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
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
Niacin
Niacin therapy has been associated with increasing levels of HDL and decreasing cardiovascular risks. Shown below is a table summarizing some studies that have investigated the role of niacin in increasing HDL.
| Trial | Treatment | Increase in HDL | Follow up |
| ARBITER 2 Trial[4] | Extended release Niacin in patients on statin | 21% | 12 months |
| ARBITER 3 Trial[5] | Extended release Niacin in patients on statin | 9.6 +/- 12.5 mg/dL | 24 months |
| CLAS 1 Trial[6] | Niacin and colestipol | 37% | 2 years |
| CLAS 2 TRIAL[6] | Niacin and colestipol | 37% | 4 years |
| HATS Trial[7] | Niacin and simvastatin +/- antioxidants | 26% | 3 years |
| Coronary Drug Project | Niacin | 6 years | |
| Stockholm Ischemic Heart Disease Study | Niacin + Clofibrate | 5 years | |
| FATS | Niacin + lovastatin + colestipol | 2.5 years | |
| FATS Extended follow-up | Niacin + lovastatin + colestipol | 10 years | |
| UCSF-SCOR | Niacin + colestipol +/- Lovastatin and diet | 2 years |
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.[8]
| Trial Name | Drug | HDL Increase | Endpoints |
| ILLUSTRATE | Torcetrapib | 61% | There was no significant decrease in coronary atherosclerosis. There was increase in blood pressure.[9] |
| 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.[10] |
| RADIANCE 2 | Torcetrapib | 63.4% | There was no significant relationship between HDL levels and carotid intima-media thickness. There was increase in blood pressure.[11] |
| 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).[12] |
| 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.[13] |
| 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.
- ↑ 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.
- ↑ Taylor AJ, Lee HJ, Sullenberger LE (2006). "The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3". Curr Med Res Opin. 22 (11): 2243–50. doi:10.1185/030079906X148508. PMID 17076985.
- ↑ 6.0 6.1 Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH (1990). "Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up". JAMA. 264 (23): 3013–7. PMID 2243429.
- ↑ Brown BG, Zhao XQ, Chait A; et al. (2001). "Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease". The New England Journal of Medicine. 345 (22): 1583–92. doi:10.1056/NEJMoa011090. PMID 11757504. Unknown parameter
|month=ignored (help) - ↑ 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.