Novel Hypolipidaemic Drugs: Mechanisms of Action and Main Metabolic Effects

Author(s): Theodosios D. Filippatos*, Angelos Liontos, Eliza C. Christopoulou, Moses S. Elisaf.

Journal Name: Current Vascular Pharmacology

Volume 17 , Issue 4 , 2019

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Graphical Abstract:


Over the last 3 decades, hypolipidaemic treatment has significantly reduced both Cardiovascular (CV) risk and events, with statins being the cornerstone of this achievement. Nevertheless, residual CV risk and unmet goals in hypolipidaemic treatment make novel options necessary. Recently marketed monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown the way towards innovation, while other ways of PCSK9 inhibition like small interfering RNA (Inclisiran) are already being tested. Other effective and well tolerated drugs affect known paths of lipid synthesis and metabolism, such as bempedoic acid blocking acetyl-coenzyme A synthesis at a different level than statins, pemafibrate selectively acting on peroxisome proliferator-activated receptor (PPAR)- alpha receptors and oligonucleotides against apolipoprotein (a). Additionally, other novel hypolipidaemic drugs are in early phase clinical trials, such as the inhibitors of apolipoprotein C-III, which is located on triglyceride (TG)-rich lipoproteins, or the inhibitors of angiopoietin-like 3 (ANGPTL3), which plays a key role in lipid metabolism, aiming to beneficial effects on TG levels and glucose metabolism. Among others, gene therapy substituting the loss of essential enzymes is already used for Lipoprotein Lipase (LPL) deficiency in autosomal chylomicronaemia and is expected to eliminate the lack of Low- Density Lipoprotein (LDL) receptors in patients with homozygous familial hypercholesterolaemia. Experimental data of High-Density Lipoprotein (HDL) mimetics infusion therapy have shown a beneficial effect on atherosclerotic plaques. Thus, many novel hypolipidaemic drugs targeting different aspects of lipid metabolism are being investigated, although they need to be assessed in large trials to prove their CV benefit and safety.

Keywords: Cholesterol, proprotein convertase subtilisin/kexin type 9, inclisiran, bempedoic acid, oligonucleotides, peroxisome proliferator-activated receptor (PPAR)-alpha, pemafibrate, apolipoprotein, angiopoietin-like 3.

Piepoli MF, Hoes AW, Agewall S, et al. 2016 European guidelines on cardiovascular disease prevention in clinical practice: The sixth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European association for cardiovascular prevention & rehabilitation (EACPR). Eur Heart J 2016; 37: 2315-81.
Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267-78.
Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (CARDS): Multicentre randomised placebo-controlled trial. Lancet 2004; 364: 685-96.
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376: 1713-22.
Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: 2387-97.
Filippatos TD, Elisaf MS. Are lower levels of LDL-cholesterol really better? Looking at the results of IMPROVE-IT: Opinions of three experts - III. Hellenic J Cardiol 2015; 56: 7-9.
Filippatos TD, Elisaf MS. Statin-ezetimibe combination therapy in diabetic individuals. Angiology 2016; 67: 507-9.
Filippatos TD, Mikhailidis DP. Lipid-lowering drugs acting at the level of the gastrointestinal tract. Curr Pharm Des 2009; 15: 490-516.
Kalogirou M, Tsimihodimos V, Gazi I, et al. Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia. Curr Med Res Opin 2007; 23: 1169-76.
Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: The evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep 2012; 14: 1-10.
Filippatos TD, Kyrou I, Georgousopoulou EN, et al. Modeling anthropometric indices in relation to 10-year (2002-2012) incidence of cardiovascular disease, among apparently healthy individuals: The ATTICA study. Diabetes Metab Syndr 2017; 11(Suppl. 2): 789-95.
Gazi I, Tsimihodimos V, Filippatos T, Bairaktari E, Tselepis AD, Elisaf M. Concentration and relative distribution of low-density lipoprotein subfractions in patients with metabolic syndrome defined according to the national cholesterol education program criteria. Metabolism 2006; 55: 885-91.
Kei AA, Filippatos TD, Tsimihodimos V, Elisaf MS. A review of the role of apolipoprotein C-II in lipoprotein metabolism and cardiovascular disease. Metabolism 2012; 61: 906-21.
Filippatos T, Tsimihodimos V, Pappa E, Elisaf M. Pathophysiology of diabetic dyslipidaemia. Curr Vasc Pharmacol 2017; 15: 566-75.
Filippatos TD, Panagiotakos DB, Georgousopoulou EN, et al. Mediterranean diet and 10-year (2002-2012) incidence of diabetes and cardiovascular disease in participants with prediabetes: The ATTICA study. Rev Diabet Stud 2016; 13: 226-35.
Agouridis AP, Rizos CV, Elisaf MS, Filippatos TD. Does combination therapy with statins and fibrates prevent cardiovascular disease in diabetic patients with atherogenic mixed dyslipidemia? Rev Diabet Stud 2013; 10: 171-90.
Filippatos TD, Rizos EC, Tsimihodimos V, Gazi IF, Tselepis AD, Elisaf MS. Small high-density lipoprotein (HDL) subclasses are increased with decreased activity of HDL-associated phospholipase A(2) in subjects with prediabetes. Lipids 2013; 48: 547-55.
Filippatos TD, Derdemezis CS, Voulgari PV, et al. Effects of 12 months of treatment with disease-modifying anti-rheumatic drugs on low and high density lipoprotein subclass distribution in patients with early rheumatoid arthritis: A pilot study. Scand J Rheumatol 2013; 42: 169-75.
Filippatos TD, Tsimihodimos V, Derdemezis CS, et al. Increased plasma visfatin concentration is a marker of an atherogenic metabolic profile. Nutr Metab Cardiovasc Dis 2013; 23: 330-6.
Seifalian AM, Filippatos TD, Joshi J, Mikhailidis DP. Obesity and arterial compliance alterations. Curr Vasc Pharmacol 2010; 8: 155-68.
Filippatos TD, Randeva HS, Derdemezis CS, Elisaf MS, Mikhailidis DP. Visfatin/PBEF and atherosclerosis-related diseases. Curr Vasc Pharmacol 2010; 8: 12-28.
Lagos KG, Filippatos TD, Tsimihodimos V, et al. Alterations in the high density lipoprotein phenotype and HDL-associated enzymes in subjects with metabolic syndrome. Lipids 2009; 44: 9-16.
Tzotzas T, Filippatos TD, Triantos A, Bruckert E, Tselepis AD, Kiortsis DN. Effects of a low-calorie diet associated with weight loss on lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in healthy obese women. Nutr Metab Cardiovasc Dis 2008; 18: 477-82.
Milionis HJ, Filippatos TD, Derdemezis CS, et al. Excess body weight and risk of first-ever acute ischaemic non-embolic stroke in elderly subjects. Eur J Neurol 2007; 14: 762-9.
Gazi I, Lourida ES, Filippatos T, Tsimihodimos V, Elisaf M, Tselepis AD. Lipoprotein-associated phospholipase A2 activity is a marker of small, dense LDL particles in human plasma. Clin Chem 2005; 51: 2264-73.
Katsiki N, Perez-Martinez P, Mikhailidis DP. Homocysteine and non-cardiac vascular disease. Curr Pharm Des 2017; 23: 3224-32.
Ntaios G, Savopoulos C, Chatzopoulos S, Mikhailidis D, Hatzitolios A. Iatrogenic hyperhomocysteinemia in patients with metabolic syndrome: A systematic review and meta analysis. Atherosclerosis 2011; 214: 11-9.
Mohan IV, Jagroop IA, Mikhailidis DP, Stansby GP. Homocysteine activates platelets in vitro. Clin Appl Thromb Hemost 2008; 14: 8-18.
Paraskevas KI, Mikhailidis DP. C-reactive protein (CRP): More than just an innocent bystander? Curr Med Res Opin 2008; 24: 75-8.
Filippatos TD, Filippas-Ntekouan S, Pappa E, Panagiotopoulou T, Tsimihodimos V, Elisaf MS. PCSK9 and carbohydrate metabolism: A double-edged sword. World J Diabetes 2017; 8: 311-6.
Katsiki N, Athyros VG, Mikhailidis DP, Mantzoros C. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors: Shaping the future after the further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER) trial. Metabolism 2017; 74: 43-6.
Banach M, Rizzo M, Nikolic D, Howard G, Howard V, Mikhailidis DP. Intensive LDL-cholesterol lowering therapy and neurocognitive function. Pharmacol Ther 2017; 170: 181-91.
Banach M, Rizzo M, Obradovic M, et al. PCSK9 inhibition - A novel mechanism to treat lipid disorders? Curr Pharm Des 2013; 19: 3869-77.
Filippatos TD, Kei A, Rizos CV, Elisaf MS. Effects of PCSK9 inhibitors on other than low-density lipoprotein cholesterol lipid variables. J Cardiovasc Pharmacol Ther 2018; 23: 3-12.
Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: A randomised, single-blind, placebo-controlled, phase 1 trial. Lancet 2014; 383: 60-8.
Fitzgerald K, Kallend D, Simon A. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med 2017; 376: e38.
Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017; 376: 1430-40.
Pinkosky SL, Newton RS, Day EA, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun 2016; 7: 13457.
Thompson PD, Rubino J, Janik MJ, et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol 2015; 9: 295-304.
Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol 2016; 10: 556-67.
Ballantyne CM, McKenney JM, MacDougall DE, et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am J Cardiol 2016; 117: 1928-33.
Cicero AFG, Colletti A, Bajraktari G, et al. Lipid lowering nutraceuticals in clinical practice: Position paper from an International Lipid Expert Panel. Arch Med Sci 2017; 13(5): 965-1005.
Cicero AFG, Colletti A, Bajraktari G, et al. Lipid-lowering nutraceuticals in clinical practice: Position paper from an International Lipid Expert Panel. Nutr Rev 2017; 75(9): 731-67.
Patti AM, Katsiki N, Nikolic D, Al-Rasadi K, Rizzo M. Nutraceuticals in lipid-lowering treatment: A narrative review on the role of chitosan. Angiology 2015; 66: 416-21.
Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: Impact on statin therapy - European atherosclerosis society consensus panel statement on assessment, aetiology and management. Eur Heart J 2015; 36: 1012-22.
Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an international lipid expert panel. Expert Opin Drug Saf 2015; 14: 935-55.
Bauman JN, Goosen TC, Tugnait M, et al. UDP-glucuronosyl-transferase 2b7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes. Drug Metab Dispos 2005; 33: 1349-54.
Bays HE, McKenney JM, Dujovne CA, et al. Effectiveness and tolerability of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Am J Cardiol 2003; 92: 538-43.
Stein E, Bays H, Koren M, Bakker-Arkema R, Bisgaier C. Efficacy and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients. J Clin Lipidol 2016; 10: 1212-22.
Kersten S. Angiopoietin-like 3 in lipoprotein metabolism. Nat Rev Endocrinol 2017; 13: 731-9.
Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010; 363: 2220-7.
Robciuc MR, Maranghi M, Lahikainen A, et al. Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arterioscler Thromb Vasc Biol 2013; 33: 1706-13.
Wang Y, McNutt MC, Banfi S, et al. Hepatic ANGPTL3 regulates adipose tissue energy homeostasis. Proc Natl Acad Sci USA 2015; 112: 11630-5.
Minicocci I, Tikka A, Poggiogalle E, et al. Effects of angiopoietin-like protein 3 deficiency on postprandial lipid and lipoprotein metabolism. J Lipid Res 2016; 57: 1097-107.
Kolovou GD, Mikhailidis DP, Kovar J, et al. Assessment and clinical relevance of non-fasting and postprandial triglycerides: An expert panel statement. Curr Vasc Pharmacol 2011; 9: 258-70.
Mihas C, Kolovou GD, Mikhailidis DP, et al. Diagnostic value of postprandial triglyceride testing in healthy subjects: A meta-analysis. Curr Vasc Pharmacol 2011; 9: 271-80.
Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med 2017; 377: 222-32.
Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; 377: 211-21.
Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol 2017; 69: 2054-63.
Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017; 377: 296-7.
Abu-Farha M, Al-Khairi I, Cherian P, et al. Increased ANGPTL3, 4 and ANGPTL8/betatrophin expression levels in obesity and T2D. Lipids Health Dis 2016; 15: 181.
Gencer B, Kronenberg F, Stroes ES, Mach F. Lipoprotein(a): The revenant. Eur Heart J 2017; 38: 1553-60.
Boffa MB. Emerging therapeutic options for lowering of lipoprotein(a): Implications for prevention of cardiovascular disease. Curr Atheroscler Rep 2016; 18: 69.
Milionis HJ, Filippatos TD, Loukas T, Bairaktari ET, Tselepis AD, Elisaf MS. Serum lipoprotein(a) levels and apolipoprotein(a) isoform size and risk for first-ever acute ischaemic nonembolic stroke in elderly individuals. Atherosclerosis 2006; 187: 170-6.
Katsiki N, Al-Rasadi K, Mikhailidis DP. Lipoprotein (a) and cardiovascular risk: The show must go on. Curr Med Chem 2017; 24: 989-1006.
Tsimikas S, Viney NJ, Hughes SG, et al. Antisense therapy targeting apolipoprotein(a): A randomised, double-blind, placebo-controlled phase 1 study. Lancet 2015; 386: 1472-83.
Cupido AJ, Reeskamp LF, Kastelein JJP. Novel lipid modifying drugs to lower LDL cholesterol. Curr Opin Lipidol 2017; 28: 367-73.
Gaudet D, Drouin-Chartier JP, Couture P. Lipid metabolism and emerging targets for lipid-lowering therapy. Can J Cardiol 2017; 33: 872-82.
Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): Two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 2016; 388: 2239-53.
Ginsberg HN, Le NA, Goldberg IJ, et al. Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo. J Clin Invest 1986; 78: 1287-95.
Galton DJ. Clarifying complex inheritance: Apolipoprotein C3 and atherosclerosis. Curr Opin Lipidol 2017; 28: 308-12.
Gordts PL, Nock R, Son NH, et al. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors. J Clin Invest 2016; 126: 2855-66.
Mendivil CO, Rimm EB, Furtado J, Chiuve SE, Sacks FM. Low-density lipoproteins containing apolipoprotein C-III and the risk of coronary heart disease. Circulation 2011; 124: 2065-72.
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.
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.
Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014; 371: 2200-6.
Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015; 373: 438-47.
Yang X, Lee SR, Choi YS, et al. Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: Phase 2 randomized trial results. J Lipid Res 2016; 57: 706-13.
Digenio A, Dunbar RL, Alexander VJ, et al. Antisense-mediated lowering of plasma apolipoprotein C-III by volanesorsen improves dyslipidemia and insulin sensitivity in type 2 diabetes. Diabetes Care 2016; 39: 1408-15.
Hennuyer N, Duplan I, Paquet C, et al. The novel selective PPARalpha modulator (SPPARMalpha) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis. Atherosclerosis 2016; 249: 200-8.
Sairyo M, Kobayashi T, Masuda D, et al. A novel selective PPARalpha modulator (SPPARMalpha), K-877 (Pemafibrate), attenuates postprandial hypertriglyceridemia in mice. J Atheroscler Thromb 2018; 25: 1086.
Honda Y, Kessoku T, Ogawa Y, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep 2017; 7: 42477.
Ishibashi S, Yamashita S, Arai H, et al. Effects of K-877, a novel selective PPARalpha modulator (SPPARMalpha), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 2016; 249: 36-43.
Arai H, Yamashita S, Yokote K, et al. Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMalpha), in combination with statin treatment: Two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Atherosclerosis 2017; 261: 144-52.
Nikolic D, Katsiki N, Montalto G, Isenovic ER, Mikhailidis DP, Rizzo M. Lipoprotein subfractions in metabolic syndrome and obesity: Clinical significance and therapeutic approaches. Nutrients 2013; 5: 928-48.
Mikhailidis DP, Elisaf M, Rizzo M, et al. European panel on low density lipoprotein (LDL) subclasses: A statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses. Curr Vasc Pharmacol 2011; 9: 533-71.
Katsiki N, Tentolouris N, Mikhailidis DP. Dyslipidaemia in type 2 diabetes mellitus: Bad for the heart. Curr Opin Cardiol 2017; 32: 422-9.
Filippatos TD, Gazi IF, Liberopoulos EN, et al. The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis 2007; 193: 428-37.
Filippatos TD, Florentin M, Georgoula M, Elisaf MS. Pharmacological management of diabetic dyslipidemia. Expert Rev Clin Pharmacol 2017; 10: 187-200.
Filippatos TD, Tsimihodimos V, Kostapanos M, et al. Analysis of 6-month effect of orlistat administration, alone or in combination with fenofibrate, on triglyceride-rich lipoprotein metabolism in overweight and obese patients with metabolic syndrome. J Clin Lipidol 2008; 2: 279-84.
Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362: 1563-74.
Filippatos TD, Klouras E, Barkas F, Elisaf M. Cholesteryl ester transfer protein inhibitors: Challenges and perspectives. Expert Rev Cardiovasc Ther 2016; 14: 953-62.
Kolovou G, Stamatelatou M, Anagnostopoulou K, et al. Cholesteryl ester transfer protein gene polymorphisms and longevity syndrome. Open Cardiovasc Med J 2010; 4: 14-9.
Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med 2017; 376: 1933-42.
Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109-22.
Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367: 2089-99.
Filippatos TD, Elisaf MS. Evacetrapib and cardiovascular outcomes: reasons for lack of efficacy. J Thorac Dis 2017; 9: 2308-10.
Filippatos TD, Kei A, Elisaf MS. Anacetrapib, a new CETP inhibitor: The new tool for the management of dyslipidemias? Diseases 2017; 5: E21.
Bowman L, Hopewell JC, Chen F, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017; 377: 1217-27.
Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): A randomised, double-blind, placebo-controlled phase 2 trial. Lancet 2015; 386: 452-60.
Miyosawa K, Watanabe Y, Murakami K, et al. New CETP inhibitor K-312 reduces PCSK9 expression: A potential effect on LDL cholesterol metabolism. Am J Physiol Endocrinol Metab 2015; 309: 177-90.
Scott LJ. Alipogene tiparvovec: A review of its use in adults with familial lipoprotein lipase deficiency. Drugs 2015; 75: 175-82.
Gaudet D, Stroes ES, Methot J, et al. Long-term retrospective analysis of gene therapy with alipogene tiparvovec and its effect on lipoprotein lipase deficiency-induced pancreatitis. Hum Gene Ther 2016; 27: 916-25.
Ajufo E, Cuchel M. Recent developments in gene therapy for homozygous familial hypercholesterolemia. Curr Atheroscler Rep 2016; 18: 22.
Ikenaga M, Higaki Y, Saku K, Uehara Y. High-density lipoprotein mimetics: A therapeutic tool for atherosclerotic diseases. J Atheroscler Thromb 2016; 23: 385-94.
Carballo-Jane E, Chen Z, O’Neill E, et al. ApoA-I mimetic peptides promote pre-beta HDL formation in vivo causing remodeling of HDL and triglyceride accumulation at higher dose. Bioorg Med Chem 2010; 18: 8669-78.
Hafiane A, Bielicki JK, Johansson JO, Genest J. Apolipoprotein E derived HDL mimetic peptide ATI-5261 promotes nascent HDL formation and reverse cholesterol transport in vitro. Biochim Biophys Acta 2014; 1842: 1498-512.
Uehara Y, Ando S, Yahiro E, et al. FAMP, a novel apoA-I mimetic peptide, suppresses aortic plaque formation through promotion of biological HDL function in ApoE-deficient mice. J Am Heart Assoc 2013; 2: e000048.
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: A randomized controlled trial. JAMA 2003; 290: 2292-300.
Nicholls SJ, Tuzcu EM, Sipahi I, et al. Relationship between atheroma regression and change in lumen size after infusion of apolipoprotein A-I Milano. J Am Coll Cardiol 2006; 47: 992-7.
Nicholls S. Impact of infusion of apoA-Milano HDL mimetic on regression of coronary atherosclerosis in acute coronary syndrome patients: MILANO-PILOT study. American Heart Association 2016 Scientific Sessions. November 15, 2016; New Orleans, LA, USA
Tardif JC, Ballantyne CM, Barter P, et al. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: A randomized trial. Eur Heart J 2014; 35: 3277-86.
Kootte RS, Smits LP, van der Valk FM, et al. Effect of open-label infusion of an apoA-I-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA. J Lipid Res 2015; 56: 703-12.
Tardif JC, Gregoire J, L’Allier PL, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: A randomized controlled trial. JAMA 2007; 297: 1675-82.
Easton R, Gille A, D’Andrea D, Davis R, Wright SD, Shear C. A multiple ascending dose study of CSL112, an infused formulation of ApoA-I. J Clin Pharmacol 2014; 54: 301-10.
Diditchenko S, Gille A, Pragst I, et al. Novel formulation of a reconstituted high-density lipoprotein (CSL112) dramatically enhances ABCA1-dependent cholesterol efflux. Arterioscler Thromb Vasc Biol 2013; 33: 2202-11.
Gibson CM, Korjian S, Tricoci P, et al. Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction. Am Heart J 2016; 180: 22-8.
Shaw JA, Bobik A, Murphy A, et al. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ Res 2008; 103: 1084-91.
Chenevard R, Hurlimann D, Spieker L, et al. Reconstituted HDL in acute coronary syndromes. Cardiovasc Ther 2012; 30: 51-7.
Nieuwdorp M, Vergeer M, Bisoendial RJ, et al. Reconstituted HDL infusion restores endothelial function in patients with type 2 diabetes mellitus. Diabetologia 2008; 51: 1081-4.
Rousset X, Vaisman B, Auerbach B, et al. Effect of recombinant human lecithin cholesterol acyltransferase infusion on lipoprotein metabolism in mice. J Pharmacol Exp Ther 2010; 335: 140-8.
Shamburek RD, Bakker-Arkema R, Auerbach BJ, et al. Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement. J Clin Lipidol 2016; 10: 356-67.
Otocka-Kmiecik A, Mikhailidis DP, Nicholls SJ, Davidson M, Rysz J, Banach M. Dysfunctional HDL: A novel important diagnostic and therapeutic target in cardiovascular disease? Prog Lipid Res 2012; 51: 314-24.
Katsiki N, Athyros VG, Karagiannis A, Mikhailidis DP. High-density lipoprotein, vascular risk, cancer and infection: A case of quantity and quality? Curr Med Chem 2014; 21: 2917-26.
Filippatos TD, Elisaf MS. High density lipoprotein and cardiovascular diseases. World J Cardiol 2013; 5: 210-4.
Filippatos TD, Liberopoulos EN, Kostapanos M, et al. The effects of orlistat and fenofibrate, alone or in combination, on high-density lipoprotein subfractions and pre-beta1-HDL levels in obese patients with metabolic syndrome. Diabetes Obes Metab 2008; 10: 476-83.
Kostapanos MS, Milionis HJ, Filippatos TD, et al. Dose-dependent effect of rosuvastatin treatment on HDL-subfraction phenotype in patients with primary hyperlipidemia. J Cardiovasc Pharmacol Ther 2009; 14: 5-13.

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Year: 2019
Page: [332 - 340]
Pages: 9
DOI: 10.2174/1570161116666180209112351
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