SEARCH STRATEGY AND SOURCES
A MEDLINE search was performed on the following MeSH terms: triglycerides (MeSH) plus randomized controlled trial, meta-analysis, review, and guideline. The databases National Guideline Clearing House, UpToDate, and the Cochrane Database were used as references.
DETAILS
The role of lipids as an important factor in the pathogenesis of heart disease has now been firmly established. The prevention and treatment of CHD are closely linked to decreasing the amount of lipids with diet, exercise, and pharmacological agents. Clinicians are routinely evaluating patients for their risk of CHD. Most screening tests for the elevation of plasma lipids include total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglyceride levels. It is generally accepted that elevations in levels of total cholesterol and LDL cholesterol and a reduction in the level of HDL cholesterol place patients at a higher risk of initial and subsequent cardiac events. The importance of an isolated triglyceride elevation is much less clear.
Much of this uncertainty stems from the complexity of triglycerides themselves. All dietary fats are initially hydrolyzed in the intestine by pancreatic lipase, then transported by chylomicrons into the bloodstream where fatty acids interact with lipoproteins. Lipoproteins aid activating enzymes such as lipoprotein lipase, or they bind with receptors on cell membranes. Triglycerides are heterogeneous, composed of complex aggregates of lipoproteins. Hypertriglyceridemia actually reflects the buildup of triglyceride-containing lipoproteins, such as very low-density lipoproteins, intermediate-density lipoproteins, and chylomicrons. These lipoproteins also aid in cholesterol transport.
Therefore, the degree of hypercholesterolemia is unavoidably linked to the triglyceride level. Cholesterol level elevation is more likely to occur when triglycerides consist of small very low-density lipoprotein or intermediate density lipoprotein particles that contain more cholesterol. Inversely, hypertriglyceridemia has less of an effect on cholesterol levels when the triglycerides contain chylomicrons and large very low-density lipoprotein particles that are low in cholesterol.1 Also, patients with insulin resistance exhibit a dyslipidemia made up of hypertriglyceridemia, high LDL levels, and low HDL levels.2 Apparently, insulin resistance leads to derangements of lipid metabolism, again demonstrating the complex interrelationship of lipids and lipid function. Many studies are currently underway to determine which of these lipoproteins contribute to atherogenesis. This may lead to fractionating triglycerides to determine whether a patient has triglycerides that are atherogenic or harmless. In the future, triglycerides may be divided into good or bad triglycerides, and hopefully the indication to treat will be less confusing.
In addition to biochemical evidence, several recent clinical studies have supported the role of triglyceride levels as a possible independent risk factor for CHD. A large meta-analysis of population-based, prospective studies demonstrated that triglyceride levels are a predictor of CHD,3 even after adjusting for low HDL and other risk factors (relative risk for men, 1.14; for women, 1.37). The Helsinki Heart Study4 showed that the patient population at highest risk of having CHD had elevated triglyceride levels and a high LDL/HDL ratio (relative risk, 3.8). Patients with elevated triglyceride levels and an LDL/HDL ratio in the reference range, however, did not have a significant risk for CHD (relative risk, 1.1). In the Copenhagen Male Study,5 there was a gradient increase in rates of CHD as triglyceride levels increased, even after adjustment for major CHD risk factors, including high LDL cholesterol levels. Thus, evidence is strong that hypertriglyceridemia is a risk factor for CHD, but since it is typically associated with other risk factors, the strength of its contribution to atherosclerosis is uncertain.
This leads to the most important question. Does treating elevated triglyceride levels lower the risk for CHD? There is a modest amount of evidence from several studies that indirectly indicates that treatment may be beneficial. In the Helsinki study,4 those high-risk patients with elevated triglyceride levels and LDL/HDL ratio showed benefit from gemfibrozil therapy. These patients had a 9% absolute risk reduction in cardiac events, but decreased mortality was not demonstrated.4 The Bezafibrate Coronary Angiographic Intervention Trial6 studied young male survivors of myocardial infarction who had elevated cholesterol and triglyceride levels. Patients randomized to treatment with bezafibrate had an 18% absolute risk reduction in cardiac events, even though mean LDL levels did not change. Triglyceride levels, however, fell markedly (31%), and HDL levels increased 9% in the treatment group.
Given the scant evidence for treatment, recommendations from guidelines and experts vary. Certain conditions, such as diabetes, hypothyroidism, obesity, renal disease, and heavy alcohol intake, have been shown to cause or exacerbate hypertriglyceridemia.1 These conditions should certainly be treated before considering drug therapy. Patients with extremely high triglyceride levels (>11.29 mmol/L [>1000 mg/dL]) need treatment with fibrates to avoid acute pancreatitis or other manifestations of the chylomicronemia syndrome. Recommendations for screening or treating isolated hypertriglyceridemia are limited. The National Cholesterol Education Program Adult Treatment Panel does not recommend drug therapy for hypertriglyceridemia except in familial dyslipidemias.7 The American College of Physicians does not recommend screening for hypertriglyceridemia.8 The US Preventive Services Task Force does not recommend for or against screening for elevated triglyceride levels.9 Several recent consensus and review articles recommended using fibrates in patients with severe hypertriglyceridemia and in those with both elevated triglyceride levels and a high risk for CHD.10-11
Thus, for patients who have mild to moderate elevation of triglyceride levels, treatment should be tailored to lowering their LDL cholesterol levels. Triglyceride levels may decrease with the treatment of elevated cholesterol levels without resorting to medications. Treating patients with isolated hypertriglyceridemia is controversial. Dietary changes should be the first line of therapy. If one elects to use medications, fibrates are the most effective drugs for lowering triglyceride levels but are not risk free (one study with clofibrate actually showed it to result in increased mortality over placebo12). Combining fibrates with statins for combined hyperlipidemia is used by some clinicians, but this increases the rate of myopathy.13 More studies are underway to investigate the clinical benefit of lowering the triglyceride level with medications.11
BOTTOM LINE
There is certainly evidence that high triglyceride levels can predict a risk for CHD, but the clinical importance is not yet known. There is currently no definitive evidence that treating isolated hypertriglyceridemia reduces morbidity or mortality. Some authors have recommended treating hypertriglyceridemia in certain high-risk patients, but these high-risk groups are not well defined.
