Elevated Triglycerides Linked to All-Cause Mortality and Coronary Artery Disease

A series of papers published recently, including one assessing clinical outcomes over a two-decade timespan, suggests that higher triglyceride levels are independently associated with an increased risk of all-cause mortality and coronary artery disease.

The question, experts say, is what should be done to mitigate that increased risk. 

In an analysis of 15,355 patients with established coronary heart disease screened for enrollment in the Bezafibrate Infarction Prevention (BIP) study, higher fasting triglyceride levels were independently associated with an increased risk of death after 22 years of follow-up, report investigators.

Published March 8, 2016, in Circulation: Cardiovascular and Quality Outcomes, Robert Klempfer, MD (Sheba Medical Center, Tel-Hashomer, Israel), and colleagues report that even after adjusting for HDL and non-HDL cholesterol, the “association between elevated triglyceride levels and death is graded in a dose-response manner.”

Moreover, they also showed that individuals with normal triglyceride levels—defined as 100 to 149 mg/dL—had a significant 68% increased risk of death during long-term follow-up compared with individuals with low triglyceride levels (< 100 mg/dL), suggesting the current threshold for defining high triglyceride levels in CHD patients may be higher than desired. 

Michael Miller, MD (University of Maryland School of Medicine, Baltimore), who was not involved in the analysis, told TCTMD that the study is the first time, to his knowledge, a study showed that elevated triglyceride levels predicted all-cause mortality. “The other thing to take home here is that for each 50 mg/dL increment in triglyceride levels above 100 mg/dL, the overall risk of all-cause mortality was somewhere around 5% to 10% higher,” he said. “It’s not trivial.”

In two other studies published March 2, 2016, in the New England Journal of Medicine, investigators provided further evidence of a causal role of plasma triglyceride levels in coronary heart disease. In those studies, genetic mutations in ANGPTL4, a gene that encodes for angiopoietin-like 4, were associated with low plasma triglyceride levels and a lower risk of coronary artery disease. Angiopoietin-like 4 is an inhibitor of lipoprotein lipase, the enzyme responsible for breaking down and removing triglycerides from the blood. 

In the first analysis, which included approximately 43,000 participants of European ancestry, individuals carrying the ANGPTL4 mutation, known as E40K, had triglyceride levels 13% lower and HDL cholesterol levels 7% higher than individuals without the mutation. Importantly, those with the E40K variant had a 19% lower risk of coronary artery disease than noncarriers. The study, conducted via a partnership between Regeneron Pharmaceuticals and researchers from Geisinger Health System, also showed that a human monoclonal antibody to the angiopoietin-like 4 protein reduced triglyceride levels in an animal model, but side effects were observed. These included mesenteric lymphadenopathy.

The second study, which was led by Nathan Stitziel (Washington University School of Medicine, St. Louis, MO), involved the sequencing of 13,715 genes in 72,868 patients with coronary artery disease and 120,770 healthy controls. Similarly, investigators reported reductions in triglyceride levels and reduced risk of coronary disease in those with ANGPTL4 mutations.

Unanswered Questions Remain  

In an editorial accompanying the BIP analysis, Karol Watson, MD, and Philipp Wiesner, MD (University of California, Los Angeles), say the 22-year-old follow-up provides evidence that triglycerides should be taken “more seriously” as a future target to improve patient outcomes. But based on evidence available to date, targeting elevated triglycerides pharmacologically has failed to lower risk of cardiovascular events, they note. For example, ACCORD, AIM-HIGH, and Heart Protection Study 2 all showed that adding a drug—agents that raised HDL cholesterol and lowered triglycerides, in these instances—failed to provide any meaningful benefit in patients well treated with statin therapy.

“The results of these outcome trials fail to support the hypothesis that a triglyceride-lowering drug reduces the risk for cardiovascular events among statin-treated patients—or at least the drugs that were studied in those trials,” write Watson and Wiesner.

To TCTMD, Miller agreed there is no evidence to date showing that lowering triglyceride above and beyond lowering LDL cholesterol levels with statin therapy reduces cardiovascular events.

“Keep in mind that none of these studies were specifically designed to evaluate a hypertriglyceridemic population,” said Miller. “Therefore, they had to tease out individuals who had high triglycerides, often with low HDL cholesterol levels, and those subgroups tend to be at higher risk of cardiovascular events and do respond to medication. The real question as we move forward is, if we test hypertriglyceridemic groups, will you be able to show that lowering triglycerides above and beyond standard of care make a difference? Herein lie the ongoing omega-3 fatty acid studies.”

The Relationship Between Triglycerides and CVD

Taken altogether, Miller said, the body of evidence is consistent in showing that increased triglyceride levels are associated with increased cardiovascular risk, but whether or not they cause cardiovascular disease has been controversial and debated in the past. Part of the problem, he noted, is that early epidemiologic studies focused solely of triglycerides and not on the “company they keep.” Triglycerides themselves are not atherogenic, said Miller, but when triglyceride-rich lipoproteins, such as chylomicrons and very low-density lipoprotein (vLDL), are broken down one of the byproducts are remnant particles.

“Remnant particles are cholesterol-enriched byproducts of triglyceride-rich lipoproteins, and it turns out that remnant particles are atherogenic,” said Miller. Chylomicrons and vLDL contain apolipoprotein C3 (apoC3), which has been shown to induce inflammation and atherosclerosis, and mutations in the gene encoding for apoC3 have been associated with decreased triglyceride levels and a low risk of cardiovascular events, he noted.

“There is now a family of proteins associated with triglyceride levels, triglyceride-rich lipoproteins, and triglyceride metabolism that invariably appears to have an influence on vascular risk,” Miller explained.  

At present, the US Food and Drug Administration does not consider a change in serum triglyceride levels enough to prove the effectiveness of a drug intended to reduce cardiovascular risk in subjects with serum triglyceride levels less than 500 mg/dL. Current US clinical guidelines for the management of cholesterol also do not advocate the routine use of triglyceride-lowering medications on top of statin therapy in patients with elevated triglycerides. In the guidelines, the focus is on LDL cholesterol and statin therapy to reduce cardiovascular risk.

To TCTMD, Miller said the optimal triglyceride level is likely around 100 mg/dL, possibly even lower. At present, he treats individuals with triglyceride levels exceeding 200 mg/dL. Treatment involves extensive lifestyle modification, although he might consider adding a fibrate or omega-3 fatty acid if the patient also has diabetes. For the patient with triglyceride levels of 120, 150, or 180 mg/dL, Miller recommends caloric/carbohydrate restriction, weight loss, increasing fish consumption, increasing physical activity, and attempting to obtain better glucose control. In doing so, patients can nearly slice their triglyceride levels in half, he added.

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Sources: 
1. Klempfer R, Erez A, Sagit BZ, et al. Elevated triglyceride level is independently associated with increased all-cause mortality in patients with established coronary heart disease. Circ Cardiovasc Qual Outcomes. 2016;Epub ahead of print.
2. Watson KE, Wiesner P. Slippery slope of triglycerides. Circ Cardiovasc Qual Outcomes. 2016;Epub ahead of print
3. Myocardial Infarction Genetics and Cardiogram Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med. 2016;Epub ahead of print. 
4. Dewey FE, Gusarova V, O’Dushlaine C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med. 2016;Epub ahead of print.

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