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Triglycerides: What the clinician must know
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The most recent scientific statement from the American Heart Association on triglycerides was published the week of April 17. It provides a useful review of the importance of triglycerides on cardiovascular health and an update on how to best manage patients with higher than normal triglyceride levels. The following is a summary for the clinician from this important document.
After ingestion of a meal, dietary fat and cholesterol are absorbed into the cells of the small intestine and are incorporated into chylomicrons. Chylomicrons, composed of 80% to 95% triglycerides, are secreted into the lymphatic system and then enter the circulation, where they are metabolized into free fatty acids and chylomicron remnant proteins by lipoprotein lipase on the surface of endothelial cells. They are then taken up by the liver, which synthesizes very low density lipoprotein (VLDL). The liver can also synthesize VLDL de novo from stored adipose tissue triglycerides. Therefore, the bulk of circulating triglycerides are present in the form of chylomicrons or VLDL.
Triglycerides are an important barometer of metabolic health. However, the ability of plasma triglyceride levels to predict CV disease remains controversial. Many early cohort studies have found a univariate association between triglycerides and coronary heart disease, but this association becomes nonsignificant after adjustment for other lipid fractions. Furthermore, most of these earlier studies did not measure HDL.
Early research
The first large meta-analysis of 17 prospective, observational studies of triglycerides and CHD events reported a RR per 89 mg/dL (1 mmol/L) of 1.14 (95% CI, 1.05-1.28) in men after adjustment for HDL and 1.37 (95% CI, 1.13-1.66) in women after adjustment for HDL. However, a recent meta-analysis from the Emerging Risk Factors Collaboration evaluated 302,430 people free of known vascular disease at baseline in 68 prospective studies and found an association with triglycerides and coronary artery disease and stroke that was not significant after adjusting for HDL and non-HDL.
It has been postulated that measurement of nonfasting triglycerides may give a more accurate assessment of risk for CAD because postprandial lipids triglyceride-rich remnant lipoproteins can penetrate the endothelial cell layer and reside in the subendothelial space, where they can contribute to the formation of atherosclerosis. Furthermore, observational studies have lent credence to this view by showing nonfasting triglyceride levels to be a superior predictor of CAD risk compared with fasting levels.
According to data from the National Health and Nutrition Examination Survey, 31% of the adult US population has a triglyceride level of at least 150 mg/dL. However, this survey shows that triglyceride levels vary according to ethnicity. In fact, Mexican-Americans have the highest rates of triglycerides (35.5%), followed by non-Hispanic whites (33%) and African-Americans (16%). The reason for this ethnic variation is currently not fully understood, but it is felt to be explained by a combination of environmental and genetic factors.
Triglyceride evaluation
The recent AHA scientific statement states that nonfasting blood can now be used to screen for high triglyceride levels. Given that a meal that contains up to 15 g of fat has been shown to be associated with an increase of 20% in peak postprandial triglycerides and that the median triglyceride levels in the US are 106 for women and 122 for men, a normotriglyceridemic patient would, therefore, not be expected to have nonfasting triglycerides of more than 200 mg/dL.
In fact, if the nonfasting triglycerides are more than 200 mg/dL, a fasting lipid profile is recommended within a month. Another possibility is to measure non-HDL, which can be assessed in the nonfasting state and is more accurately determined because it does not depend on fasting triglyceride concentrations, as is the case with calculated LDL. According to the Adult Treatment Panel III (ATP III) guidelines, non-HDL should serve as a secondary treatment target if elevated levels of triglycerides (≥200 mg/dL) persisted after LDL target levels had been achieved, with a non-HDL target that was 30 mg/dL higher than LDL.
According to ATP III guidelines, triglyceride levels are classified as normal (<150 mg/dL), borderline high (150 to 199 mg/dL), high (200 to 499 mg/dL), or very high (≥500 mg/dL) based on measurements after a 12-hour fast. However, the recent AHA scientific statement on triglycerides notes the low fasting triglyceride levels (ie, <100 mg/dL) that are commonly found in countries at relatively low CAD risk (eg, Africa, China, Greece and Japan) compared with the US, where mean levels are 15% to 30% higher. For this reason, the recommendation is for an optimal fasting triglyceride level of less than 100 mg/dL and an optimal nonfasting triglyceride level of less than 150 mg/dL.
The AHA statement indicated that a triglyceride level of less than 100 mg/dL is not a therapeutic target because there is insufficient evidence that lowering triglyceride levels improves CAD risk prediction beyond LDL and non-HDL target goal recommendations. Rather, similar to the new AHA women’s guidelines that indicate that women with a Framingham risk score of at least 10% are at high (lifetime) risk for CV events — but this risk level should not necessarily trigger aspirin or statin therapy — the hope is that this new optimal level would help encourage appropriate lifestyle changes.
Effect of lifestyle adjustments
It is well known that simple sugars (foods high in fructose such as non-diet soda, corn syrup, table sugar, honey, apples, raisins and chocolate bars), saturated fats, and trans-fats raise triglyceride levels, whereas weight loss or use of unsaturated fats, especially those containing marine omega-3 fatty acids, lower triglyceride levels. Furthermore, consuming too many simple sugars, refined grains (eg, white rice, white bread) and alcohol will increase triglyceride levels for those who have not been diagnosed with triglycerides outside the normal range.
A weight loss of 5% to 10% generally results in an approximate 20% decrease in triglycerides, 15% in LDL and an 8% to 10% increase in HDL. Mediterranean-style diets, as well as diets high in fiber, have also been associated with lower triglyceride levels. Overall, adopting and maintaining healthy lifestyle measures (ie, diet and physical activity) are very effective and can lower triglyceride levels by up to 50%.
Ongoing studies
Triglyceride elevations (levels more than 1,000 mg/dL) are associated with acquired causes such as poorly controlled diabetes, medications such as steroids or estrogens, and/or poor diet with excess alcohol, and especially if there is an underlying genetic disorder of triglyceride metabolism. Pharmacologic therapy to lower triglyceride levels has not been shown to improve outcomes, except for the subgroup of patients with triglyceride levels of more than 204 mg/dL and HDL of less than 34 mg/dL, as shown in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. However, it is noteworthy that the average triglyceride level in this trial was relatively low at 165 mg/dL.
As illustrated in the ACCORD trial, lowering triglyceride levels beyond LDL has not been shown to reduce the risk for heart disease. Moreover, more research is needed to validate triglycerides as an independent risk factor for CVD. Two ongoing trials, AIM-HIGH and HPS2-THRIVE, are currently testing whether combining statin therapy with a niacin formulation improves CV outcomes. It will be interesting to see how the CV outcomes in the subset of patients with high triglycerides in these trials compare with the rest of the patients.
The results of these studies promise to inform our current understanding of triglyceride pharmacotherapy, but for now, triglycerides can serve as an important motivator to help our patients make better lifestyle choices, thereby improving their overall CV health.
For more information:
- Bansal S. JAMA. 2007;298:309-316.
- Di Angelantonio E. JAMA. 2009;302:1993-2000.
- Ginsberg H. N Engl J Med. 2010;362:1563-1574.
- Hokanson J. J Cardiovasc Risk.1996; 3:213-219.
Jose Vargas, MD, DPhil, is a cardiology fellow at the Johns Hopkins University Heart and Vascular Institute.
Roger S. Blumenthal, MD, is a professor of medicine at Johns Hopkins University Medical School and is director of the Ciccarone Center for the Prevention of Heart Disease.
Disclosures: Drs. Blumenthal and Vargas report no relevant financial disclosures.