Epidemiologic evidence supports triglycerides as an independent risk biomarker for coronary disease

ByMichael Miller, MD, FACC, FAHA

According to the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), elevated triglycerides are a biomarker for increased risk of coronary heart disease (CHD). Elevations in serum triglycerides are associated with increased levels of atherogenic remnant lipoproteins. Because very low density lipoprotein (VLDL) cholesterol is the most available measure of atherogenic remnant lipoproteins, it can be combined with low density lipoprotein (LDL) to estimate the non-high density lipoprotein (non-HDL = total cholesterol-HDL, target for non-HDL <130 mg/dL) level thereby representing the concentrations of atherogenic lipoproteins more effectively than LDL alone.

When serum triglycerides are elevated, the non-HDL level enhances CVD risk prediction, and the NCEP ATP III recommends that non-HDL be a secondary target of therapy when triglyceride levels are >200 mg/dL. The NCEP ATP III does not have a target triglyceride level at this time.¹

In 2007 the American Diabetes Association (ADA) and the American Heart Association (AHA) issued a joint scientific statement for the primary prevention of CVD in patients with diabetes.² They recommend that LDL be the primary target of lipid-lowering therapy in patients with diabetes with a goal of <100 mg/dL. They also report that triglyceride-rich lipoproteins, especially VLDL, are often elevated in patients with diabetes, and serve as a precursor for atherogenic VLDL remnant particles. The AHA and NCEP recommends a non-HDL cholesterol goal of <130 mg/dL in patients with triglyceride levels of 200 mg/dL to 499 mg/dL. If levels of triglyceride >500 mg/dL, then triglyceride lowering becomes a priority in the management of dyslipidemia.

Evidence of risk

Several studies indicate that an elevated level of triglycerides is associated with increased CHD risk. The 8-year Prospective Cardiovascular Munster Study (PROCAM) found that high triglyceride levels increased CHD risk among middle-aged men in addition to their LDL or HDL levels. PROCAM included 4,639 men with no history of myocardial infarction or stroke and showed a six-fold increased CHD risk in those with triglyceride levels >200 mg/dL and LDL/HDL ratios >5 (P =.01).³

PROCAM researchers found that 44 CHD events occurred per 1,000 patients with triglyceride levels <200 mg/dL, 93 events per 1,000 patients with triglyceride levels of 200 mg/dL to 399 mg/dL, 132 events per 1,000 patients having triglyceride levels of 400 mg/dL to 799 mg/dL, and 81 events per 1,000 patients with triglyceride levels of >800 mg/dL.⁴

The largest and most comprehensive epidemiological assessment of the association between triglyceride values and CHD risk in Western populations was a meta-analysis of 29 studies including 262,525 participants and 10,158 patients with CHD. Researchers reported an adjusted odds ratio of 1.72 (95% CI, 1.56-1.90) for those with log-triglyceride values in the top third of the population compared to those in the bottom third.⁵ This odds ratio was adjusted in all but one of the 29 studies for age, sex, smoking status, and lipid concentrations, and most studies also adjusted for blood pressure.

The data indicate that the impact of triglycerides on risk is similar in women and men, regardless of follow-up duration. The data also suggest no important differences in the strength of associations between triglycerides and CHD in studies of fasting participants compared with those of nonfasting participants. A highly significant association exists between triglyceride value and CHD risk.

The basis for elevated levels of triglycerides serving as a CHD risk biomarker stems from associated increases in cholesterol-enriched atherogenic remnant particles, the byproduct of the hydrolysis of triglyceride-rich lipoproteins.⁶ In addition, hypertriglyceridemia may also be associated with increased blood viscosity that in part may be related to upregulation of coagulation factor VIII and plasminogen activator inhibitor.⁷

Hypertriglyceridemia and mechanisms of atherosclerosis

Chylomicron remnants may promote inflammation following endothelial transcytosis by upregulating adhesion molecule expression and macrophage chemotaxis. Remnant particles may be directly incorporated by macrophages analogous to modified LDL, which in turn serves to contribute to foam cell formation and plaque growth. Growth factors that are also elaborated in this proinflammatory milieu promote smooth muscle cell proliferation. Migration of smooth muscle cells from the media to the intimal surface leads to deposition of fibrous tissue, producing raised plaques protruding into the lumen⁸ (Figure).

In patients with hyperinsulinemia or excessive visceral fat, free fatty acids are released from adipocytes leading to hepatic VLDL overpopulation. The increase in triglyceride-rich particles enhances CETP mediated exchange of triglyceride for cholesteryl ester contained in HDL and LDL. The results are hypertriglyceridemic LDL and HDL particles that are further catabolized by hepatic lipase to small and dense cholesterol-depleted particles. Whether and to what extent particle compositional changes in LDL and/or HDL impact vascular disease rates if at all, however, remains controversial. Therefore, the best evidence supporting elevated trigylceride as it relates to CHD is due to its association with atherogenic remnant particles.

Chylomicron Remnant-Induced Development of Atherosclerosis

Figure. Chylomicron Remnant-Induced Development of Atherosclerosis
Figure. Chylomicron remanants may induce changes in endothelial cells and monocytes that cause monocyte rolling.

Image courtesy of Kenneth C, Yu W. Postprandial lipoproteins and atherosclerosis. Front Biosci. 2001;6:D332-54.

Mixed hyperlipidemia

Clinicians should recognize that elevated triglyceride levels are often accompanied by mixed hyperlipidemia, defined as elevations in LDL and triglyceride, often with reciprocal low HDL. In some cases however, elevated triglycerides remain an independent risk factor for CHD after adjustment for HDL. For example, in the Baltimore Coronary Observational Long-Term study (COLTS), 740 patients presenting for coronary arteriography between 1977 and 1978 were followed for 18 years. Of these, 350 had arteriographically defined CAD, and 199 events occurred during the follow-up period. The mean LDL and HDL levels were 153 mg/dL and 35 mg/dL in CAD patients compared to 149 mg/dL and 39 mg/dL in controls. Moreover, triglyceride levels were 160 mg/dL among CAD patients (consistent with a pattern of mixed hyperlipidemia) vs. 137 mg/dL among controls (P =.03). Patients with triglyceride levels of 100 mg/dL had significantly reduced CAD event survival compared with those with triglyceride levels of <100 mg/dL (P =.008).¹⁰

Moreover, a subanalysis of the Helsinki Heart Study demonstrated that the group at highest risk of initial CHD events were placebo-treated patients with triglyceride levels >204 mg/dL and an LDL/HDL ratio >5. This group evidenced approximately three times as many events than those more favorable LDL/HDL ratios.

In the Scandinavian Simvastatin Survival Study, in which all patients had high LDL (mean = 190 mg/dL), the highest event rates were observed in association with elevated triglycerides and low HDL. Specifically, the 5-year event rate in untreated patients was 35.9% as compared to the 20.9% event rate with isolated elevation in LDL.¹¹ Once again, these results support the concept that patients at highest risk of CHD events (primary and recurrent events) barring monogenic abnormalities are those with mixed hyperlipidemia.

In a recent subanalysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy, the combination of low on-treatment LDL <70 mg/dL and triglyceride (<150 mg/dL) was associated with reduced death, myocardial infarction, and recurrent acute coronary syndrome (ACS) as compared to higher levels of each during the 2-year follow-up (HR 0.72, 95% CI 0.54 to 0.94, P = 0.017).¹²

In summary, the epidemiologic evidence supports triglycerides as associated with increased coronary risk owing to increases in atherogenic remnant particles. The higher risk is magnified when combined with elevated LDL. Conversely, lowering both LDL and triglycerides appears to be clinically superior to reduction of LDL alone following an acute coronary syndrome.

References

Third Report of the NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). Circulation. 2002;106:3143-3421.
Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007;30:162-172.
Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated lipoprotein(a) are risk factors for major coronary events in middle-aged men. Am J Cardiol. 1996;77:1179-1184.
Assman G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol. 1992;70:733-737.
Sarwar N, Danesh J, Elrlksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450-458.
Ooi TC, Cousins M, Ooi DS, et al. Postprandial remnant-like lipoproteins in hypertriglyceridemia. J Clin Endocrinol Metab. 2001;86:3134-3142.
Rosenson RS, Shott S, Tangney CC. Hypertriglyceridemia is associated with an elevated blood viscosity Rosenson: triglycerides and blood viscosity. Atherosclerosis. 2002;161:433-439.
Kenneth C, Yu W. Postprandial lipoproteins and atherosclerosis. Front Biosci. 2001;6:D332-D354.
Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation. 1990;82:495-506.
Miller M, Seidler A, Moalemi A, Pearson TA. Normal triglyceride levels and coronary artery disease events: the Baltimore Coronary Observational Long-Term Study. J Am Coll Cardiol. 1998;31:1252-1257.
Ballantyne CM, Olsson AG, Cook TJ, et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104:3046-3051.
Miller M, Cannon C, Murphy SA, Qin J, Ray KK, Braunwald E, for the PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low density lipoprotein cholesterol after an acute coronary syndrome in the PROVE IT-TIMI 22 Trial. J Am Coll Cardiol. 2008;51:724-730.