In patients with very high levels of triglycerides (TGs; e.g., ≥500 mg/dL), the national guidelines are to treat the TGs first and then attack the low-density lipoprotein (LDL) cholesterol and then levels of non–high-density lipoprotein (HDL) cholesterol. This makes sense, as patients with very high TGs are at high risk of pancreatitis, besides adding to the risk of developing CHD.

However, for the very large number of patients with CHD or who are at high risk for CHD who also have lesser degrees of high TGs (200-499 mg/dL) and/or low levels of HDL—and high TGs and low HDL usually occur in combination—there remains some controversy on how to proceed beyond optimally treating levels of LDL. There is no doubt that some of these controversies have been delaying the release of the National Cholesterol Education Program's (NCEP) new recommendations (NCEP IV). For patients with CHD or high risk for CHD, NCEP III recommended lowering LDL levels to <100 mg/dL, and many of us strive for the "optional" goal of getting LDL <70 mg/dL or as close as possible. Notably, the major Treatment to New Targets (TNT) trial barely obtained LDL levels <80 mg/dL on those treated with the intensive 80 mg atorvastatin dose.

Nevertheless, despite quite good levels of LDL-C, many patients continue to have high residual risk. In fact, in the TIMI 22 trial (PROVE-IT), the 2-year major clinical event rate >20%, even in those who had an average LDL-C of only 62 mg/dL and treated with atorvastatin 80 mg. A 2008 paper from Mike Miller, MD, in JACC showed that patients with LDL <70 mg/dL still had substantial residual risk when TGs were elevated. Likewise, data from Philip Barter, MD, a few years ago in The New England Journal of Medicine show that patients with LDL <70 mg/dL but low HDL-C values, usually treated with atorvastatin 80 mg dose in the TNT trial, continued to have considerably higher risk than those with higher levels of HDL. These data supported efforts to treat high TGs/low HDL with agents such as fibrates and niacin.

However, a few years ago the ACCORD-LIPID trial assessed the impact of adding the fibrate, fenofibrate, to statin therapy in high-risk diabetic patients. The conclusion of the abstract of this paper, published in NEJM, basically said that fenofibrate provided no benefit for diabetic patients treated with statins. The media reports that followed were much crueler to fenofibrate, suggesting that this medication was worthless! However, in this trial, the average TG level was about 160 mg/dL, and HDL values were in the upper 30s. In clinical practice, most patients who were prescribed fenofibrate had much higher TGs and lower levels of HDL. In fact, in this trial, the 17% of patients with high TGs and low HDL (lipid values consistent with those patients who clinicians treat with fenofibrate), actually had well over 30% reductions in major events with fenofibrate.

Likewise, the AIM-HIGH trial published more than a year ago in NEJM suggested that niacin offered no benefits for CHD patients on statins (and at times, ezetimibe) with LDL averaging just over 70 mg/dL. I feel that this study should have been continued for much longer; the original trials to lower LDL took many years before clinical event reductions were noted, but AIM-HIGH was stopped after <3 years. A recent JACC paper by Drs. Lavigne and Karas of 11 trials of almost 10,000 patients on niacin, including the AIM-HIGH trial, demonstrated a nearly 30% clinical event reduction with niacin.

Although the recent HPS-THRIVE II trial was also a disappointment, I discuss in editorial comments in an upcoming JACC that the findings from this study are likely due to the adverse effects of the anti-flushing agent, laropiprant, and not necessarily niacin. There will be more to follow on this, and I predict that subgroup studies of AIM-HIGH will also show greater benefits in those with high TGs and low levels of HDL treated with niacin.

Additionally, high-dose omega-3 fatty acids can also be used to treat TGs, especially when levels are extremely high (but modest benefits can be obtained with moderately elevated TGs 200-499 mg/dL). The combination of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also leads to increases in HDL, whereas HDL remains unchanged or slightly falls with EPA alone (although this latter omega-3 does not lead to increases in LDL). Although clinical event data on lower doses of omega-3 in various clinical situations are available (these results are controversial, but even the recent meta-analysis in JAMA suggests modest benefits, in my opinion, for such a cheap and benign therapy), clinical event data about the higher doses used to treat very high TGs are not yet available. Nevertheless, this remains another option, as omega-3 can easily and safely be combined with almost every other therapies.

For now, clinicians should continue to aggressively treat LDL with intense doses of statins. As we anxiously await NCEP IV, continued attention directed at non-HDL, TGs, and HDL will likely prevail in primary and, especially, secondary CHD intervention.

References

Lavigne PM, Karas RH. J Am Coll Cardiol. 2013;61:440-46.

Lavie CJ, DiNicolantonio JJ, Milani RV, O'Keefe JH. J Am Coll Cardiol. 2013, in press.

Lavie CJ, Milani RV, Mehra MR, Ventura HO. J Am Coll Cardiol. 2009;54:585-94.

Mozaffarian D, Wu JH. J Am Coll Cardiol. 2011;58:2047-67.

Chip J. Lavie, MD, is medical director of cardiac rehabilitation and director of exercise laboratories at the John Ochsner Heart and Valvular Institute at the University of Queensland School of Medicine in New Orleans. Dr. Lavie also works in the department of preventive medicine at the Pennington Biomedical research Laboratory in Baton Rouge.

Keywords: Lipoproteins, LDL, Pyrroles, Cholesterol, Trinitrotoluene, Azetidines, Pancreatitis, Fatty Acids, Omega-3, Indoles, Heptanoic Acids, Lipoproteins, HDL, Triglycerides

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