April 10, 2008 (Chicago, IL) – The diabetes drug rosiglitazone (Avandia, GlaxoSmithKline) showed a trend toward a slowing of the progression of atherosclerosis and an overall positive effect on metabolic factors in the Vein-Coronary Atherosclerosis and Rosiglitazone After Bypass Surgery (VICTORY) study in post-CABG diabetes patients.

Lead investigator Dr Olivier Bertrand (Laval University, Quebec, QC) said that, while this was chiefly a mechanistic study, the results "provide reassurance about the safety of rosiglitazone, which has been under fierce attack compared with pioglitazone [Actos, Takeda Pharmaceuticals]."

But rosiglitazone critic Dr Steven Nissen (Cleveland Clinic) is not impressed with the VICTORY results, pointing out that the study failed to meet its primary end point and did not include enough patients to reach any meaningful conclusions on safety.

High-risk patients

Presenting the study last week at the American College of Cardiology (ACC) 57th Annual Scientific Session, Bertrand explained that more than 500 000 patients with type 2 diabetes undergo CABG surgery each year, but the saphenous vein grafts used for the bypass often become reoccluded--this occurs in around 50% of patients 10 years after CABG.

In the VICTORY study, Bertrand and his colleagues investigated whether rosiglitazone could prevent the progression of atherosclerosis in post-CABG patients with type 2 diabetes. The study enrolled 193 stable diabetic patients who had undergone CABG in the past 10 years. All patients underwent a baseline coronary angiogram, and atherosclerosis was measured with intravascular ultrasound (IVUS) in a segment length of at least 40 mm in a saphenous-vein-graft segment. Patients were then randomized to either rosiglitazone or placebo in addition to their standard clinical care for a period of one year. Rosiglitazone was titrated over an eight-week period up to a dose of 8 mg/day. IVUS and angiography were repeated at 12 months.

A range of physiological and metabolic evaluations were taken at regular intervals throughout the study. These assessed fat-tissue distribution (using CT scanning), body composition or percent fat (using dual energy X-ray absorptiometry [DEXA]), and metabolic markers including lipids, plasma glucose-insulin homeostasis, and inflammation.

The primary end point was the change in plaque volume over 12 months in the vein graft. This showed a trend toward benefit in the rosiglitazone group.

VICTORY primary end point: Plaque volume in vein graft

Measure Placebo Rosiglitazone
Baseline (mm3) 360 321
Increase after 12 mo (mm3) +10 +3
% increase +2.8 +0.9

The difference between the two groups was not significant (p=0.22)

Other results showed that rosiglitazone was associated with a moderate weight gain. Patients in the rosiglitazone group gained an average of 3 kg compared with the placebo group, which was mainly explained by an increase in adipose-fat mass and only a small, nonsignificant gain in body water.

Other results showed that the drug had beneficial effects on the lipid profile, increasing HDL and reducing small dense LDL, while there was no change in overall LDL.

Rosiglitazone also reduced HBA1c levels, C-reactive protein, and plasminogen activator inhibitor-1 and was associated with a marked increase in adiponectin. Cardiovascular events were few in both groups, and there was no difference between the two groups.

Bertrand commented to heartwire : "We wanted to see whether rosiglitazone was safe in a very high-risk population. We know that patients who have had CABG have a high rate of atherosclerosis in the vein graft, so this seemed to be a suitable measurement to evaluate."

On the gain in body fat, coinvestigator Dr Jean-Pierre Despres (Laval Hospital, Quebec, QC) explained to heartwire that type 2 diabetes patients often had increases in abdominal visceral fat that is associated with increased risk of heart disease. In contrast, there is some evidence to suggest that fat stored as subcutaneous adipose tissue is protective of tissues such as the liver and beta cells, he added. "This is the first study of this type to look at the full-blown metabolic profile of a drug, and it shows that the weight gain with rosiglitazone is caused by an increase in the good subcutaneous fat, with no increase in the bad visceral fat. The positive effects on other metabolic factors measured fits in with this. Our study shows that the weight gained with rosiglitazone is not harmful," he added.

In line with PERISCOPE study with pioglitazone?

Bertrand said the results of VICTORY were in line with those of PERISCOPE, an IVUS study presented at the ACC meeting that showed a reduction in atherosclerosis progression with pioglitazone. Although pioglitazone showed a significant reduction in progression in PERISCOPE, whereas rosiglitazone did not in VICTORY, Bertrand pointed out that patients in VICTORY were better treated in terms of other risk factors than those in PERISCOPE, with 100% on antiplatelet agents, 95% on statins, and baseline HbA1C levels of 6.9%, whereas they were 7.5% in PERISCOPE. In addition, PERISCOPE was a large study with 500 patients and had an 18-month follow-up, which also could have contributed to the better results, he added. "But we showed a promising trend, and if our study were bigger or longer, this might have been significant," he suggested. A larger trial (APPROACH) looking at the effect of rosiglitazone on atherosclerosis is under way, with results due out quite soon, he added.

Despres said the increase in MI suggested by Nissen's meta-analysis of rosiglitazone studies published last year raised a red flag for the drug. "But we can't find any signal of harm in this study," he added.

Bertrand added that he disagrees with Nissen that there is no class effect with these drugs. "Rosiglitazone and pioglitazone appear to show similar effects on both metabolic and atherosclerosis parameters, and I would say there is a class effect," he commented to heartwire .

Nissen not impressed

But Nissen has a very different interpretation of the VICTORY study. "A p value of 0.25 is not a trend; it's a negative result. You can't assess risk with less than 100 patients. Rosiglitazone and pioglitazone are very different. Lipid effects are not favorable with rosiglitazone. The drug raises LDL about 18%. When a trial is negative, the authors need to have the courage to accurately report the results. No amount of 'spin' can alter the failure to meet the primary end point," he commented to heartwire .

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.



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