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Is triglyceride therapy worth the effort?

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ABSTRACTA scientific statement from the American Heart Association notes that triglyceride levels are an important biomarker of cardiovascular disease risk. Although as yet there is no evidence that lowering elevated triglyceride levels reduces cardiovascular risk, the statement recommends that patients undertake weight loss and dietary changes if fasting levels exceed 150 mg/dL, and that the intensity of these lifestyle measures be increased with higher triglyceride levels. Aerobic activity at least twice a week is also encouraged. Drug therapy is indicated for levels exceeding 500 mg/dL because of an association with pancreatitis.

KEY POINTS

  • Triglycerides are an excellent marker of coronary heart disease risk and should be treated when fasting levels exceed 150 mg/dL.
  • The cornerstone of therapy for triglyceride levels up to 500 mg/dL is intensive lifestyle therapy aimed at reducing excess weight through diet and aerobic activity.
  • Drug therapy with fibrates, niacin, and omega-3 fatty acids is indicated for levels exceeding 500 mg/dL because of concern related to pancreatitis risk.
  • It remains to be established whether lowering elevated triglyceride levels in patients with coronary heart disease or at risk of it will translate into clinical benefit. However, two studies are under way.


 

References

Triglyceride levels do matter. Not only are they a marker of risk of cardiovascular disease, they may be mechanistically linked to it. Although we still lack evidence that specifically lowering elevated triglyceride levels reduces the risk of cardiovascular disease, the reason is that controlled trials have not yet been done. Such studies are under way to determine whether fish-oil-derived omega-3 preparations added to statin therapy can reduce coronary heart disease risk in high-risk patients with hypertriglyceridemia.

POSSIBLY MECHANISTICALLY LINKED TO CORONARY HEART DISEASE

Hypertriglyceridemia does not cause atherosclerosis directly, but there is evidence that it is mechanistically linked to it.

While lipolysis of triglyceride-rich lipoproteins, chylomicrons, and very-low-density lipoprotein cholesterol serves as a mammalian source of energy, the cholesterol-enriched byproducts are atherogenic.1 The higher the triglyceride level, the greater the likelihood of accumulation of atherogenic remnant particles.2 A high-triglyceride state, defined as a fasting level greater than 200 mg/dL, is associated with several atherogenic factors:

  • Higher levels of apolipoprotein C3-containing particles, which promote inflammation and insulin resistance3
  • A higher concentration of atherogenic low-density lipoprotein cholesterol (LDL-C) particles4
  • Dysfunctional high-density lipoprotein cholesterol (HDL-C) particles.5

In general, the risk of death from cardiovascular disease is 25% higher with triglyceride levels above 200 mg/dL than with levels below 150 mg/dL.6 Hypertriglyceridemic phenotypes, most notably dysbetalipoproteinemia and mixed hyperlipidemia, may be particularly atherogenic in the presence of other risk factors for cardiovascular disease.7

LOW LEVELS ARE BEST

In US adults, the mean age-adjusted triglyceride level is 128 mg/dL in men and 110 mg/dL in women.1 Currently, a “desirable” fasting level is less than 150 mg/dL, with borderline-high levels between 150 and 199 mg/dL. In its 2011 scientific statement on triglycerides and cardiovascular disease,1 the American Heart Association defined a fasting triglyceride level of less than 100 mg/dL as “optimal” in order to define a metric of metabolic health.

Supporting the concept that low levels are best, a study of 1,962 middle-aged Norwegian men found that the risk of incident diabetes over a 7-year period was 2.6 times lower in the lowest triglyceride tertile (mean 69 mg/dL) compared with levels in higher tertiles (mean 177 mg/dL).8

The higher the triglyceride level, the more likely that atherogenic remnant particles will accumulate

Moreover, in contrast to the atherogenic phenotype of combined or mixed hyperlipidemia, levels below 100 mg/dL seem to pose a low risk of cardiovascular disease as seen in studies of hunter-gatherer populations.9 Recent genetic studies have extended these findings: specifically, mutations in the gene encoding apolipoprotein C3 (APOC3) have been associated with fasting triglyceride levels less than 100 mg/dL, reduced coronary calcification,10 and decreased risk of cardiovascular disease.11,12

The Baltimore Coronary Observational Long-term Study observed a 50% lower rate of recurrent coronary heart disease events in patients whose baseline triglyceride level was less than 100 mg/dL compared with higher levels.13 In the Copenhagen Heart Study,14 levels in the lowest quartile (< 89 mg/dL) were associated with a 41% lower risk of all-cause mortality compared with the highest quartile (> 265 mg/dL).

The Framingham Offspring Study15 recently reported that an isolated low level of HDL-C—ie, below the median of less than 42 mg/dL in men and less than 54 mg/dL in women—was associated with a very low risk of incident coronary heart disease when accompanied by a triglyceride level below 100 mg/dL and an LDL-C level below 100 mg/dL. However, at higher levels of triglyceride and LDL-C, the risk of myocardial infarction or death from cardiovascular disease was more than twice as high after adjustment for other covariates.15 This raises the possibility that “isolated” low HDL-C itself is not an atherogenic lipoprotein phenotype, but rather requires other triggers (eg, an increase in triglyceride-rich and LDL-C particles) to drive the process.

WHERE DO TRIGLYCERIDES FIT IN THE NEW CHOLESTEROL GUIDELINES?

The 2013 joint guidelines of the American College of Cardiology and the American Heart Association on the treatment of blood cholesterol16 provide evidenced-based recommendations from randomized clinical trials. While they recommend measuring the fasting triglyceride level if nonfasting levels exceed 500 mg/dL, there are no recommendations for triglyceride-lowering therapies unless fasting levels exceed 500 mg/dL.

This in no way implies that lowering triglyceride levels may not be beneficial when levels are below 500 mg/dL; rather, it stems from a lack of clinical trials designed to address this issue. That is, studies of triglyceride-lowering therapies such as niacin, fibrates, and omega-3 fatty acids from fish oil have focused on patients who did not have hypertriglyceridemia (mean triglyceride levels were less than 200 mg/dL). Yet in subgroup analyses of patients with triglyceride levels greater than 200 mg/dL or in the upper tertile (often in association with low levels of HDL-C), either a trend toward or a statistically significant reduced risk of cardiovascular disease was observed.17–19

Until results of ongoing randomized controlled trials dictate otherwise, it may be reasonable to consider drug therapy in patients at high risk (eg, those with preexisting cardiovascular disease) whose levels may be insufficiently responsive to lifestyle measures (see discussion below) after the risks of treatment are weighed against the possible benefits.

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