Boston, MA and Copenhagen, Denmark - Two new studies published this week provide support for the role of nonfasting triglyceride levels as a significant risk factor for coronary heart disease [1,2]. Even after adjustment for other CHD risk factors, including obesity, diabetes mellitus, and other lipoproteins such as HDL cholesterol, the investigators report that triglyceride levels were still associated with an increased risk of heart disease.

"These two papers, each strongly suggesting that nonfasting triglyceride levels carry more important prognostic information than fasting triglyceride levels, should get us to rethink the value of nonfasting triglyceride levels for assessing cardiovascular risk," Dr Paul Ridker (Harvard Medical School, Boston, MA) told heartwire.

As the senior author of one of the papers, both of which are published in the July 18, 2007 issue of the Journal of the American Medical Association, Ridker said the findings support the idea that how and what individuals eat is important as well as support the concept that atherosclerosis is, at least in part, a "postprandial phenomenon."

The second study, with lead author Dr Børge Nordestgaard (Herlev University Hospital, Copenhagen, Denmark), also suggests that atherosclerosis might be a disease initiated after a meal, a time when remnant lipoproteins play a dominant role. "If this is true, increased levels of nonfasting triglycerides, reflecting increased levels of remnant lipoproteins, may predict risk of myocardial infarction, ischemic heart disease, and death," the Danish authors write.

In an editorial accompanying the published studies [3], Dr Patrick McBride (University of Wisconsin School of Medicine, Madison) writes that the evidence suggesting elevated serum triglyceride levels are associated with increased risk of atherosclerosis events is increasing. He points out that elevated triglyceride levels are associated with abnormal lipoprotein metabolism, as well as obesity, diabetes, insulin resistance, and low levels of HDL cholesterol. He wonders how important it is to know which came first—high serum triglyceride levels or the risk factors that cause these high levels—when determining coronary heart disease risk.

"In the end, is it the triglyceride levels or the associated changes in metabolism that explains the high risk associated with postprandial triglyceride levels?" writes McBride. "This question is important scientifically, but in clinical practice the argument may be as academic as the debate about which came first, the chicken or the egg. For clinicians, it is important to recognize that when triglyceride levels are between 150 and 1000 mg/dL, the risk for atherosclerosis-related events is significantly increased. Therefore, it is important to aggressively and comprehensively treat patients with dyslipidemias that include high levels of triglycerides, low levels of HDL-C, and the presence of small LDL-C particles, using both lifestyle change and medications if necessary."

Speaking with heartwire, Ridker said there is a great deal of controversy about whether or not triglyceride levels are predictive of future cardiovascular events. While the evidence suggests an association between triglyceride levels and future coronary risk, this risk is attenuated after adjustment for other risk factors. The relationship is particularly weakened after adjustment for HDL-cholesterol levels, he said.

However, in addition to these concerns, there is also some controversy stemming from the manner in which triglyceride levels are measured. While the national guidelines recommend that blood for lipid profiles be taken after an eight- to 12-hour fast, plasma levels vary considerably after a meal. Moreover, say the investigators, led by Dr Sandeep Bansal (Harvard Medical School, Boston, MA), there is also evidence suggesting that postprandial lipids might play an important role in the pathogenesis of cardiovascular disease, likely as postprandial triglyceride-rich remnant lipoproteins penetrate the endothelium.

For this reason, Ridker told heartwire, the group sought to determine whether there was a fundamental difference between fasting and nonfasting triglyceride levels in the prediction of future cardiovascular events in a cohort of 26 509 initially healthy women participating in the Women's Health Study. Triglyceride levels were measured in blood samples obtained at time of enrollment. During a median follow-up of 11.4 years, 1001 participants experienced a new cardiovascular event, including 276 nonfatal MIs, 265 ischemic strokes, 628 coronary revascularizations, and 163 cardiovascular deaths.

Investigators found that higher nonfasting triglyceride levels were strongly associated with an increased risk of future cardiovascular events, independent of baseline cardiac risk factors, levels of other lipids, and markers of insulin resistance. Fasting triglyceride levels, on the other hand, showed little independent association with cardiovascular events. The association between triglyceride levels and future events was particularly strong among individuals who had their blood drawn two to four hours after a meal, and this relationship weakened as more time elapsed after the meal.

Ridker said high levels of nonfasting triglyceride levels could reflect either a higher peak level or delay in the clearance of triglyceride-rich particles, which can lead to an accumulation of these atherogenic particles.

He said the results, suggesting a strong difference between nonfasting and fasting triglyceride levels in terms of risk prediction, might help explain some of the previously inconsistent findings. In those studies, emphasizing fasting triglyceride measures, the association between triglyceride levels and cardiovascular risk might have been underestimated, or trials with triglyceride-lowering medications might even have targeted the wrong patient population. At the moment, Ridker said it is difficult to recommend therapy given the lack of clinical trial data, but these new findings "should greatly increase interest in performing trials of triglyceride reduction, but based on nonfasting rather than fasting triglyceride levels."

In the study by Nordestgaard and colleagues, the Danish investigators also tested the hypothesis that nonfasting triglyceride levels predict the risk of MI, ischemic heart disease, and death. To do so, the group studied 7587 women and 6394 men aged 20 to 93 years from the general population in Copenhagen, Denmark.

During a mean follow-up of 26 years, 1793 participants had an MI, 3479 developed ischemic heart disease, and 7818 died. In men and women, the incidence of MI, ischemic heart disease, and death increased with increasing levels of nonfasting triglyceride levels. In women, for example, after adjustment for various confounding variables, the risk of MI was more than five times greater among those with the most elevated triglyceride levels compared with those with the lowest. The same trend was observed for men and was observed for both men and women in terms of ischemic heart disease and death. In addition, they observed that with increasing levels of nonfasting triglyceride levels, the levels of remnant lipoproteins increased.

Like the US investigators, Nordestgaard and colleagues say the findings reflect the effects of remnant lipoproteins, which might be of considerable interest in the design of future clinical trials. In addition, if the "findings are confirmed, clinical care might be simplified by using nonfasting lipid profiles for atherosclerosis risk prediction," they write.

In his editorial, McBride writes that further research is needed to clarify the role of postprandial triglyceride levels and their use in clinical practice. Using a two- to four-hour postprandial triglyceride equation is simpler, he notes, and may be more predictive than LDL-cholesterol levels calculated using the Friedewald equation. Fasting triglyceride measurements, though, might still be more reliable due to controlled conditions.

In addition to these comments, McBride writes that both studies suggest that women have a greater risk associated with hypertriglyceridemia than men, although men and women both have a risk associated with elevated postprandial triglyceride levels. He also notes that the studies support describing atherosclerosis as a postprandial phenomenon, with nonfasting triglyceride levels a better prognostic measure than fasting levels.