R3i Editorial

Atherogenic dyslipidaemia, the combination of elevated triglycerides and low plasma concentration of high-density lipoprotein cholesterol (HDL-C), is a contributing factor to residual cardiovascular risk ¹. Until recently, much of the focus for therapeutic intervention has been on HDL-C, given extensive epidemiologic evidence that low HDL-C is a risk factor for cardiovascular disease ². However, the consistent failure of clinical trials testing numerous approaches to raising HDL-C, or its major apolipoprotein, apoA-I, most recently reported for apoAI Milano at the American Heart Association Scientific Sessions ^3,4, highlights the need for new thinking.

Triglycerides have long been the Cinderella in this story. Epidemiologic studies have shown that adjustment for HDL-C attenuated the association of triglycerides with cardiovascular risk ². However, new data have clearly implicated triglyceride-rich lipoproteins (for which triglycerides are a marker) and their apolipoprotein constituents in the causal pathway for atherosclerosis ⁵.

To understand this connection, we need to take a step back to consider what regulates triglycerides levels. Lipoprotein lipase (LPL) is a key player, as well as the products of APOC3 (apo CIII), APOA5 (apoAV) and ANGPTL4 genes. ApoCIII not only inhibits LPL, thus preventing the catabolism of triglyceride-rich lipoproteins, but also inhibits uptake of triglyceride-rich lipoprotein particles by remnant lipoprotein receptors, leading to a further increase in plasma levels of these lipoproteins. Incidentally, apoCIII also has direct inflammatory effects (5-7). ANGPTL4 also inhibits LPL and thus slows the catabolism of triglyceride-rich lipoproteins. In contrast, the effects of apoAV are potentially protective, due to acceleration of the hydrolysis of plasma triglycerides by LPL, as well as involvement in receptor or proteoglycan-mediated uptake of remnants into the liver, resulting in a lowering of plasma triglycerides ⁸.

Genetic studies, often using a Mendelian randomization approach, a type of ‘natural’ randomized trial, have provided the link between these mechanistic insights and potential therapeutic benefit. There is now accumulating evidence to support a causal role for triglyceride-rich lipoproteins and their remnants in atherosclerotic cardiovascular disease ⁶. Additionally, studies have provided new insights to implicate the apolipoprotein constituents of these lipoproteins. Simultaneously, two major studies have shown that carriage of APOC3 loss-of-function variants was associated with reduced coronary risk in humans (9,10). Additionally, another study showed that carriers of loss-of-function variants in ANGPTL4 had lower plasma levels of triglycerides and were also significantly less likely than noncarriers to have coronary artery disease ¹¹. In contrast, collaborative analysis of 101 studies showed that specific loss-of-function APOA5 variants were associated with higher plasma triglycerides and increased risk for coronary heart disease ¹². These key findings are summarised in the Figure.

Figure: Summary of key findings from genetic studies showing that variants in four LPL pathway genes all affect plasma triglyceride-rich lipoproteins and coronary risk




Surely the holy grail for lipid-related residual risk would be if a single agent could influence all these targets. The peroxisome proliferator-activated receptor ? (PPAR?) agonists may be such a candidate. Studies over the last two decades have shown that PPAR? has a pivotal role in the regulation of fatty acid oxidation, lipid and lipoprotein metabolism and inflammatory and vascular responses ¹³. Notably, PPAR? controls key target genes encoding for a number of lipoproteins, including apoA-I, A-II, AV and CIII, as well as LPL. However, the PPAR? agonists available to date have had relatively low potency and selectivity, highlighting the need for new approaches.

Each PPAR ligand has a unique cofactor recruitment pattern associated with a specific profile of pharmacological effects. By modulating this receptor–cofactor binding profile there may be the opportunity to both improve desirable biological effects (by transactivation of desirable target genes) and limit adverse effects of the PPAR ligand (by transrepression of specific genes). Such thinking underpins the development of selective peroxisome proliferator-activated receptor-alpha modulators (SPPARM?), the first of which is pemafibrate (K-877) ¹⁴. Clinical studies have established the pharmacological profile of pemafibrate, and shown greater reduction of triglycerides, remnants and apoCIII, and greater elevation in HDL-C levels compared with fenofibrate, as well as reduction in inflammation and atherosclerosis (preclinical studies) ^15,16.

The key question is whether the lipid and vascular effects of this SPPARM? translate to reduction in cardiovascular events in statin-treated patients with the characteristic atherogenic diabetic dyslipidaemia of elevated triglycerides and low HDL-C. The PROMINENT (Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN diabetic patiENTs) study, as discussed in this month’s Focus, will provide an answer.

References

1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol;13:26.
2. Emerging Risk Factors Collaboration., Di Angelantonio E, Sarwar N, Perry P et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000.
3. Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet 2014;384:618–25.
4. Nicholls SJ. Impact of infusion of an apoA-IMilano HDL mimetic on regression of coronary atherosclerosis in acute coronary syndrome patients: the MILANO-PILOT Study. Available at Impact of Infusion of an ApoA-IMilano HDL Mimetic on regression of coronary atherosclerosis in acute coronary syndrome patients: the MILANO-PILOT Study. http://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_489908.pdf
5. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2015;36:774-6.
6. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
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9. 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.
10. TG and HDL Working Group of the Exome Sequencing Project, National Heart, Lung, and Blood Institute., Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014;371:22-31.
11. 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.
12. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 2010;375:1634-9.
13. Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARalpha): at the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis 2009;205:1-8.
14. Fruchart JC. Selective peroxisome proliferator-activated receptor ? modulators (SPPARM?): the next generation of peroxisome proliferator-activated receptor ?-agonists. Cardiovasc Diabetol 2013;12:82.
15. Hennuyer N, Duplan I, Paquet C et al. The novel selective PPAR? modulator (SPPARM?) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis. Atherosclerosis 2016;249:200-8.
16. Ishibashi S, Yamashita S, Arai H et al. Effects of K-877, a novel selective PPAR? modulator (SPPARM?), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 2016;249:36-43.