High HDL prognosis and complications

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mugilan Poongkunran M.B.B.S [2]

Overview

The antiatherogenic actions of HDL-C through reverse cholesterol transport and the cardioprotective effect through endothelial protection, anti-inflammatory activity, as well as antioxidant and antithrombotic effects has been the basis trials to increase HDL and to determine prognosis. High-density lipoprotein (HDL) cholesterol levels are inversely related to risk for coronary artery disease (CAD), but because HDL particles are heterogeneous in size and composition, they may be differentially associated with other cardiovascular risk factors and with cardiovascular risk.

Prognosis and Complications

Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risk.[1][2] This strong negative association has lead to the development of the “HDL-C hypothesis” which proposes that pharmacological intervention to raise HDL-C will reduce cardiovascular risk; in fact, recent studies reports that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease. Some of the trials are :

VA-HIT Trial

The VA-HIT Trial is a multicentered, randomized, double-blinded, placebo-controlled trial wherein 2531 patients with CAD along with LDL levels ≤140 mg/dL (mean 111 mg/dL) and HDL ≤40 mg/dL (mean 32 mg/dL) were randomly assigned to treatment with gemfibrozil (1200mg) or placebo. Results of the trial showed that the mean HDL-C level was higher by 6% in the group treated with gemfibrozil. Results of the trial showed that cardiac death and nonfatal myocardial infarction occurred less often in the gemfibrozil treated group. Acute coronary events were reduced by 11% with gemfibrozil for every 5 mg/dL rise in HDL-C; however, they did not correlate with any changes in LDL-cholesterol or triglycerides levels.[3]

Trial of Simvastatin Plus Niacin

In this study patients receiving simvastatin plus niacin were significantly less likely to sustain a cardiovascular event such as cardiac death, myocardial infarction or revascularization and experienced angiographic regression of the most significant coronary stenosis.[4]

AIM-HIGH Trial

A randomized trial comparing-extended release niacin (target dose 2000 mg per day) with placebo (100 to 200 mg of immediate release niacin) in 3414 patients with cardiovascular disease though increased levels of HDL-C and lowered levels of triglycerides and LDL-C was stopped early for futility after a mean follow-up of three years.[5]

ARBITER 2 Study

A randomized trial that examined the effects of extended-release niacin 1000 mg daily in 167 patients with known CHD and an HDL-cholesterol concentration below 45 mg/dL who were already receiving a statin showed patients treated with niacin experienced a mean increase in HDL-cholesterol of 8 mg/dL (0.21 mmol/L) and had a trend toward decreased progression of carotid intima-media thickness.[6]

Infusion of Apo A-I Milano

A pilot trial of intravenous therapy with recombinant apo A-1 Milano phospholipid complexes (ETC-216) was conducted in 57 patients who were within two weeks of onset of an acute coronary syndrome and showed a significant decrease in the mean percentage of coronary artery volume occupied by atheroma.[7]

Infusion of Reconstituted HDL

The ERASE trial on 183 CHD patients with reconstituted human HDL estimating the coronary atheroma volume was associated with a high incidence of liver function test abnormalities, which led to early study discontinuation in this group.[8]

Theobromine Study

Theobromine, as found in cocoa, has been associated with an increase in HDL-C and has been associated with a decreased risk of cardiovascular disease in observational studies.[9][10]

CETP Inhibition

Torcetrapib, anacetrapib, evacetrapib, and dalcetrapib inhibit cholesteryl ester transfer protein (CETP) and raise HDL-cholesterol levels. Though investigation of torcetrapib and dalcetrapib has stopped due to the finding of an increased risk of cardiovascular events in the ILLUMINATE trial and dal-OUTCOMES, Anacetrapib in the DEFINE study has shown to increase HDL, but the overall safety in CHD is yet to be proved.[11]

Current Trends

HDL-P as an alternative to HDL-C
  • Few studies have evaluated HDL-P associations with CHD risk, and we know of none that evaluated it jointly with HDL-C and LDL-P.
    • Multi-Ethnic Study of Atherosclerosis (MESA) study on multi-ethnic men and women without clinical CVD or lipid-lowering medication use at baseline showed HDL-C (cholestrol content of HDL) associations with carotid intima-media thickness (cIMT) and its CHD incidence to be substantially attenuated by adjusting for atherogenic lipoproteins, particularly LDL-P. In contrast, HDL-P (particle concentrations) associations with cIMT and incident CHD were relatively unaffected by adjusting for atherogenic lipoproteins, HDL-C, and mean HDL particle size.[12]
    • Multiple Risk Factor Intervention Trial (MRFIT) : Low HDL-P levels predicted CHD death over 18 years of follow-up among men with metabolic syndrome in the MRFIT cohort. In the MRFIT, high levels of HDL-P and especially medium HDL-P were associated with a reduced risk of CHD[13]
    • EPIC-Norfolk Study : In this study lower HDL-P levels predicted incident events independent of age, sex, apoB, triglycerides, mean HDL particle size, smoking, myeloperoxidase, paraoxonase-1, and hsCRP.[14]
    • VA-HIT Study : In this study lower levels of baseline and on-trial HDL-P predicted CHD events among men with low HDL-C randomized to gemfibrozil vs. placebo.[15]
    • Women’s Health Study : This large study showed the inverse association of HDL-P with incident CVD over an 11 year follow-up was not significant.[16] However, HDL-P was inversely associated with incident CHD among postmenopausal women in the Women’s Health Initiative Hormone Trial, adjusted for treatment arm, and the inverse association of HDL-P with cIMT was statistically significant for women in the current study.[17]

Challenging HDL-C hypothesis

  • The theory of HDL-C levels to predict CVD risk has been challenged in clinical trials where LDL-C has reached a very low level. The recent failure of the large the following trials raised questions about the benefits of this therapeutic strategy to raise HDL.[18]
    • In the ILLUMINATE study adverse events caused by torcetrapib were likely to represent off-target effects of the drug but raised question about the value of raising HDL-C. Attempts to decrease cardiovascular risk in statin-treated patients with the CETP inhibitor torcetrapib have failed, despite an increase in HDL-C by 72%. The failure of torcetrapib and dalcetrapib may be explained by off-target adverse effects and weak CETP inhibition, respectively.[19]
    • The dal-OUTCOMES trial using dalcetrapib raised HDL-C by 31 to 40% but had no effects on cardiovascular events.[20]
    • Niacin, used at pharmacological doses (up to 2gm/day), led to a neutrality of results in terms of cardiovascular outcomes in the AIM-HIGM. This study was also criticized for having a relatively small sample size.[5]
    • The recent failure of the large (>25,000 subjects) HPS2-THRIVE trial with niacin raised questions about the benefits of this therapeutic strategy to raise HDL..[21]

Attention is focusing on specific HDL subfractions and on biomarkers of HDL function (reflecting its pleiotropic effects) as potential therapeutic targets for cardiovascular protection. Such studies have reinforced the need for validated assays of HDL function rather than static measurement of HDL-C. A variety of HDL/apoA-I-based therapies are currently under investigation. To better understand the relation between HDL and atherosclerosis, we should consider developing and measuring better markers of HDL function, rather than the cholesterol mass within HDL particles.

References

  1. ↑ Khera AV, Rader DJ (2010). "Future therapeutic directions in reverse cholesterol transport". Curr Atheroscler Rep. 12 (1): 73–81. doi:10.1007/s11883-009-0080-0. PMC 3315100. PMID 20425274.
  2. ↑ Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK; et al. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMC 3284229. PMID 19903920. Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212
  3. ↑ Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ; et al. (2001). "Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial". JAMA. 285 (12): 1585–91. PMID 11268266.
  4. ↑ Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS; et al. (2001). "Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease". N Engl J Med. 345 (22): 1583–92. doi:10.1056/NEJMoa011090. PMID 11757504.
  5. ↑ 5.0 5.1 AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P; et al. (2011). "Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy". N Engl J Med. 365 (24): 2255–67. doi:10.1056/NEJMoa1107579. PMID 22085343. Review in: Ann Intern Med. 2012 Apr 17;156(8):JC4-08
  6. ↑ Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA (2004). "Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins". Circulation. 110 (23): 3512–7. doi:10.1161/01.CIR.0000148955.19792.8D. PMID 15537681.
  7. ↑ Ameli S, Hultgardh-Nilsson A, Cercek B, Shah PK, Forrester JS, Ageland H; et al. (1994). "Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits". Circulation. 90 (4): 1935–41. PMID 7923682.
  8. ↑ Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM; et al. (2007). "Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial". JAMA. 297 (15): 1675–82. doi:10.1001/jama.297.15.jpc70004. PMID 17387133.
  9. ↑ Baba S, Osakabe N, Kato Y, Natsume M, Yasuda A, Kido T; et al. (2007). "Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans". Am J Clin Nutr. 85 (3): 709–17. PMID 17344491.
  10. ↑ Neufingerl N, Zebregs YE, Schuring EA, Trautwein EA (2013). "Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: a randomized controlled trial". Am J Clin Nutr. 97 (6): 1201–9. doi:10.3945/ajcn.112.047373. PMID 23595874.
  11. ↑ Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM; et al. (2010). "Safety of anacetrapib in patients with or at high risk for coronary heart disease". N Engl J Med. 363 (25): 2406–15. doi:10.1056/NEJMoa1009744. PMID 21082868.
  12. ↑ Mackey RH, Greenland P, Goff DC, Lloyd-Jones D, Sibley CT, Mora S (2012). "High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis)". J Am Coll Cardiol. 60 (6): 508–16. doi:10.1016/j.jacc.2012.03.060. PMC 3411890. PMID 22796256.
  13. ↑ Kuller LH, Grandits G, Cohen JD, Neaton JD, Prineas R, Multiple Risk Factor Intervention Trial Research Group (2007). "Lipoprotein particles, insulin, adiponectin, C-reactive protein and risk of coronary heart disease among men with metabolic syndrome". Atherosclerosis. 195 (1): 122–8. doi:10.1016/j.atherosclerosis.2006.09.001. PMC 2098784. PMID 17011566.
  14. ↑ El Harchaoui K, Arsenault BJ, Franssen R, Després JP, Hovingh GK, Stroes ES; et al. (2009). "High-density lipoprotein particle size and concentration and coronary risk". Ann Intern Med. 150 (2): 84–93. PMID 19153411.
  15. ↑ Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ, McNamara JR; et al. (2006). "Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial". Circulation. 113 (12): 1556–63. doi:10.1161/CIRCULATIONAHA.105.565135. PMID 16534013.
  16. ↑ Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM (2009). "Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women". Circulation. 119 (7): 931–9. doi:10.1161/CIRCULATIONAHA.108.816181. PMC 2663974. PMID 19204302.
  17. ↑ Hsia J, Otvos JD, Rossouw JE, Wu L, Wassertheil-Smoller S, Hendrix SL; et al. (2008). "Lipoprotein particle concentrations may explain the absence of coronary protection in the women's health initiative hormone trials". Arterioscler Thromb Vasc Biol. 28 (9): 1666–71. doi:10.1161/ATVBAHA.108.170431. PMC 2701372. PMID 18599797.
  18. ↑ Cook C, Sheets C (2011). "Clinical equipoise and personal equipoise: two necessary ingredients for reducing bias in manual therapy trials". J Man Manip Ther. 19 (1): 55–7. doi:10.1179/106698111X12899036752014. PMC 3172958. PMID 22294855.
  19. ↑ Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M; et al. (2007). "Effects of torcetrapib in patients at high risk for coronary events". N Engl J Med. 357 (21): 2109–22. doi:10.1056/NEJMoa0706628. PMID 17984165.
  20. ↑ Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J; et al. (2012). "Effects of dalcetrapib in patients with a recent acute coronary syndrome". N Engl J Med. 367 (22): 2089–99. doi:10.1056/NEJMoa1206797. PMID 23126252.
  21. ↑ HPS2-THRIVE Collaborative Group (2013). "HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment". Eur Heart J. 34 (17): 1279–91. doi:10.1093/eurheartj/eht055. PMC 3640201. PMID 23444397.


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