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R3i EDITORIAL

8 June 2015

Targeting triglycerides: what lies on the horizon for novel therapies?

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco Accumulating evidence strengthens the case for consideration of an appropriate marker of triglyceride (TG)-rich lipoproteins in guidelines for the management of dyslipidaemia.1 The consensus of opinion from epidemiologic, genetic and mechanistic studies supports remnant cholesterol as a possible contender, although apolipoprotein (apo) CIII may represent an alternative approach. However, in translating such evidence to the clinic, what are the available therapeutic options?

To date, fibrates (peroxisome proliferator-activated receptor alpha [PPAR-alpha] ligands), represent the preferable approach to therapeutic targeting of elevated TG to reduce residual vascular risk. Analyses have shown that these agents are especially effective in patients with elevated TG and low high-density lipoprotein cholesterol (HDL-C), against a background of well-controlled low-density lipoprotein cholesterol (LDL-C) levels with statin therapy.2 There is also evidence of benefit in reducing the residual risk of diabetic microvascular complications with fenofibrate.3,4 While there is undoubtedly a clear rationale for definitive evidence from a clinical trial with a fibrate specifically in statin-treated non-diabetic patients with atherogenic dyslipidaemia, it is also recognised that these agents have limitations in terms of potency, tolerability and potential for drug interactions. New options are needed.

So what is the line-up for potential contenders to supersede the fibrates?

Insights from the 17th International Symposium on Atherosclerosis (ISA), held in Amsterdam, the Netherlands, suggest a number of agents with potential. Perhaps the first in line in terms of development are the selective PPAR alpha modulators (SPPARM?s), which offer the advantages of improved selectivity and potency compared with available fibrates.5 K-877 is a SPPARM? in advanced development, with evidence of a favourable benefit versus risk ratio in patients with atherogenic dyslipidaemia from phase II and III clinical trials. To take this agent forward, longer-term trials assessing the impact of this therapy on clinical outcomes are clearly the next step; we await news of such developments.

Beyond the SPPARM?s, what are the other therapeutic possibilities? Antisense agents to apoCIII may represent one approach. ApoCIII plays a key role in hepatic assembly and secretion of TG-rich lipoproteins and also has been shown to promote proinflammatory responses in vascular cells. Phase I data show dose-dependent reductions in plasma apoC-III concentration (by up to ?80%), together with lowering of TG levels (by up to ?50%) and no clinically meaningful adverse signals, although clearly longer-term studies in the target patient population are needed.6,7

Monoclonal antibody therapy may represent another approach, already tested in the management of high cardiovascular risk patients with elevated LDL-C levels with treatments targeting PCSK9. Such agents may offer advantages over pharmacologic therapy given their high specificity and long half-life, offering the possibility of less frequent administration than current therapies. On the horizon is the possibility of monoclonal antibody therapy targeting angiopoietin-like protein 3 (ANGPTL3), a key regulator of lipoprotein metabolism. Indeed, evidence from genetic studies suggests a possible role for ANGPTL3 at the crossroads of lipoprotein, fatty acid and glucose metabolism, and by inference, an attractive approach to target cardiometabolic risk.8 Preclinical studies have shown that inactivation of ANGPTL3 by monoclonal therapy reduces plasma levels of TG, very low-density lipoprotein cholesterol, and LDL-C, which implies increased clearance of TG-rich and TG-poor apoB-containing lipoproteins.9,10

This decade represents an exciting time in lipid research. The future holds the possibility of new approaches to targeting atherogenic dyslipidaemia, specifically elevated TG-rich apoB-containing lipoproteins, to reduce the high residual vascular risk that persists despite control of LDL-C levels.

References

1. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
2. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med;363:692-4.
3. Keech AC, Mitchell P, Summanen PA et al. FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687–97.
4. Chew EY, Ambrosius WT, Davis MD et al; ACCORD Eye Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010;363:233–44.
5. Fruchart JC. Selective peroxisome proliferator-activated receptor ? modulators (SPPARM?): the next generation of peroxisome proliferator-activated receptor ?-agonists. Cardiovasc Diabetol 2013;12:82.
6. Graham MJ, Lee RG, Bell TA et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013;112):1479-90.
7. Huff MW, Hegele RA. Apolipoprotein C-III: going back to the future for a lipid drug target. Circ Res 2013;112:1405-8.
8. Arca M, Minicocci I, Maranghi M. The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism. Curr Opin Lipidol 2013;24:313-20.
9. Wang Y, Gusarova V, Banfi s et al. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 2015 [Epub ahead of print].
10. Gusarova V, Alexa CA, Wang Y et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res 2015 [Epub ahead of print].