Triglyceride-rich Lipoprotein Cholesterol (Remnant Cholesterol) as a Therapeutic Target for Cardiovascular Disease Risk

The cholesterol content of triglyceride-rich lipoproteins, in short, remnant cholesterol, is elevated in one in three adults in affluent societies, particularly in the obese and those with diabetes. Triglyceride-rich lipoproteins or remnants can like low-density lipoprotein (LDL) enter and get trapped in the arterial intima. In the intima, these lipoproteins are taken up by macrophages directly without modification. While degradation of triglycerides liberates tissue-toxic free fatty acids and cause local inflammation, cholesterol cannot be degraded and will lead to foam cell formation, intimal accumulation, and atherosclerosis. Intimal inflammation together with atherosclerosis leads to plaque rupture and eventually cardiovascular disease. Observationally, elevated remnant cholesterol is associated with increased risk of atherosclerotic cardiovascular disease, that is, ischemic heart disease and ischemic stroke. Genetic Mendelian randomization studies have confirmed that this relationship is causal. After maximal LDL cholesterol reduction, elevated remnant cholesterol represents substantial residual risk for atherosclerotic cardiovascular disease. Reduction in triglyceride-rich lipoproteins in those with elevated levels leads to reduced atherosclerotic cardiovascular disease, as documented in post hoc analyses of fibrate trials and in the REDUCE-IT trial using 100% EPA. Two further triglyceride-lowering trials in high-risk, statin-treated patients are ongoing, the STRENGTH trial using 75% EPA and 25% DHA and the PROMINENT trial using pemafibrate.