Using a nonfasting measure of triglycerides in a large population, the researchers report a "previously unnoticed" association between linear increases in triglycerides and a stepwise increase in the risk for ischemic stroke.

"Our results, together with those from two previous studies, suggest that elevated levels of nonfasting triglycerides and remnant lipoprotein cholesterol could be considered together with elevated levels of low-density-lipoprotein cholesterol for prediction of cardiovascular risk," the researchers, with first author Dr Jacob J Freiberg (Herlev Hospital, Copenhagen, Denmark), conclude, although they add that these findings will require replication in other populations.

The results are published in the November 12, 2008 issue of the Journal of the American Medical Association and were presented here at the American Heart Association 2008 Scientific Sessions.

Last year, this group reported a relationship between the incidence of MI, ischemic heart disease, and death and increasing nonfasting triglyceride levels in both women and men, raising the possibility that they might also be associated with stroke risk [2]. However, the role of triglycerides in the risk of ischemic stroke is controversial, the authors write.

Elevated levels of nonfasting triglycerides indicate the presence of increased levels of remnants from chylomicrons and very low-density lipoproteins, they note. "These cholesterol-containing, triglyceride-rich lipoproteins penetrate the arterial endothelium and may get trapped within the subendothelial space, potentially leading to the development of atherosclerosis," the authors write.

Triglycerides are usually measured in a fasting state, which would exclude most remnant lipoproteins; however, except for a few hours in the morning, most individuals are in a nonfasting state most of the time, they add.

"Therefore, by mainly studying fasting rather than nonfasting triglyceride levels, several previous studies may have missed an association between triglycerides and ischemic stroke," Freiberg and colleagues write. "Also, because former studies mainly focused on moderately elevated levels of triglycerides, an association of very high levels with risk of ischemic stroke could have gone unnoticed."

The current study used data on 13 956 men and women enrolled in the Copenhagen City Heart Study, a prospective, population-based study begun in 1976, with follow-up through July 2007. In this study, the researchers looked at baseline levels of nonfasting triglycerides, other risk factors at baseline and follow-up examinations, and the incidence of ischemic stroke.

They also carried out a cross-sectional study of 9637 participants in the prospective study who attended the 1991-1994 examination, since levels of nonfasting remnant lipoprotein cholesterol as well as the lipid profile were measured at that examination, the authors note. In the cross-sectional study, they looked at levels of nonfasting triglycerides, remnant cholesterol, and the prevalence of ischemic stroke.

Of the 13 956 participants in the prospective study, 1529 had an ischemic stroke during follow-up. "We observed an increased risk of ischemic stroke with increasing levels of nonfasting triglycerides, both in men and in women [p for trend <0.001 for both men and women]," Freiberg told the meeting here.

After adjustment for conventional cerebrovascular risk factors; for age, body-mass index (BMI), and diabetes mellitus; and finally for age and HDL cholesterol, risk estimates were attenuated only slightly, Freiberg noted.

The absolute 10-year risk for ischemic stroke ranged from 2.6% in men younger than 55 with nonfasting triglyceride levels of less than 89 mg/dL to 16.7% in those with levels of 443 mg/dL and above. The corresponding values for women were 1.9% and 12.2%.

In the cross-sectional study, they found nonfasting triglycerides were highest in those who had a previous ischemic stroke in both men and in women vs controls. Likewise, Freiberg noted, levels of remnant cholesterol were highest in those who developed ischemic stroke in both men and women.

"This led to the final conclusion that nonfasting triglycerides as a marker of remnant cholesterol were associated with increased risk of ischemic stroke, with the risk being three times higher in men and four times higher in women," Freiberg concluded.

Dr Børge G Nordestgaard (Herlev Hospital and Copenhagen University Hospital, Denmark), senior author on the paper, said that these findings suggest the need for large, randomized intervention trials aimed at reducing triglycerides in those with elevated nonfasting levels.

"I think it's an area that has been neglected because first the focus was on lowering LDL cholesterol, and then there was a lot of focus on trying to raise HDL, which had a major setback because of torcetrapib," Nordestgaard said. Torcetrapib, an agent that raised HDL, was found to increase mortality and cardiovascular events in a trial reported at the end of 2006.

"People have missed this idea of thinking about triglycerides and remnants, so there may be a key there for the future to prevent stroke, but we need a large, randomized, intervention trial," he said.

He pointed out that although compounds like fibrates and nicotinic acid would be the best way to address high triglycerides, they are not very well tolerated by patients. Statins also reduce triglycerides to some degree in addition to lowering LDL and could be a place to start. "Because there's so much evidence that statins are good, I tend to favor using a statin to see how much you can lower triglycerides together with LDL if it's not too high, and if that doesn't work, then you can use the fibrates and nicotinic acid."

Triglyceride levels are increased in those with higher BMI and those with diabetes mellitus, he noted, but importantly, the risk associated with higher levels of nonfasting triglycerides seen in this study persisted after they stratified for BMI.

Drs Michael A Sloan (University of South Florida, Tampa) and David Z Wang (University of Illinois College of Medicine, Peoria) moderated the session here and were asked for comment on these findings.

"It's novel data in the sense that we really haven't seen a large study looking at the risk of stroke associated with triglycerides and nonfasting triglycerides, because what we've focused on is the association between cholesterol and stroke, LDL and stroke, so this is something new," Sloan said. "This is the largest study looking at this issue, so it really forces us to rethink how comprehensive we should be in terms of lowering not only cholesterol but triglycerides."

Wang agreed. "You could now say that higher lipids are not good in any sense; not only high cholesterol, which is not good in terms of higher risk for stroke and myocardial infarction, but now we learn that higher triglycerides are also not good, even at a nonfasting level," he said. "This adds another dimension to our prevention plan as we lower LDL—the lower the better—but now we also need to emphasize strategies that lower triglycerides."

Clinical-trial data to prove that lowering triglycerides would affect stroke risk would be ideal, they both added, but Wang noted that there may be little economic incentive for industry to fund trials of approaches like omega-3 fatty acids or weight loss or off-patent agents like niacin, to reduce triglycerides. "It may be a good thing for [the National Institutes of Health] NIH to do, for example," he added.