The following are key points to remember from this clinical review on triglycerides:

1. Recent epidemiologic and genetic studies establish triglyceride (TG)-rich lipoproteins (TRLs) and their remnants (very low-density lipoprotein [VLDL] and VLDL remnants which are smaller and cholesterol rich) as important contributors to atherosclerotic cardiovascular disease (ASCVD), as well as a causative for pancreatitis. Elevated nonfasting TGs are associated with a marked increase in ASCVD and all-cause mortality. TGs >250 mg/dl in 40- to 65-year-olds have a similar ASCVD risk as those who are statin eligible (European guidelines), and TG levels are independent predictors of long- and short-term ASCVD risk in post–acute coronary syndrome patients treated with statins. In support of the findings is that loss of function mutations in apolipoproteins responsible for clearance of VLDL TG-rich particles is associated with low TG levels and reduction in ASCVD, which has led to novel gene targets to reduce ASCVD including apo C-3 and ANGPTL3. Importantly, it appears TGs per se are not the culprit. The correlation of TGs with ASCVD risk is lost or attenuated, adjusting for non–high-density lipoprotein cholesterol or apo B, which is on the surface of each of the atherogenic lipoprotein particles.
2. Increased VLDL production is the most common trigger for hypertriglyceridemia (HTG). Endothelial-derived lipoprotein lipase (LPL) and hepatic lipase lipolysis and rate of uptake of VLDL remnant particles determine the levels of fasting and post-prandial TG, and its inherited capacity determines the steady-state levels.
3. Primary causes of severe HTG include the very rare familial chylomicronemia, which is due to a mutation at one or more of five sites or multifactorial or polygenic chylomicronemia inferring several small-effect TG-raising polymorphisms. Mild to moderate HTG (200-1000 mg/dl) is multifactorial, polygenic, or familial HTG, dysbetalipoproteinemia usually with apo E2/E2, and familial combined hyperlipidemia, which is polygenic with variable elevation of LDL cholesterol and TGs depending on genetic risk and secondary factors (e.g., diabetes, diet). Secondary causes of HTG include diet high in fat and/or high glycemic index; alcohol defined as >1 drink in women and >2 in men; metabolic syndrome and insulin resistance; diabetes; hypothyroid; renal disease; pregnancy; paraproteinemias and systemic lupus erythematosus; and medication such as steroids, estrogens, bile-acid sequestrants, proteinase inhibitors, and second-generation anti-psychotics.
4. Pancreatitis is rare in absolute terms in those with less than severely elevated TGs (3% in 1000-2000 mg/dl, and 15% with levels above 2000 mg/dl). The mechanism of pancreatitis related to severe HTG is not clear, but has been thought related to change in local pH due to free fatty acids, and inflammation associated with HTG. For severe HTG and fasting chylomicronemia, total fat should be reduced to <30 g/day. Treatment for TG-associated acute pancreatitis includes fluids with saline and not intravenous glucose, insulin in uncontrolled diabetes, and plasmapheresis in pregnancy.
5. The most important and first step to reducing TGs is lifestyle by nutrition and exercise, and abstinence of alcohol. TGs are lowered by approximately 8 mg/dl/kg of weight loss, about 10-20% with aerobic exercise, and 10-15% with n-3 polyunsaturated fatty acids from fish and flaxseed. Diet principles include to reduce net caloric intake, low-glycemic index, and markedly reduced saturated replaced by mono- or polyunsaturated fats with avoidance of trans-fats (hardened).
6. All commonly available lipid-lowering drugs including statins, ezetimibe, PCSK9 inhibitors, fibrates, omega-3 fatty acids, and niacin affect TG levels. The effect of LDL-lowering drugs on TG levels is usually modest (5–15%), while fibrates, omega-3 fatty acids, and niacin have more profound effects (25–45%). Clinically, there are two distinct aspects to TG reduction: (1) modifying lipid levels to decrease ASCVD risk, and (2) reducing TG to decrease the risk for acute pancreatitis. Once the LDL cholesterol goal is achieved, it must be decided, whether residual TG-associated risk for acute pancreatitis and/or ASCVD is sufficiently high to justify initiation of specific TG-lowering drugs, such as fibrates or niacin.
7. There is a lack of convincing outcomes evidence for ASCVD reduction when TG medications are added to statin therapy including >1 g of omega-3 fatty acids. However, the REDUCE-IT study, which evaluated the effect of 4 g of icosapent ethyl on background statin therapy in 9,000 high-risk patients with TG >135 mg/dl to <500 mg/dl, reported a 25% reduction in ASCVD events at 4.9 years in those with coronary artery disease or diabetes with one or more risk factors. The benefit seemed mediated by factors other than TG reduction since the benefit was independent of baseline TG levels. Several novel promising TG-lowering drugs are in various stages of development.

Keywords: Atherosclerosis, Cholesterol, Cholesterol, LDL, Diabetes Mellitus, Diet, Dyslipidemias, Exercise, Hypertriglyceridemia, Lipoproteins, Metabolic Syndrome, Niacin, Pancreatitis, Primary Prevention, Triglycerides, Weight Loss

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