High density lipoprotein medical therapy: Difference between revisions

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==Overview==
==Overview==
Several clinical trials have demonstrated that raising the serum level of HDL cholesterol is associated with a decreased risk for [[coronary heart disease]].  The ATP III guidelines clearly provided a guide on whom to treat (those with CHD or CHD risk equivalents), but the question regarding when to treat was not clearly stated.  The treatment of a patient with low HDL cholesterol should be holistic and individualized - involving risk assessment for CHD, ruling out secondary causes, lifestyle modification, achieving LDL and non-HDL cholesterol goals, and then making a choice of the HDL-raising medication to be used based on the drug efficacy, tolerability to patients, interaction with other drugs, and side effects.  This page has also provided a step-wise approach to managing a patient with a low HDL.
Since low HDL is associated with an increased risk of [[cardiovascular disease]] events, elevation of [[HDL]] concentration among subjects with low [[HDL]] is advised.  The treatment of a patient with low HDL cholesterol should be individualized.  Before the initiation of any medical treatment to elevate the [[HDL]] concentration, the initial treatment should aim to reduce the [[LDL]] and non-HDL lipoprotein concentrations if they are elevated.  The management of low HDL should also begin with life style modification targeting diet, exercise, and smoking cessation.  If HDL concentration remains high despite optimal LDL and non-HDL concentrations and life style modifications, then medical therapy with [[fibrates]] or [[niacin]] might be considered among patients with risk factors of [[coronary artery disease]] or its equivalent.


==Who To Treat==
==Treatment==
The question on whom to treat should be answered on a patient-by-patient basis.  According to ATP III guidelines, treating low HDL cholesterol has now become a tertiary target in the management of patients with low HDL, with the primary and secondary goals targeting [[LDL]] and non-HDL cholesterol respectively.<ref name="-2001">{{Cite journal  | title = Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). | journal = JAMA | volume = 285 | issue = 19 | pages = 2486-97 | month = May | year = 2001 | doi =  | PMID = 11368702 }}</ref>  There are other variables to be considered including the serum [[triglyceride]] levels and metabolic abnormalities - [[diabetes mellitus]], [[metabolic syndrome]].
===Who To Treat===
The question on who to treat should be answered on a patient-by-patient basis.  According to the ATP III guidelines, the treatment of low HDL cholesterol has become a tertiary target in the management of patients with low HDL, with the primary and secondary goals targeting [[LDL]] and non-HDL cholesterol, respectively.<ref name="-2001">{{Cite journal  | title = Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). | journal = JAMA | volume = 285 | issue = 19 | pages = 2486-97 | month = May | year = 2001 | doi =  | PMID = 11368702 }}</ref>  There are several variables to be considered in a patient with low HDL such as serum [[triglyceride]] levels and metabolic abnormalities ([[diabetes mellitus]], [[metabolic syndrome]]).


==When To Treat==
===When To Treat===
National Cholesterol Education Program (NCEP) has not set a formal goal for HDL levels as a therapeutic target because of lack of evidence for decrease in primary CHD risk reduction with pharmacotherapy.  Drug therapy for HDL can be considered in patients in presence of other risk factors for CHD such as hypertension, smoking, family history of premature coronary heart disease. The following are the ATP III guidelines for low HDL management (i.e., HDL-C≤40 mg/dl):
The National Cholesterol Education Program (NCEP) has not set a formal goal for HDL levels as a therapeutic target because of lack of evidence for decrease in primary CHD risk reduction with pharmacotherapy.  Drug therapy for HDL can be considered in the presence of other risk factors for CHD such as hypertension, smoking, family history of premature coronary heart disease.  
* First LDL goal should be achieved
* Weight reduction and physical exercise
* If serum [[triglycerides]] is between 200 and 499 mg/dL, achieve non-HDL goal first
* If triglycerides <150 mg/dL (isolated low HDL) in CHD or CHD equivalent, consider [[nicotinic acid]] or [[fibrate]]


==Treatment==
The following are the ATP III guidelines for low HDL management (i.e., HDL-C≤40 mg/dl):[http://www.nhlbi.nih.gov/files/docs/resources/heart/atp3full.pdf]
* Among patients with [[high LDL]], achieve the LDL goal first
* Among patients with elevated HDL, rule out secondary causes:
** [[Hypothyroidism]]
** [[Diabetes mellitus]]
** [[Uremia]]
** [[Liver disease]]
** [[Medications]] ([[diuretics]], [[progestin]], [[androgen]]s, [[beta blocker]]s)
* Recommend weight reduction, physical exercise, and smoking cessation to elevate HDL
* If serum [[triglyceride]] concentration is between 200 and 499 mg/dL, achieve non-HDL goal before the initiation a treatment for HDL
* If triglycerides <200 mg/dL (isolated low HDL) in CHD or CHD equivalent, consider [[nicotinic acid]] or [[fibrate]]
 
Among patients with low HDL, attempts towards a reduction in [[LDL]] and non-HDL concentration should be performed before the administration of medical therapy to raise [[HDL]].  Non-HDL-C represents the cholesterol content present in all the atherogenic lipoproteins i.e., a combination of LDL-C, VLDL-C, IDL-C, and lipoprotein(a) cholesterol.<ref name="Ballantyne-2000">{{Cite journal  | last1 = Ballantyne | first1 = CM. | last2 = Grundy | first2 = SM. | last3 = Oberman | first3 = A. | last4 = Kreisberg | first4 = RA. | last5 = Havel | first5 = RJ. | last6 = Frost | first6 = PH. | last7 = Haffner | first7 = SM. | title = Hyperlipidemia: diagnostic and therapeutic perspectives. | journal = J Clin Endocrinol Metab | volume = 85 | issue = 6 | pages = 2089-112 | month = Jun | year = 2000 | doi =  | PMID = 10852435 }}</ref>  Non-HDL-C is the difference between the total cholesterol and HDL cholesterol (Non-HDL-C = Total cholesterol minus HDL-C).  Some studies have demonstrated that non-HDL cholesterol fraction may be a better predictor of future cardiovascular risk than LDL cholesterol.<ref name="Ridker-2005">{{Cite journal  | last1 = Ridker | first1 = PM. | last2 = Rifai | first2 = N. | last3 = Cook | first3 = NR. | last4 = Bradwin | first4 = G. | last5 = Buring | first5 = JE. | title = Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. | journal = JAMA | volume = 294 | issue = 3 | pages = 326-33 | month = Jul | year = 2005 | doi = 10.1001/jama.294.3.326 | PMID = 16030277 }}</ref><ref name="Di Angelantonio-2009">{{Cite journal  | last1 = Di Angelantonio | first1 = E. | last2 = Sarwar | first2 = N. | last3 = Perry | first3 = P. | last4 = Kaptoge | first4 = S. | last5 = Ray | first5 = KK. | last6 = Thompson | first6 = A. | last7 = Wood | first7 = AM. | last8 = Lewington | first8 = S. | last9 = Sattar | first9 = N. | title = Major lipids, apolipoproteins, and risk of vascular disease. | journal = JAMA | volume = 302 | issue = 18 | pages = 1993-2000 | month = Nov | year = 2009 | doi = 10.1001/jama.2009.1619 | PMID = 19903920 }}</ref>  The treatment goal for non-HDL-C is '''30 mg/dL''' above the LDL-C treatment target.
 
Below is a table showing the non-HDL and LDL cholesterol goals to be achieved in the management of patients with a low HDL cholesterol according to the ATP III guidelines:
{| cellpadding=3 cellspacing=0 border=1 style="border-collapse:collapse"
|bgcolor="#cccccc"| '''RISK CATEGORY'''
|bgcolor="#cccccc"| '''NON-HDL-GOAL mg/dl'''
|bgcolor="#cccccc"| '''LDL GOAL mg/dl'''
|-
| 0 to 1 CHD risk factor
| <190
| <160
|-
| Two or more CHD risk factors (10-year risk for CHD≤20%)
| <160
| <130
|-
| Coronary heart disease (CHD) and CHD risk equivalent (10-year risk for CHD>20% )
| <130
| <100
|}


===Non-pharmacologic Therapies===
===Non-pharmacologic Therapies===
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|-
|-


 
|Monounsaturated fat
| Increase in HDL
|-
| Moderate [[alcohol]] consumption
| Moderate [[alcohol]] consumption
| 5-10% increase in HDL<ref name="Rimm-1999">{{Cite journal  | last1 = Rimm | first1 = EB. | last2 = Williams | first2 = P. | last3 = Fosher | first3 = K. | last4 = Criqui | first4 = M. | last5 = Stampfer | first5 = MJ. | title = Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. | journal = BMJ | volume = 319 | issue = 7224 | pages = 1523-8 | month = Dec | year = 1999 | doi =  | PMID = 10591709 }}</ref>
| 5-10% increase in HDL<ref name="Rimm-1999">{{Cite journal  | last1 = Rimm | first1 = EB. | last2 = Williams | first2 = P. | last3 = Fosher | first3 = K. | last4 = Criqui | first4 = M. | last5 = Stampfer | first5 = MJ. | title = Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. | journal = BMJ | volume = 319 | issue = 7224 | pages = 1523-8 | month = Dec | year = 1999 | doi =  | PMID = 10591709 }}</ref>
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===Pharmacologic Therapy===
===Pharmacologic Therapy===


{| cellpadding=3 cellspacing=0 border=1 style="border-collapse:collapse"
{| cellpadding=3 cellspacing=0 border=1 style="border-collapse:collapse"
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| [[Nicotinic acid]] (Niacin)
| [[Nicotinic acid]] (Niacin)
|Decreases VLDL synthesis in the liver through diaglycerol acyl transferase-2 (DGAT-2),<ref name="Wierzbicki-2011">{{Cite journal  | last1 = Wierzbicki | first1 = AS. | title = Niacin: the only vitamin that reduces cardiovascular events. | journal = Int J Clin Pract | volume = 65 | issue = 4 | pages = 379-85 | month = Apr | year = 2011 | doi = 10.1111/j.1742-1241.2011.02630.x | PMID = 21401825 }}</ref> decreases HDL-apo A-I catabolism<ref name="Kamanna-2008">{{Cite journal  | last1 = Kamanna | first1 = VS. | last2 = Kashyap | first2 = ML. | title = Mechanism of action of niacin. | journal = Am J Cardiol | volume = 101 | issue = 8A | pages = 20B-26B | month = Apr | year = 2008 | doi = 10.1016/j.amjcard.2008.02.029 | PMID = 18375237 }}</ref>
|Decreases VLDL synthesis in the liver through diaglycerol acyl transferase-2 (DGAT-2),<ref name="Wierzbicki-2011">{{Cite journal  | last1 = Wierzbicki | first1 = AS. | title = Niacin: the only vitamin that reduces cardiovascular events. | journal = Int J Clin Pract | volume = 65 | issue = 4 | pages = 379-85 | month = Apr | year = 2011 | doi = 10.1111/j.1742-1241.2011.02630.x | PMID = 21401825 }}</ref> decreases HDL-apo A-I catabolism<ref name="Kamanna-2008">{{Cite journal  | last1 = Kamanna | first1 = VS. | last2 = Kashyap | first2 = ML. | title = Mechanism of action of niacin. | journal = Am J Cardiol | volume = 101 | issue = 8A | pages = 20B-26B | month = Apr | year = 2008 | doi = 10.1016/j.amjcard.2008.02.029 | PMID = 18375237 }}</ref>
|15-35% increase
|15-30% increase
|Cutaneous [[flushing]], [[hyperglycemia]], [[hyperuricemia]], [[hepatotoxicity]]
|Cutaneous [[flushing]], [[hyperglycemia]], [[hyperuricemia]], [[hepatotoxicity]]
|-
|-
| [[Fibrate]]s
| [[Fibrate]]s
|Direct stimulation of apo-A1 and apo-AII synthesis via [[peroxisome proliferator-activated receptor]]s,<ref name="Vu-Dac-1995">{{Cite journal  | last1 = Vu-Dac | first1 = N. | last2 = Schoonjans | first2 = K. | last3 = Kosykh | first3 = V. | last4 = Dallongeville | first4 = J. | last5 = Fruchart | first5 = JC. | last6 = Staels | first6 = B. | last7 = Auwerx | first7 = J. | title = Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. | journal = J Clin Invest | volume = 96 | issue = 2 | pages = 741-50 | month = Aug | year = 1995 | doi = 10.1172/JCI118118 | PMID = 7635967 }}</ref>  
|Direct stimulation of apo-A1 and apo-AII synthesis via [[peroxisome proliferator-activated receptor]]s,<ref name="Vu-Dac-1995">{{Cite journal  | last1 = Vu-Dac | first1 = N. | last2 = Schoonjans | first2 = K. | last3 = Kosykh | first3 = V. | last4 = Dallongeville | first4 = J. | last5 = Fruchart | first5 = JC. | last6 = Staels | first6 = B. | last7 = Auwerx | first7 = J. | title = Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor. | journal = J Clin Invest | volume = 96 | issue = 2 | pages = 741-50 | month = Aug | year = 1995 | doi = 10.1172/JCI118118 | PMID = 7635967 }}</ref>  
|10-20% increase
|5-15% increase
|Increased risk of [[myopathy]] when combined with statins, [[gallstones]], [[dyspepsia]]
|Increased risk of [[myopathy]] when combined with statins, [[gallstones]], [[dyspepsia]]
|-
|-
| [[HMG-CoA reductase inhibitor]]
| [[HMG-CoA reductase inhibitor]]
| Increases synthesis of apo-A1 and HDL in the liver,<ref name="Yamashita-2010">{{Cite journal  | last1 = Yamashita | first1 = S. | last2 = Tsubakio-Yamamoto | first2 = K. | last3 = Ohama | first3 = T. | last4 = Nakagawa-Toyama | first4 = Y. | last5 = Nishida | first5 = M. | title = Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions. | journal = J Atheroscler Thromb | volume = 17 | issue = 5 | pages = 436-51 | month = May | year = 2010 | doi =  | PMID = 20513953 }}</ref> increases [[ABCA1]] mRNA in hepG2 cells,<ref name="Maejima-2011">{{Cite journal  | last1 = Maejima | first1 = T. | last2 = Sugano | first2 = T. | last3 = Yamazaki | first3 = H. | last4 = Yoshinaka | first4 = Y. | last5 = Doi | first5 = T. | last6 = Tanabe | first6 = S. | last7 = Nishimaki-Mogami | first7 = T. | title = Pitavastatin increases ABCA1 expression by dual mechanisms: SREBP2-driven transcriptional activation and PPARα-dependent protein stabilization but without activating LXR in rat hepatoma McARH7777 cells. | journal = J Pharmacol Sci | volume = 116 | issue = 1 | pages = 107-15 | month =  | year = 2011 | doi =  | PMID = 21521932 }}</ref> inhibits CETP mass and activities<ref name="van Venrooij-2003">{{Cite journal  | last1 = van Venrooij | first1 = FV. | last2 = Stolk | first2 = RP. | last3 = Banga | first3 = JD. | last4 = Sijmonsma | first4 = TP. | last5 = van Tol | first5 = A. | last6 = Erkelens | first6 = DW. | last7 = Dallinga-Thie | first7 = GM. | title = Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes. | journal = Diabetes Care | volume = 26 | issue = 4 | pages = 1216-23 | month = Apr | year = 2003 | doi =  | PMID = 12663600 }}</ref>
| Increases synthesis of apo-A1 and HDL in the liver,<ref name="Yamashita-2010">{{Cite journal  | last1 = Yamashita | first1 = S. | last2 = Tsubakio-Yamamoto | first2 = K. | last3 = Ohama | first3 = T. | last4 = Nakagawa-Toyama | first4 = Y. | last5 = Nishida | first5 = M. | title = Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions. | journal = J Atheroscler Thromb | volume = 17 | issue = 5 | pages = 436-51 | month = May | year = 2010 | doi =  | PMID = 20513953 }}</ref> increases [[ABCA1]] mRNA in hepG2 cells,<ref name="Maejima-2011">{{Cite journal  | last1 = Maejima | first1 = T. | last2 = Sugano | first2 = T. | last3 = Yamazaki | first3 = H. | last4 = Yoshinaka | first4 = Y. | last5 = Doi | first5 = T. | last6 = Tanabe | first6 = S. | last7 = Nishimaki-Mogami | first7 = T. | title = Pitavastatin increases ABCA1 expression by dual mechanisms: SREBP2-driven transcriptional activation and PPARα-dependent protein stabilization but without activating LXR in rat hepatoma McARH7777 cells. | journal = J Pharmacol Sci | volume = 116 | issue = 1 | pages = 107-15 | month =  | year = 2011 | doi =  | PMID = 21521932 }}</ref> inhibits CETP mass and activities<ref name="van Venrooij-2003">{{Cite journal  | last1 = van Venrooij | first1 = FV. | last2 = Stolk | first2 = RP. | last3 = Banga | first3 = JD. | last4 = Sijmonsma | first4 = TP. | last5 = van Tol | first5 = A. | last6 = Erkelens | first6 = DW. | last7 = Dallinga-Thie | first7 = GM. | title = Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes. | journal = Diabetes Care | volume = 26 | issue = 4 | pages = 1216-23 | month = Apr | year = 2003 | doi =  | PMID = 12663600 }}</ref>
|5-15% increase
|5-10% increase
|[[Myopathy]], [[rhabdomyolysis]]
|[[Myopathy]], [[rhabdomyolysis]]
|-
|-
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|}
|}


====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.<ref name="pmid18239670">{{cite journal| author=Joy T, Hegele RA| title=Is raising HDL a futile strategy for atheroprotection? | journal=Nat Rev Drug Discov | year= 2008 | volume= 7 | issue= 2 | pages= 143-55 | pmid=18239670 | doi=10.1038/nrd2489 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18239670 }} </ref>


Shown below is a table summarizing the trials that demonstrated a secondary preventive role of [[niacin]] for cardiovascular events along with the associated percent increase in HDL.


{| {| class="wikitable" border="1"
|-
| '''Trial Name''' || '''Drug'''|| '''HDL Increase''' || '''Follow up'''
|-
| '''[[ARBITER 2 Trial]]'''<ref name="pmid15537681">{{cite journal| author=Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA| title=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. | journal=Circulation | year= 2004 | volume= 110 | issue= 23 | pages= 3512-7 | pmid=15537681 | doi=10.1161/01.CIR.0000148955.19792.8D | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15537681 }} </ref>|| Extended release Niacin in patients on statin|| 21% || 12 months
|-
| '''[[ARBITER 3 Trial]]'''<ref name="pmid17076985">{{cite journal| author=Taylor AJ, Lee HJ, Sullenberger LE| title=The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. | journal=Curr Med Res Opin | year= 2006 | volume= 22 | issue= 11 | pages= 2243-50 | pmid=17076985 | doi=10.1185/030079906X148508 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17076985 }} </ref>|| Extended release Niacin in patients on statin||9.6 +/- 12.5 mg/dL ||24 months
|-
| '''[[CLAS 1 Trial]]'''<ref name="pmid2243429">{{cite journal| author=Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH| title=Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. | journal=JAMA | year= 1990 | volume= 264 | issue= 23 | pages= 3013-7 | pmid=2243429 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2243429 }} </ref>|| Niacin and colestipol||37% || 2 years
|-
| '''[[CLAS 2 TRIAL]]'''<ref name="pmid2243429">{{cite journal| author=Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH| title=Beneficial effects of colestipol-niacin on coronary atherosclerosis. A 4-year follow-up. | journal=JAMA | year= 1990 | volume= 264 | issue= 23 | pages= 3013-7 | pmid=2243429 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2243429 }} </ref>|| Niacin and colestipol||37% || 4 years
|-
| '''[[HATS Trial]]'''<ref name="pmid11757504">{{cite journal |author=Brown BG, Zhao XQ, Chait A, ''et al.'' |title=Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease |journal=[[The New England Journal of Medicine]] |volume=345 |issue=22 |pages=1583–92 |year=2001 |month=November |pmid=11757504 |doi=10.1056/NEJMoa011090 |url=}}</ref>|| Niacin and simvastatin +/- antioxidants||26%|| 3 years
|-
| '''[[Coronary Drug Project]]'''<ref name="pmid1088963">{{cite journal| author=| title=Clofibrate and niacin in coronary heart disease. | journal=JAMA | year= 1975 | volume= 231 | issue= 4 | pages= 360-81 | pmid=1088963 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1088963 }} </ref>|| Niacin or clofibrate||-||6 years and 15 years
|-
| '''[[Stockholm Ischemic Heart Disease Study]]'''<ref name="pmid3287837">{{cite journal| author=Carlson LA, Rosenhamer G| title=Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. | journal=Acta Med Scand | year= 1988 | volume= 223 | issue= 5 | pages= 405-18 | pmid=3287837 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3287837 }} </ref>|| Niacin + Clofibrate||-||5 years
|-
| '''[[FATS]]'''<ref name="pmid2215615">{{cite journal| author=Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C et al.| title=Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. | journal=N Engl J Med | year= 1990 | volume= 323 | issue= 19 | pages= 1289-98 | pmid=2215615 | doi=10.1056/NEJM199011083231901 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2215615 }} </ref>||Lovastatin + colestipol<br> Niacin + Colestipol||15% <br> 43%|| 2.5 years
|-
| '''[[FATS Extended follow-up]]'''|| Niacin + lovastatin + colestipol||-||10 years
|-
| '''[[UCSF-SCOR]]'''<ref name="pmid2243428">{{cite journal| author=Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ| title=Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. | journal=JAMA | year= 1990 | volume= 264 | issue= 23 | pages= 3007-12 | pmid=2243428 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2243428 }} </ref>|| Niacin + colestipol +/- Lovastatin and diet||28%||2 years
|-
|}


==Treatment Approach==
====Fibrates====
Several studies on [[fibrates]] proved their efficacy in lowering cardiovascular events through improving the lipid profile in general and increasing the HDL level in particular.  Shown below is a table summarizing the trials that showed a secondary preventive role of [[fibrates]] for cardiovascular events along with the associated percent increase in HDL.
 
{| {| class="wikitable" border="1"
|-
| '''Trial Name''' || '''Drug'''|| '''HDL Increase''' || '''Follow up'''
|-
| '''[[VA-HIT Trial]]'''<ref name="pmid10438259">{{cite journal| author=Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB et al.| title=Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. | journal=N Engl J Med | year= 1999 | volume= 341 | issue= 6 | pages= 410-8 | pmid=10438259 | doi=10.1056/NEJM199908053410604 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10438259 }} </ref>||Gemfibrozil||6%|| 5 years
|-
| '''[[BECAIT Trial]]'''<ref name="pmid9822092">{{cite journal |author=Ruotolo G, Ericsson CG, Tettamanti C, ''et al.'' |title=Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) |journal=J. Am. Coll. Cardiol. |volume=32 |issue=6 |pages=1648–56 |year=1998 |month=November |pmid=9822092 |doi= |url=}}</ref><ref name="pmid7555614">{{cite journal |author=de Faire U, Ericsson CG, Hamsten A, Nilsson J |title=Design features of a five-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) |journal=Drugs Exp Clin Res |volume=21 |issue=3 |pages=105–24 |year=1995 |pmid=7555614 |doi= |url=}}</ref><ref name="pmid8622389">{{cite journal |author=Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U |title=Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients |journal=Lancet |volume=347 |issue=9005 |pages=849–53 |year=1996 |month=March |pmid=8622389 |doi= |url=}}</ref><ref name="pmid9717064">{{cite journal |author=Ericsson CG |title=Results of the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) and an update on trials now in progress |journal=Eur. Heart J. |volume=19 Suppl H |issue= |pages=H37–41 |year=1998 |month=July |pmid=9717064 |doi= |url=}}</ref>||Bezafibrate||9%|| 5 years
|-
| '''[[Helsinki Heart Study]]'''<ref name="pmid3313041">{{cite journal| author=Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P et al.| title=Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. | journal=N Engl J Med | year= 1987 | volume= 317 | issue= 20 | pages= 1237-45 | pmid=3313041 | doi=10.1056/NEJM198711123172001 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3313041 }} </ref>||Gemfibrozil||11%|| 5 years
|-
| '''[[LOCAT]]'''<ref name="pmid9337181">{{cite journal| author=Frick MH, Syvänne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V et al.| title=Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. | journal=Circulation | year= 1997 | volume= 96 | issue= 7 | pages= 2137-43 | pmid=9337181 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9337181 }} </ref>||Gemfibrozil||21%|| 3years
|-
| '''[[DAIS]]'''<ref name="pmid11289345">{{cite journal| author=| title=Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. | journal=Lancet | year= 2001 | volume= 357 | issue= 9260 | pages= 905-10 | pmid=11289345 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11289345 }} </ref>||Fenofibrate||8-9%|| 3 years
|-
|}


===Non-HDL-Cholesterol Goal===
===Challenging HDL-C Hypothesis===
Non-HDL-C represents the cholesterol content present in all the atherogenic lipoproteins i.e., a combination of LDL-C, VLDL-C, IDL-C, and Lipoprotein(a) cholesterol.<ref name="Ballantyne-2000">{{Cite journal  | last1 = Ballantyne | first1 = CM. | last2 = Grundy | first2 = SM. | last3 = Oberman | first3 = A. | last4 = Kreisberg | first4 = RA. | last5 = Havel | first5 = RJ. | last6 = Frost | first6 = PH. | last7 = Haffner | first7 = SM. | title = Hyperlipidemia: diagnostic and therapeutic perspectives. | journal = J Clin Endocrinol Metab | volume = 85 | issue = 6 | pages = 2089-112 | month = Jun | year = 2000 | doi =  | PMID = 10852435 }}</ref>  It is the difference between the total cholesterol and HDL cholesterol (Non-HDL-C = Total cholesterol minus HDL-C). Some studies have demonstrated that non-HDL cholesterol fraction may be a better predictor of future cardiovascular risk than LDL cholesterol.<ref name="Ridker-2005">{{Cite journal | last1 = Ridker | first1 = PM. | last2 = Rifai | first2 = N. | last3 = Cook | first3 = NR. | last4 = Bradwin | first4 = G. | last5 = Buring | first5 = JE. | title = Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. | journal = JAMA | volume = 294 | issue = 3 | pages = 326-33 | month = Jul | year = 2005 | doi = 10.1001/jama.294.3.326 | PMID = 16030277 }}</ref><ref name="Di Angelantonio-2009">{{Cite journal  | last1 = Di Angelantonio | first1 = E. | last2 = Sarwar | first2 = N. | last3 = Perry | first3 = P. | last4 = Kaptoge | first4 = S. | last5 = Ray | first5 = KK. | last6 = Thompson | first6 = A. | last7 = Wood | first7 = AM. | last8 = Lewington | first8 = S. | last9 = Sattar | first9 = N. | title = Major lipids, apolipoproteins, and risk of vascular disease. | journal = JAMA | volume = 302 | issue = 18 | pages = 1993-2000 | month = Nov | year = 2009 | doi = 10.1001/jama.2009.1619 | PMID = 19903920 }}</ref> The treatment goal for non-HDL-C is '''30 mg/dL''' above the LDL-C treatment target.
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.<ref name="pmid18239670">{{cite journal| author=Joy T, Hegele RA| title=Is raising HDL a futile strategy for atheroprotection? | journal=Nat Rev Drug Discov | year= 2008 | volume= 7 | issue= 2 | pages= 143-55 | pmid=18239670 | doi=10.1038/nrd2489 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18239670  }} </ref>


Shown below is a table summarizing the trials that failed to show any secondary preventive role of CETP inhibitors, [[niacin]] or [[fibrates]] for cardiovascular events along with the associated percent increase in HDL.


Below is a table showing the non-HDL and LDL cholesterol goals to be achieved in the management of patients with a low HDL cholesterol according to the ATP III guidelines:
{| class="wikitable" border="1"
{| cellpadding=3 cellspacing=0 border=1 style="border-collapse:collapse"
|-
|bgcolor="#cccccc"| '''RISK CATEGORY'''
| '''Trial Name''' || '''Drug''' || '''HDL Increase'''||'''Endpoints'''
|bgcolor="#cccccc"| '''NON-HDL-GOAL mg/dl'''
|-
|bgcolor="#cccccc"| '''LDL GOAL mg/dl'''
| '''[[ILLUSTRATE]]''' || Torcetrapib || 61% || There was no significant decrease in coronary atherosclerosis. <br> There was increase in blood pressure.<ref name="pmid17387129">{{cite journal| author=Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT et al.| title=Effect of torcetrapib on the progression of coronary atherosclerosis. | journal=N Engl J Med | year= 2007 | volume= 356 | issue= 13 | pages= 1304-16 | pmid=17387129 | doi=10.1056/NEJMoa070635 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17387129  }} </ref>
|-
| '''[[RADIANCE 1]]''' || Torcetrapib ||24.5±0.4 mg/dL|| There was no significant relationship between HDL levels and carotid intima-media thickness. <br> There was increase in blood pressure.<ref name="pmid19029469">{{cite journal| author=Vergeer M, Bots ML, van Leuven SI, Basart DC, Sijbrands EJ, Evans GW et al.| title=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. | journal=Circulation | year= 2008 | volume= 118 | issue= 24 | pages= 2515-22 | pmid=19029469 | doi=10.1161/CIRCULATIONAHA.108.772665 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19029469  }} </ref>
|-
| '''[[RADIANCE 2]]''' || Torcetrapib || 63.4% ||There was no significant relationship between HDL levels and carotid intima-media thickness. <br> There was increase in blood pressure.<ref name="pmid17630038">{{cite journal| author=Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH et al.| title=Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. | journal=Lancet | year= 2007 | volume= 370 | issue= 9582 | pages= 153-60 | pmid=17630038 | doi=10.1016/S0140-6736(07)61088-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17630038  }} </ref>
|-
| '''[[ILLUMINATE Trial]]''' || Torcetrapib || 72.1% || Hazard ratio for death was 1.58 in torcetrapib group at the end of the study (p=0.006).<br>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).<br>Significant increase in adverse events in torcetrapib group was reported: Hypertension, peripheral edema, angina pectoris, dyspnea, and headache (p<0.001).<ref name="pmid17984165">{{cite journal| author=Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M et al.| title=Effects of torcetrapib in patients at high risk for coronary events. | journal=N Engl J Med | year= 2007 | volume= 357 | issue= 21 | pages= 2109-22 | pmid=17984165 | doi=10.1056/NEJMoa0706628 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17984165  }} </ref>
|-
| '''[[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.<ref name="pmid23126252">{{cite journal| author=Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J et al.| title=Effects of dalcetrapib in patients with a recent acute coronary syndrome. | journal=N Engl J Med | year= 2012 | volume= 367 | issue= 22 | pages= 2089-99 | pmid=23126252 | doi=10.1056/NEJMoa1206797 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23126252  }} </ref>
|-
| '''[[AIM-HIGH Trial]]'''|| Niacin + Statin || 25% || There was no reduction in the rate of primary endpoint or all-cause mortality with niacin. <br> Moreover, there was a trend towards more ischemic strokes in the niacin group.<ref name="pmid22085343">{{cite journal| author=AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P et al.| title=Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. | journal=N Engl J Med | year= 2011 | volume= 365 | issue= 24 | pages= 2255-67 | pmid=22085343 | doi=10.1056/NEJMoa1107579 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22085343 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22508748 Review in: Ann Intern Med. 2012 Apr 17;156(8):JC4-08] </ref>
|-
| '''[[BIP Trial]]''' ||Bezafibrate||18%|| There was no difference in fatal and non fatal [[MI]].<ref name="pmid10880410">{{cite journal| author=Bezafibrate Infarction Prevention (BIP) study| title=Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. | journal=Circulation | year= 2000 | volume= 102 | issue= 1 | pages= 21-7 | pmid=10880410 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10880410 }} </ref>
|-
|-
| 0 to 1 CHD risk factor
| '''[[The FIELD study]]'''|| Fenofibrate||3%||There was no difference in mortality and cardiovascular disease events.<ref name="pmid16310551">{{cite journal| author=Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR et al.| title=Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. | journal=Lancet | year= 2005 | volume= 366 | issue= 9500 | pages= 1849-61 | pmid=16310551 | doi=10.1016/S0140-6736(05)67667-2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16310551 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16646609 Review in: ACP J Club. 2006 May-Jun;144(3):65] [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213107 Review in: Evid Based Med. 2006 Jun;11(3):86] </ref>
| <190
| <160
|-
|-
| Two or more CHD risk factors (10-year risk for CHD≤20%)
| <160
| <130
|-
| Coronary heart disease (CHD) and CHD risk equivalent (10-year risk for CHD>20% )
| <130
| <100
|}
|}
{{familytree/start |summary=Treatment of low HDL}}
{{familytree | | | | | | | | | | | | | | | A01 | | | | | A01='''Low HDL'''}}
{{familytree | | | | | | | | | | | | | | | |!| | | | | | | }}
{{familytree | | | | | | | | | | | | | | | B02 | | | | | | B02=<u>Rule out secondary causes</u><br>[[Hypothyroidism]]<br>[[Diabetes mellitus]]<br>[[Uremia]]<br>[[Liver disease]]<br>Medications - [[diuretic]]s, [[progestin]], [[androgen]]s, [[beta blocker]]s<br>Acute illness - MI, burns, surgery}}
{{familytree | | | | | | | | | | | | | | | |!| | | | | | | }}
{{familytree | | | | | | | | | | | | | | | C01 | | | | | | C01=<u>Lifestyle modification</u><br>[[Diet]]<ref name="Wood-1988">{{Cite journal  | last1 = Wood | first1 = PD. | last2 = Stefanick | first2 = ML. | last3 = Dreon | first3 = DM. | last4 = Frey-Hewitt | first4 = B. | last5 = Garay | first5 = SC. | last6 = Williams | first6 = PT. | last7 = Superko | first7 = HR. | last8 = Fortmann | first8 = SP. | last9 = Albers | first9 = JJ. | title = Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise. | journal = N Engl J Med | volume = 319 | issue = 18 | pages = 1173-9 | month = Nov | year = 1988 | doi = 10.1056/NEJM198811033191801 | PMID = 3173455 }}</ref><br>[[Physical exercise]]<br>[[Smoking cessation]]<br>[[Weight loss]]<ref name="Berns-1989">{{Cite journal  | last1 = Berns | first1 = MA. | last2 = de Vries | first2 = JH. | last3 = Katan | first3 = MB. | title = Increase in body fatness as a major determinant of changes in serum total cholesterol and high density lipoprotein cholesterol in young men over a 10-year period. | journal = Am J Epidemiol | volume = 130 | issue = 6 | pages = 1109-22 | month = Dec | year = 1989 | doi =  | PMID = 2589304 }}</ref><br>Intake of unhydrogenated [[monounsaturated fat]]<ref name="Oh-2005">{{Cite journal  | last1 = Oh | first1 = K. | last2 = Hu | first2 = FB. | last3 = Manson | first3 = JE. | last4 = Stampfer | first4 = MJ. | last5 = Willett | first5 = WC. | title = Dietary fat intake and risk of coronary heart disease in women: 20 years of follow-up of the nurses' health study. | journal = Am J Epidemiol | volume = 161 | issue = 7 | pages = 672-9 | month = Apr | year = 2005 | doi = 10.1093/aje/kwi085 | PMID = 15781956 }}</ref><ref name="Mensink-1990">{{Cite journal  | last1 = Mensink | first1 = RP. | last2 = Katan | first2 = MB. | title = Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects. | journal = N Engl J Med | volume = 323 | issue = 7 | pages = 439-45 | month = Aug | year = 1990 | doi = 10.1056/NEJM199008163230703 | PMID = 2374566 }}</ref>
e.g., olive oil, canola oil}}
{{familytree | | | | | | | | |,|-|-|-|-|-|-|^|-|-|-|-|-|-|-|.| | | | | | }}
{{familytree | | | | | | | | D01 | | | | | | | | | | | | | D02 | | D01='''[[Coronary heart disease]]'''|D02='''No [[Coronary heart disease]]'''}}
{{familytree | | | | | | | | |!| | | | | | | | | | | | | | |!| | | | | | | | | | | | |}}
{{familytree | | | | | | | | E01 | | | | | | | | | | | | | E02 | | E01=Lipid profile|E02=Assess risk}}
{{familytree | | | |,|-|-|-|-|^|-|-|-|-|.| | | | | | | |,|-|^|-|-|-|-|.| | | | | |}}
{{familytree | | | F01 | | | | | | | | F02 | | | | | | F03 | | | | | F04 | | F01='''[[Low density lipoprotein]]'''|F02='''[[Triglyceride]]'''|F03=<u>'''High risk'''</u><br><br> CHD risk>20% per 10 years|F04=<u>'''Low risk'''</u><br><br> CHD≤20% per 10 years}}
{{familytree | |,|-|^|-|.| | | | |,|-|-|^|-|-|.| | | | |!| | | | | | |!| | | |}}
{{familytree | G01 | | G02 | | | G03 | | | | | G04 | | |!| | | | | | |!| | | G01='''Low LDL'''<br> <100 mg/dl|G02='''High LDL'''<br> >100 mg/dl|G03='''TG<150 mg/dl'''|G04='''TG 200-499 mg/dl'''}}
{{familytree | |!| | | |!| | | | |!| | | | | | |!| | | |!| | | | | | |!| | }}
{{familytree | H01 | | H02 | | | |!| | | | | | H03 | | H04 | | | | | |!| | |H01=Consider [[fibrate]]s/[[niacin]] or [[statin]]s|H02=[[Statins]]|H03=Assess non-HDL goals|H04=[[Statins]] or [[Niacin]]}}
{{familytree | | | | | |!| | | | |!| | | | | | |!| | | | | | | | | | |!| | | | | | | |}}
{{familytree | | | | | |!| | | | |!| | | | |,|-|^|-|.| | | | |,|-|-|-|^|-|-|-|.| | }}
{{familytree | | | | | I01 | | | I02 | | | I03 | | I04 | | | I05 | | | | | | I06 | |I01=Assess LDL goal|I02='''Isolated low HDL Cholesterol'''<br> (with established CHD or CHD equivalent)|I03=Achieved non-HDL goal but TG>200|I04=Not achieved|I05=Positive family history of premature CHD|I06=Negative family history of premature CHD}}
{{familytree | | | | | |!| | | | |!| | | | |!| | | |!| | | | |!| | | | | | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | | | | J01 | | | |!| | | | J02 | | J03 | | | |!| | | | | | | |!| | | | J01=Target reached|J02=[[Fenofibrate]]|J03=Lipid lowering drugs}}
{{familytree | | |,|-|-|^|.| | | |!| | | | | | | | | | | | | |!| | | | | | | |!| | | | | | | | | | | | |}}
{{familytree | | K01 | | K02 | | K03 | | | | | | | | | | | | K04 | | | | | | K05 | K01='''HDL<40'''|K02='''HDL>40'''|K03=consider [[niacin]],<ref name="Guyton-2000">{{Cite journal  | last1 = Guyton | first1 = JR. | last2 = Blazing | first2 = MA. | last3 = Hagar | first3 = J. | last4 = Kashyap | first4 = ML. | last5 = Knopp | first5 = RH. | last6 = McKenney | first6 = JM. | last7 = Nash | first7 = DT. | last8 = Nash | first8 = SD. | title = Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Niaspan-Gemfibrozil Study Group. | journal = Arch Intern Med | volume = 160 | issue = 8 | pages = 1177-84 | month = Apr | year = 2000 | doi =  | PMID = 10789612 }}</ref> [[fibrates]] or [[niacin]]/[[gemfibrozil]]<ref name="Zema-2000">{{Cite journal  | last1 = Zema | first1 = MJ. | title = Gemfibrozil, nicotinic acid and combination therapy in patients with isolated hypoalphalipoproteinemia: a randomized, open-label, crossover study. | journal = J Am Coll Cardiol | volume = 35 | issue = 3 | pages = 640-6 | month = Mar | year = 2000 | doi =  | PMID = 10716466 }}</ref>|K04=consider [[statin]]s or [[niacin]]|K05=Continue non-pharmacological approach}}
{{familytree | | |!| | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |}}
{{familytree | | |!| | | |!| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | }}
{{familytree | | L01 | | L02 | | | | | | | | | | | | | | | | | | | | | | | | L01=Add [[niacin]] or [[gemfibrozil]]|L02=Continue [[statins]]}}
{{familytree/end}}


==References==
==References==

Latest revision as of 21:55, 9 October 2014

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Since low HDL is associated with an increased risk of cardiovascular disease events, elevation of HDL concentration among subjects with low HDL is advised. The treatment of a patient with low HDL cholesterol should be individualized. Before the initiation of any medical treatment to elevate the HDL concentration, the initial treatment should aim to reduce the LDL and non-HDL lipoprotein concentrations if they are elevated. The management of low HDL should also begin with life style modification targeting diet, exercise, and smoking cessation. If HDL concentration remains high despite optimal LDL and non-HDL concentrations and life style modifications, then medical therapy with fibrates or niacin might be considered among patients with risk factors of coronary artery disease or its equivalent.

Treatment

Who To Treat

The question on who to treat should be answered on a patient-by-patient basis. According to the ATP III guidelines, the treatment of low HDL cholesterol has become a tertiary target in the management of patients with low HDL, with the primary and secondary goals targeting LDL and non-HDL cholesterol, respectively.[1] There are several variables to be considered in a patient with low HDL such as serum triglyceride levels and metabolic abnormalities (diabetes mellitus, metabolic syndrome).

When To Treat

The National Cholesterol Education Program (NCEP) has not set a formal goal for HDL levels as a therapeutic target because of lack of evidence for decrease in primary CHD risk reduction with pharmacotherapy. Drug therapy for HDL can be considered in the presence of other risk factors for CHD such as hypertension, smoking, family history of premature coronary heart disease.

The following are the ATP III guidelines for low HDL management (i.e., HDL-C≤40 mg/dl):[2]

Among patients with low HDL, attempts towards a reduction in LDL and non-HDL concentration should be performed before the administration of medical therapy to raise HDL. Non-HDL-C represents the cholesterol content present in all the atherogenic lipoproteins i.e., a combination of LDL-C, VLDL-C, IDL-C, and lipoprotein(a) cholesterol.[2] Non-HDL-C is the difference between the total cholesterol and HDL cholesterol (Non-HDL-C = Total cholesterol minus HDL-C). Some studies have demonstrated that non-HDL cholesterol fraction may be a better predictor of future cardiovascular risk than LDL cholesterol.[3][4] The treatment goal for non-HDL-C is 30 mg/dL above the LDL-C treatment target.

Below is a table showing the non-HDL and LDL cholesterol goals to be achieved in the management of patients with a low HDL cholesterol according to the ATP III guidelines:

RISK CATEGORY NON-HDL-GOAL mg/dl LDL GOAL mg/dl
0 to 1 CHD risk factor <190 <160
Two or more CHD risk factors (10-year risk for CHD≤20%) <160 <130
Coronary heart disease (CHD) and CHD risk equivalent (10-year risk for CHD>20% ) <130 <100

Non-pharmacologic Therapies

LIFESTYLE MEASURE EFFECT ON HDL
Physical exercise[5] 5-30% increase
Weight reduction 5-20% increase[6]
Smoking cessation 5% increase[7]
Multivitamins 31% increase in HDL
DASH diet 21% increase in HDL[8]
Low carbohydrate diet 4.5mg/dl increase in HDL[9]
Soy protein with isoflavones 3% increase in HDL[10]
Fish oil (omega-3 fatty acid) Significant increase in HDL2 fraction[11]
Fish oil with exercise 8% increase in HDL[12]
Low fat diet 5-14% increase in HDL when combined with exercise[13]
Monounsaturated fat Increase in HDL
Moderate alcohol consumption 5-10% increase in HDL[14]

Significant increase in HDL was observed when a calorie restricted version of DASH diet was used. Liese et al found a lower level of HDL with DASH diet in diabetic patients.[15]

Pharmacologic Therapy

DRUGS MECHANISM OF ACTION EFFECT ON HDL SIDE EFFECTS
Nicotinic acid (Niacin) Decreases VLDL synthesis in the liver through diaglycerol acyl transferase-2 (DGAT-2),[16] decreases HDL-apo A-I catabolism[17] 15-30% increase Cutaneous flushing, hyperglycemia, hyperuricemia, hepatotoxicity
Fibrates Direct stimulation of apo-A1 and apo-AII synthesis via peroxisome proliferator-activated receptors,[18] 5-15% increase Increased risk of myopathy when combined with statins, gallstones, dyspepsia
HMG-CoA reductase inhibitor Increases synthesis of apo-A1 and HDL in the liver,[19] increases ABCA1 mRNA in hepG2 cells,[20] inhibits CETP mass and activities[21] 5-10% increase Myopathy, rhabdomyolysis
Ezetimibe Inhibits cholesterol absorption at intestine level 3% increase in HDL along with statins[22] Headache, diarrhea, hypersensitivity
Thiazolidinediones Increase in adiponectin which increases insulin resistance 14% increase in HDL[23] Fluid retention
Hormone replacement therapy Increases Apo-A1 and decreases activity of hepatic lipase 5 to 20% increase Increases risk of stroke and thromboembolic diseases
Bile acid sequestrants Increases apo A-1 production[24] 3-5% increase GI discomfort, constipation, reduces absorption of other medications

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.[25]

Shown below is a table summarizing the trials that demonstrated a secondary preventive role of niacin for cardiovascular events along with the associated percent increase in HDL.

Trial Name Drug HDL Increase Follow up
ARBITER 2 Trial[26] Extended release Niacin in patients on statin 21% 12 months
ARBITER 3 Trial[27] Extended release Niacin in patients on statin 9.6 +/- 12.5 mg/dL 24 months
CLAS 1 Trial[28] Niacin and colestipol 37% 2 years
CLAS 2 TRIAL[28] Niacin and colestipol 37% 4 years
HATS Trial[29] Niacin and simvastatin +/- antioxidants 26% 3 years
Coronary Drug Project[30] Niacin or clofibrate - 6 years and 15 years
Stockholm Ischemic Heart Disease Study[31] Niacin + Clofibrate - 5 years
FATS[32] Lovastatin + colestipol
Niacin + Colestipol		 15%
43%		 2.5 years
FATS Extended follow-up Niacin + lovastatin + colestipol - 10 years
UCSF-SCOR[33] Niacin + colestipol +/- Lovastatin and diet 28% 2 years

Fibrates

Several studies on fibrates proved their efficacy in lowering cardiovascular events through improving the lipid profile in general and increasing the HDL level in particular. Shown below is a table summarizing the trials that showed a secondary preventive role of fibrates for cardiovascular events along with the associated percent increase in HDL.

Trial Name Drug HDL Increase Follow up
VA-HIT Trial[34] Gemfibrozil 6% 5 years
BECAIT Trial[35][36][37][38] Bezafibrate 9% 5 years
Helsinki Heart Study[39] Gemfibrozil 11% 5 years
LOCAT[40] Gemfibrozil 21% 3years
DAIS[41] Fenofibrate 8-9% 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.[25]

Shown below is a table summarizing the trials that failed to show any secondary preventive role of CETP inhibitors, niacin or fibrates for cardiovascular events along with the associated percent increase in HDL.

Trial Name Drug HDL Increase Endpoints
ILLUSTRATE Torcetrapib 61% There was no significant decrease in coronary atherosclerosis.
There was increase in blood pressure.[42]
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.[43]
RADIANCE 2 Torcetrapib 63.4% There was no significant relationship between HDL levels and carotid intima-media thickness.
There was increase in blood pressure.[44]
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).[45]
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.[46]
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.[47]
BIP Trial Bezafibrate 18% There was no difference in fatal and non fatal MI.[48]
The FIELD study Fenofibrate 3% There was no difference in mortality and cardiovascular disease events.[49]

References

  1. ↑ "Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)". JAMA. 285 (19): 2486–97. 2001. PMID 11368702. Unknown parameter |month= ignored (help)
  2. ↑ Ballantyne, CM.; Grundy, SM.; Oberman, A.; Kreisberg, RA.; Havel, RJ.; Frost, PH.; Haffner, SM. (2000). "Hyperlipidemia: diagnostic and therapeutic perspectives". J Clin Endocrinol Metab. 85 (6): 2089–112. PMID 10852435. Unknown parameter |month= ignored (help)
  3. ↑ Ridker, PM.; Rifai, N.; Cook, NR.; Bradwin, G.; Buring, JE. (2005). "Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women". JAMA. 294 (3): 326–33. doi:10.1001/jama.294.3.326. PMID 16030277. Unknown parameter |month= ignored (help)
  4. ↑ Di Angelantonio, E.; Sarwar, N.; Perry, P.; Kaptoge, S.; Ray, KK.; Thompson, A.; Wood, AM.; Lewington, S.; Sattar, N. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMID 19903920. Unknown parameter |month= ignored (help)
  5. ↑ Thompson PD (1990). "What do muscles have to do with lipoproteins?". Circulation. 81 (4): 1428–30. PMID 2317921.
  6. ↑ Dattilo AM, Kris-Etherton PM (1992). "Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis". Am J Clin Nutr. 56 (2): 320–8. PMID 1386186.
  7. ↑ Gepner AD, Piper ME, Johnson HM, Fiore MC, Baker TB, Stein JH (2011). "Effects of smoking and smoking cessation on lipids and lipoproteins: outcomes from a randomized clinical trial". Am Heart J. 161 (1): 145–51. doi:10.1016/j.ahj.2010.09.023. PMC 3110741. PMID 21167347.
  8. ↑ Azadbakht, L.; Mirmiran, P.; Esmaillzadeh, A.; Azizi, T.; Azizi, F. (2005). "Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome". Diabetes Care. 28 (12): 2823–31. PMID 16306540. Unknown parameter |month= ignored (help)
  9. ↑ Nordmann, AJ.; Nordmann, A.; Briel, M.; Keller, U.; Yancy, WS.; Brehm, BJ.; Bucher, HC. (2006). "Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials". Arch Intern Med. 166 (3): 285–93. doi:10.1001/archinte.166.3.285. PMID 16476868. Unknown parameter |month= ignored (help)
  10. ↑ Zhan, S.; Ho, SC. (2005). "Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile". Am J Clin Nutr. 81 (2): 397–408. PMID 15699227. Unknown parameter |month= ignored (help)
  11. ↑ Sacks FM, Hebert P, Appel LJ, Borhani NO, Applegate WB, Cohen JD; et al. (1994). "The effect of fish oil on blood pressure and high-density lipoprotein-cholesterol levels in phase I of the Trials of Hypertension Prevention. Trials of Hypertension Prevention Collaborative Research Group". J Hypertens Suppl. 12 (7): S23–31. PMID 7769501.
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  13. ↑ Varady KA, Jones PJ (2005). "Combination diet and exercise interventions for the treatment of dyslipidemia: an effective preliminary strategy to lower cholesterol levels?". J Nutr. 135 (8): 1829–35. PMID 16046704.
  14. ↑ Rimm, EB.; Williams, P.; Fosher, K.; Criqui, M.; Stampfer, MJ. (1999). "Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors". BMJ. 319 (7224): 1523–8. PMID 10591709. Unknown parameter |month= ignored (help)
  15. ↑ Liese, AD.; Bortsov, A.; Günther, AL.; Dabelea, D.; Reynolds, K.; Standiford, DA.; Liu, L.; Williams, DE.; Mayer-Davis, EJ. (2011). "Association of DASH diet with cardiovascular risk factors in youth with diabetes mellitus: the SEARCH for Diabetes in Youth study". Circulation. 123 (13): 1410–7. doi:10.1161/CIRCULATIONAHA.110.955922. PMID 21422385. Unknown parameter |month= ignored (help)
  16. ↑ Wierzbicki, AS. (2011). "Niacin: the only vitamin that reduces cardiovascular events". Int J Clin Pract. 65 (4): 379–85. doi:10.1111/j.1742-1241.2011.02630.x. PMID 21401825. Unknown parameter |month= ignored (help)
  17. ↑ Kamanna, VS.; Kashyap, ML. (2008). "Mechanism of action of niacin". Am J Cardiol. 101 (8A): 20B–26B. doi:10.1016/j.amjcard.2008.02.029. PMID 18375237. Unknown parameter |month= ignored (help)
  18. ↑ Vu-Dac, N.; Schoonjans, K.; Kosykh, V.; Dallongeville, J.; Fruchart, JC.; Staels, B.; Auwerx, J. (1995). "Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor". J Clin Invest. 96 (2): 741–50. doi:10.1172/JCI118118. PMID 7635967. Unknown parameter |month= ignored (help)
  19. ↑ Yamashita, S.; Tsubakio-Yamamoto, K.; Ohama, T.; Nakagawa-Toyama, Y.; Nishida, M. (2010). "Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions". J Atheroscler Thromb. 17 (5): 436–51. PMID 20513953. Unknown parameter |month= ignored (help)
  20. ↑ Maejima, T.; Sugano, T.; Yamazaki, H.; Yoshinaka, Y.; Doi, T.; Tanabe, S.; Nishimaki-Mogami, T. (2011). "Pitavastatin increases ABCA1 expression by dual mechanisms: SREBP2-driven transcriptional activation and PPARα-dependent protein stabilization but without activating LXR in rat hepatoma McARH7777 cells". J Pharmacol Sci. 116 (1): 107–15. PMID 21521932.
  21. ↑ van Venrooij, FV.; Stolk, RP.; Banga, JD.; Sijmonsma, TP.; van Tol, A.; Erkelens, DW.; Dallinga-Thie, GM. (2003). "Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes". Diabetes Care. 26 (4): 1216–23. PMID 12663600. Unknown parameter |month= ignored (help)
  22. ↑ Ballantyne, CM.; Houri, J.; Notarbartolo, A.; Melani, L.; Lipka, LJ.; Suresh, R.; Sun, S.; LeBeaut, AP.; Sager, PT. (2003). "Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial". Circulation. 107 (19): 2409–15. doi:10.1161/01.CIR.0000068312.21969.C8. PMID 12719279. Unknown parameter |month= ignored (help)
  23. ↑ Szapary, PO.; Bloedon, LT.; Samaha, FF.; Duffy, D.; Wolfe, ML.; Soffer, D.; Reilly, MP.; Chittams, J.; Rader, DJ. (2006). "Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome". Arterioscler Thromb Vasc Biol. 26 (1): 182–8. doi:10.1161/01.ATV.0000195790.24531.4f. PMID 16284192. Unknown parameter |month= ignored (help)
  24. ↑ Shepherd, J. (1989). "Mechanism of action of bile acid sequestrants and other lipid-lowering drugs". Cardiology. 76 Suppl 1: 65–71, discussion 71-4. PMID 2713876.
  25. ↑ 25.0 25.1 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 28.0 28.1 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.
  29. ↑ 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)
  30. ↑ "Clofibrate and niacin in coronary heart disease". JAMA. 231 (4): 360–81. 1975. PMID 1088963.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB; et al. (1999). "Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group". N Engl J Med. 341 (6): 410–8. doi:10.1056/NEJM199908053410604. PMID 10438259.
  35. ↑ Ruotolo G, Ericsson CG, Tettamanti C; et al. (1998). "Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT)". J. Am. Coll. Cardiol. 32 (6): 1648–56. PMID 9822092. Unknown parameter |month= ignored (help)
  36. ↑ de Faire U, Ericsson CG, Hamsten A, Nilsson J (1995). "Design features of a five-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT)". Drugs Exp Clin Res. 21 (3): 105–24. PMID 7555614.
  37. ↑ Ericsson CG, Hamsten A, Nilsson J, Grip L, Svane B, de Faire U (1996). "Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients". Lancet. 347 (9005): 849–53. PMID 8622389. Unknown parameter |month= ignored (help)
  38. ↑ Ericsson CG (1998). "Results of the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) and an update on trials now in progress". Eur. Heart J. 19 Suppl H: H37–41. PMID 9717064. Unknown parameter |month= ignored (help)
  39. ↑ Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P; et al. (1987). "Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease". N Engl J Med. 317 (20): 1237–45. doi:10.1056/NEJM198711123172001. PMID 3313041.
  40. ↑ Frick MH, Syvänne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V; et al. (1997). "Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group". Circulation. 96 (7): 2137–43. PMID 9337181.
  41. ↑ "Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study". Lancet. 357 (9260): 905–10. 2001. PMID 11289345.
  42. ↑ 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.
  43. ↑ 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.
  44. ↑ 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.
  45. ↑ 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.
  46. ↑ 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.
  47. ↑ 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
  48. ↑ Bezafibrate Infarction Prevention (BIP) study (2000). "Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease". Circulation. 102 (1): 21–7. PMID 10880410.
  49. ↑ Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR; et al. (2005). "Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial". Lancet. 366 (9500): 1849–61. doi:10.1016/S0140-6736(05)67667-2. PMID 16310551. Review in: ACP J Club. 2006 May-Jun;144(3):65 Review in: Evid Based Med. 2006 Jun;11(3):86


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