Perspective:

This article is the third in a series on lipids and cardiovascular disease (CVD). The following are 10 points to remember about triglycerides and CVD:

1. After the introduction of statins in the 1990s, clinical emphasis first focused on low-density lipoprotein (LDL) cholesterol-lowering, then on the potential for raising high-density lipoprotein (HDL) cholesterol, with less focus on lowering triglycerides. Furthermore, the observation that some adults with elevated triglycerides do not develop atherosclerosis led to skepticism regarding the association of triglycerides and CVD.

2. However, many randomized controlled trials of lipid-lowering therapies excluded patients with elevated triglycerides; thus, data on such patients and associated risk for CVD are lacking.

3. Current data (from observational and genetic studies) support the hypothesis that triglycerides can be measured in the nonfasting or fasting states, with concentrations of 2–10 mmol/L conferring increased risk of CVD, and concentrations >10 mmol/L conferring increased risk of acute pancreatitis and possibly CVD.

4. Meta-analyses examining triglycerides have observed that both fasting and nonfasting levels were associated with increased risk of coronary heart disease, even after adjustment for HDL cholesterol concentrations. In combined data from the Copenhagen City Heart Study and the Copenhagen General Population Study, increased risks for nonfasting triglycerides of 6.6 mmol/L versus 0.8 mmol/L, the age-adjusted and sex-adjusted hazard ratios were 5.1 (95% confidence interval, 3.5–7.2) for myocardial infarction, 3.2 (2.5–4.1) for ischemic heart disease, 3.2 (2.2–4.7) for ischemic stroke, and 2.2 (1.8–2.7) for all-cause mortality.

5. Genetic data also support the association of elevated triglycerides and CVD risk. A Mendelian randomization study with genetic variants in several candidate genes that affect the concentrations of remnant cholesterol or HDL cholesterol, or both, showed that an increase of 1 mmol/L in remnant cholesterol was associated with a 2.8-times increased risk of ischemic heart disease that was not attributable to low HDL cholesterol concentrations. Furthermore, genetically high levels of ruminant cholesterol have been associated with inflammatory markers, which were not observed in genetically elevated levels of LDL cholesterol.

6. In terms of treatment, for mild to moderately raised triglycerides, the secondary causes of raised triglycerides should be ruled out and treated.

7. Lifestyle modification is an important therapy and often includes weight loss and reducing alcohol intake.

8. Statin therapy or intensified statin therapy with a potent statin that lowers both triglyceride and LDL concentrations should be implemented; the effect of the statin on triglycerides depends on its capacity to lower LDL cholesterol and on baseline triglyceride concentrations. A fibrate can be added as needed for further triglyceride lowering. Fish oils and niacin can also reduce triglycerides; however, whether they also reduce CVD is unknown. For those with diabetes, improved glycemic control can lower triglyceride concentrations.

9. In the future, several new drugs with properties for lowering mild-to-moderately raised or very high concentrations of triglycerides are being developed or are already being tested in clinical trials, including some that are specifically aimed at reducing triglycerides. These drugs include n-3 fatty acids (fish oils), apolipoprotein C3 inhibitors, and LPL gene replacement therapy. Other new drugs in development have triglyceride-lowering properties among their functions; these drugs include proprotein convertase subtilisin/kexin type-9 inhibitors, microsomal triglyceride protein inhibitors, apolipoprotein B antisense therapies, cholesteryl ester transfer protein inhibitors, peroxisome proliferator-activated receptor agonists, and diacylglycerol O-acyltransferase-1 inhibitors; at present, the role of such drugs in treating raised triglycerides is unclear.

10. Although most novel therapies are only in the process of documenting safe triglyceride and remnant cholesterol-reducing properties, two large-scale, randomized, placebo-controlled n-3 fatty acid intervention trials of individuals with raised triglycerides have just been initiated: REDUCE-IT and STRENGTH. The REDUCE-IT trial aims to enroll 8,000 patients receiving a statin who either have CVD or are at high risk of CVD, and also have hypertriglyceridemia, with an estimated completion date in 2016. The STRENGTH trial aims to enroll 13,000 similar patients who also have low HDL cholesterol; the estimated completion date for this trial is 2019. Compared with previous studies with conventional fish oils, these two trials use purified, concentrated n-3 fatty acids.