MSI Newsletter - October 2008

By: Robert S. Rosenson, MD
Director of Lipoprotein Disorders and Clinical Atherosclerosis Research
Division of Cardiovascular Medicine, University of Michigan
Ann Arbor, MI, USA

The objectives of this review are to discuss the associations between fasting compared with non-fasting triglycerides and the risk of atherosclerosis and cardiovascular events, provide mechanistic insights into the concept that atherosclerosis may be a postprandial phenomenon, and provide a framework for future studies necessary for incorporation of postprandial triglyceride measurements into guidelines for cardiovascular risk assessment and potential targets of therapy.

The triglyceride controversy

Elevated plasma triglycerides have not been considered an important risk factor for cardiovascular events, in part, due to controversy as to whether these associations are independent of other lipoproteins, hemostatic markers and insulin resistance. High triglyceride levels are associated with increased cholesterol content of remnant particles,¹ small, dense low density lipoproteins (LDL),² and low levels of high-density lipoprotein cholesterol (HDL-c).³ A meta-analysis reported that fasting triglycerides in the highest tertile compared to the lowest tertile were associated with an adjusted risk ratio for coronary heart disease (CHD) of 2.04 (95% confidence interval [CI]: 1.78 to 2.32) fold that diminished to 1.52 (95% CI: 1.24 to 1.89) after further adjustment for HDL-c concentration (Figure 1).⁴

Figure 1. Triglyceride level is a significant coronary heart disease (CVD) risk factor: meta-analysis of 29 studies involving 262 525 subjects.4

In a prospective population study, fasting triglycerides predicted increased rates of atherosclerosis progression in models that included age, gender, race, hypertension, and smoking; however these results were no longer significant after adjustment for LDL particle concentration.⁵

A second aspect of the controversy relates to the timing of triglyceride measurements. Triglycerides are conventionally measured after an 8 to 12 hour fast⁶ in order to avoid the variability in triglycerides after a meal, and provide more reproducible calculations of LDL-cholesterol concentrations⁷ that serve as the primary emphasis of national guidelines to assess cardiovascular risk.⁶ However, except in the first hours of the morning individuals are in the postprandial state most of the time.

Postprandial versus fasting triglyceridaemia and risk of coronary heart disease events

Cross-sectional analyses have shown associations between the postprandial triglyceride concentration and the extent of carotid atherosclerosis,^8,9 and case-control series report higher nonfasting triglycerides among individuals with coronary atherosclerosis than healthy controls.^10-14

Several prospective population studies have reported an independent association between nonfasting triglyceride concentration and cardiovascular events.^1,15-19

A Norwegian study investigated the predictive value of nonfasting triglyceride concentrations on the risk of cardiovascular morbidity and mortality in 25,058 men and 24,535 women aged 35-49 years who were followed for an average of 14.6 years. In models that adjusted for age, systolic blood pressure, number of cigarettes a day, total cholesterol concentration and time since last meal, nonfasting triglyceride levels =3.5 mmol/L (=309.7 mg/dL) versus <1.5 mmol/L (132.7 mg/dL) were associated with a 4.7-fold (95% CI: 2.5-8.9) increased risk of cardiovascular mortality and a 2.3-fold (1.8-2.9) increased risk of all-cause mortality in women.¹⁵ In a meta-analysis, the risk of CHD was higher for fasting versus nonfasting triglyceride levels and the risk of CHD.⁴

The Copenhagen City Heart Study is a prospective cardiovascular study of the general Danish population.1 A cohort of 7587 women and 6394 men were followed for an average of 26 years in order to investigate whether nonfasting triglycerides predict the risk of myocardial infarction, CHD death and mortality. In 2003 through 2005, nonfasting triglyceride levels were measured in each participant by noting the amount of time (range 1 to 9 h) that had elapsed from the last meal. The cumulative incidence of myocardial infarction, CHD death and mortality increased in women and men with increasing nonfasting triglyceride concentrations as shown in the Figures 2 and 3.

Figure 2. Hazard ratios for cardiovascular disease in women.1

Figure 3. Hazard ratios for cardiovascular events in men.1

The risk persisted even in those participants with nonfasting triglycerides =5 mmol/L (=442.5 mg/dL).The risk of myocardial infarction, CHD death and mortality associated with a 1-mmol/L increase in nonfasting triglyceride levels is shown in Table 1.

The Women’s Health Study is a prospective study of 26 509 (20 118 fasting and 6391 nonfasting) initially healthy women who were followed for an average 11.4 years in order to determine the association of fasting versus nonfasting triglyceride levels and future risk of cardiovascular events.18 Fasting and nonfasting triglyceride levels predicted cardiovascular events in models that adjusted for age, blood pressure, smoking, and hormone therapy use (Figure 4).

For fasting triglyceride levels, the adjusted hazard ratio (95% CI) for cardiovascular events increased with each tertile of triglyceride concentration (=90 mg/dL, 91-147 mg/dL, and =148 mg/dL):1 1.63 (1.31-2.02) and 2.23 (1.82-274), P<0.001 for trend. With increasing nonfasting triglyceride levels, the hazard ratio for cardiovascular events increased with each tertile of triglyceride concentration (=104 mg/dL, 105-170 mg/dL and =171 mg/dL):1 1.48 (0.90-2.29) and 2.53 (1.69-3.79), P<0.001 for trend. However, in models that included total cholesterol and HDL-c, the associations with cardiovascular events were no longer significant (P=0.09). In contrast, nonfasting triglyceride levels remained an independent predictor of cardiovascular events in fully adjusted models that also included diabetes mellitus, body mass index, and high-sensitivity (C-reactive protein) for increasing tertiles of levels:1 1.44 (0.90-2.29) and 1.98 (1.21-3.25), P=0.006 for trend.
In analyses stratified by the time since the last meal, triglyceride levels measured 2 to 4 hours postprandially were most highly associated with cardiovascular events (Figure 5). Unlike other studies that combined data from individuals in various postprandial states, the Women’s Health Study18 suggests that the early postprandial peak is associated with the highest risk and thereby infers that other population studies may have underestimated risk associated with postprandial triglyceridaemia by combining data.

Figure 4. Risk of cardiovascular events per 1-mmol/L increase in
non-fasting triglyceride level.1

Figure 5. Association of triglyceride levels with individual
cardiovascular end points, according to fasting status.18

Biological mechanisms provide a plausible mechanism for the increased association between postprandial triglycerides and cardiovascular disease

Postprandial triglyceride elevations may play an important role in cardiovascular disease because triglyceride-rich remnants contribute to impaired endothelial-dependent vasodilation19 and facilitate penetration of remnant particles through the endothelial layer where they are accumulate in macrophages and lead to foam cell formation.²⁰ Further, small LDL and total LDL particles remain elevated amongst hypertriglyceridaemia individuals with delayed postprandial responses.²¹ Prolonged interactions of small LDL particles with the vessel wall facilitate penetration through the endothelium and accumulation in the subendothelial space where they contribute to the formation of foam cells.

Phenotypic associations between abnormal postprandial triglyceridaemia

Elevated postprandial triglyceride concentrations have been suggested as indicating more severe states of insulin resistance.^22,23 However, the Women’s Health Study showed that postprandial triglycerides were predictive of cardiovascular events independent of the insulin resistance markers (body mass index, diabetes mellitus, high-sensitivity C-reactive protein). In a controlled trial of metabolic syndrome patients, abnormal postprandial triglyceride responses were unrelated to an index of insulin sensitivity.²¹

Unresolved issues

Fasting triglyceride concentrations are highly variable upon repeat testing,²⁴ and the casual measurement of nonfasting triglyceride concentrations will inevitably diminish the utility of an oral fat load as a diagnostic test. For example, nonfasting triglycerides are lower than those obtained during a fat tolerance test. In the Copenhagen City Heart Study,²⁵ plasma triglycerides reached their peak of 2.3 mmol/L (203.5 mg/dL) at 4 hours during a fat tolerance test (1 gram dairy cream per kilogram of body weight), whereas in the Copenhagen General Population Study the peak triglyceride concentration was 1.6 mmol/L (141.6 mg/dL) at 4 hours during normal food intake.¹ In order to standardize postprandial measures of triglycerides, it is essential to use a standardized oral fat load that is adjusted for body size, minimize physical activity during the test period and avoid alcohol use for several days before the test. Even with these procedures, the timing of the postprandial triglyceride measurement remains unresolved. In the Women’s Health Study, cardiovascular risk was highest when the non-fasting triglyceride concentration was measured 2 to 4 hours after a meal, but this postprandial peak may be delayed in individuals who exhibit fasting hypertriglyceridaemia or varying degrees of insulin resistance.¹⁸ Among individuals with fasting hypertriglyceridaemia (=150 mg/dL to <600 mg/dL) and other characteristics of the metabolic syndrome, we observed that the postprandial triglyceride peak was seen 3 to 4 hours after the test meal in nearly two-thirds of subjects and it remained elevated 8 hours after the test meal in more than one-third of subjects.²¹ This heterogeneous postprandial response was not explained by major CHD risk factors, body mass index or waist circumference or an insulin sensitivity index. As the studies were essentially limited to Caucasians, potentially important ethnic and racial differences in postprandial responses and associated cardiovascular risk remain unknown. Another unresolved issue is whether there is differential information on cardiovascular risk obtained from the magnitude of postprandial triglyceride excursion above the fasting level or whether a single non-fasting measurement suffices.

Conclusions

Prospective population studies support the concept that atherosclerosis is a “postprandial phenomenon.”^26,27 It remains uncertain whether the triglyceride-containing particles are atherogenic per se or whether the associated increase in small LDL particles, low levels of HDL particles or hemostatic abnormalities account for the increased cardiovascular rate. It is likely that a combination of factors contributes to the higher rates of atherosclerosis and cardiovascular events, but differences in the contribution of these factors may be highly variable in certain subsets of patients.

Looking ahead, it is important to conduct a trial that compares the cardiovascular risk associated with fasting and non-fasting triglycerides in the same individual, and includes individuals with different ethnicities.

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