcomes and blood glucose control , compared to the conventional medications metformin and sulfonylureas, and the results show that, provided known contraindications and cautions are observed, physicians should be comfortable prescribing rosiglitazone for their diabetes patients," said Philip D. Home, DM, DPhil, chairman of the study's Steering Committee and Professor of Diabetes Medicine, Newcastle University, UK.

"Overall, the cardiovascular safety of rosiglitazone has been confirmed in more than 4,000 participants. Indeed, on the composite outcomes of cardiovascular death, stroke, and heart attack -- an outcome used in many cardiovascular trials -- the result was slightly but not statistically significantly in favor of rosiglitazone versus metformin and sulfonylureas," said Home. The researchers concluded that when used in appropriately selected patients, rosiglitazone carries no overall increase in cardiovascular (CV) risk with regard to major morbidity or mortality.

"Further, at the end of the study, rosiglitazone was shown to be superior in controlling blood glucose levels compared to the older metformin and sulfonylurea therapies, thus demonstrating the longevity of its benefits," said Home. After five years, rosiglitazone patients had A1C levels 0.29% lower than people on sulfonylureas and 0.26% lower than metformin, which he noted was similar to results in the earlier ADOPT (A Diabetes Outcome Progression Trial) study, which evaluated blood glucose control over five years, comparing rosiglitazone, metformin, and the sulfonylurea glyburide. A1C is a measure of average blood glucose control over the prior two to three months.

Type 2 Diabetes

Nearly 24 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, and amputation. It is a leading cause of death by disease in the United States. Type 2 diabetes accounts for about 90% to 95% of all diagnosed cases of diabetes and involves insulin resistance -- the body's inability to properly use its own insulin. Type 2 occurs mainly in adults who are overweight and age 40 and older. More than 65% of people with diabetes die from heart disease or stroke. With diabetes, heart attacks occur earlier in life and often result in death.

The RECORD Study

Rosiglitazone is an insulin sensitizer used for glucose-lowering either alone or in combination with metformin and/or a sulfonylurea in people with type 2 diabetes. As an insulin sensitizer, it lowers insulin resistance, a primary defect in people with type 2 diabetes.

RECORD was an open-label study, conducted at 338 centers in 23 countries in Europe, Australia, and New Zealand. The researchers randomized 4,447 people with type 2 diabetes who were already taking metformin or a sulfonylurea alone and with a mean A1C of 7.9%, to either add-on rosiglitazone (n=2220), or to a combination of metformin and a sulfonylurea (active control group, n=2227). All doses were progressively increased towards achieving and maintaining a target A1C of 7.0% or less. If A1C rose to 8.5% or more, either a third oral glucose-lowering drug was added (for the rosiglitazone-treated group) or insulin was started (for the non-rosiglitazone group).

Outcomes

"The primary outcome question was whether rosiglitazone was equivalent to its comparators in terms of CV hospitalization and CV death, and RECORD found that to be the case," reported Home. Within that data, the only adverse finding was a doubled risk of heart failure, but positive findings in other areas -- especially CV death and stroke -- almost exactly balanced out the total numbers for the primary outcome, thus meeting the criterion of non-inferiority for rosiglitazone (hazard ratio 0.99: CI 0.85, 1.16).

"Heart failure is a serious issue and clinicians prescribing rosiglitazone need to monitor their patients carefully to detect it at the earliest stages and discontinue the drug should this problem arise," said Home. Rosiglitazone is not recommended in people with a history of heart failure.

The key secondary outcome, mentioned above, is a composite of CV death, stroke, and heart attack, in which the result was slightly but not statistically significantly in favor of rosiglitazone versus its metformin and sulfonylurea comparators, with a hazard ratio of 0.93 (CI 0.74, 1.15).

CV and all-cause death were also slightly in favor of rosiglitazone compared to active controls but were not statistically significant, with a hazard ratio of 0.84 (CI 0.59, 1.18) and 0.86 (CI 0.68, 1.08), respectively.

In a secondary analysis, when compared to metformin or sulfonylureas separately, rosiglitazone was equivalent to either of them in terms of CV events.

"We have also confirmed that it is not wise to prescribe rosiglitazone for older women who are fragile and at risk of falling because the risk of arm and lower leg fractures is doubled in women," said Home. This finding confirmed results in the ADOPT study and was statistically significant.

The trial had less statistical power than initially planned because the overall primary event rate was substantially lower than that anticipated because with better treatment of CV risk factors, the overall CV event rate in the population has fallen. Nevertheless, non-inferiority for the primary endpoint was still achieved because the point estimate of the hazard ratio was close to unity. In other words, evidence for equivalence was still achieved because the best estimate of the hazard ratio was close to 1.0.

Source
American Diabetes Association