2025: The year in cardiovascular disease – the year of triglyceride lowering therapies. Can we effectively reduce triglyceride-related residual cardiovascular disease and pancreatitis risk?

Figure 1. Hypertriglyceridemia and development of atherogenic dyslipidemia. When lipoprotein lipase activity is impaired, metabolic alterations occur in the process of triglyceride-rich lipoproteins to facilitate their catabolism in serum. CETP and hepatic lipase are activated which leads to the progressive loading of triglyceride into LDL and HDL particles. These lipoproteins are then lipolyzed by hepatic lipase resulting in the formation of both small, dense LDL (sdLDL) and small HDL (sdHDL) particles. The sdLDL particles become more numerous; the sdHDL particles are catabolized and liberated apoAI binds to cubilin and megalin in the glomerular ultrafiltrate and is eliminated, resulting in low serum levels of HDL-C. Based on Miller M et al. Circulation 2011; 123: 2292-2333 CE – cholesteryl ester, CETP – ester transfer protein, FFA – free fatty acid, sdHDL – small – dense high-density lipoprotein, sdLDL – small – dense low-density lipoprotein, TG – triglyceride, VLDL – very low-density lipoprotein.

Figure 2. Highly schematic depiction of lipoprotein lipase and its regulation. Lipoprotein lipase is comprised of two identical subunits comprising a homodimer in a head to tail topology whose conformation is stabilized by 5 disulfide bonds as well as hydrophobic and electrostatic interactions. There is a hydrophobic pore next to the active site allowing for the release of free fatty acid. True views of the enzyme based on crystallography and microscopy are available. Based on: Gunn KH et al. Proc Natl Acad Sci USA 2020; 117: 10254-64, Birrane G et al. Proc Natl Acad Sci USA 2019; 116: 1723-32 apo – apoprotein, CREBH-C – carboxylterminal fragment of cyclic adenosine 3′ –5′-monophosphate–responsive element-binding protein – hepatic-specific, GPIHBP-1 – glycosyl-phosphatidylinositol-anchored high-density lipoprotein binding protein-1, LMF-1 – lipase maturation factor-1.

Figure 3. Triglyceride metabolism scheme. When lipoprotein lipase activity is either inhibited or functionally severely impaired, lipoprotein (chylomicrons, VLDL and remnant lipoproteins) triglycerides are not hydrolyzed efficiently in serum. However, other enzymes continue to lipolyze triglycerides and can release fatty acids from cholesterol esters. In serum, endothelial lipase and hepatic lipase have the capacity to hydrolyze triglycerides. In adipose tissue, both hormone sensitive lipase and adipose triglyceride lipase work in a complementary manner to liberate fatty acids from stored triglyceride. In the gut pancreatic lipase can hydrolyze triglycerides for enterocyte absorption of free fatty acids. Within cells, phospholipases, diacylglycerol and monoglycerol lipases, and lysosomal acid lipase (LAL) participate in triglyceride metabolism. LAL also hydrolyzes cholesterol esters to liberate fatty acid

Figure 4. Triglyceride-lowering potency of available and emerging therapies. Reduction estimates are based on available data and are not stratified by investigated dose, background therapy, study population (e.g., severe hypertriglyceridemia), or comorbid conditions