the high - density lipoprotein cholesterol ( hdl - c ) is a group of heterogeneous lipoproteins that are involved in the transport of sterols and lipids .
guidelines for management of patients with dyslipidemia primarily focus on achievement of target low - density lipoprotein cholesterol ( ldl - c ) levels for coronary heart disease ( chd ) risk reduction ( ncep - atp iii ) .
however , there is increasing interest in high - density lipoprotein cholesterol ( hdl - c ) as a second line target of therapy .
it is well - established that low concentration of hdl - c is associated with a higher risk of chd and rising concentrations are associated with a fall in risk of chd .
however , how high serum concentration of hdl - c is good enough , is not very clear .
hdl - c is popularly known as  good cholesterol  and high levels are associated with low cardiovascular risk , but the role of hdl in vascular disease is complex .
anti - atherosclerotic effects of hdl - c include increment in reverse cholesterol transport and macrophage cholesterol efflux , anti - inflammatory activity , inhibition of low - density lipoprotein ( ldl ) cholesterol oxidation , endothelial cell apoptosis .
it also interferes with the thrombotic component of atherosclerosis by inhibiting platelet aggregation and reducing expression of cellular adhesion molecules .
the protective effect of hdl on atherosclerosis is suggested by the observation in humans that plasma hdl - c concentrations above 75 mg / dl are associated with prolonged life ( the longevity syndrome ) and relative freedom from coronary heart disease .
studies in animals have shown that overexpression of the apolipoprotein a - i gene ( the major apolipoprotein in hdl cholesterol ) prevents the development or progression of atherosclerosis . in an analysis of 4 prospective studies
, it was shown that the risk of chd with low hdl - c is independent of the risk attributed to elevated levels of ldl - c .
an increase of 1 mg / dl of hdl - c resulted in decrease of chd by 2% in men and 3% in women .
low serum hdl - c can occur alone or be combined with insulin resistance , hypertriglyceridemia , and small dense ldl - c .
the inverse association between hdl - c and chd risk is a continuous variable ; no threshold relationship has been identified .
ncep - atp ii specified low hdl - c ( < 35 mg / dl ) as one of several major coronary risk factors used to modify the therapeutic goal for ldl cholesterol .
but , in atp iii , a level of less than 40 mg / dl was set as a low hdl - c both in men and women and a level of greater than 60 mg / dl as high hdl - c . in the framingham heart study , the risk for myocardial infarction increased by about 25% for every 5 mg / dl decrement in serum hdl - c . when using hdl - c of 35 - 59 mg / dl as a reference stratum , chd was increased in those with hdl - c < 35 mg / dl while it was less in those with hdl - c > 60 mg / dl
{ multivariate adjusted relative risk 1.47 ( men ) and 2.02 ( women ) vs. 0.56 ( men ) and 0.58 ( women ) , respectively}. ) serum hdl - c inversely predicts the time to a first major cardiovascular event as well as the risk of coronary events in patients with known chd across a broad range of ldl - cholesterol levels .
low hdl - c is also a stronger predictor of chd events in patients with an ldl - c < 125 mg / dl .
when divided into quintiles , the highest quintile of hdl - c ( mean  sd 61.5  10.1 mg / dl ) had 40% lower rates of chd than the lowest quintile ( 35.7  4.5 mg / dl ) . in a meta - analysis of studies in the asia - pacific region , there was a negative correlation between hdl - c and chd events ( hazard ratio 1.57 ; 95% ci 1.31 - 1.87 ) , again underscoring the role of low hdl - c .
patients with diabetes mellitus have a higher risk of chd and in general , have been assigned a lower target value for serum ldl - c .
however , in chinese patients with type 2 diabetes mellitus , hdl - c was again found to have no definite threshold for chd risk . with every 1 mmol / l ( mmol / l= mg / dl x 0.02586 ) increase in hdl - c , the risk of chd decreased ( hr 0.61 , 95% ci 0.45 - 0.84 ) .
use of statins reduced the risk of chd by 51% in those with low hdl ( < 1 mmol / l in males and < 1.3
however , certain conditions with low hdl - c do not have increased risk for chd , such as tangier disease , and stand out as exceptions to the hdl - c and chd association .
it has also been reported that it may not be the hdl - c concentrations but the hdl - c particle number that is protective for markers of atherosclerosis .
the drugs in clinical use that alter the serum hdl - c concentration favorably are niacin and gemfibrozil . however , many other drugs like statins , cholestyramine , and colestipol have been known to have some effect .
a new class of drugs , cholesteryl ester transfer protein ( cetp ) inhibitors , is currently under trial for the same purpose .
on intervention with pravastatin for each 10 mg / dl increase in hdl - c , the event rate decreased by 29% in those with ldl - c < 125 mg / dl compared to 10% in those with an ldl - c  125 mg / dl . with atorvastatin ,
1 mg / dl increment in hdl at 3 months has been reported to decrease the risk of chd by 1.1% irrespective of sex .
however , no threshold of hdl - c for the beneficial effect was observed in either of the trial .
similarly , use of gemfibrozil has also been found to be effective in elevating hdl - c and reducing vascular events in patients with chd having ldl - c  140 mg / dl , an hdl - c  40 mg / dl , and triglycerides  300 mg / dl . in a trial of combined use of simvastatin and niacin for 3 years in patients with chd who also had hdl - c < 35 mg / dl and
ldl - c < 145 mg / dl , hdl - c improved by 26% .
it also resulted in reduction in vascular events much more than that expected with statins alone , possibly due to improvement in hdl - c .
trials of niacin in patients with chd or chd risk equivalent , having low hdl - c have , shown elevation of hdl - c with niacin with reduction in carotid intima medial thickness . cetp and cardiovascular risk 
cetp is involved in metabolism of hdl - c and its role has also been studied .
polymorphisms affecting the activity of cetp reduce the activity of cetp and increase hdl - c .
cetp inhibitors have been tried to modify hdl - c , and they are still under trial .
torcetrapib , anacetrapib , evacetrapib , and dalcetrapib inhibit cetp and raise hdl - c .
however , torcetrapib was reported to increase risk of chd and interest in it has waned .
hdl - c is popularly known as  good cholesterol  and high levels are associated with low cardiovascular risk , but the role of hdl in vascular disease is complex .
anti - atherosclerotic effects of hdl - c include increment in reverse cholesterol transport and macrophage cholesterol efflux , anti - inflammatory activity , inhibition of low - density lipoprotein ( ldl ) cholesterol oxidation , endothelial cell apoptosis .
it also interferes with the thrombotic component of atherosclerosis by inhibiting platelet aggregation and reducing expression of cellular adhesion molecules .
the protective effect of hdl on atherosclerosis is suggested by the observation in humans that plasma hdl - c concentrations above 75 mg / dl are associated with prolonged life ( the longevity syndrome ) and relative freedom from coronary heart disease .
studies in animals have shown that overexpression of the apolipoprotein a - i gene ( the major apolipoprotein in hdl cholesterol ) prevents the development or progression of atherosclerosis . in an analysis of 4 prospective studies
, it was shown that the risk of chd with low hdl - c is independent of the risk attributed to elevated levels of ldl - c .
an increase of 1 mg / dl of hdl - c resulted in decrease of chd by 2% in men and 3% in women .
low serum hdl - c can occur alone or be combined with insulin resistance , hypertriglyceridemia , and small dense ldl - c .
the inverse association between hdl - c and chd risk is a continuous variable ; no threshold relationship has been identified .
ncep - atp ii specified low hdl - c ( < 35 mg / dl ) as one of several major coronary risk factors used to modify the therapeutic goal for ldl cholesterol .
but , in atp iii , a level of less than 40 mg / dl was set as a low hdl - c both in men and women and a level of greater than 60 mg / dl as high hdl - c . in the framingham heart study , the risk for myocardial infarction increased by about 25% for every 5 mg / dl decrement in serum hdl - c . when using hdl - c of 35 - 59 mg / dl as a reference stratum , chd was increased in those with hdl - c < 35 mg / dl
while it was less in those with hdl - c > 60 mg / dl { multivariate adjusted relative risk 1.47 ( men ) and 2.02 ( women ) vs. 0.56 ( men ) and 0.58 ( women ) , respectively}. ) serum hdl - c inversely predicts the time to a first major cardiovascular event as well as the risk of coronary events in patients with known chd across a broad range of ldl - cholesterol levels .
low hdl - c is also a stronger predictor of chd events in patients with an ldl - c < 125 mg / dl .
when divided into quintiles , the highest quintile of hdl - c ( mean  sd 61.5  10.1 mg / dl ) had 40% lower rates of chd than the lowest quintile ( 35.7  4.5 mg / dl ) . in a meta - analysis of studies in the asia - pacific region
, there was a negative correlation between hdl - c and chd events ( hazard ratio 1.57 ; 95% ci 1.31 - 1.87 ) , again underscoring the role of low hdl - c .
patients with diabetes mellitus have a higher risk of chd and in general , have been assigned a lower target value for serum ldl - c .
however , in chinese patients with type 2 diabetes mellitus , hdl - c was again found to have no definite threshold for chd risk . with every 1 mmol / l ( mmol / l= mg / dl x 0.02586 ) increase in hdl - c , the risk of chd decreased ( hr 0.61 , 95% ci 0.45 - 0.84 ) .
use of statins reduced the risk of chd by 51% in those with low hdl ( < 1 mmol / l in males and < 1.3 mmol / l in females ) .
however , certain conditions with low hdl - c do not have increased risk for chd , such as tangier disease , and stand out as exceptions to the hdl - c and chd association .
it has also been reported that it may not be the hdl - c concentrations but the hdl - c particle number that is protective for markers of atherosclerosis .
the drugs in clinical use that alter the serum hdl - c concentration favorably are niacin and gemfibrozil .
however , many other drugs like statins , cholestyramine , and colestipol have been known to have some effect .
a new class of drugs , cholesteryl ester transfer protein ( cetp ) inhibitors , is currently under trial for the same purpose . on intervention with pravastatin for each 10 mg / dl increase in hdl - c ,
the event rate decreased by 29% in those with ldl - c < 125 mg / dl compared to 10% in those with an ldl - c  125 mg / dl . with atorvastatin , 1 mg / dl increment in hdl at 3 months has been reported to decrease the risk of chd by 1.1% irrespective of sex . however , no threshold of hdl - c for the beneficial effect was observed in either of the trial .
similarly , use of gemfibrozil has also been found to be effective in elevating hdl - c and reducing vascular events in patients with chd having ldl - c  140 mg / dl , an hdl - c  40 mg / dl , and triglycerides  300 mg / dl . in a trial of combined use of simvastatin and niacin for 3 years in patients with chd who also had hdl - c < 35 mg / dl and ldl - c < 145 mg / dl ,
it also resulted in reduction in vascular events much more than that expected with statins alone , possibly due to improvement in hdl - c .
trials of niacin in patients with chd or chd risk equivalent , having low hdl - c have , shown elevation of hdl - c with niacin with reduction in carotid intima medial thickness .
cetp is involved in metabolism of hdl - c and its role has also been studied .
polymorphisms affecting the activity of cetp reduce the activity of cetp and increase hdl - c .
cetp inhibitors have been tried to modify hdl - c , and they are still under trial .
torcetrapib , anacetrapib , evacetrapib , and dalcetrapib inhibit cetp and raise hdl - c .
however , torcetrapib was reported to increase risk of chd and interest in it has waned .
the national cholesterol education program ( adult treatment program [ atp ] iii ) guidelines , published in 2001 , identified hdl - c more than 60 mg / dl as reasonably good level while less than 40 mg / dl was considered low .
the goals of treating patients with low hdl - cholesterol have not been firmly established .
relationship of hdl - c and chd risk is linear , and no upper limit of hdl - c has been identified . among all the drugs tried to improve serum hdl - c concentrations , statins only have shown reduction in chd risk and mortality .
as far as chd risk is concerned , it appears that higher the hdl cholesterol is , better it is .
 the high - density lipoprotein cholesterol ( hdl - c ) is considered anti - atherogenic good cholesterol . 
 it is involved in reverse transport of lipids . 
 epidemiological studies have found inverse relationship of hdl - c and coronary heart disease ( chd ) risk . when grouped according to hdl - c , subjects having hdl - c more than 60 mg / dl had lesser risk of chd than those having hdl - c of 40 - 60 mg / dl , who in turn had lesser risk than those who had hdl - c less than 40 mg / dl . 
 no upper limit for beneficial effect of hdl - c on chd risk has been identified . 
 the goals of treating patients with low hdl - c have not been firmly established . 
 though many drugs are known to improve hdl - c concentration , statins are proven to improve chd risk and mortality . 
 cholesteryl ester transfer protein ( cetp ) is involved in metabolism of hdl - c and its inhibitors are actively being screened for clinical utility . however , final answer is still awaited on cetp - inhibitors . 
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Data from observational studies
Data from intervention studies
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