Triglyceride-rich lipoprotein cholesterol (TRL-C): the ugly stepsister of LDL-C

Lowering LDL-C for reducing cardiovascular risk has been a key therapeutic strategy for >30 years. This strategy has been adopted globally primarily by recommending statin therapy to lower LDL-C. There is a general consensus that the lower the LDL-C, the better the clinical outcomes. However, there is growing evidence that triglycerides are not just a marker of increased cardiovascular (CV) risk but rather a causal factor that rivals LDL-C. Madsen et al. in this issue of the journal have added to the evidence base that targeting patients with hypertriglyceridaemia with statins or other triglyceridelowering therapies may significantly reduce CV events in patients without pre-existing atherosclerotic cardiovascular disease (ASCVD) and therefore represents a population that deserves special attention for the primary prevention of coronary heart disease. One issue that affects the clinician’s understanding of the role of triglycerides in assessing CV risk is the nomenclature. Non-HDL-C is very simple to calculate: total cholesterol minus HDL-C (both total cholesterol and HDL-C are directly measured). Non-HDL-C is superior to LDL-C as a CV risk predictor and, in the statin trials when non-HDL-C and LDL-C are discordant, risk follows non-HDL-C. The reason that non-HDL-C is a better risk predictor than LDL-C is because the cholesterol content in the triglyceride-rich lipoproteins [very low-density lipoprotein (VLDL), VLDL remnants, intermediatedensity lipoprotein (IDL), and chylomicrons] is also atherogenic. The cholesterol content in these triglyceride-rich lipoproteins has been estimated by the Freidwald formula as approximately triglyceride levels divided by five, because these lipoproteins have 60% triglyceride and 12% cholesterol (a 5:1 ratio). The confusion arises as to what to call this “other” cholesterol (non-HDL-C minus LDL-C). The most accurate term is triglyceride-rich lipoprotein cholesterol (TRL-C) but it has also been called ‘remnant cholesterol’ and most commonly VLDL-C. Defining the cholesterol content in these triglyceride-rich lipoproteins is clinically important because this is the substrate for development of the atherosclerotic plaque rather than the triglycerides. In fact, a study suggests that 50% of the cholesterol found in atherosclerotic plaque is derived from TRL-C even though, in most patients, TRL-C levels are much lower than calculated LDL-C. Another area of confusion is that hypertriglyceridaemia is associated with a myriad of lipoprotein modifications and it is unclear which of these changes (if not all) are causal for atherosclerosis. In the setting of increased hepatic lipogenesis (Take home figure), the liver secretes enlarged VLDL which is enriched but results in delayed peripheral lipolysis and clearance of these triglyceride-rich particles. Therefore, there is delayed conversion of VLDL to LDL, resulting in elevation in TRL-C. Since lipolysis is impaired, LDL particles are also enriched in apoCIII and triglycerides which ultimately transform into smaller and more numerous particles. The end result is that hypertriglyceridaemia is associated with elevated TRL-C (and hence non-HDL-C), ApoB, ApoCIII, small dense LDL-C, and LDL particles (LDL-Ps) in the setting of a normal or low level of LDL-C. All of these lipoprotein changes are associated with increased CV risk and, based on genome-wide association trials, are more casually validated than the accompanying low HDL-C for the development of atherosclerosis. If triglycerides are lowered by lifestyle changes, fibrates, or omega-3 fatty acids, there is a reduction in TRL-C, apoB, and apoCIII, and this shifts from small dense LDL particles (and hence small dense LDL-C) to larger LDL particles. Statins effectively lower TRL-C, ApoB, ApoCIII, small dense LDL-C, and LDL-Ps, and therefore represent the best therapeutic option to affect CV risk in the hypertriglyceridaemic patient. Madsen et al. raise two important clinical issues in regards to the management of CV risk in patients with hypertriglyceridaemia. They have identified, through the Copenhagen Heart Study which has provided a plethora of insights into the role of triglyceride levels and CV risk, a primary prevention population with hypertriglyceridaemia (>3 mmol/L) that is not statin eligible as defined according to the 2016