Portal de Periódicos da CAPES

Current therapies for lowering lipoprotein (a)

2015; Elsevier BV; Volume: 57; Issue: 9 Linguagem: Inglês

10.1194/jlr.r053066

1539-7262

Julian C. van Capelleveen, Fleur M. van der Valk, ErikS.G. Stroes,

Cancer, Lipids, and Metabolism

Lipoprotein (a) [Lp(a)] is a human plasma lipoprotein with unique structural and functional characteristics. Lp(a) is an assembly of two components: a central core with apoB and an additional glycoprotein, called apo(a). Ever since the strong association between elevated levels of Lp(a) and an increased risk for CVD was recognized, interest in the therapeutic modulation of Lp(a) levels has increased. Here, the past and present therapies aiming to lower Lp(a) levels will be reviewed, demonstrating that these agents have had varying degrees of success. The next challenge will be to prove that Lp(a) lowering also leads to cardiovascular benefit in patients with elevated Lp(a) levels. Therefore, highly specific and potent Lp(a)-lowering strategies are awaited urgently. Lipoprotein (a) [Lp(a)] is a human plasma lipoprotein with unique structural and functional characteristics. Lp(a) is an assembly of two components: a central core with apoB and an additional glycoprotein, called apo(a). Ever since the strong association between elevated levels of Lp(a) and an increased risk for CVD was recognized, interest in the therapeutic modulation of Lp(a) levels has increased. Here, the past and present therapies aiming to lower Lp(a) levels will be reviewed, demonstrating that these agents have had varying degrees of success. The next challenge will be to prove that Lp(a) lowering also leads to cardiovascular benefit in patients with elevated Lp(a) levels. Therefore, highly specific and potent Lp(a)-lowering strategies are awaited urgently. Lipoprotein (a) [Lp(a)] is a unique plasma lipoprotein first described half a century ago (1.Berg K. A new serum type system in man–the LP system.Acta Pathol. Microbiol. Scand. 1963; 59: 369-382Crossref PubMed Scopus (1040) Google Scholar). Lp(a) consists of two critical elements: a central LDL-like core containing a single molecule of apoB linked by a disulfide bridge to a signature protein called apo(a). Initial case-control studies showed a strong association between Lp(a) and the risk of CVD (2.Seed M. Hoppichler F. Reaveley D. McCarthy S. Thompson G.R. Boerwinkle E. Utermann G. Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia.N. Engl. J. Med. 1990; 322: 1494-1499Crossref PubMed Scopus (504) Google Scholar, 3.Jansen A.C.M. van Aalst-Cohen E.S. Tanck M.W. Trip M.D. Lansberg P.J. Liem A.H. van Lennep H.W.O.R. Sijbrands E.J.G. Kastelein J.J.P. The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2,400 patients.J. Intern. Med. 2004; 256: 482-490Crossref PubMed Scopus (230) Google Scholar), which was corroborated by recent genetic studies describing Lp(a) as a causal risk factor for CVD (4.Danesh J. Collins R. Peto R. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies.Circulation. 2000; 102: 1082-1085Crossref PubMed Scopus (814) Google Scholar, 5.Bennet A. Di Angelantonio E. Erqou S. Eiriksdottir G. Sigurdsson G. Woodward M. Rumley A. Lowe G.D.O. Danesh J. Gudnason V. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data.Arch. Intern. Med. 2008; 168: 598-608Crossref PubMed Scopus (228) Google Scholar, 6.Clayton D. McKeigue P.M. Epidemiological methods for studying genes and environmental factors in complex diseases.Lancet. 2001; 358: 1356-1360Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar, 7.Kamstrup P.R. Tybjaerg-Hansen A. Steffensen R. Nordestgaard B.G. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.JAMA. 2009; 301: 2331-2339Crossref PubMed Scopus (849) Google Scholar, 8.Clarke R. Peden J.F. Hopewell J.C. Kyriakou T. Goel A. Heath S.C. Parish S. Barlera S. Franzosi M.G. Rust S. PROCARDIS Consortium et al.Genetic variants associated with Lp(a) lipoprotein level and coronary disease.N. Engl. J. Med. 2009; 361: 2518-2528Crossref PubMed Scopus (1017) Google Scholar). However, for Lp(a) to reach an established modifiable CVD risk factor status, it should also be demonstrated that lowering Lp(a) levels leads to a reduction in CVD. In the present review, we will describe the therapeutic approaches evaluated for their ability to lower Lp(a) levels. Prior to discussing the available therapeutic strategies, we will describe how to identify the patients that are eligible for Lp(a)-lowering therapy. Despite the strong genetic component underlying Lp(a) levels in plasma, Lp(a) has not been fully acknowledged as a CVD risk factor in clinical practice. To improve the awareness of Lp(a), expert panels of the National Cholesterol Education Program Adult Treatment Panel, the European Atherosclerosis Society, and the National Lipid Association made an effort to advise clinicians on screening for and modulation of elevated Lp(a) (9.Grundy S.M. National Cholesterol Education Program (NCEP)-The National Cholesterol Guidelines in 2001, Adult Treatment Panel (ATP) III Approach to lipoprotein management in 2001 National Cholesterol Guidelines.Am. J. Cardiol. 2002; 90: 11i-21iAbstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 10.Davidson M.H. Ballantyne C.M. Jacobson T.A. Bittner V.A. Braun L.T. Brown A.S. Brown W.V. Cromwell W.C. Goldberg R.B. McKenney J.M. et al.Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists.J. Clin. Lipidol. 2011; 5: 338-367Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 11.Nordestgaard B.G. Chapman M.J. Ray K. Borén J. Andreotti F. Watts G.F. Ginsberg H. Amarenco P. Catapano A. Descamps O.S. European Atherosclerosis Society Consensus Panel et al.Lipoprotein(a) as a cardiovascular risk factor: current status.Eur. Heart J. 2010; 31: 2844-2853Crossref PubMed Scopus (1245) Google Scholar). Whereas screening for elevated Lp(a) in the general population is not recommended at present, Lp(a) should be measured at least once in subjects at intermediate to high risk of CVD who present with: i) premature CVD; ii) familial hypercholesterolemia (FH); iii) a positive family history of elevated Lp(a) or premature CVD; iv) recurrent CVD despite statin therapy; or v) high risk scores [according to European guidelines ≥3% 10 year risk of fatal CVD; according to the US guidelines ≥10% 10 year risk of (non)fatal CHD]. In particular, if these subjects also lack signs of the more established risk factors for CVD, screening for Lp(a) level is warranted (9.Grundy S.M. National Cholesterol Education Program (NCEP)-The National Cholesterol Guidelines in 2001, Adult Treatment Panel (ATP) III Approach to lipoprotein management in 2001 National Cholesterol Guidelines.Am. J. Cardiol. 2002; 90: 11i-21iAbstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, 10.Davidson M.H. Ballantyne C.M. Jacobson T.A. Bittner V.A. Braun L.T. Brown A.S. Brown W.V. Cromwell W.C. Goldberg R.B. McKenney J.M. et al.Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists.J. Clin. Lipidol. 2011; 5: 338-367Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 11.Nordestgaard B.G. Chapman M.J. Ray K. Borén J. Andreotti F. Watts G.F. Ginsberg H. Amarenco P. Catapano A. Descamps O.S. European Atherosclerosis Society Consensus Panel et al.Lipoprotein(a) as a cardiovascular risk factor: current status.Eur. Heart J. 2010; 31: 2844-2853Crossref PubMed Scopus (1245) Google Scholar). Once identified, it has been recommended to strive for a desirable level of Lp(a) below the 80th percentile (less than 50 mg/dl for Caucasians) (11.Nordestgaard B.G. Chapman M.J. Ray K. Borén J. Andreotti F. Watts G.F. Ginsberg H. Amarenco P. Catapano A. Descamps O.S. European Atherosclerosis Society Consensus Panel et al.Lipoprotein(a) as a cardiovascular risk factor: current status.Eur. Heart J. 2010; 31: 2844-2853Crossref PubMed Scopus (1245) Google Scholar). Target levels for therapy are based on level Ia evidence obtained from meta-analysis of randomized controlled trials, as has also been done in the case of LDL cholesterol (LDL-C) (12.Graham I. Atar D. Borch-Johnsen K. Boysen G. Burell G. Cifkova R. Dallongeville J. De Backer G. Ebrahim S. European Society of Cardiology (ESC) Committee for Practice Guidelines (CPG) et al.European guidelines on cardiovascular disease prevention in clinical practice: executive summary: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts).Eur. Heart J. 2007; 28: 2375-2414Crossref PubMed Scopus (1292) Google Scholar, 13.Grundy S.M. Cleeman J.I. Merz C.N.B. Brewer H.B. Clark L.T. Hunninghake D.B. Pasternak R.C. Smith S.C. Stone N.J. Coordinating Committee of the National Cholesterol Education Program Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Arterioscler. Thromb. Vasc. Biol. 2004; 24: e149-e161Crossref PubMed Google Scholar). At present, however, evidence from Lp(a)-lowering trials is still very limited. Hence, larger studies of longer duration of potent Lp(a)-lowering therapeutics in high-risk individuals are warranted to substantiate this advice. Below, we will discuss past and present therapeutics that have achieved varying levels of Lp(a) lowering (Table 1) and highlight the concomitant effects of these compounds on apoB and Lp(a) levels. (Fig. 1).TABLE 1Lp(a)-lowering strategies rated for the capacity to lower Lp(a)StrategyMechanismReduction in Lp(a) (%)Reduction in LDL-C (%)ReferenceStatinsIncreased LDLR expression0 to +750(14.Arsenault B.J. Barter P. DeMicco D.A. Bao W. Preston G.M. LaRosa J.C. Grundy S.M. Deedwania P. Greten H. Wenger N.K. Treating to New Targets (TNT) Investigators et al.Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers.PLoS One. 2014; 9: e114519Crossref PubMed Scopus (38) Google Scholar, 15.Khera A.V. Everett B.M. Caulfield M.P. Hantash F.M. Wohlgemuth J. Ridker P.M. Mora S. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).Circulation. 2014; 129: 635-642Crossref PubMed Scopus (270) Google Scholar, 16.Fraley A.E. Schwartz G.G. Olsson A.G. Kinlay S. Szarek M. Rifai N. Libby P. Ganz P. Witztum J.L. Tsimikas S. MIRACL Study Investigators Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: Results from the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering).J. Am. Coll. Cardiol. 2009; 53: 2186-2196Crossref PubMed Scopus (80) Google Scholar, 17.Choi S.H. Chae A. Miller E. Messig M. Ntanios F. DeMaria A.N. Nissen S.E. Witztum J.L. Tsimikas S. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study.J. Am. Coll. Cardiol. 2008; 52: 24-32Crossref PubMed Scopus (87) Google Scholar, 18.Capoulade R. Chan K.L. Yeang C. Mathieu P. Bossé Y. Dumesnil J.G. Tam J.W. Teo K.K. Mahmut A. Yang X. et al.Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis.J. Am. Coll. Cardiol. 2015; 66: 1236-1246Crossref PubMed Scopus (231) Google Scholar, 19.Takagi H. Umemoto T. Atorvastatin decreases lipoprotein(a): a meta-analysis of randomized trials.Int. J. Cardiol. 2012; 154: 183-186Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 20.van Wissen S. Smilde T.J. Trip M.D. de Boo T. Kastelein J.J.P. Stalenhoef A.F.H. Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia.Heart. 2003; 89: 893-896Crossref PubMed Scopus (69) Google Scholar)NiacinReduced apo(a) transcription, or reduced apoB-100 secretion via inhibition of TG synthesis2013(24.Croyal M. Ouguerram K. Passard M. Ferchaud-Roucher V. Chétiveaux M. Billon-Crossouard S. de Gouville A-C. Lambert G. Krempf M. Nobécourt E. Effects of extended-release nicotinic acid on apolipoprotein (a) kinetics in hypertriglyceridemic patients.Arterioscler. Thromb. Vasc. Biol. 2015; 35: 2042-2047Crossref PubMed Scopus (40) Google Scholar, 25.Boden W.E. Probstfield J.L. Anderson T. Chaitman B.R. Desvignes-Nickens P. Koprowicz K. McBride R. Teo K. Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.N. Engl. J. Med. 2011; 365: 2255-2267Crossref PubMed Scopus (2267) Google Scholar, 26.Landray M.J. Haynes R. Hopewell J.C. Parish S. Aung T. Tomson J. Wallendszus K. Craig M. Jiang L. HPS2-THRIVE Collaborative Group Effects of extended-release niacin with laropiprant in high-risk patients.N. Engl. J. Med. 2014; 371: 203-212Crossref PubMed Scopus (1165) Google Scholar)CETP inhibitorAttenuation of apoB-100 lipidation due to inhibited transfer of TG and cholesterol esters between apoB-100 lipoproteins and HDL24–3636–42(35.Cannon C.P. Shah S. Dansky H.M. Davidson M. Brinton E.A. Gotto A.M. Stepanavage M. Liu S.X. Gibbons P. Ashraf T.B. Determining the Efficacy and Tolerability Investigators et al.Safety of anacetrapib in patients with or at high risk for coronary heart disease.N. Engl. J. Med. 2010; 363: 2406-2415Crossref PubMed Scopus (680) Google Scholar, 37.Nicholls S.J. Brewer H.B. Kastelein J.J.P. Krueger K.A. Wang M-D. Shao M. Hu B. McErlean E. Nissen S.E. 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: 2099-2109Crossref PubMed Scopus (368) Google Scholar, 36.Hovingh G.K. Kastelein J.J.P. van Deventer S.J.H. Round P. Ford J. Saleheen D. Rader D.J. Brewer H.B. Barter P.J. 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: 452-460Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar)apoB antisenseDecrease hepatic apoB-100 synthesis through blockage of mRNA translation of apoB-10026–2738–48(39.Visser M.E. Wagener G. Baker B.F. Geary R.S. Donovan J.M. Beuers U.H.W. Nederveen A.J. Verheij J. Trip M.D. Basart D.C.G. et al.Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial.Eur. Heart J. 2012; 33: 1142-1149Crossref PubMed Scopus (161) Google Scholar, 40.Thomas G.S. Cromwell W.C. Ali S. Chin W. Flaim J.D. Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial.J. Am. Coll. Cardiol. 2013; 62: 2178-2184Crossref PubMed Scopus (181) Google Scholar, 41.Santos R.D. Duell P.B. East C. Guyton J.R. Moriarty P.M. Chin W. Mittleman R.S. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension.Eur. Heart J. 2015; 36: 566-575Crossref PubMed Scopus (103) Google Scholar, 42.Santos R.D. Raal F.J. 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Group of Clinical Investigators et al.Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.Nat. Clin. Pract. Cardiovasc. Med. 2009; 6: 229-239Crossref PubMed Scopus (258) Google Scholar, 57.Leebmann J. Roeseler E. Julius U. Heigl F. Spitthoever R. Heutling D. Breitenberger P. Maerz W. Lehmacher W. Heibges A. Pro(a)LiFe Study Group et al.Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study.Circulation. 2013; 128: 2567-2576Crossref PubMed Scopus (233) Google Scholar)Apo(a) antisenseDecrease hepatic apo(a) synthesis through blockage of mRNA translation of apo(a)Up to 78No effect(70.Tsimikas S. Viney N.J. Hughes S.G. Singleton W. Graham M.J. Baker B.F. Burkey J.L. Yang Q. Marcovina S.M. Geary R.S. et al.Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study.Lancet. 2015; 386: 1472-1483Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar) Open table in a new tab Therapeutic options for Lp(a) arose alongside the developmental track for LDL-C-lowering drugs (Table 1). Statins have been around for more than 20 years and exert the majority of their LDL-lowering capacity by upregulating LDL receptor (LDLR) expression, subsequently leading to increased LDL-C clearance. Due to the structural similarities between Lp(a) and LDL, a hitchhiking-like process was proposed whereby Lp(a) attached to LDL could be removed by the LDLR pathway. Although statins represent one of the best-studied compounds in clinical research, there is no final answer to their effect on Lp(a) levels. Most recent studies report that statins do not affect Lp(a) levels [i.e., post hoc analysis of the Treating to New Targets (TNT) (14.Arsenault B.J. Barter P. DeMicco D.A. Bao W. Preston G.M. LaRosa J.C. Grundy S.M. Deedwania P. Greten H. Wenger N.K. Treating to New Targets (TNT) Investigators et al.Prediction of cardiovascular events in statin-treated stable coronary patients of the treating to new targets randomized controlled trial by lipid and non-lipid biomarkers.PLoS One. 2014; 9: e114519Crossref PubMed Scopus (38) Google Scholar) and Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trials (15.Khera A.V. Everett B.M. Caulfield M.P. Hantash F.M. Wohlgemuth J. Ridker P.M. Mora S. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin).Circulation. 2014; 129: 635-642Crossref PubMed Scopus (270) Google Scholar)] or perhaps even increase Lp(a) levels [Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACLE) (16.Fraley A.E. Schwartz G.G. Olsson A.G. Kinlay S. Szarek M. Rifai N. Libby P. Ganz P. Witztum J.L. Tsimikas S. MIRACL Study Investigators Relationship of oxidized phospholipids and biomarkers of oxidized low-density lipoprotein with cardiovascular risk factors, inflammatory biomarkers, and effect of statin therapy in patients with acute coronary syndromes: Results from the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering).J. Am. Coll. Cardiol. 2009; 53: 2186-2196Crossref PubMed Scopus (80) Google Scholar), Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) (17.Choi S.H. Chae A. Miller E. Messig M. Ntanios F. DeMaria A.N. Nissen S.E. Witztum J.L. Tsimikas S. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study.J. Am. Coll. Cardiol. 2008; 52: 24-32Crossref PubMed Scopus (87) Google Scholar), and Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) (18.Capoulade R. Chan K.L. Yeang C. Mathieu P. Bossé Y. Dumesnil J.G. Tam J.W. Teo K.K. Mahmut A. Yang X. et al.Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis.J. Am. Coll. Cardiol. 2015; 66: 1236-1246Crossref PubMed Scopus (231) Google Scholar) trials]. In contrast, several smaller studies report decreases in Lp(a) levels (19.Takagi H. Umemoto T. Atorvastatin decreases lipoprotein(a): a meta-analysis of randomized trials.Int. J. Cardiol. 2012; 154: 183-186Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 20.van Wissen S. Smilde T.J. Trip M.D. de Boo T. Kastelein J.J.P. Stalenhoef A.F.H. Long term statin treatment reduces lipoprotein(a) concentrations in heterozygous familial hypercholesterolaemia.Heart. 2003; 89: 893-896Crossref PubMed Scopus (69) Google Scholar). Overall, there is no clear evidence that statin treatment lowers Lp(a) levels. Hence, the LDLR does not seem to be a major contributor to Lp(a) clearance in humans (21.Rader D.J. Mann W.A. Cain W. Kraft H.G. Usher D. Zech L.A. Hoeg J.M. Davignon J. Lupien P. Grossman M. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans.J. Clin. Invest. 1995; 95: 1403-1408Crossref PubMed Scopus (176) Google Scholar). A detailed discussion of this topic will be presented elsewhere in this review. The role of LDLR in Lp(a) clearance will be co-discussed again in the section on PCSK9 inhibition. Beyond the well-known capacity of niacin (nicotinic acid) to favorably influence the levels of HDL cholesterol (HDL-C), LDL-C, and TGs, niacin also decreases plasma levels of Lp(a). Potential mechanisms by which niacin lowers Lp(a) comprise a reduced apo(a) transcription (22.Chennamsetty I. Kostner K.M. Claudel T. Vinod M. Frank S. Weiss T.S. Trauner M. Kostner G.M. Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice.J. Lipid Res. 2012; 53: 2405-2412Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar), or a reduced apoB secretion via the inhibition of TG synthesis (23.Kamanna V.S. Kashyap M.L. Mechanism of action of niacin.Am. J. Cardiol. 2008; 101: 20B-26BAbstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar). The inhibitory effect of niacin on Lp(a) production was recently substantiated in vivo in an apo(a) kinetic study investigating the effect of extended-release niacin in eight obese male subjects with hypertriglyceridemia. Niacin resulted in a 50% reduction of newly synthesized apo(a), which was partly compensated by decreased catabolic clearance. The net effect was a 20% lowering of Lp(a) levels by niacin in this study (24.Croyal M. Ouguerram K. Passard M. Ferchaud-Roucher V. Chétiveaux M. Billon-Crossouard S. de Gouville A-C. Lambert G. Krempf M. Nobécourt E. Effects of extended-release nicotinic acid on apolipoprotein (a) kinetics in hypertriglyceridemic patients.Arterioscler. Thromb. Vasc. Biol. 2015; 35: 2042-2047Crossref PubMed Scopus (40) Google Scholar). In recent years, two large randomized controlled trials have studied the clinical effects of nicotinic acid derivatives. In the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial, the effect of extended release niacin on a background of statin treatment was tested in 3,414 patients with stable atherosclerotic disease, low baseline HDL-C, and elevated TG levels, and niacin treatment resulted in 21% Lp(a) reduction compared with placebo (25.Boden W.E. Probstfield J.L. Anderson T. Chaitman B.R. Desvignes-Nickens P. Koprowicz K. McBride R. Teo K. Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.N. Engl. J. Med. 2011; 365: 2255-2267Crossref PubMed Scopus (2267) Google Scholar). The larger Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial had a similar approach and enrolled 25,773 high-risk patients with prior CVD who were randomized to receive extended-release niacin in combination with laropiprant or placebo, on top of statin with or without ezetimibe background therapy (26.Landray M.J. Haynes R. Hopewell J.C. Parish S. Aung T. Tomson J. Wallendszus K. Craig M. Jiang L. HPS2-THRIVE Collaborative Group Effects of extended-release niacin with laropiprant in high-risk patients.N. Engl. J. Med. 2014; 371: 203-212Crossref PubMed Scopus (1165) Google Scholar). The prostaglandin D2 antagonist, laropiprant, was added to improve study adherence by reducing skin flushing, a common side-effect of niacin treatment. In HPS2-THRIVE, Lp(a) levels were only measured at 1 year in a randomly selected subset of 1,999 subjects and baseline levels are lacking. However results (50.7 vs. 60.3 nmol/l at year 1, 17.8% difference) were comparable to AIM-HIGH. Both studies did not show a reduction in cardiovascular event rate, despite a potential beneficial effect on lipoprotein levels, including an average 20% reduction in Lp(a) levels. Of greater concern was the increased rate of serious adverse events in patients receiving niacin/laropiprant in HPS2-THRIVE, including increased occurrence of diabetic complications and incidence, serious infections, serious bleeding, gastrointestinal complaints, and myopathy (26.Landray M.J. Haynes R. Hopewell J.C. Parish S. Aung T. Tomson J. Wallendszus K. Craig M. Jiang L. HPS2-THRIVE Collaborative Group Effects of extended-release niacin with laropiprant in high-risk patients.N. Engl. J. Med. 2014; 371: 203-212Crossref PubMed Scopus (1165) Google Scholar). In AIM-HIGH, without the addition of laropiprant, a similar profile of serious adverse event rates was observed, although not statistically significant, which is likely a reflection of the smaller study size (27.Anderson T.J. Boden W.E. Desvigne-Nickens P. Fleg J.L. Kashyap M.L. McBride R. Probstfield J.L. AIM-HIGH Investigators Safety profile of extended-release niacin in the AIM-HIGH trial.N. Engl. J. Med. 2014; 371: 288-290Crossref PubMed Scopus (64) Google Scholar). Patients enrolled in HPS2-THRIVE and AIM-HIGH had very well-controlled baseline lipid profiles and the main criticism on these studies is centered on the question of whether these patients should have been treated at all, as they already met the most stringent criteria for lipid control at baseline (28.Tuteja S. Rader D.J. Dyslipidaemia: cardiovascular prevention–end of the road for niacin?.Nat. Rev. Endocrinol. 2014; 10: 646-647Crossref PubMed Scopus (5) Google Scholar). The same goes for Lp(a) levels in these studies, no current guidelines advise treatment of baseline levels of 36 nmol/l (AIM-HIGH) or 60 nmol/l (HPS2-THRIVE) (roughly equivalent to 15 mg/dl and 25 mg/dl) (29.Brown W.V. Ballantyne C.M. Jones P.H. Marcovina S. Management of Lp(a).J. Clin. Lipidol. 2010; 4: 240-247Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), and it must be stressed that these studies were not specifically designed for patients with elevated Lp(a). Apart from the average Lp(a) reduction of 20% by niacin, the inter-individual response is variable and more potent Lp(a) lowering by niacin has been reported in some cases (30.Li M. Saeedi R. Rabkin S.W. F