Clinical review on triglycerides

Abstract

Hypertriglyceridaemia is a common clinical problem. Epidemiologic and genetic studies have established that triglyceride-rich lipoproteins (TRL) and their remnants as important contributors to ASCVD while severe hypertriglyceridaemia raises risk of pancreatitis. While low-density lipoprotein is the primary treatment target for lipid lowering therapy, secondary targets that reflect the contribution of TRL such as apoB and non-HDL-C are recommended in the current guidelines. Reduction of severely elevated triglycerides is important to avert or reduce the risk of pancreatitis. Here we discuss interventions for hypertriglyceridaemia, including diet and lifestyle, established treatments such as fibrates and omega-3 fatty acid preparations and emerging therapies, including various biological agents.

Keywords: Hypertriglyceridaemia; Lipoproteins; Review; Treatment; Triglycerides.

Figure 1

Overview of triglyceride-rich lipoprotein metabolism focused on disease genes and drug targets. Triglyceride-rich lipoprotein assembly begins with triglyceride synthesis, which derive from fatty acids in the intestine from the diet or in the liver taken up from plasma, fatty acids released from lysosomes after breakdown of endocytosed triglyceride-rich lipoproteins, and fatty acids generated from glucose by de novo lipogenesis. A series of enzymes, culminating in tissue-specific isoforms of diacylglycerol acyltransferase in intestine and liver, produce triglyceride. Microsomal triglyceride transfer protein unites triglyceride, cholesterol, and phospholipids, with tissue-specific isoforms of apolipoprotein (apo) B, i.e. small B-48, shortened as a result of RNA editing in enterocytes and full-length B-100 in hepatocytes, forming chylomicrons and very-low-density lipoprotein, respectively. Chylomicrons formation also requires Sar1 homolog B GTPase (SAR1B gene product, not shown). Chylomicrons enter plasma indirectly through lymphatics while very-low-density lipoprotein is secreted directly into the circulation. Hydrolysis of circulating chylomicrons and very-low-density lipoprotein by lipoprotein lipase releases free fatty acids and produce chylomicron remnant clearance and intermediate-density lipoprotein particles, respectively. Chylomicrons remnant clearance by the liver (not shown) requires apo E, as apo B-48 does not have the low-density lipoprotein receptor binding domain. Intermediate-density lipoprotein can also be removed by the liver (not shown) with apo B-100 and apo E both acting as ligands for the low-density lipoprotein receptor. Intermediate-density lipoprotein can be further lipolyzed by lipoprotein lipase and also remodelled by hepatic lipase to generate low-density lipoprotein, which is cleared by the low-density lipoprotein receptor, whose activity is reduced by proprotein convertase subtilisin kexin 9. The inset depicts lipoprotein lipase activity on a triglyceride-rich lipoprotein particle as well as several interacting proteins at the endothelial surface that affect lipoprotein lipase activity. A plus sign indicates enhancement or stimulation of lipolysis, whereas a minus sign indicates inhibition. Lipase maturation factor 1 (LMF1) is a chaperone protein that ensures that lipoprotein lipase attains functionality and is properly secreted from adipose cells or myocytes. Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein-1 (GPIHBP1) is necessary for transcytosis of lipoprotein lipase across the endothelium of capillaries in adipose and muscle tissues as well as tethering lipoprotein lipase to the endothelium, thereby stabilizing it. Apo C-II activates lipoprotein lipase, while apo A-V is a stabilizing cofactor. Lipolysis is reduced by apo C-III, which is a component of triglyceride-rich lipoproteins, and by angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4), which both operate near the endothelium. Volanesorsen and AKCEA-APOCIII-LRx reduce triglyceride by targeting apo C-III, while evinacumab and IONIS-ANGPTL3-LRx lower triglyceride by targeting ANGPTL3. Peroxisome proliferator-activated receptors (not shown), particularly alpha and delta types, form a regulatory network that influences several of the above target molecules. Adapted from Ref.

Take home figure

Treatment algorithm for patients with elevated fasting triglycerides. ^aLow-density lipoprotein cholesterol goal depends on absolute cardiovascular risk. ^bPotential secondary causes for hypertriglyceridaemia are listed in Table 2. ^cFurther low-density lipoprotein cholesterol reduction will also help in achieving non-high-density lipoprotein cholesterol goals. ^dOmega-3-FA, omega-3 fatty acids. ^eMCT, fats containing medium-chain fatty acids. ^fExperimental therapies are listed in Table 6.