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Overall Cardiovascular Safety of Rosiglitazone Confirmed in 5˝ Year Study
Posted: Wednesday, June 10, 2009
Scores comparable to standard therapy on heart attacks, strokes and CV death but doubled incidence of heart failure warrants monitoring by physician.
Results of the long-awaited Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) study were presented in New Orleans at the 69th ADA 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.
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).
“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.
They also said that the effects of pioglitazone and rosiglitazone on cardiovascular outcomes will be assessed in the direct-comparison TIDE study.
Source: Diabetes In Control: The ADA 69th Scientific sessions, June 6th, 2009
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