FIELD: Mixed results for fenofibrate in diabetics

September 14, 2005

Dallas, TX - The fibrate hypolipemic fenofibrate failed to significantly reduce the primary end point (CHD death or nonfatal MI) vs placebo in diabetic patients in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study[1]. While the nonfatal MI part of the primary end point was significantly reduced, there was a small, nonsignificant increase in CHD death with fenofibrate.

But the study, presented today at the American Heart Association (AHA) Scientific Sessions 2005, did show improvements in some secondary and tertiary outcomes: the fenofibrate group showed a significant reduction in total cardiovascular events, mainly due to decreases in nonfatal MI and revascularizations, and several microvascular complications such as albuminuria and retinopathy were also reduced.

Dr Antony Keech

In an interview with heart wire , lead investigator Dr Antony Keech (University of Sydney, Australia) said that while the results were not as good as the investigators had hoped, he still believed fenofibrate could confer a meaningful benefit in diabetic patients. Noting that statins had already been shown to produce significant benefits in diabetics, Keech commented: "These results do not support using fenofibrate instead of a statin in diabetic patients, but there is probably a case for adding fenofibrate on top of a statin in such patients, as the benefits are likely to be additive to those of statins."

Keech explained that fibrates work in a completely different way from statins and affect different components of the lipid profile; whereas the main action of statins is to lower LDL, fibrates tend to preferentially increase HDL, lower triglycerides, and increase the size of LDL particles. He noted that these properties could be particularly beneficial for diabetics, in whom low HDL, raised triglycerides, and small LDL particles are more common than in the general population. He also noted that while trials of statins had shown more impressive reductions in cardiovascular events in diabetics than fenofibrate showed in this trial, statins have not been shown to reduce microvascular complications, whereas the FIELD trial suggests that fenofibrate does reduce such complications.

However, the author of an editorial accompanying the Lancet paper is not in favor of using fenofibrate in combination with statins in diabetics on the basis of this trial[2]. Dr Helen Colhoun (University College Dublin, Ireland) says she would like to see more safety data for the patients receiving both fenofibrate and statin treatment and information on which particular statins were used. She also points out that cardiac mortality showed a nonsignificant increase of 19%, largely reflecting an increase in sudden cardiac deaths in the fenofibrate group, and asks, "Should this increase in sudden deaths be a concern?" Colhoun concludes that the results of the FIELD trial "do not warrant a recommendation for increased fenofibrate use in patients with diabetes, nor do they provide convincing evidence of the benefit of fenofibrate therapy in patients already at target serum LDL cholesterol."

Designated discussant of the FIELD trial at the AHA late-breaking clinical-trials session, Dr Henry Ginsberg (Columbia University, New York, NY) said: "Some important good things happened in this trial, but lives were clearly not saved, so some important good things were also not happening."

Ginsberg is heading up a new trial testing whether the combination of a statin and fenofibrate is superior to statin alone in reducing clinical events in diabetic patients. The ACCORD trial is randomizing around 5000 diabetics to either fenofibrate or placebo, with all patients taking simvastatin. But results are not expected until 2009.

FIELD design

The FIELD trial randomized 9795 patients with type 2 diabetes and a total cholesterol level below 6.5 mmol/L to micronized fenofibrate 200 mg daily or placebo. Patients already taking statins were not recruited into the study, but statins were allowed to be prescribed to patients already enrolled at the discretion of their own doctor. Of the patients, 78% had no evidence of heart disease at baseline.

After a follow-up of five years, the primary end point of CHD death/nonfatal MI was nonsignificantly reduced by 11%. Nonfatal MI was significantly reduced, but CHD death was nonsignificantly increased.

FIELD: Primary outcome

End point Placebo (n=4900), n (%) Fenofibrate (n=4895), n (%) HR (95% CI) p
CHD death/nonfatal MI 288 (6) 256 (5) 0.89 (0.75-1.05) 0.16
CHD death 93 (2) 110 (2) 1.19 (0.90-1.57) 0.22
Nonfatal MI 207 (4) 158 (3) 0.76 (0.62-0.94) 0.010
Significant benefit after adjusting for statin use

Keech reported that the results were probably affected by an uneven use of statins between the two groups, with 17% of the placebo group prescribed a statin during the trial compared with 7% of patients in the fenofibrate group. After adjustment for this, the primary end point was actually significantly reduced by 19% (p=0.01). But Keech cautioned that this result might have been slightly overestimated, as the stain treatment was not randomized. He commented to heart wire : "We believe the real reduction in the primary end point is probably more than the 11% shown in the main analysis but a little bit less than the 19% calculated from the adjusted analysis."

In terms of secondary outcomes, total cardiovascular events were significantly reduced, driven mainly by the reduction in nonfatal MI and a reduction in revascularizations.

FIELD: Secondary outcomes

End point Placebo (n=4900), n (%) Fenofibrate (n=4895), n (%) HR (95% CI) p
Total CV events 683 (14) 612 (13) 0.89 (0.80-0.99) 0.035
CV mortality 127 (3) 140 (3) 1.11 (0.87-1.41) 0.41
Total mortality 323 (7) 356 (7) 1.11 (0.95-1.29) 0.18
Stroke 175 (4) 158 (3) 0.90 (0.73-1.12) 0.36
Coronary revascularization 364 (7) 290 (6) 0.79 (0.68-0.93) 0.003
All revascularization 471 (10) 380 (8) 0.80 (0.70-0.92) 0.001

A prespecified subgroup analysis showed that all the benefit appeared to occur in patients without heart disease at baseline, with these patients showing a 19% reduction in total cardiovascular events, whereas there was no benefit in the secondary-prevention population.

Improvements in albuminuria/retinopathy

Several diabetic complications, which were tertiary outcomes, were reduced in the fenofibrate group. Specifically, progression of albuminuria occurred in 11% of placebo patients vs 10% of fenofibrate patients, and regression of albuminuria occurred in 8% of placebo and 9% of fenofibrate. "This represents 2.6% more patients allocated fenofibrate than placebo regressing or not progressing (p=0.002)," the FIELD investigators report in the Lancet paper. In addition, more patients on placebo underwent laser treatments for retinopathy (5.2% vs 3.6%, p=0.0003). "These are dramatic reductions in microvascular events, which can lead to gangrene and amputations and don't appear to be seen with statins," Keech told an AHA press conference.

Keech said that fenofibrate was well tolerated, with 90% of patients staying on their medication for the study duration. The fenofibrate group showed slight increases in pancreatitis (0.5% vs 0.8%, p=0.031) and pulmonary embolism (0.7% vs 1.1%, p=0.022), but there were no other significant adverse effects.

Lipid changes

As expected, fenofibrate reduced triglycerides (by 30%) and showed a modest reduction in LDL (12%). But the 5% increase in HDL seen at the start of the trial in the fenofibrate group was attenuated during the study period.

In his discussion of the trial, Ginsberg noted that HDL also barely increased in diabetic patients in the VA-HIT study with gemfibrozil, but the drug still showed a benefit. "I really don't have much explanation as to why better results were not seen in FIELD," he said, adding: "I am not clear what the lipid effects of fibrates are anymore."

Commenting on the FIELD study for heart wire , Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD) said he was disappointed with the results. "I was hoping to see much greater reductions in event rates, but the improvement in microvascular complications was encouraging." He added that he would continue to use fenofibrate on top of a statin in his diabetic patients with high triglycerides, but that in those with triglycerides close to target and low HDL, niacin may be a better bet to raise the HDL.

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