despite the substantial improvement in medical care for patients suffering from cardiovascular disease ( cvd ) , this condition contributes to about 50% of deaths in europe . treatment of hyperlipoproteinemia , especially of elevated ldl - cholesterol ( ldl - c ) and treatment of arterial hypertension , which decreases the risk of thrombotic events , are among the main therapeutic targets . it has been proved that intensive hypolipidemic treatment targeting recommended goals , of which statins are the most powerful ldl - c decreasing drug , significantly decreases cardiovascular risk . moreover , statins favorably influence other parameters of lipoprotein metabolism , such as triacylglycerols ( tag ) and hdl - cholesterol ( hdl - c ) . nevertheless , even if the target goals of ldl - c are achieved , the risk of cardiovascular events during the following five years remains high ranging from about 6575% . residual cardiovascular risk  , is probably particularly high in patients with manifest coronary heart disease or diabetes mellitus . decrease of hdl - c , elevation of serum tag , apolipoprotein ( apo ) b , small dense ldl particles , lipoprotein [ a ] ( lp[a ] ) concentrations and some other factors significantly contribute to residual cardiovascular risk . in order to reduce residual risk , a combination of statins with fibrates , niacin or n3 polyunsaturated fatty acids is usually recommended . niacin is considered to be the most powerful drug from the point of view of hdl - c increase . furthermore , niacin significantly decreases concentrations of all apob containing lipoproteins , i.e. , vldl , idl , ldl , and lp[a ] ) . the effects on lipid parameters and cardiovascular effects reached in these studies are displayed in table 2 . the occurrence of undesirable effects , such as cephalea , gastrointestinal discomfort , pruritus and flush , are among the major drawbacks of niacin administration , decreasing compliance with the treatment . niacin is a ligand for gpr109a receptors , which are expressed on the surface of several cell types , including adipocytes , mature neutrophils , the retinal pigment epithelium , and epidermal langerhans cells . these compounds bind to the receptors dp1 , ep2 , and ep4 and cause flushing . to overcome this problem , the selective antagonist of pgd2 receptors , laropiprant , has been introduced into clinical practice . new formulations of niacin with extended release ( er ) as well as combinations with laropiprant have been the subjects of large randomized clinical studies : aim - high ( atherothrombosis intervention in metabolic syndrome with low hdl / high triglycerides )   and hps2-thrive ( heart protection study 2-treatment of hdl to reduce the incidence of vascular events ) . these studies delivered disappointing results leading to the conclusion that no further benefit ( decreased parameters of cardiovascular risk ) is achieved by adding niacin to existing statin therapy in patients with high cardiovascular risk . moreover , in these studies , several adverse effects of the treatment were observed ; therefore , niacin treatment for hyperlipidemias is not recommended . however , some authors still believe that niacin monotherapy has beneficial effects on lipid profile in specific groups of patients , such as in individuals with atherogenic dyslipidemia . these positive effects of niacin can be caused not only by its effects on lipid / lipoprotein metabolism , but also by pleiotropic extra - hypolipidemic effects , of which the most important are anti - oxidative and anti - inflammatory actions and increasing serum adiponectin . the aim of this paper is to provide a critical perspective on the exclusion of niacin from hypolipidemic treatment as a response to the results of the abovementioned aim - high and hps2-thrive studies . the recent meta - analysis by lavigne and karas   dealing with studies using niacin in monotherapy as well as in combination with other hypolipidemics , which does not include the results of hps2 thrive , demonstrated the favorable effects of niacin treatment on cardiovascular events . these include increase of hdl - c in addition to other effects of niacin , such as possible anti - inflammatory effects , inhibition of free oxygen radical generation , increase of serum adiponectin levels and positive influence on pro - coagulation states . due to the great number of patients included in the abovementioned aim - high ( atherothrombosis intervention in metabolic syndrome with low hdl / high triglycerides ) and hps2-thrive studies , which produced the inconsistent results , these studies deserve more detailed analysis . in our opinion , these 2 studies are characterized by some methodological flaws , which reduce the value of the published conclusions . the aim - high ( atherothrombosis intervention in metabolic syndrome with low hdl / high triglycerides ) study tested whether extended - release niacin combined with intensive statin therapy , compared with statin therapy alone , would reduce the risk of cardiovascular events in patients with established atherosclerotic cardiovascular disease and atherogenic dyslipidemia . baseline lipid values were quite low : ldl - c , 72 mg / dl , i.e. , 1.86 mmol / l ; hdl - c , 35 mg / dl , i.e. , 0.90 mmol / l ; triacylglycerols , 163 mg / dl , i.e. , 1.84 mmol / l . participants in this study included 3 424 subjects with established cardiovascular disease and low hdl - c levels . the treatment group was given er 15002000 mg of niacin + simvastatin ; the placebo group was treated with simvastatin + placebo ( + 50 mg of niacin ir ) . both groups were supplemented with 10 mg / d of ezetimibe in cases where the target ldl - c needed to be reached . ldl - c concentrations during treatment with statins ( in some cases combined with ezetimibe ) varied between 4080 mg / dl ( 1.042.08 mmol / l ) . mmol / l ) in the niacin group , whereas it had increased by 9.8% in the placebo group ( p<0.001 ) . triglyceride levels had decreased by 28.6% in the niacin group and by 8.1% in the placebo group . the ldl cholesterol level had further decreased by 12.0% in the niacin group and by 5.5% in the placebo group . insignificant differences in cardiovascular events after a duration of three years led to cessation of the clinical observation . according to some researchers , the aim - high study was prematurely terminated . moreover , in this study , administration of niacin in combination with simvastatin or ezetimibe , respectively , was not well balanced in both study arms . in the niacin group , the average daily dose of simvastatin was 43 mg , while in the control group it was 49 mg . furthermore , ezetimibe was administered to 10% of patients in the niacin group , but to up to 22% of those in the control group . this seems to show significant bias in light of the recently published results of the improve - it trial , where it was proved that , in patients with post high - risk acute coronary syndrome , adding 10 mg of ezetimibe to 40 mg of simvastatin daily significantly reduces cardiovascular events in comparison with 40 mg of simvastatin alone . moreover , in post - hoc analysis of the aim - high study , the possible benefits of niacin administration were discovered in the subgroup of patients with hdl - c<32 mg / dl ( 0.83 mmol / l ) and tag>200 mg / dl ( 2.26 mmol / l ) , in which the primary endpoint decreased by 37% ( hr 0.63 , p=0.017 ) . there are even more controversial areas in the design of the hps2-thrive ( heart protection study 2-treatment of hdl to reduce the incidence of vascular events ) study . this study was carried out on a high - risk group of patients suffering from clinical manifestations of atherosclerosis ( enrolled patients with coronary atherosclerosis , cerebrovascular disease and peripheral vascular disease ) . in this study , probands were randomized to er - niacin and laropiprant ( an anti - flushing agent ) versus a placebo . before randomization , both arms received 40 mg of simvastatin daily , with or without ezetimibe , to maintain a total cholesterol target of < 135 mg / dl ( 3.50 mmol / l ) . baseline lipid values , calculated as mean sd were as follows : total plasma cholesterol , 12822 mg / dl , i.e. , 3.310.57 mmol / l ; ldl 6317 mg / dl , i.e. 1.630.44 mmol / l ; hdl , 4411 mg / dl , i.e. , 1.130.28 mmol / l ; and triglycerides , 12574 mg / dl , i.e. , 1.410.83 mmol / l . the merck company stated in its report that adding er - niacin / laropiprant in combination with statin treatment did not reduce the risk of combined endpoints ( coronary death , non - fatal myocardial infarction , stroke or revascularization ) in comparison with treatment with statins alone . moreover , in the er - niacin / laropiprant group , a significant increase of non - fatal adverse effects was recorded . in the er - niacin / laropiprant arm , the risk of diabetic complications was increased by 3.7% ( p<0.05 ) and the risk of new diabetes manifestation was also increased ( by 1.8% ) . furthermore , in the er - niacin / laropiprant arm , the risk of infections was increased by 1.4% and the risk of bleeding by 0.7% . adding er - niacin / laropiprant to statins increased the risk of myopathy [ 75 cases ( 0.16%/year ) vs. 17 cases ( 0.04%/year ) ] . the number of patients , treated with a combination of extended release formulation of niacin and laropiprant , enrolled in the hps2-thrive study , was three times higher than the number of niacin - treated patients participating in the other studies . therefore , meta - analysis including probands from the hps2-thrive study revealed substantially different results from other recently published meta - analysis . looking at the entry lipid values ( see above ) , one could question whether there was a need for any additional treatment of these patients . moreover , the design used in the study  could lead to more drug interactions and , therefore , more side - effects in the group receiving multiple drugs  . it was not possible to evaluate the effects of er - niacin in monotherapy , so one can not assess whether the results obtained ( including the adverse effects ) were caused by er - niacin , or by laropiprant , which can cause a number of yet unknown vascular or immune - modifying effects . the principal product of pgd2 metabolism , the 15-deoxy prostaglandin j2 , acts as an agonist of ppar ( peroxisome proliferator - activated receptor)- , the activation of which can cause some favorable effects of niacin . recently , it was found that administration of laropiprant could block the contributory effects of macrophage - released prostanoids on the camp - mediated modulation of reverse cholesterol transport , thus negating the macrophage - mediated anti - atherosclerotic activity of niacin . moreover , it should be noted that dp1 receptors occur not only in muscle cells of the dermis vasculature , but are also expressed on dendritic and other cells of the immune system . their activation modulates crosstalk between the individual components of the immune system and influences adaptive immune reactions . moreover , the hps2 thrive study included more than 11 000 chinese probands , and these particular patients have a higher risk of side - effects than other patient subgroups . recently , it was discovered that the chinese population may have some genetic predisposition to unpredictable adverse events after er - niacin / laropiprant medication . later analysis of the data presented in the hps2 thrive study revealed that there was a significant interaction between baseline lipids and the impact of er - niacin / laropiprant on outcomes with those with an ldl - c level of > 77 mg / dl ( 2.0 mmol / l ) or a tag level of > 151 mg / dl ( 1.70 mmol / l ) , which suggests there is some benefit . moreover , post hoc analysis showed potential benefits of niacin in men and european populations with significant decreases in rates of coronary revascularizations . therefore , we believe that it would be appropriate to selectively evaluate the functioning of er - niacin alone in the subgroup of patients suffering from low hdl - c and high tag . these patients could serve as a target group , in which case , adding er - niacin to statin treatment could be of benefit in lowering residual cardiovascular risk . niacin ( vitamin b3 ) is used in a variety of multivitamin supplements together with other vitamins of class b , such as thiamine ( vitamin b1 ) , riboflavin ( vitamin b2 ) , and pyridoxine ( vitamin b6 ) . according to the national institutes of health ( nih ) , the u.s . . daily intake of niacin via multivitamin supplements maximally reaches tens of milligrams , which is far below the pharmacologically active hypolipidemic dosage ( 13 g / day ) . both experimental and clinical data provide evidence for the importance of b vitamins in the pathophysiology of metabolic syndrome and in the prevention of cardiovascular diseases . recent studies have shown that low levels of thiamine , niacin , and pyridoxine are associated with increased insulin resistance , metabolic syndrome , diabetes , and cardiovascular disease . in a recently published study , high dietary content of b vitamins ( thiamine , riboflavin , and niacin ) was the only nutritional factor to correlate negatively with the incidence of metabolic syndrome . pyridoxine ( vitamin b6 ) considerably influences the metabolism of lipids . the active form of pyridoxine , pyridoxal-5-phosphate , is an important cofactor of many enzymes . in the boston puerto rican health study , this is connected with flavin coenzyme activity , e.g. , studies in humans and animals have shown impaired synthesis of plp in riboflavin deficiency . it was found that hdl levels were reduced and triacylglycerol and total cholesterol ( tc ) levels were increased in thiamine - deficient diabetic rats as well , while high - dose thiamine administration ( 70 mg / kg ) normalized tag and tc levels , but no effect was found on hdl . this effect can be partly explained by the influence of thiamine on the activities of enzymes of lipid metabolism , such as the lowering of liver fatty acid synthase activity . the study on volunteers with marginal nutritional deficiency of vitamin b6 showed decreased plasma concentrations of polyunsaturated fatty acids ( pufa ) of the n6 and n3 families , whereas the levels of tc , ldl - c , hdl - c , and tag did not change . altered synthesis of unsaturated , particularly n6 and n3 pufa , was proved in cultured human hepatoma ( hepg2 ) cells under the condition of vitamin b-6 restriction . recently , it was found that , in the isolated gonadal white adipose tissue of hyperlipidemic mice , niacin causes the upregulation of the biosynthesis of pufa accompanied by high secretion of dha and a consequent increase of dha content in serum , a higher dha / aa ratio , as well as a higher concentration of a dha metabolite  19,20-dihydroxydocosapentaenoic acid ( 19,20-dihdpa ) . this influence on the profiles of pufa that were synthesized by adipose tissue could be a part of the mechanism by which niacin favorably influences cardiovascular risk . in conclusion , niacin , in addition to its hypolipidemic effects , is characterized by complex metabolic functioning , exhibiting a plethora of pleiotropic effects , of which the most important are anti - oxidative and anti - inflammatory actions and increasing serum adiponectin . by combining these effects with the anti - lipolytic action of niacin and the amplification of reverse cholesterol transport , niacin treatment could serve as a treatment which specifically targets atherogenic dyslipidemia influencing metabolic syndrome , notwithstanding the fact that treatment with niacin in the hps2-thrive study led to slightly increased levels of blood glucose and a mild increase of new diabetes incidence . we believe that the observed slight dysregulation of glucose homeostasis caused by niacin is comparable to a similar problem observed in patients treated with statins . it has been reported that although treatment with statins slightly increases the risk of the new - onset of type 2 diabetes , the benefits of statins in reducing cardiovascular events clearly compensate for this risk . therefore , the clinical evaluation of niacin , especially with regard to its extended release formulations , is worthy of further attention . niacin could find a place among the group of hypolipidemic drugs used for patients with concomitant hypercholesterolemia and statin intolerance , high non - hdl cholesterol , and metabolic syndrome , or for patients who are unresponsive to hypolipidemic therapy of targeted ldl cholesterol values .
niacin is considered to be a powerful drug for the treatment of lipid and lipoprotein abnormalities connected with 
 residual cardiovascular risk  , which persist in high - risk patients even when the target goals of ldl - c are achieved with statin therapy . 
 recent large randomized clinical studies  aim - high ( atherothrombosis intervention in metabolic syndrome with low hdl / high triglycerides ) and hps2-thrive ( heart protection study 2-treatment of hdl to reduce the incidence of vascular events )  delivered some disappointing results , leading to the conclusion that no further benefit ( decreased parameters of cardiovascular risk ) is achieved by adding niacin to existing statin therapy in patients with high cardiovascular risk . 
 moreover , in these studies , several adverse effects of the treatment were observed ; therefore , niacin treatment for hypolipidemias is not recommended . in this paper 
 , we analyze the mechanisms underlying the hypolipidemic and antiatherogenic effects of niacin as well as some limitations of the designs of the aim high and hp2-thrive studies . 
 we also provide the possibilities of rational usage of niacin for specific types of dyslipidemias .