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
Niacin
According to several studies, niacin therapy is associated with improved lipoprotein profile in general and increase in the level of HDL in particular, which has been associated with decrease in cardiovascular events, decrease in mortality and regression of atherosclerosis plaques. Increase in HDL level by niacin can be attributed to the direct effect of the drug itself as well as to the niacin-induced decrease in the triglycerides level. The link between increasing HDL and improving cardiovascular outcomes is difficult to interpret as niacin's effects are not only limited to HDL but also include decreasing LDL and triglyceride levels.[4]
Shown below is a table summarizing some studies that have investigated the role of niacin in increasing HDL.
| Trial Name | Drug | HDL Increase | Follow up |
| ARBITER 2 Trial[5] | Extended release Niacin in patients on statin | 21% | 12 months |
| ARBITER 3 Trial[6] | Extended release Niacin in patients on statin | 9.6 +/- 12.5 mg/dL | 24 months |
| CLAS 1 Trial[7] | Niacin and colestipol | 37% | 2 years |
| CLAS 2 TRIAL[7] | Niacin and colestipol | 37% | 4 years |
| HATS Trial[8] | Niacin and simvastatin +/- antioxidants | 26% | 3 years |
| Coronary Drug Project[9] | Niacin or clofibrate | - | 6 years and 15 years |
| Stockholm Ischemic Heart Disease Study[10] | Niacin + Clofibrate | - | 5 years |
| FATS[11] | Lovastatin + colestipol Niacin + Colestipol |
15% 43% |
2.5 years |
| FATS Extended follow-up | Niacin + lovastatin + colestipol | - | 10 years |
| UCSF-SCOR[12] | Niacin + colestipol +/- Lovastatin and diet | 28% | 2 years |
Fibrates
| Trial Name | Drug | HDL Increase | Follow up |
| VA-HIT Trial | Gemfibrozil | 6% | 5 years |
| BECAIT Trial | Bezafibrate | 9% | 5 years |
| BIP Trial | Bezafibrate | 18% | 6.2 years |
| Helsinki Heart Study | Gemfibrozil | 11% | 5 years |
| Frick et al | Gemfibrozil | 3years | |
| DAIS | Fenofibrate | 3 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.[4]
| Trial Name | Drug | HDL Increase | Endpoints |
| ILLUSTRATE | Torcetrapib | 61% | There was no significant decrease in coronary atherosclerosis. There was increase in blood pressure.[13] |
| 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.[14] |
| RADIANCE 2 | Torcetrapib | 63.4% | There was no significant relationship between HDL levels and carotid intima-media thickness. There was increase in blood pressure.[15] |
| 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).[16] |
| 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.[17] |
| 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.
- ↑ 4.0 4.1 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.
- ↑ 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.
- ↑ 7.0 7.1 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) - ↑ "Clofibrate and niacin in coronary heart disease". JAMA. 231 (4): 360–81. 1975. PMID 1088963.
- ↑ Carlson LA, Rosenhamer G (1988). "Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid". Acta Med Scand. 223 (5): 405–18. PMID 3287837.
- ↑ Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C; et al. (1990). "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. 323 (19): 1289–98. doi:10.1056/NEJM199011083231901. PMID 2215615.
- ↑ Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ (1990). "Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens". JAMA. 264 (23): 3007–12. PMID 2243428.
- ↑ 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.