Clinical Laboratory Strategies: March 27, 2008
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Linking Triglycerides to Recurrent Coronary Risk
Optimal Practice Involves Lowering LDL-C and Triglycerides
By Phil Kibak  

Low-density lipoprotein cholesterol (LDL-C) is the primary lipid target for cardiovascular risk reduction in patients who have experienced a heart attack, but emerging data suggest that the quest to reduce the rate of subsequent coronary episodes should not ignore other lipid indices. This issue of Strategies examines a recent study suggesting that lowering serum triglycerides to levels below 150 mg/dL in conjunction with lowering serum LDL-C to levels below 70 mg/dL cuts the risk of subsequent cardiac events to a greater degree than lowering LDL-C alone. The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction (PROVE IT-TIMI) 22 trial showed that heart attack survivors who received intensive drug therapy to lower LDL had significantly reduced chances of experiencing another heart attack or dying of coronary heart disease (CHD). Now, further analysis of data from the PROVE IT-TIMI 22 trial demonstrates that reducing serum triglycerides along with LDL-C appears to be a better strategy for treating heart attack survivors than just lowering LDL-C to therapeutic levels, a finding that strengthens the case for routinely measuring triglyceride levels (JACC 2008; 51:724–30).

A Therapy Built For Two

“No studies to date have examined whether lowering triglyceride levels beyond lowering LDL-C actually has an impact on CHD,” said lead study author Michael Miller, MD, Associate Professor of Medicine, Epidemiology, and Preventive Medicine and Director of the Center for Preventive Cardiology at the University of Maryland Medical Center in Baltimore, Md. “The National Cholesterol Education Program (NCEP) recommends that once you reduce LDL-C—the primary target of therapy—then you may consider a secondary goal, such as lowering non-high density lipoprotein cholesterol (HDL-C) . But this study suggests that reducing LDL-C and triglycerides together should be the main goal of lipid treatment. It strengthens the case for putting triglycerides and LDL-C together on the same, level playing field.”

In the original study—designed to assess the efficacy of two statin drugs to lower LDL-C— 4,162 men and women hospitalized for acute coronary syndrome (ACS) were randomly assigned to receive intensive cholesterol lowering therapy (atorvastatin 80 mg daily) or standard therapy (pravastatin 40 mg daily) for a mean follow-up period of 2 years. The new study analyzed the data to examine the association between serum triglyceride levels and the incidence of subsequent heart attack, recurrent ACS, and death. The scientists directly measured fasting total cholesterol, triglycerides, and high density lipoprotein (HDL-C) cholesterol and estimated LDL-C using the formula[total cholesterol – (triglycerides/5 +HDL-C)], or directly measured LDL-C if triglycerides exceeded 400 mg/dL. Measurements were obtained at baseline and at 1, 4, 8, 16, and 24 months.

“What was most surprising was that LDL-C remained associated with increased residual risk if accompanied by high triglycerides,” noted Miller. The study’s most noteworthy finding was a reduced risk of CHD in people whose serum triglyceride was less than 150 mg/dL, and this result was independent of LDL-C. For each 10 mg/dL decline in triglycerides there was an observed 1.6% lower risk of the composite end points after adjusting for LDL-C and other factors. In addition, the combination of LDL-C less than 70 mg/dL and triglycerides less than 150 mg/dL was associated with the lowest event rates compared with higher LDL-C levels, higher triglycerides, or both.

Blood Levels Don’t Tell the Whole Story

“Over the last decade there have been meta-analyses indicating that triglycerides clearly contribute to cardiovascular risk,” said G. Russell Warnick, MS, MBA, Chief Scientific Officer and Vice President for Lab Operations at the Berkeley Heart Lab in Alameda, Calif. “But triglycerides are metabolically quite variable in that they are very responsive to diet and other lifestyle factors. Therefore, an individual’s serum triglyceride levels can vary substantially from one measurement to the next.”

The guidelines for managing triglycerides and other lipoprotein constituents were set by the NCEP in 1985. The program initially recommended that serum triglyceride levels be no more than 250 mg/dL; the guidelines now recommend that serum triglycerides above 150 mg/dL constitute a potential cardiovascular risk factor.

But clinicians and laboratorians also have to consider factors other than just the serum level of triglycerides when thinking about the connection with cardiovascular risk, explained Warnick, who is a member of the AACC’s Lipoproteins and Vascular Diseases Division. “For decades the usual practice has been to measure fasting triglyceride levels to decrease variability and to capture results in a consistent state. Recently, however, a few high profile studies have shown that nonfasting triglycerides are more strongly associated with cardiovascular risk than fasting triglycerides.”

Yet another factor that affects the estimation of risk, he added, is the distribution of the various lipoprotein particles that includes very low density lipoprotein (VLDL-C) and small, dense LDL-C. “Some of these are quite atherogenic and others are not. After a meal, a lot of triglycerides are released in chylomicrons, which are relatively large particles but do not contribute greatly to the buildup of plaque in artery walls. But upon being metabolized, we find groups of what we call remnant particles that do contribute to heart disease risk. So it’s more than just determining serum triglyceride level, although that is straightforward, inexpensive, and can be somewhat useful. What’s much more informative is to determine the distribution of the various lipoprotein particles, but that’s generally done routinely only in a handful of specialty labs like ours.”

What’s Next?

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, a 10,000-person clinical trial sponsored by the National Heart, Lung, and Blood Institute, is looking at the best approaches to lower the risk of heart disease and stroke in adults with type 2 diabetes, said Miller. A portion of this study is comparing the effects of lowering LDL-C and serum triglycerides with an intervention that only lowers LDL-C, all in the context of good blood sugar control. Two types of drugs to treat hyperlipidemia—a fibrate drug to lower triglycerides and increase HDL cholesterol, and a statin drug to lower LDL-C—are being used in the trial, which is expected to end in 2009.

Warnick thinks that in addition to completing clinical studies to confirm if the combination of lowering LDL and triglycerides in tandem offers a benefit, trials also should focus on comparing fasting versus nonfasting triglycerides at various time intervals after defined fat loads and after representative meals. In an article in a recent issue of Clinical Chemistry (54: 2008; 14–16), he also suggested determining the effect of nonfasting collections on other laboratory measurements, especially important for lipoprotein parameters including the LDL-C calculation, HDL-C, and the lipoprotein subclasses. A third direction, he noted, would be to characterize the postprandial effects on contributions of mono- and diglycerides and free glycerol to triglyceride measurement and the CVD risk associations.

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