Novel therapeutics in hypertriglyceridemia

Current Opinion in Lipidology

Volumn 26, Issue 6, 2015, Pages 484-491

  Gryn, Steven E ^a,b   Hegele, Robert A ^a  

^a WESTERN UNIVERSITY   (Canada)

^b LONDON HEALTH SCIENCES CENTRE   (Canada)

Author keywords

antisense oligonucleotide; cardiovascular risk; chylomicron; pancreatitis; very low density lipoprotein

Indexed keywords

ANGIOPOIETIN; ANGIOPOIETIN LIKE PROTEIN 3; ANTILIPEMIC AGENT; ANTISENSE OLIGONUCLEOTIDE; APOLIPOPROTEIN B; APOLIPOPROTEIN C3; DIACYLGLYCEROL ACYLTRANSFERASE 1; LIPOPROTEIN LIPASE; LOMITAPIDE; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN; MONOCLONAL ANTIBODY; OMEGA 3 FATTY ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PROTEIN INHIBITOR; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

CARDIOVASCULAR DISEASE; DRUG EFFICACY; DRUG SAFETY; DYSLIPIDEMIA; FAMILIAL HYPERCHOLESTEROLEMIA; GENE THERAPY; HUMAN; HYPERTRIGLYCERIDEMIA; NONALCOHOLIC FATTY LIVER; NONHUMAN; PRIORITY JOURNAL; REVIEW; TREATMENT OUTCOME; ANIMAL; GENETICS; METABOLISM; MOLECULARLY TARGETED THERAPY;

ANIMALS; GENETIC THERAPY; HUMANS; HYPERTRIGLYCERIDEMIA; HYPOLIPIDEMIC AGENTS; MOLECULAR TARGETED THERAPY;

EID: 84957613960     PISSN: 09579672     EISSN: 14736535     Source Type: Journal    
DOI: 10.1097/MOL.0000000000000231     Document Type: Review

References (59)

1. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996; 3:213-219.
2. Emerging Risk Factors Collaboration,. Di Angelantonio E, Sarwar N, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302:1993-2000.
3. Triglyceride Coronary Disease Genetics Consortium, Emerging Risk Factors Collaboration. Sarwar N, et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 2010; 375:1634-1639.
4. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013; 45:1345-1352.
5. TG, HDL Working Group of the Exome Sequencing Project National Heart Lung Blood Institute,. Crosby J, Peloso GM, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med 2014; 371:22-31.
6. Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014; 371:32-41.
7. Do R, Stitziel NO, Won HH, et al. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 2015; 518:102-106.
8. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 2012; 380:572-580.
9. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diab Endocrinol 2014; 2:655-666.
10. Brahm AJ, Hegele RA. Chylomicronaemia-current diagnosis and future therapies. Nat Rev Endocrinol 2015; 11:352-362.
11. Brinton EA. Management of hypertriglyceridemia for prevention of atherosclerotic cardiovascular disease. Cardiol Clin 2015; 33:309-323.
12. Maki KC, Bays HE, Dicklin MR. Treatment options for the management of hypertriglyceridemia: strategies based on the best-available evidence. J Clin Lipidol 2012; 6:413-426.
13. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999; 341:410-418.
14. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987; 317:1237-1245.
15. Accord Study Group. Ginsberg HN, Elam MB, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362:1563-1574.
16. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010; 375:1875-1884.
17. Canner PL, Berge KG, Wenger NK, et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 1986; 8:1245-1255.
18. Aim-High Investigators. Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011; 365:2255-2267.
19. Hps Thrive Collaborative Group. Landray MJ, Haynes R, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371:203-212.
20. Pirillo A, Catapano AL. Update on the management of severe hypertriglyceridemia-focus on free fatty acid forms of omega-3. Drug Des Devel Ther 2015; 9:2129-2137.
21. Erdmann E, Califf R, Gerstein HC, et al. Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with type 2 diabetes mellitus or prediabetes. Am Heart J 2015; 170:117-122.
22. Lincoff AM, Tardif JC, Schwartz GG, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA 2014; 311:1515-1525.
23. Cariou B, Zair Y, Staels B, Bruckert E. Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 2011; 34:2008-2014.
24. Cariou B, Hanf R, Lambert-Porcheron S, et al. Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 2013; 36:2923-2930.
25. Liu ZM, Hu M, Chan P, Tomlinson B. Early investigational drugs targeting PPAR-alpha for the treatment of metabolic disease. Expert Opin Investig Drugs 2015; 24:611-621.
26. Millar JS, Duffy D, Gadi R, et al. Potent and selective PPAR-alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome. Arterioscler Thromb Vasc Biol 2009; 29:140-146.
27. Khera AV, Millar JS, Ruotolo G, et al. Potent peroxisome proliferator-activated receptor-alpha agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome. Eur Heart J 2015. [Epub ahead of print]
28. Bays HE, Schwartz S, Littlejohn T 3rd, et al. MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J Clin Endocrinol Metab 2011; 96:2889-2897.
29. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381:40-46.
30. Panta R, Dahal K, Kunwar S. Efficacy and safety of mipomersen in treatment of dyslipidemia: a meta-analysis of randomized controlled trials. J Clin Lipidol 2015; 9:217-225.
31. Meyers CD, Tremblay K, Amer A, et al. Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome. Lipids Health Dis 2015; 14:8.
32. Denison H, Nilsson C, Lofgren L, et al. Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial. Diab Obes Metab 2014; 16:334-343.
33. Gaudet D, Methot J, Dery S, et al. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther 2013; 20:361-369.
34. Carpentier AC, Frisch F, Labbe SM, et al. Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab 2012; 97:1635-1644.
35. Graham MJ, Lee RG, Bell TA 3rd, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013; 112:1479-1490.
36. Alexander V, Gaudet D, Cheng W, et al. An antisense inhibitor of apolipoprotein C-III significantly decreases apolipoprotein C-III, triglycerides, very low-density lipoprotein cholesterol and particle number, and increases highdensity lipoprotein cholesterol and particle number in hypertriglyceridemic patients on a fibrate. JACC 2014; 63 (Suppl):A1453.
37. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014; 371:2200-2206.
38. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015; 373:438-447.
39. 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; 56:1308-1317.
40. Wang Y, Gusarova V, Banfi S, et al. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 2015; 56:1296-1307.
41. Kastelein JJ, Maki KC, Susekov A, et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the Epanova for Lowering Very high triglycerides (EVOLVE) trial. J Clin Lipidol 2014; 8:94-106.
42. Bays HE, Ballantyne CM, Braeckman RA, et al. Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects upon high-sensitivity C-reactive protein and lipid parameters in patients with metabolic syndrome. Metab Syndr Relat Disord 2015; 13:239-247.
43. Li C, Lin L, Zhang W, et al. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: a metaanalysis of 20 randomized controlled trials. J Am Heart Assoc 2015; 4:e001937.
44. Li C, Zhang W, Zhou F, et al. Cholesteryl ester transfer protein inhibitors in the treatment of dyslipidemia: a systematic review and meta-analysis. PLoS One 2013; 8:e77049.
45. Hanf R, Millatt LJ, Cariou B, et al. The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts antidiabetic effects in db/db mice without peroxisome proliferator-activated receptor gammaassociated adverse cardiac effects. Diab Vasc Dis Res 2014; 11:440-447.
46. Stefanutti C, Blom DJ, Averna MR, et al. The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post hoc analysis of a phase 3, single-arm, open-label trial. Atherosclerosis 2015; 240:408-414.
47. Sacks FM, Stanesa M, Hegele RA. Severe hypertriglyceridemia with pancreatitis: thirteen years' treatment with lomitapide. JAMA Intern Med 2014; 174:443-447.
48. Stroes ES, Nierman MC, Meulenberg JJ, et al. Intramuscular administration of AAV1-lipoprotein lipase S447X lowers triglycerides in lipoprotein lipase-deficient patients. Arterioscler Thromb Vasc Biol 2008; 28:2303-2304.
49. Ferreira V, Twisk J, Kwikkers K, et al. Immune responses to intramuscular administration of alipogene tiparvovec (AAV1-LPL(S447X)) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy. Hum Gene Ther 2014; 25:180-188.
50. Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010; 363:2220-2227.
51. Romeo S, Pennacchio LA, Fu Y, et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat Genet 2007; 39:513-516.
52. Larsson M, Caraballo R, Ericsson M. Identification of a small molecule that stabilizes lipoprotein lipase in vitro and lowers triglycerides in vivo. Biochem Biophys Res Commun 2014; 450:1063-1069.
53. Lee P, Hegele RA. Current Phase II proprotein convertase subtilisin/kexin 9 inhibitor therapies for dyslipidemia. Expert Opin Investig Drugs 2013; 22:1411-1423.
54. Goldberg AS, Hegele RA. Cholesteryl ester transfer protein inhibitors for dyslipidemia: focus on dalcetrapib. Drug Des Devel Ther 2012; 6:251-259.
55. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1500-1509.
56. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1489-1499.
57. Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol 2015; 115:1212-1221.
58. Kastelein JJ, Besseling J, Shah S, et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet 2015; 385:2153-2161.
59. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011; 306:2099-2109.