A series of recently published articles have shown that high triglyceride levels are independently associated with increased risk of all-cause mortality and coronary heart disease. The question is, what to do to mitigate the increased risk. A recent related study. The BIP study, published March 8 in Circulation, analyzed data from 15,355 patients with coronary heart disease followed for 22 years and found that fasting triglyceride levels were independently associated with increased mortality. The investigators said that even after correcting for high-density lipoprotein cholesterol (HDL-C) and non-HDL-C levels, elevated triglyceride levels were still linearly associated with mortality. In addition, individuals with normal triglyceride levels (100 to 149 mg/dl) had a significant 68% increased risk of death during long-term follow-up compared with those with lower triglyceride levels (100 to 149 mg/dl), suggesting that the current definition of the threshold for high triglyceride levels in patients with coronary artery disease may be higher than expected. Two studies published March 2 in the New England Journal of Medicine (NEJM) provide evidence of a causal relationship between plasma triglyceride levels and coronary heart disease, pointing to mutations in the gene encoding angiopoietin-like protein 4 (ANGPTL4), which is associated with low plasma triglyceride levels and low risk of coronary heart disease.ANGPTL4 is an inhibitor of lipoprotein lipase, the enzyme responsible for degrading and removal of blood triglycerides. In the first study, which included nearly 43,000 subjects of European ancestry, triglyceride levels were 13% lower and HDL-C levels were 7% higher in individuals carrying the ANGPTL4 mutation (i.e., E40K) than in those without the mutation. Importantly, the risk of coronary heart disease was 19% lower in those carrying the E40K variant than in those who did not. The study also found that a human monoclonal antibody to ANGPTL4 lowered triglyceride levels in an animal model, but side effects were also observed. The second study involved the sequencing of 13,715 genes, including 72,868 patients with coronary heart disease and 120,770 healthy controls. Again, lower triglyceride levels were found to be associated with a reduced risk of coronary heart disease in individuals carrying the ANGPTL4 mutation. The open question. In response to the BIP study, Professor Michael Miller of the University of Maryland School of Medicine commented that this is the first study to find that triglyceride levels predict all-cause mortality, and noted that after triglyceride levels >100 mg/dl, the overall all-cause mortality risk increases by approximately 5% to 10% for each 50 mg/dl increase, which is not trivial. Whereas Professors Karol Watson and Philipp Wiesner of the University of California, Los Angeles, commented that 22 years of follow-up demonstrated that triglyceride levels may be used as a target to improve patient outcomes in the future, drugs targeting elevated triglyceride levels have not been successful in reducing cardiovascular event rates based on the available evidence. For example, the ACCORD study, the AIM-HIGH study, and the Cardioprotection Study2 all found no meaningful benefit from drugs that increased elevated HDL-C levels and lowered triglyceride levels in patients who were well treated with statins. The results of these studies do not support the hypothesis that triglyceride-lowering drugs reduce cardiovascular events in statin-treated patients. Professor Miller agrees, but also points out that none of these studies were designed to assess hypertriglyceridemia, so there is a need to sort out individuals with high triglyceride levels and often low HDL-C levels, and those subgroups that tend to have a high risk of cardiovascular events and respond to medications. The real question is, if a trial is conducted on a hypertriglyceridemic population, can it be demonstrated that lowering triglyceride levels above or below the therapeutic standard makes a difference? Triglyceride levels and cardiovascular disease. Currently, the U.S. Food and Drug Administration (FDA) does not consider a change in triglyceride levels to be sufficient to demonstrate that a drug is effective, i.e., it cannot be shown to reduce cardiovascular risk in patients with triglyceride levels <500 mg/dl. U.S. clinical guidelines in cholesterol management also do not recommend the addition of triglyceride-lowering drugs to conventional therapy in statin-treated patients with elevated triglyceride levels. The guidelines suggest that the focus of cardiovascular risk reduction should be on lowering dense lipoprotein cholesterol and statin therapy. Professor Miller said that the available evidence consistently demonstrates that elevated triglycerides can increase cardiovascular risk, but whether this causes cardiovascular disease has been controversial in the past, in part because early epidemiology focused only on triglycerides themselves. However, it does not cause atherosclerosis by itself, but rather when triglyceride-rich lipoproteins are degraded, the byproduct is more than the substance. The family of proteins associated with triglyceride levels, triglyceride-rich lipoproteins and triglyceride metabolites all have an impact on cardiovascular risk. Finally, Professor Miller says that optimal triglyceride levels may be at 100 mg/dl or even lower. He currently treats patients with triglyceride levels >200 mg/dl in an approach that involves a wide range of lifestyle changes. For patients with triglyceride levels of 120 mg/dl, 150 mg/dl or 180 mg/dl, Professor Miller recommends calorie/carbohydrate restriction, weight loss, increased fish intake, increased physical activity and better glycemic control. By doing these, patients’ triglyceride levels can be reduced by nearly half.