hypertension and dyslipidemia , two powerful risk factors for cardiovascular disease , often coexist , and their combined effect is much greater than the sum of their individual effects .
moreover , a growing body of evidence supports that dyslipidemia may predate the onset of hypertension , while a genetic link between dyslipidemia and hypertension can not be excluded [ 2 , 3 ] .
statins , the mainstay of lipid - lowering therapy , result in a significant clinical benefit both in primary and secondary cardiovascular prevention .
in addition to their hypolipidemic capacity , other properties may contribute to statin - induced benefits , including a reduction of blood pressure ( bp ) [ 59 ] .
in this context , rosuvastatin has been associated with reductions in bp and bp variability in animal studies [ 6 , 10 ] .
nicotinic acid ( na ) comprises the oldest hypolipidemic drug in use since 1955 , and it has been associated with bp decrease in a number of studies [ 11 , 12 ] .
recently , the european medicine agency approved a fixed combination of extended release ( er ) na with laropiprant ( a prostaglandin d2 receptor antagonist ) which reduces na - induced flushing without altering the beneficial effects of na on lipid profile or bp [ 1315 ] .  
we aimed to compare the possible bp effects of switching to high - dose rosuvastatin with add - on - current statin er - na / laropiprant in normotensive and hypertensive patients with primary dyslipidemia who were currently treated with a conventional statin regimen but had not achieved the treatment goals . to our best of knowledge ,
consecutive subjects with primary hypercholesterolemia ( n = 70 ) attending the outpatient lipid and obesity clinic of the university hospital of ioannina , ioannina , greece were recruited .
eligible patients were those treated for at least 3 months with a conventional statin dose ( 1040  mg simvastatin or 1020  mg atorvastatin or 520  mg rosuvastatin ) and their low - density lipoprotein cholesterol ( ldl - c ) or non - high - density lipoprotein cholesterol ( non - hdl - c ) levels were above those recommended by the national cholesterol education program adult treatment panel iii ( ncep - atp ) iii based on each patient risk factors . subjects with triglycerides ( tg ) > 500  mg / dl ( 5.65  mmol / l ) , renal disease ( serum creatinine levels > 1.6  mg / dl , 141  mol / l ) , hypothyroidism ( thyroid stimulating hormone ( tsh ) > 5  iu / ml ) , and liver disease ( alanine aminotransferase ( alt ) and/or aspartate aminotransferase ( ast ) levels > 3-fold upper limit of normal in 2 consecutive measurements ) were excluded from the study .
patients with hypertension and/or diabetes were considered eligible if they were on stable medication for at least 3  months and their bp and/or glycemic profile were adequately controlled ( no change in their treatment was allowed during study period ) .  
patients were randomly allocated ( without a washout phase ) to open - label high - dose rosuvastatin ( 40  mg / day ) or to add - on current statin treatment with er - na / laropiprant ( 1000/20  mg / day for the first 4  weeks , followed by 2000/40  mg / day for the next 8  weeks ) for a total of 3  months .  
all study participants gave their written informed consent prior to enrolment , and the ethics committee of the university hospital of ioannina approved the study protocol .
visits took place at baseline and 12  weeks after the start of treatment . at each visit ,
bp was measured in triplicate in the right arm after patients had rested for 10  minutes in a sitting position .
measurements were performed by trained clinicians using an electronic sphygmomanometer ( watchbp office , microlife watchbp ag , widnau , switzerland ) .
levels of total cholesterol ( tc ) , hdl - c , and triglycerides ( tg ) were determined enzymatically in the laboratory of the university hospital of ioannina using an olympus au 600 analyzer ( olympus diagnostica gmbh , hamburg , germany ) .
ldl - c was calculated using the friedewald equation ( provided that tgs were < 350  mg / dl ( 3.95  mmol / l ) ) .
based on previous studies we estimated that er - na / laropiprant would result in a 3% reduction of bp , while switching to rosuvastatin would not alter bp since patients were already receiving a statin .
power analysis revealed that a sample size of 30 patients per group would give a 99% power to detect differences between groups at an  level lower than 0.05 .
the kolmogorov - smirnov test was used to evaluate whether each parameter followed a gaussian distribution , and logarithmic transformations were accordingly performed .
values are given as mean  standard deviation ( sd ) and median ( range ) for parametric and nonparametric data , respectively .
the differences of study parameters between baseline and posttreatment values were evaluated by paired sample t - test ( or wilcoxon 's rank test for non - gaussian variables ) .
analysis of covariance ( ancova ) adjusted for baseline values was used for the comparisons between treatment groups . statistical significance was set at p < .05 . analyses were performed using spss version 15.0 ( spss inc . , chicago , illinois ) .
recruitment took place from october 2009 to september 2010 , and followup ended in december 2010 .
sixty patients ( 27 men , 59  11 years ) completed the study , since 7 participants in the er - na / laropiprant group dropped out due to flushing as well as 1 patient in the rosuvastatin group due to alt elevation > 3-fold upper normal limit .
no changes in body weight , dietary habits ( including salt intake ) , or antihypertensive or antidiabetic medications were reported during the followup . in the switch - to - rosuvastatin 40  mg / day group ,
in contrast , the addition of er - na / laropiprant to current statin treatment resulted in a significant 7% reduction of systolic bp ( p < .001 versus baseline and p = .01 versus rosuvastatin 40  mg ) and a significant 5% reduction of diastolic bp ( p = .009 versus baeline and p = .01 versus rosuvastatin 40  mg ) ( table 2 ) .   in the subgroup of hypertensive subjects ( n = 18 ) the add - on - current - statin er - na /
laropiprant was associated with a 7% and 6% significant reduction of systolic and diastolic bp , respectively , compared with baseline ( systolic bp from 133  6 to 124  11  mmhg , p = .009 and diastolic bp from 80  9 to 75  6  mmhg , p = .03 ) . in normotensive subjects
( n = 12 ) the add - on - current - statin er - na / laropiprant resulted in similar though not significant bp alterations ( 6% ( from 131  5 to 125  6  mmhg ) and -5% ( from 83  5 to 79  6  mmhg ) , respectively , p = ns versus baseline and p = ns versus hypertensive subgroup ) . in the switch - to - rosuvastatin 40  mg group , both hypertensive and normotensive subjects demonstrated no significant bp alterations ( data not shown ) .  
both the switch to rosuvastatin 40  mg and add - on - statin er - na / laropiprant significantly decreased tc , ldl - c , tgs and non - hdl - c compared with baseline ( all p < .001 ) ( table 2 ) .
the change in ldl - c was more pronounced in the switch - to - rosuvastatin 40  mg compared with add - on - current - statin er - na / laropiprant group . in contrast , tgs and hdl - c levels were improved more with add - on - statin er - na / laropiprant compared with switch - to - rosuvastatin 40  mg ( table 2 ) .
the observed bp reductions were not significantly correlated with hdl - c increase or other lipid changes in the add - on - statin er - na group ( data not shown ) .
this is the first study to directly compare the antihypertensive potential of switching to high - dose statin with add - on - current statin er - na / laropiprant .
we demonstrated that add - on - current - statin er - na / laropiprant but not the switch to rosuvastatin 40  mg is associated with significant reductions of both systolic and diastolic bp in patients with primary dyslipidemia , especially in the subgroup of hypertensives .
a growing body of evidence suggests that statins may reduce bp [ 5 , 8 , 9 , 17 , 18 ] .
the effects of rosuvastatin on systemic and regional hemodynamics were evaluated in 2 hypertensive rat models ( one genetically determined and one hypertensive - induced via inhibition of nitric oxide ( no ) synthesis ) .
regional hemodynamics improved with rosuvastatin in both hypertensive models , as evidenced by increased blood flow and decreased vascular resistance .
in addition , rosuvastatin has been associated with improved bp variability in genetically dyslipidemic mice ( apolipoprotein e / ) and reduced systolic bp in obese rats with chronic kidney injury [ 6 , 19 ] . moreover ,
in obese and dyslipidemic ( leptin- and ldl - receptor - deficient ) mice rosuvastatin reduced systolic bp to the same levels compared with age - matched wild type control mice despite incomplete correction of insulin resistance and regardless of dose .   the mechanisms by which statin may reduce bp remain unknown .
it is possible that statin effects on bp are mediated by endothelial function improvement . of note , among
the pleiotropic actions of rosuvastatin are the reduction of proinflammatory cytokines and endogenous no synthase inhibitor levels , the promotion of no function and peroxisome proliferator - activated receptor gamma ( ppar ) expression , and the increase of superoxide dismutase 1 which represent major antioxidants in the vasculature [ 6 , 7 , 10 ] . moreover , in a placebo - controlled study , rosuvastatin ( 10  mg / day ) decreased p - selectin in 60 patients with pulmonary arterial hypertension ( pah ) .
p - selectin is a crucial player in inflammation and thrombosis , and its reduction by rosuvastatin is relevant to the pathophysiological scenario of pah and potentially to arterial bp .
indeed , a growing body of evidence suggests that vitamin d may decrease bp [ 22 , 23 ] .   
in our study , the switch to rosuvastatin 40  mg / day was not associated with significant bp reductions .
a possible explanation could be that all patients were already receiving baseline statin treatment . as the bp - lowering effect of rosuvastatin has been demonstrated to be independent of dose and changes in lipids , at least in animal models ,
it is possible that the switch to high - dose rosuvastatin does not result in any further reduction in bp compared with preexisting statin treatment [ 6 , 7 , 9 , 10 ] . despite the use of na for approximately 50 years , there are only few reports on the effects of na on bp [ 11 , 24 , 25 ] . in one study
na was intravenously infused to 11 normotensive and 10 hypertensive subjects . in the normotensives , systolic , diastolic , and
in contrast , the hypertensive subjects experienced a decrease in mean bp from 105  2  mmhg to 100  3  mmhg ( p < .01 ) accompanied by significant decreases in systolic , diastolic , and pulse pressures .
another study reached similar results , supporting that na ( 500  mg / day for 7  days and then 1  g / day for further 7  days ) does not have an acute effect on bp in normotensive subjects .
a post - hoc analysis of the coronary drug project ( cdp ) demonstrated that 1-year therapy with na in patients with metabolic syndrome was associated with a 2.2  mmhg reduction of systolic bp compared with a rise of 0.8  mmhg in the placebo group ( p < .0001 ) .
additionally , diastolic bp declined by 2.9  mmhg compared with 0.9  mmhg decrease in the placebo group ( p < .0001 ) . in a post - hoc analysis of a 24-weeks , phase 3 trial , 1613 dyslipidemic patients were randomized in er - na alone or er - na / laropiprant combination or placebo .
bp decreased with er - na , while laropiprant did not attenuate or abolish this effect .
specifically , the placebo - adjusted mean changes from baseline in systolic bp were 2.2 and 3.1  mmhg in the er - na and er - na / laropiprant groups ( p < .05 and p < .001 , resp . ) , while similar changes were reported for diastolic bp ( 2.7 and 2.5  mmhg in the er - na and er - na / laropiprant groups , respectively , both p < .001 ) . of note ,
the reduction of systolic bp in the er - na and er - na / laropiprant groups was more pronounced in patients not receiving antihypertensive treatment compared with those on such treatment . on the contrary , diastolic bp decreased similarly in all patients receiving er - na or er - na / laropiprant regardless of concomitant antihypertensive therapy .
there were also a few cases reported of hypotension ( in 0.3% , 0.0% , and 0.7% of patients receiving er - na , er - na / laropiprant and placebo , resp . ) and orthostatic hypotension ( in 0.1% , 0.2% and 0.0% of patients receiving er - na , er - na / laropiprant and placebo , resp . ) .
in contrast , in a smaller ( n = 412 ) and shorter study ( 8  weeks ) , the combination of er - na ( 1 - 2  g / day ) with laropiprant did not significantly alter bp levels .  
the mechanisms by which na can reduce bp remain unknown . studies with na and laropiprant suggest that the latter does not affect bp [ 15 , 30 ] .
thus , it is unlikely that these changes are mediated by prostaglandin d2 or cutaneous vasodilatation .
another possible mechanism may be the improvement in endothelial function , as hdl promotes no endothelial generation .
thus , the na - induced elevation of hdl may result in a no - mediated decrease of bp .   in our study ,
add - on - statin er - na / laropiprant was associated with significant bp reductions , mainly in hypertensive subjects .
the observed bp reductions were not significantly correlated with hdl - c increase or other lipid changes .
thus , the er - na / laropiprant - induced bp lowering may be independent of lipid changes and may be associated with the pleiotropic effects of this agent .
na apart from raising hdl improves several pleiotropic properties of hdl including improved capacity of hdl to stimulate endothelial no , to reduce superoxide production , and to promote endothelial progenitor cell - mediated endothelial repair which may be beneficial for endothelial function .
moreover , na has been directly associated with the reduction of asymmetric dimethylarginine ( adma ) , a methylated amino acid that causes endothelial dysfunction by competitive inhibition of the no synthase [ 33 , 34 ] . of note ,
although er - na / laropiprant - associated bp reduction was numerically similar between normotensives and hypertensives , it was significant only in hypertensive subjects .
however , the small number of patients in the normotensive subgroup does not allow firm conclusions .
we noticed more pronounced reduction in ldl - c in the switch - to - rosuvastatin 40  mg group compared with the add - on - statin er - na / laropiprant group .
as expected , tgs and hdl - c were improved more with the add - on - statin er - na / laropiprant compared with the switch - to - rosuvastatin 40  mg .
a major limitation of our study is its open - label design . on the other hand
, it was an adequately powered randomized study that used a validated method for the assessment of bp .
this study design is relevant to every day clinical practice when the treating physician is in dilemma over what to do in a patient who has failed to achieve lipid targets while on conventional statin treatment .
the bp - lowering effect of na may be more pronounced in inadequately controlled hypertensives , but further research in this field is needed .
the addition of er - na / laropiprant to a conventional statin regimen , but not the switch to high - dose rosuvastatin , is associated with significant reductions of both systolic and diastolic bp in dyslipidemic patients , especially in those with hypertension .
addition of er - na / laropiprant to a conventional statin regimen may further improve both bp and lipid profile in hypertensives who have not achieved lipid targets .
 
 introduction . nicotinic acid ( na ) and 
 statins have been associated with reductions in blood pressure ( bp ) . 
 
 patients and methods . 
 we recruited 68 normotensive and hypertensive dyslipidemic patients who were treated with a conventional statin dose and had not achieved lipid targets . 
 patients were randomized to switch to high - dose rosuvastatin ( 40  mg / day ) or to add - on current statin treatment with extended release ( er ) na / laropiprant ( 1000/20  mg / day for the first 4 weeks followed by 2000/40  mg / day for the next 8 weeks ) for 3 months . 
 
 results . switching to rosuvastatin 40  mg / day was not associated with significant bp alterations . 
 in contrast , the addition of er - na / laropiprant to current statin treatment resulted in a 7% reduction of systolic bp ( from 134  12 to 125  10  mmhg , p < .001 versus baseline and p = .01 versus rosuvastatin group ) and a 5% reduction of diastolic bp ( from 81  9 to 77  6  mmhg , p = .009 versus baseline and p = .01 versus rosuvastatin group ) . 
 these reductions were significant only in the subgroup of hypertensives and were independent of the hypolipidemic effects of er - na / laropiprant . 
 conclusions . 
 contrary to the switch to high - dose rosuvastatin , the addition of er - na / laropiprant to statin treatment was associated with significant reductions in both systolic and diastolic bp . 
1. Introduction
2. Patients and Methods
3. Results
4. Discussion
5. Study Limitations and Strengths
6. Conclusion