Treatment   

• The European Consensus Report recommends the use of niacin at a dose of 1g to 3g in people with elevated lipoprotein(a) (Lp(a)). A meta-analysis of randomized, controlled intervention trials documenting benefit of niacin (nicotinic acid) treatment has recently been published.¹ 

• Recommendations proposing desirable levels are based on evidence from a meta-analysis of randomized, controlled intervention trials documenting benefit of treatment (level I A evidence). Desirable levels for LDL-cholesterol (low-density lipoprotein cholesterol) are based on such evidence from statin trials.^{2, 3} Several outcome studies using niacin that significantly lowers Lp(a) are nearing completion.

• Due to its overwhelming benefit in reducing CVD (cardiovascular disease) risk, LDL-C lowering therapy, preferably with a statin, is recommended for people with elevated Lp(a) levels and CVD, diabetes, or those with intermediate or high absolute risk of CVD.^2-4

• For reduction of blood Lp(a) as a secondary priority after reduction in LDL-C, the European consensus paper recommends a desirable level < 50 mg/dL (below the 80th percentile).

• In those with premature CVD, familial hypercholesterolemia (high cholesterol), a family history of premature CVD, and elevated Lp(a), or recurrent CVD despite aggressive LDL cholesterol reduction with statin treatment, niacin may be justified.⁵ The FDA has not recommended the use of niacin to lower the Lp(a).

• Niacin reduces Lp(a) levels by up to 30-40% in a dose-dependent manner. In addition, niacin exerts other potential beneficial effects by reducing LDL-C, triglycerides, and remnant cholesterol and by raising HDL-C (high-density lipoprotein cholesterol).⁶ Studies using niacin alone or in combination with statins have shown cardiovascular benefit.^{1, 7-11}

• In a meta-analysis of 11 randomized controlled trials (RCTs) with 2,682 patients in the active group and 3,934 in the control group, niacin 1-3 g/day reduced major coronary events by 25%, stroke by 26%, and any cardiovascular event by 27%.¹ Outcome studies are underway to demonstrate the benefits of niacin on Lp(a) and other lipopriteins.¹²

• In addition to lowering Lp(a), niacin lowers LDL-C, triglycerides, remnant cholesterol, and concomitantly increases HDL-C levels. Therefore, the favorable effects of niacin on CVD cannot be ascribed solely to Lp(a) reduction. Lowering Lp(a) with niacin is safe and in all likelihood beneficial. Nevertheless, larger studies of longer duration of Lp(a) lowering against background statin therapy in high risk individuals are needed.⁵ 

• There have been no RCTs with selective reduction in blood Lp(a) levels aimed to reduce CVD. Until such trials are published, reduction in Lp(a) should mainly be achieved using niacin, as use of niacin for CVD risk reduction as described above is evidence based.⁵

• In the Women’s Health Study, carriers of an apolipoprotein(a) variant (rs3798220) had elevated Lp(a), doubled cardiovascular risk, and appeared to benefit more from aspirin than non-carriers.¹³

• A similar observation was made in HERS. Increased baseline Lp(a) levels were associated with subsequent CAD (coronary artery disease) events and estrogen and progestin therapy reduced that risk.¹⁴ Thus women with high Lp(a) levels appears to benefit from both aspirin and HRT.^{13, 14}

• Many doctors like Virgil brown treat women with high Lp(a) with estrogens, when they enter menopause based on the results of HERS study. This is particularly true if they also have a family history of premature CVD. Very premature CAD is common with vey high Lp(a) even in women.

• Effective therapeutic modalities to reduce Lp(a) levels in humans, and particularly drugs that specifically target only Lp(a), are lacking. Pharmacotherapies that are currently under development may offer additional Lp(a) lowering armamentarium.

• Antisense oligonucleotides (ASO) that are directly targeting apo(a), mRNA synthesis are able to specifically lower plasma apo(a)/Lp(a) levels by 30%.¹⁵ These data also suggest that targeting a kringle repeat sequence may result in optimal apo(a) lowering in humans paving the way for outcome studies.¹⁵ 

• Mipomersen, a subcutaneously administered ASO directed to human apoB-100 that is currently being evaluated to lower LDL levels in human subjects also lowers Lp(a) levels.¹⁶  One study demonstrated a 25% reduction in LDL-C and 32% reduction in Lp(a).¹⁷ In another study, mipomersen resulted in a 90% reduction in human apoB levels and a 75% reduction in Lp(a) levels in mice.¹⁶

• Anacetrapib, a novel CETP inhibitor with no apparent hypertensive effect, decreased Lp(a) by 40% to 50% in addition to reducing LDL-C by 40% and increasing the HDL-C by 140% when administered as monotherapy.^{18, 19} 

• LDL apheresis can lower Lp(a) levels by 40% to 80% with significant reduction in CVD events.^{20, 21}

• Such therapy is recommended in patients with Lp(a) >60 mg/dl in the presence of aggressive progressing CAD and LDL-C >125 mg/dl despite maximal drug therapy.²⁰

• In young or middle-aged patients with evidence of progressive CAD and markedly elevated plasma Lp(a),       serious consideration should be given to instituting LDL-apheresis which removes Lp(a) efficaciously.²⁰       However, this form of treatment is prohibitively expensive and impractical for most patients and most       clinical centers (average cost over $10,000/month).⁵

Sources

1. Bruckert  E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis. Jun 2010;210(2):353-361.

2. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. Jul 13 2004;110(2):227-239.

3. Graham I, Atar D, Borch-Johnsen K, Boysen G, Durrington PN. 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. Oct 2007;28(19):2375-2414.

4. Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Extreme Lipoprotein(a) Levels and Risk of Myocardial Infarction in the General Population. The Copenhagen City Heart Study. Circulation. Dec 17 2007:176-184.

5. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. Oct 21 2010.

6. Chapman M. J, Redfern JS, McGovern ME, Giral P. Niacin and fibrates in atherogenic dyslipidemia: pharmacotherapy to reduce cardiovascular risk. Pharmacol Ther. Jun 2010;126(3):314-345.

7. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand. 1988;223(5):405-418.

8. 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(6):1245-1255.

9. Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH. Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. Jama. Dec 19 1990;264(23):3013-3017.

10. Brown BG, Albers JJ, Fisher LD, et al. Regression of coronary artery disease as a result of intensive lipid- lowering therapy in men with high levels of apolipoprotein B. N Engl J Med. 1990;323(19):1289-1298.

11. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-Release Niacin or Ezetimibe and Carotid Intima-Media Thickness. N Engl J Med. Nov 15 2009.

12. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: Baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J. Mar 2011;161(3):538-543.

13. Chasman DI, Shiffman D, Zee RY, et al. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. Apr 2009;203(2):371-376.

14. Shlipak MG, Simon JA, Vittinghoff E, et al. Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause. JAMA. 2000;283(14):1845-1852.

15. Merki E, Graham M, Taleb A, et al. Antisense Oligonucleotide Lowers Plasma Levels of Apolipoprotein (a) and Lipoprotein (a) in Transgenic Mice. J Am Coll Cardiol. Apr 12 2011;57(15):1611-1621.

16. Merki E, Graham MJ, Mullick AE, et al. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation. Aug 12 2008;118(7):743-753.

17. Raal F J, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. Mar 20 2010;375(9719):998-1006.

18. Bloomfield  D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. Feb 2009;157(2):352-360 e352.

19. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. Dec 16 2010;363(25):2406-2415.

20. Thompson GR. Recommendations for the use of LDL apheresis. Atherosclerosis. Jun 2008;198(2):247-255.

21. Jaeger BR, Richter Y, Nagel D, 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. Mar 2009;6(3):229-239.