Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease

Abstract

Scientific interest in triglyceride-rich lipoproteins has fluctuated over the past many years, ranging from beliefs that these lipoproteins cause atherosclerotic cardiovascular disease (ASCVD) to being innocent bystanders. Correspondingly, clinical recommendations have fluctuated from a need to reduce levels to no advice on treatment. New insight in epidemiology now suggests that these lipoproteins, marked by high triglycerides, are strong and independent predictors of ASCVD and all-cause mortality, and that their cholesterol content or remnant cholesterol likewise are strong predictors of ASCVD. Of all adults, 27% have triglycerides >2 mmol/L (176 mg/dL), and 21% have remnant cholesterol >1 mmol/L (39 mg/dL). For individuals in the general population with nonfasting triglycerides of 6.6 mmol/L (580 mg/dL) compared with individuals with levels of 0.8 mmol/L (70 mg/dL), the risks were 5.1-fold for myocardial infarction, 3.2-fold for ischemic heart disease, 3.2-fold for ischemic stroke, and 2.2-fold for all-cause mortality. Also, genetic studies using the Mendelian randomization design, an approach that minimizes problems with confounding and reverse causation, now demonstrate that triglyceriderich lipoproteins are causally associated with ASCVD and all-cause mortality. Finally, genetic evidence also demonstrates that high concentrations of triglyceride-rich lipoproteins are causally associated with low-grade inflammation. This suggests that an important part of inflammation in atherosclerosis and ASCVD is because of

Rationale and design of REDUCE‐IT: Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

“…Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy 3, 4, 5, 6, 7, 8, 9, 10, 11.…”

“…Epidemiological, biological, and genetic studies have provided robust evidence of a strong association between elevated TG levels and higher rates of CV events 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. Furthermore, TG reduction lowers several inflammatory markers associated with CV risk, and subgroup and post hoc analyses of outcome studies suggest possible reductions in major CV events with TG‐lowering therapy 3, 4, 5, 6, 7, 8, 9, 10, 11. Finally, studies administering higher‐dose EPA suggest additional beneficial effects beyond lipid‐lowering that may be unique to EPA relative to other TG‐lowering therapies, such as beneficial changes in coronary plaque characteristics, which may lead to reductions in major CV events 4, 16, 25, 26, 27, 28, 29, 30, 31, 32, 33…”

“…Statin therapy has been well established as a cornerstone of cardiovascular prevention, and yet despite potent therapies for lowering low‐density lipoprotein cholesterol (LDL‐C), substantial residual risk remains 1, 2, 3. Clinical and epidemiological studies have demonstrated that triglyceride (TG) elevation is an independent risk factor for increased cardiovascular (CV) events, and therefore may represent one contributive factor of residual CV risk beyond statin therapy 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11.…”

“…Clinical and epidemiological studies have demonstrated that triglyceride (TG) elevation is an independent risk factor for increased cardiovascular (CV) events, and therefore may represent one contributive factor of residual CV risk beyond statin therapy 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. More recently, elegant Mendelian randomization studies have supported a causal role for TG in the pathogenesis of cardiovascular disease (CVD), showing that elevated TG are not merely a risk marker, but rather a risk factor and thus potentially modifiable 3. Despite the available data, an important question that remains is whether treatment of modest degrees of TG elevation would decrease CV events, in particular in patients already receiving LDL‐C–lowering therapy with statins.…”

Residual Risk of Atherosclerotic Cardiovascular Events in Relation to Reductions in Very‐Low‐Density Lipoproteins

“…However, among individuals with achieved lower levels of LDL‐C, atherosclerotic cardiovascular disease (ASCVD) events continue to occur with unacceptable frequency 4. Such residual risk may reflect aspects of atherogenesis not captured by LDL‐C, including effects of very‐low‐density lipoproteins (VLDLs) and their contents (cholesterol and triglycerides) 5, 6, 7, 8, 9. Enzymatic hydrolysis of VLDL results in the formation of smaller, cholesterol‐enriched lipoprotein particles,5, 10, 11 which experimental studies suggest could contribute to the development of ASCVD 5, 7, 10, 12, 13, 14, 15, 16.…”