Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal

Ext1 heterozygosity causes a modest effect on postprandial lipid clearance in humans

Elevated nonfasting TG-rich lipoprotein levels are a risk factor for CVD. To further evaluate the relevance of LDL-receptor (LDLr) pathway and heparan sulfate proteoglycans (HSPGs) in TG homeostasis, we analyzed fasting and postprandial TG levels in mice bearing combined heterozygous mutations in both Exostosin (Ext) 1 and Ldlr, in subjects with hereditary multiple exostosis (HME) due to a heterozygous loss-of-function mutation in EXT1 or EXT2 (N = 13), and in patients with heterozygous mutations in LDLR [familial hypercholesterolemia (FH)] and SNPs in major HSPG-related genes (n = 22). Mice bearing a homozygous mutation in hepatic Ext1 exhibited elevated plasma TGs similar to mice lacking other key enzymes involved in HSPG assembly. Compound heterozygous mice lacking Ldlr and Ext1 showed synergy on plasma TG accumulation and postprandial clearance. In human subjects, a trend was observed in HME patients toward reduced postprandial TG clearance with a concomitant reduction in chylomicron clearance [area under the curve (AUC)-retinyl ester (RE) HME, 844 ± 127 vs. controls, 646 ± 119 nM/h, P = 0.09]. Moreover, in FH subjects with a high HSPG gene score, retinyl palmitate excursions were higher (AUC-RE, 2,377 ± 293 vs. 1,565 ± 181 nM/h, P < 0.05). Incremental AUC-apoB48 was similar between the groups. In conclusion, the data are supportive for a minor yet additive role of HSPG in human postprandial TG clearance, and further studies are warranted