Nonfasting triglycerides and ischemic heart disease in men and women

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Cardiology Review® Online, March 2008, Volume 25, Issue 3

Strategic Alliance Partnership | <b>FAST: Foundation for Angelman Syndrome Therapeutics</b>

Triglyceride levels are usually measured after the patient has fasted, and then exclude remnant lipoproteins. Except for the first few hours of the morning, individuals are usually in a nonfasting state for most of the day. We investigated whether nonfasting triglyceride levels predicted the risk of myocardial infarction (MI), ischemic heart disease, and death in the general population. Results showed that increased nonfasting triglyceride levels were associated with an increased risk of MI, ischemic heart disease, and death.

Premature atherosclerosis occurs in patients with moderately increased triglyceride levels and with such conditions as metabolic syndrome, familial combined hyperlipidemia, hypertriglyceridemia, and remnant hyperlipidemia.1-3 Chylomicron remnants and very—low-density lipoprotein remnants are present in plasma when triglyceride levels are moderately increased. These smaller triglyceride-rich lipoproteins enter into the arterial intima,4 appear to be trapped in the arterial wall,5 and thus cause atherosclerosis,6 leading to myocardial infarction (MI), ischemic heart disease, and death.

Triglyceride levels are usually measured after the patient has fasted, and then exclude remnant lipoproteins. Except for the first few hours of the morning, individuals are usually in a nonfasting state for most of the day. We therefore assessed whether nonfasting triglyceride levels predicted the risk of MI, ischemic heart disease, and death in the general population.

Subjects and methods

The study sample included a prospective cohort of 13,691 Danish subjects who were enrolled in the Copenhagen City Heart Study. The participants were aged 20 to 93 years and were followed for a period of 26 years. A total of 1793 subjects developed MI, 3479 developed ischemic heart disease, and 7818 died.

Subjects were considered to have ischemic heart disease if they had a previous MI or typical symptoms of unstable or stable angina pectoris. Those with at least 2 of the following criteria were considered to have MI: increased levels of cardiac enzymes, electrocardiographic changes characteristic of MI, or chest pain suggestive of MI.

We performed a fat tolerance test among 66 healthy participants from the Copenhagen City Heart Study. A total of 10,284 subjects from the Copenhagen General Population Study, aged 20 to 90 years, underwent the same evaluation as those in the Copenhagen City Heart Study and also underwent assessment of nonfasting triglycerides and remnant lipoproteins.

To determine plasma levels of nonfasting triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and total cholesterol levels, we used enzymatic methods on fresh samples. To obtain the remnant lipoprotein cholesterol values, we subtracted the cholesterol in HDLs and LDLs from total cholesterol. To convert triglyceride and cholesterol values from mmol/L to mg/dL, multiply by 88 and 38.6, respectively. Hazard ratios (HRs) were corrected for regression dilution bias.

Results

As shown in Figure 1, plasma triglyceride levels increased 1 hour after the previous meal and stayed elevated for up to 7 hours after the last meal. Increased levels of cholesterol in remnant lipoproteins were indicated by the measured levels of nonfasting triglycerides after normal food intake. A mean peak level of 2.3 mmol/L was achieved 4 hours after fat intake, as shown during a fat tolerance test; however, the mean peak level was 1.6 mmol/L 4 hours after normal food intake among individuals from the general population. As shown in Figure 2, levels of remnant lipoprotein cholesterol increased with increasing levels of nonfasting triglycerides.

Figure 1. Triglyceride levels and levels of remnant lipoprotein cholesterol as a function of time since the last meal. Values are median and interquartile range. Upper and middle panels: values after normal food intake in participants of the Copenhagen General Population Study. Lower panel: values during a fat tolerance test (FTT) performed on participants from the Copenhagen City Heart Study. After a 12-hour overnight fast, these participants consumed 1 g of dairy cream per kg of body weight. For the upper, middle, and lower panels, we compared the various nonfasting values (at 1-8 hours after the last meal) with fasting levels: *P <.05, †P <.01, and ‡P <.001 by Student's t test (unpaired upper and middle panel, and paired lower panel) without correction for multiple comparisons. GP indicates general population. To convert triglyceride and cholesterol values from mmol/L to mg/dL, multiply by 88 and 38.6, respectively. (Adapted with permission from Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298[3]:299-308. Copyright © 2007, American Medical Association. All rights reserved.)

Figure 2. Levels of remnant lipoprotein cholesterol as a function of levels of nonfasting triglycerides. Values are median and interquartile range. These levels were measured in 6677 of the original participants from the Copenhagen City Heart Study, who also had nonfasting triglycerides and remnant lipoprotein cholesterol measured 15 years after study entry. *P <.001 by unpaired Student's t test vs individuals with <1 mmol/L in nonfasting triglycerides. To convert triglyceride and cholesterol values from mmol/L to mg/dL, multiply by 88 and 38.6, respectively. (Adapted with permission from Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298[3]:299-308. Copyright © 2007, American Medical Association. All rights reserved.)

For MI, women with increased nonfasting triglyceride levels had age-adjusted HRs of 2.2 (95% confidence interval [CI], 1.6-3.2) for triglyceride levels of 1 to 1.99 mmol/L, 4.4 (95% CI, 2.9-6.8) for levels of 2 to 2.99 mmol/L, 3.9 (95% CI, 2.0-7.7) for levels of 3 to 3.99 mmol/L, 5.1 (95% CI, 2.0-13) for levels of 4 to 4.99 mmol/L, and 17 (95% CI, 6.8-42) for levels ≥5 mmol/L vs women with nonfasting triglyceride levels <1 mmol/L (Figure 3). Corresponding values for men were 1.6 (95% CI, 1.1-2.3), 2.3 (95% CI, 1.5-3.4), 3.6 (95% CI, 2.3-5.7), 3.3 (95% CI, 1.9-5.9), and 4.6 (95% CI, 2.7-8.0).

Figure 3. Hazard ratios for myocardial infarction, ischemic heart disease, and death for increasing levels of nonfasting triglycerides from the Copenhagen City Heart Study. Multifactorial adjustment was for age, total cholesterol, body mass index, hypertension, diabetes mellitus, smoking, alcohol consumption, physical inactivity, lipid-lowering therapy, and, in women, postmenopausal status and hormone replacement therapy. P values for trend tests examined whether increased levels of triglycerides were associated with increased hazard ratios (triglyceride groups were coded 0, 1, 2, 3, 4, and 5 for increasing triglyceride levels). To convert triglyceride values from mmol/L to mg/dL, multiply by 88. (Adapted with permission from Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007;298[3]:299-308. Copyright © 2007, American Medical Association. All rights reserved.)

For ischemic heart disease, women with increased nonfasting triglycerides had age-adjusted HRs of 1.7 (95% CI, 1.4-2.1) for triglyceride levels of 1 to 1.99 mmol/L, 2.8 (95% CI, 2.1-3.7) for levels of 2 to 2.99 mmol/L, 3.0 (95% CI, 1.9-4.7) for levels of 3 to 3.99 mmol/L, 2.1 (95% CI, 1.0-4.3) for levels of 4 to 4.99 mmol/L, and 5.9 (95% CI, 2.8-12) for levels ≥5 mmol/L vs women with nonfasting triglyceride levels <1 mmol/L (Figure 3). Corresponding figures for men were 1.3 (95% CI, 1.0-1.7), 1.7 (95% CI, 1.3-2.3), 2.1 (95% CI, 1.5-3.0), 2.0 (95% CI, 1.2-3.1), and 2.9 (95% CI, 1.9-4.5).

For total death, women with increased nonfasting triglyceride levels had age-adjusted HRs of 1.3 (95% CI, 1.2-1.5) for triglyceride levels of 1 to 1.99 mmol/L, 1.7 (95% CI, 1.5-2.1) for levels of 2 to 2.99 mmol/L, 2.2 (95% CI, 1.7-3.0) for levels of 3 to 3.99 mmol/L, 2.2 (95% CI, 1.4-3.4) for levels of 4 to 4.99 mmol/L, and 4.3 (95% CI, 2.7-7.0) for levels ≥5 mmol/L vs women with nonfasting triglycerides <1 mmol/L (Figure 3). Corresponding values in men were 1.3 (95% CI, 1.1-1.5), 1.4 (95% CI, 1.2-1.7), 1.7 (95% CI, 1.3-2.1), 1.8 (95% CI, 1.3-2.4), and 2.0 (95% CI, 1.5-2.8).

Following multifactorial adjustment, HRs for the risk of MI, ischemic heart disease, and death were attenuated, but still highly significant in women (Figure 3). For men, post hoc analyses showed that age-adjusted HRs were more significant among men who were light vs heavy alcohol drinkers and for those who were aged 55 years or younger at the start of the study compared with those who were older than 55 years.7

Discussion

The results of our study showed that nonfasting triglyceride levels ≥5 mmol/L, which indicate the presence of remnant lipoproteins, predict a 5-fold and 17-fold increased risk of MI, 3-fold and 6-fold increased risk of ischemic heart disease, and 2-fold and 4-fold increased risk of total death in men and women, respectively, in the general population. The predictive ability of nonfasting triglyceride levels ≥5 mmol/L has been overlooked because most prior studies have assessed predominantly tertiles or quartiles of triglycerides rather than very high levels, and they have focused on fasting levels of triglycerides that exclude remnant lipoproteins.

We achieved these results most likely because the increased nonfasting triglyceride levels indicate the presence of elevated levels of remnant lipoproteins, which probably directly cause atherosclerosis6 and, as a result, MI, ischemic heart disease, and death. It is therefore the cholesterol content of remnant lipoproteins that causes atherosclerosis and not the triglycerides per se. The most important finding of our study, therefore, was not the multifactorially adjusted HRs, but the age-adjusted HRs; multifactorial adjustment masks the effect of triglycerides by adjusting for such factors as diabetes mellitus and being overweight, which are known to lead to increased levels of triglycerides and remnant lipoproteins. Very high levels of nonfasting triglycerides simply identify a patient with very high risk regardless of other risk factors.

Because all human cells can break down triglycerides but not cholesterol and because remnant lipoproteins like LDL carry large quantities of cholesterol, it is the cholesterol content of remnant particles that causes atherosclerosis on entrance into the arterial intima.6,8 Remnant lipoproteins can enter into the arterial intima, as do LDLs,4 and they may even be trapped within the arterial walls.5 In support of this mechanism, patients with genetically large quantities of remnant lipoproteins in plasma develop atherosclerosis prematurely.2 Furthermore, there is an increased risk of cardiovascular death among individuals with familial forms of hypertriglyceridemia.1 In addition, among patients with increased triglyceride levels, a 20% to 40% decrease in triglyceride levels has been shown to result in a 30% to 40% reduction in risk of ischemic heart disease in subanalyses of 3 randomized, double-blind trials.9-11

Because individuals in the general population had less of an increase in triglyceride levels in response to normal food intake than during a fat tolerance test of 1 g of dairy cream per kg body weight, results of our study also suggest that most people eat less fat during normal food intake than during a fat tolerance test. The modest increase in triglyceride levels during normal food intake and the demonstration in the current study of a high predictive value of nonfasting triglycerides for the risk of MI and ischemic heart disease indicate that nonfasting rather than fasting triglyceride levels can be used for risk prediction. This would simplify lipid measurement for millions of patients.

The ability of nonfasting triglyceride levels to predict MI and ischemic heart disease was more pronounced among women than among men in our study. Our results concur with some,12,13 but not all, previous meta-analyses.14 Based on our subanalyses, the predictive ability of nonfasting triglycerides for the risk of MI and ischemic heart disease was similar between young men who only consumed small amounts of alcohol and women. Therefore, in the current and previous studies, a high alcohol intake may have affected the relationship between MI, ischemic heart disease, and death in men because a high alcohol intake often leads to increased triglyceride levels and because these triglyceride-rich lipoproteins may differ from most remnant lipoproteins present in the nonfasting plasma (type V vs type IIb hyperlipidemia).

Advantages of the present study include a large, ethnically homogenous sample from the white general population and a very high participation rate. In addition, the duration of follow-up, which was 100% complete, was 26 years. We also corrected for regression dilution bias. Future studies should include randomized intervention trials, with the goal of decreasing plasma levels of nonfasting triglycerides and thus remnant lipoproteins, leading to a reduction in the risk of MI, ischemic heart disease, and death.

Conclusions

There are potential clinical implications of the present study. If nonfasting rather than fasting triglycerides were used, blood sampling for lipid measurements would be simplified for millions of patients worldwide. Furthermore, nonfasting triglyceride levels ≥5 mmol/L can identify patients at very high risk, who should be carefully evaluated.