R3i Editorial

Driven by genetics, elevated triglycerides, a marker of triglyceride-rich lipoproteins and their remnants have regained the focus of attention. Since 2013, studies have provided consistent evidence for specific loci with an exclusive effect on triglycerides, notably variants associated with APOA5 and APOC3; these were also associated convincingly with clinical coronary artery disease and subclinical atherosclerosis.^1,5 However, further elucidation of the heritability of triglycerides and their causality with cardiovascular disease was needed.

Experimental evidence in animal models has implicated a role for modulators of the functionality of lipoprotein lipase (LPL), which plays a key role in the metabolism and clearance of triglyceride-rich lipoproteins. Angiopoietin-Like Protein 4 (ANGPTL4) is well recognized as an inhibitor of LPL in vitro and in vivo.⁶ ANGPTL4 overexpression in transgenic mouse models was shown to result in increased levels of triglycerides, whereas ANGPTL4 knockout mice had markedly decreased levels of triglycerides, as well as lower levels of very low-density lipoprotein.^7,8

This month’s Focus article adds important new information, with two recent reports linking ANGPTL4 variants with triglycerides and coronary risk.(9,10) Importantly, the studies provide independent evidence that genetic loss of ANGPTL4 function confers not only favourable lipid profiles, but also protection from coronary artery disease. The magnitude of this effect, with reduction in coronary risk, by up to 53%, represents the benefit from lifelong exposure to low levels of triglycerides associated with these variants. Taken together, these studies add important insights into the heritability of elevated triglycerides and reaffirm that beyond elevated low-density lipoprotein (LDL) cholesterol, disordered metabolism of triglyceride-rich lipoproteins, mediated via the LPL pathway, is an important contributor to coronary disease risk. Thus, ANGPTL4 may represent a novel treatment target. Indeed, in the study reported by Dewey and co-workers,⁹ mice bred with human ANGPTL4 and ApoE deficiency and with a genetic predisposition to hypertriglyceridaemia, showed marked and sustained reduction in triglycerides after treatment with a humanized monoclonal antibody to ANGPTL4 (REGN1001). Similar triglyceride lowering effects were reported in other preclinical models. There was, however, a word of caution as to whether abdominal lymphadenopathy secondary to granulomatous lipid accumulation seen in some preclinical models, would also be an issue clinically. However, there was no evidence of this in human carriers of E40K or other inactivating mutations in ANGPTL4.

With a renewal of interest in the relevance of elevated triglycerides to cardiovascular risk, genomic data have driven the search for new therapeutic targets. Apolipoprotein CIII and latterly, ANGPLT4, are the next in line for testing. Elevated triglyceride-rich lipoproteins and their remnants are key drivers of residual cardiovascular risk.¹¹ The relevance of this is underscored by trends for increasing levels of triglycerides in the general population; for example, in the USA data from the National Health and Nutrition Examination Survey (NHANES) show that in 2010, 47% of the population had triglyceride levels >150 mg/dl, driven to a large extent by lifestyle factors.¹² While statins are indisputably effective in lowering elevated low-density lipoprotein cholesterol, evidence from the VOYAGER analysis discussed in this month’s Landmark study, show that even with high-dose, high-intensity statin therapy, about 50% of triglyceridaemic patients do not attain desirable levels (<1.7 mmol/l or 150 mg/dl).¹³

It is clear that we need new options; genetic and mechanistic insights have and will continue to be key to identifying novel approaches to the management of hypertriglyceridaemia and potentially, reduction in residual cardiovascular risk.

References

1. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013;45:1345-52.
2. Pollin TI, Damcott CM, Shen H et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science. 2008; 322:1702–5.
3. The TG and HDL Working Group of the Exome Sequencing Project. Loss-of function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371: 22-31.
4. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014; 371: 32-41.
5. Do R, Stitziel NO, Won HH et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015; 518: 102-6.
6. Mehta N, Qamar A, Qu L et al. Differential association of plasma angiopoietin-like proteins 3 and 4 with lipid and metabolic traits. Arterioscler Thromb Vasc Biol 2014;34:1057–63.
7. Yin W, Romeo S, Chang S et al. Genetic variation in angptl4 provides insights into protein processing and function. J Biol Chem 2009;284:13213–22.
8. Adachi H, Fujiwara Y, Kondo T et al. Angptl 4 deficiency improves lipid metabolism, suppresses foam cell formation and protects against atherosclerosis. Biochemical and biophysical research communications. 2009;379:806–11.
9. Dewey FE, Gusarova V, O’Dushlaine C et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N Engl J Med 2016;374:1123-33.
10. Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N Engl J Med 2016;374:1134-44.
11. Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease. New insights from epidemiology, genetics, and biology. Circulation Res 2016;118:547-63.
12. Carroll MD, Kit BK, Lacher DA et al. Trends in lipids and lipoproteins in US adults, 1988-2010. JAMA 2012;308:1545–54.
13. Karlson BW, Palmer MK, Nicholls SJ et al. VOYAGER meta-analysis of the impact of statin therapy on low-density lipoprotein cholesterol and triglyceride levels in patients with hypertriglyceridemia.