A new analysis of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial has shown that the lipid-lowering therapy works just as well in women as in men. These results are key, say the researchers, as prior research from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study has suggested fenofibrate was not as effective in females and could even be harmful.
"The important finding of this study is that the effect in women is at least equivalent to that in men," lead author of the new FIELD analysis, Dr. Michael C. d'Emden of the Royal Brisbane Hospital, Queensland, Australia, told Medscape Medical News.
"This provides reassuring data that fenofibrate is effective and safe in women and, in particular, is effective in women with dyslipidemia (high triglycerides, low HDL cholesterol). This is in contrast with the results of the ACCORD Lipid trial, which had fewer women in its study, most likely at lower cardiovascular disease risk. In that study, decreased effectiveness was observed in women overall," he added.
Dr. d'Emden and colleagues report their new results in Diabetologia.
Asked what the general criteria should be for use of fenofibrate in diabetes patients, he said: "The data to date clearly show that statin therapy should be first-line therapy in patients with type 2 diabetes."
"The results of this study and ACCORD Lipid demonstrate that fenofibrate can lower lipids and further reduce cardiovascular events, especially in patients who remain dyslipidemic despite statin therapy," he added.
Asked to comment on the new findings, Henry Ginsberg, MD, at Columbia University Medical Center, New York, who was the lead investigator for the ACCORD Lipid Working Group, told Medscape Medical News: "It does look from their data that women and men are similar in their response to fenofibrate."
Dr. Ginsberg added that he presented an analysis by gender of ACCORD Lipid, also conducted in diabetes patients, to the FDA 3 years ago, but the work has not yet been published.
"We were very surprised to find that in ACCORD, women who have already had a prior cardiovascular event seemed to do worse overall on fenofibrate than women on placebo, but it was a small group. However, if they were also dyslipidemic, that risk seemed to go away and they did the same or better on fenofibrate, similar to what [the FIELD investigators] say. But in ACCORD, we are dealing with very small subgroups of women in these analyses. We've looked at a whole bunch of variables and we can't find a reason.
"I would agree that in the FIELD trial I don't see a difference between men and women. My own personal view is that diabetics who remain dyslipidemic on a statin [with triglycerides over 2.3mmol/L, or 200 mg/dL, and a low HDL cholesterol] likely benefit [from fenofibrate], but that's a subgroup analysis."
Dr. Ginsberg said a new VA trial examining exactly this issue is slated to begin soon, but the results won't be available for a number of years.
FIELD and ACCORD: Questions Arose on Use of Fenofibrate in Women
FIELD was a double-blind, placebo-controlled study in which almost 10,000 patients aged 50 to 75 years with type 2 diabetes and no clear indication for lipid-lowering therapy (and not using statins) were assigned to 200 mg fenofibrate per day or placebo for 5 years. Additional cardiovascular medications could be commenced during the trial, including statins, at the treating physician's discretion.
The main results presented in 2005 were negative: they showed that fenofibrate failed to significantly reduce the primary end point (coronary heart disease death or nonfatal myocardial infarction) vs placebo. However, the nonfatal MI part of the primary end point was significantly reduced, set against a small, nonsignificant increase in CHD death with fenofibrate.
The fenofibrate group also had a significant reduction in several microvascular complications such as albuminuria and retinopathy. In fact, last December, on the basis of the FIELD study and the ACCORD Eye trial, fenofibrate was approved in Australia as the first oral medical therapy anywhere in the world for slowing the progression of existing diabetic retinopathy in people with type 2 diabetes.
But questions remained about the role of fenofibrate as a therapy for women with diabetes. ACCORD Lipid evaluated fenofibrate added to background simvastatin therapy and reported a 9.1% rate of CVD events for 851 women receiving fenofibrate and a nonsignificantly lower rate of 6.6% in 843 women on placebo; there was a significant interaction between treatment and sex, in favor of men (P = .01)
This led to a safety alert being issued by the US Food and Drug Administration (FDA) in November 2011.
New Analysis Shows Fenofibrate as Good in Women
Now, Dr. d'Emden and colleagues have reported a prespecified analysis of FIELD by gender. In FIELD, 3657 women and 6138 men with type 2 diabetes were assigned to fenofibrate or placebo.
Baseline total, LDL-, HDL-, and non-HDL cholesterol and apolipoproteins differed between sexes, and these and triglyceride levels improved with fenofibrate among both men and women (all P < .001).
Importantly, the new analysis shows fenofibrate reduced total, LDL- and non-HDL cholesterol and apolipoprotein B more in women (all P < .001), independent of menopausal status and statin uptake.
After adjustment for covariates, fenofibrate reduced total cardiovascular outcomes (cardiovascular death, fatal and nonfatal stroke, and carotid and coronary revascularization) by 30% in women (P = .008) and 13% in men (P = 0.07) with no treatment-by-sex interaction (P > .1).
And in patients with very high triglycerides and low HDL-cholesterol, who are at particularly high risk of diabetic complications, fenofibrate reduced total cardiovascular outcomes by 30% in women and 24% in men, with no treatment-by-sex interaction (P > .1).
Still, said Dr. Ginsberg, there is no getting away from the fact that "the primary end point they chose [in FIELD] was negative. Everything else is what it is: post hoc, or prespecified, subgroup analyses."
Fenofibrate Reduces Microvascular Complications, Too...
Dr. d'Emden also noted the strong findings with regard to reduction of microvascular events in patients with diabetes taking fenofibrate, pointing to the recent Australian approval of the agent for type 2 diabetes patients having established retinopathy.
"This is the first oral medical therapy that has been shown to have significant effects on retinopathy, and it has been demonstrated only with fenofibrate and not other fibrates. FIELD also demonstrated an effect on other microvascular diseases — peripheral vascular disease/peripheral neuropathy and diabetic nephropathy," he added.
"The consistency of this effect suggests a role for fenofibrate in reducing the risk of developing microvascular disease. Its use in patients with evidence of early microvascular disease, principally retinopathy, should be considered."
But Dr. Ginsberg said the findings with regard to microvascular disease with fenofibrate have not really "caught on" stateside and therefore do not really play into the decision to treat with a fibrate or not.
"In the US, unfortunately, the eye studies [ACCORD Eye and the findings from FIELD] have had no impact on the treatment of retinopathy. The ophthalmologists have not really picked this up, and there would have to be a much larger study, I guess," he observed.
He added also that, somewhat counterintuitively, the benefit on retinopathy in ACCORD Eye seen for fenofibrate was in the nondyslipidemic patients, suggesting that the mechanism is very different [for microvascular benefits vs macrovascular].
He notes also that he is not sure that endocrinologists "have paid much attention" to the findings of FIELD, either, in relation to reductions in microvascular complications of diabetes.
Fenofibrate for All Diabetics Who Remain Dyslipidemic Despite Statins
Dr. d'Emden said in conclusion that the new results from FIELD support the use of fenofibrate in all diabetic patients who remain dyslipidemic despite statin therapy.
"FIELD confirms that the lipid-therapy recommendations should not differ according to gender," he observed. He noted, however, that the study did not have enough subjects of differing ethnicity to make any recommendations regarding indications based on race
"We all agree that statins come first," Dr. Ginsberg concluded.
Dr. d'Emden has received speaker's bureau fees from Solvay (now part of Abbott Pharmaceuticals). Disclosures for the coauthors are listed in the article.
Diabetologia. Published online August 18, 2014.
Medscape Medical News © 2014
Cite this: Fenofibrate Works as Well in Women With Diabetes as in Men - Medscape - Aug 18, 2014.