High HDL prognosis and complications
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High Density Lipoprotein Microchapters |
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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
Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risks.[1][2][3] The protective role of HDL against CVD can be explained by the antiatherogenic and cardioprotective actions of HDL through reverse cholesterol transport, endothelial protection, anti-inflammatory activity, antioxidant and antithrombotic effects; however, it should be noted that HDL particles are heterogeneous in size and composition and they may be differentially associated with cardiovascular risks. The strong negative association between HDL level and CVD risks has lead to the development of the “HDL-C hypothesis” which suggests that raising HDL level with pharmacological intervention is likely to reduce cardiovascular risks. In fact, HDL based therapies are challenging and their efficacy in reducing cardiovascular risks has not been uniform among all studies. While some studies reported that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease, other studies failed to decrease cardiovascular risks by raising HDL.
Prognosis and Complications
HDL Raising Therapies
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.[4]
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.[5]
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.[6]
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.[7]
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.[8]
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.[9]
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.[10][11]
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.[12]
Challenging HDL-C Hypothesis
Studies have proven the inverse relationship between HDL levels and cardiovascular risks. Several therapies were designed to increase HDL levels aiming for secondary prevention of coronary heart diseases. While some trials succeeded to improve the cardiovascular outcomes by increasing HDL quantity, other trials failed to achieve this goal. The failure of these trials have raised questions regarding the efficacy of HDL-targeted therapies and the concept of improving HDL quality rather than quantity. The main trials that failed to improve cardiovascular outcomes by raising HDL levels are ILLUSTRATE, RADIANCE 1, RADIANCE 2, ILLUMINATE Trial and Dal-OUTCOMES Trial which investigated CETP inhibitors as well as AIM-HIGH Trial which investigated the combination of niacin and statin. The failure of the CETP inhibitors studies can be attributed to the associated increase in blood pressure or direct impairment of the HDL quality by the CETP inhibitor.[13]
| Trial Name | Drug | HDL Increase | Endpoints |
| ILLUSTRATE | Torcetrapib | 61% | There was no significant decrease in coronary atherosclerosis. There was increase in blood pressure.[14] |
| RADIANCE 1 | Torcetrapib | 24.5±0.4 mg/dL | There was no significant relationship between HDL levels and carotid intima-media thickness. There was increase in blood pressure.[15] |
| RADIANCE 2 | Torcetrapib | 63.4% | There was no significant relationship between HDL levels and carotid intima-media thickness. There was increase in blood pressure.[16] |
| ILLUMINATE Trial | Torcetrapib | 72.1% | Hazard ratio for death was 1.58 in torcetrapib group at the end of the study (p=0.006). Torcetrapib group had a 1.25 hazard ratio for primary outcomes (p=0.001), mostly significant for unstable angina (p=0.001) and least important for stroke (0.74). Significant increase in adverse events in torcetrapib group was reported: Hypertension, peripheral edema, angina pectoris, dyspnea, and headache (p<0.001).[17] |
| Dal-OUTCOMES Trial | Dalcetrapib | 31-40% | Dalcetrapib had no significant effect on primary end point or the frequency of any primary end point component with a hazard ratio of 1.04 only.[18] |
| AIM-HIGH Trial | Niacin + Statin | 25% | There was no reduction in the rate of primary endpoint or all-cause mortality with niacin. Moreover, there was a trend towards more ischemic strokes in the niacin group. |
References
- ↑ 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.
- ↑ 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
- ↑ Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD; et al. (1989). "High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies". Circulation. 79 (1): 8–15. PMID 2642759.
- ↑ 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.
- ↑ 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.
- ↑ 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
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Joy T, Hegele RA (2008). "Is raising HDL a futile strategy for atheroprotection?". Nat Rev Drug Discov. 7 (2): 143–55. doi:10.1038/nrd2489. PMID 18239670.
- ↑ Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT; et al. (2007). "Effect of torcetrapib on the progression of coronary atherosclerosis". N Engl J Med. 356 (13): 1304–16. doi:10.1056/NEJMoa070635. PMID 17387129.
- ↑ Vergeer M, Bots ML, van Leuven SI, Basart DC, Sijbrands EJ, Evans GW; et al. (2008). "Cholesteryl ester transfer protein inhibitor torcetrapib and off-target toxicity: a pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials". Circulation. 118 (24): 2515–22. doi:10.1161/CIRCULATIONAHA.108.772665. PMID 19029469.
- ↑ Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH; et al. (2007). "Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial". Lancet. 370 (9582): 153–60. doi:10.1016/S0140-6736(07)61088-5. PMID 17630038.
- ↑ 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.
- ↑ 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.