Fasting versus nonfasting triglycerides and the prediction of cardiovascular risk: do we need to revisit the oral triglyceride tolerance test?

Historically, triglycerides have been measured in the fasting state for 2 reasons. First, because of the marked increase in triglycerides after fat ingestion, the variability in triglyceride measurements is much smaller in the fasting state. Second, before the availability of direct assays for LDL cholesterol (LDL-C), estimation of LDL-C was performed in clinical practice almost exclusively by use of the Friedewald equation, which requires that both the HDL-C concentration and the fasting triglyceride concentration divided by 5 be subtracted from the total cholesterol concentration. The recommendations to measure triglycerides in the fasting state did not, however, derive from a consistent set of prospective cohort studies showing that fasting concentrations were superior to nonfasting concentrations for the detection of cardiovascular risk. Instead, following screening guidelines, most epidemiologic investigations simply relied on fasting triglycerides. Taken as a whole, such studies indicate that fasting triglycerides are a univariate predictor of vascular disease. Controversy exists, however, regarding the clinical usefulness of fasting triglycerides as an independent predictor of risk, because adjustment for other covariates—in particular HDL-C—markedly decreases both the magnitude and significance of observed epidemiologic effects (1 ). The extent to which investigators have sought to avoid nonfasting triglycerides as a method for risk detection is evident in a recent metaanalysis that limited evaluation only to those epidemiologic studies that measured fasting triglycerides, specifically “to exclude the possibility of postprandial effects” (2 ). Is it possible, then, that recommendations to measure triglycerides in the fasting state have systematically underestimated the impact of hypertriglyceridemia in clinical practice? Atherosclerosis has long been hypothesized to be a disorder influenced by postprandial effects. As early as 1950, J. R. Moreton, writing in the Journal of Laboratory and Clinical Medicine, suggested a linkage between chylomicronemia, fat tolerance, and atherosclerosis (3 ). A major source of circulating triglycerides is dietary fat, which, after hydrolysis into free fatty acids and glycerides, is transported through the intestinal villi and absorbed by enterocytes, where these particles are synthesized into chylomicron-associated triglycerides for entry into the blood compartment and ultimately storage in adipose tissue. Postprandial lipids and their associated partially hydrolyzed chylomicron remnants appear to promote early atherogenesis, adversely affect endothelial function, associate with atherogenic small LDL particles, and correlate with both prothrombotic and proinflammatory biomarkers, including factor VII, plasminogen activator inhibitor-1, and C-reactive protein (4 ). Thus, measurement of postprandial triglycerides—particularly because they peak 3– 4 h after ingestion of a fat-rich meal— might well provide more relevant information on vascular risk than measurements based on fasting concentrations. Two manuscripts recently published in the Journal of the American Medical Association directly address these issues by comparing fasting with nonfasting triglycerides with respect to the prediction of future cardiovascular events. The first report derived from the Women’s Health Study cohort, in which 26 509 initially healthy American women were followed over an 11-year period for myocardial infarction, stroke, coronary revascularization procedures, and cardiovascular death (5 ). In that analysis, both fasting and nonfasting triglycerides were associated with future cardiovascular risk after adjustments were made for age, blood pressure, smoking status, and hormone-replacement therapy. Among the fasting participants, further adjustment for total cholesterol and HDL-C markedly weakened this association. These data were consistent with prior work; however, nonfasting triglycerides maintained a strong independent relationship with future cardiovascular events in fully adjusted analyses: Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Boston, MA. * Address correspondence to the author at: Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave. East, Boston, MA 02215. Fax 617-734-1508; e-mail [email protected]. Received September 18, 2007; accepted October 16, 2007. Previously published online at DOI: 10.1373/clinchem.2007.097907 1 Nonstandard abbreviations: LDL-C, LDL cholesterol; and OTTT, oral triglyceride tolerance test. Clinical Chemistry 54:1 11–13 (2008) Perspectives