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Title page

DETRIMENTAL EFFECTS OF NIACIN/LAROPIPRANT ON MICROVASCULAR REACTIVITY AND RED CELL DEFORMABILITY IN PATIENTS WITH ELEVATED LIPOPROTEIN(a) LEVELS.
Cioni Gabriele, MD, PhD
Mannini Lucia, MD
Liotta Alessandrello Agatina, MSc
D�Alessandri Giovanna*, MD
Fatini Cinzia, MD
Bandinelli Brunella
Costanzo Maria
Abbate Rosanna, MD
Marcucci Rossella, MD, PhD

Affiliations
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
*SIMT, USL 3, Pistoia, Italy.
Corresponding author: 
Gabriele Cioni, 
Department of Experimental and Clinical Medicine 
University of Florence, 
Largo Brambilla 3, 50132 Florence, Italy 
Telephone number +39 055 7949420 
FAX number: +39 055 7949418
E-mail address:  HYPERLINK "mailto:gabriele.cioni@unifi.it" gabriele.cioni@unifi.it

Abstract
Background. 
Several studies found a beneficial effect of nicotinic acid on lipid profile, but a limitation in the clinical use of nicotinic acid is related to its side effects.

Material and methods. 
Forty-six (F/M=22/24, age=58.74�10.02 yrs) patients with Lp(a)e" 500 mg/L and with a previous arterial thrombotic event, were treated with nicotinic acid/laropiprant (Tredaptive�).

Results. 
We found a significant reduction in Lp(a) values at T1 (after 12 months), with a decrease of 32.3% from baseline levels. At T1 11 patients (23.9%) showed Lp(a) levels <500 mg/L. PAT values were significantly decreased after treatment (2.13�0.81 vs 1.74�0.42, p=0.001), showing a worsening of endothelial function in 27 (58.6%) patients. A significantly higher number of patients had RHI<1.5 after the treatment [18 (39.1%) vs 8 (17.4%)]. Blood rheology worsened as ED was impaired (p<0.0001) after 12 months, whereas WHV, plasma viscosity, and red cell aggregation did not show significant differences in comparison to baseline. Patients with a worsening in microvascular reactivity in comparison to baseline showed a marked impairment in ED (0.3327�0.037 vs 0.3091�0.0351; p<0.0001) while others showed only a mild, even though significant, reduction (0.3347�0.0299 vs 0.3272�0.0235; p=0.044).

Conclusions.
In the light of the results of HPS2-THRIVE study, we may hypothesize that the addition of laropiprant to niacin might be responsible for these negative effects. In turn, these effects might explain, at least in part, the lack of a clinical net benefit of niacin/laropiprant in that trial.
Text
Lp(a) represents a marker of cardiovascular atherosclerotic diseases and several studies confirmed its association with arterial and venous thrombosis (1,2). In the last years, mendelian association studies indicated the causal role of Lp(a) in cardiovascular disease (3). 
Several studies found a beneficial effect of nicotinic acid on lipid profile by reducing triglycerides, LDL cholesterol, but also reducing Lp(a) of about 30%, and by elevating HDL cholesterol (4,5). 
A limitation in the clinical use of nicotinic acid is related to its side effects, namely flushing of the face and the chest. Nicotinic acid evokes flushing mainly by releasing prostaglandin D2 from skin cells. In recent years, laropiprant, a selective PGD2 receptor antagonist, has been added to nicotinic acid in a formulation (Tredaptive�, Trevaclyn�, Pelzont�).
At the end of 2012, preliminary results of HPS2-THRIVE indicated that taking nicotinic acid / laropiprant together with a statin has no significant additional benefit in reducing the risk of major vascular events such as heart attack and stroke, compared with statin therapy alone, although the presentation of detailed data is still expected.
Aim of our study was to evaluate the impact on endothelial function and haemorheological parameters of nicotinic acid/laropiprant in patients with elevated Lp(a) levels.

From September 2011 to December 2012, 46 (F/M=22/24, age=58.74�10.02 yrs) patients with Lp(a)e" 500 mg/L and with a previous arterial thrombotic event, were treated with nicotinic acid/laropiprant (Tredaptive�) which was the only formulation of nicotinic acid available in Italy.
Nicotinic acid/laropiprant (in addition to standard therapy) was administered at the dosage of 1000 mg/20 mg in the first month, followed for 12 months by the dosage of 2000 mg/ 40 mg.
Venous blood samples were collected from antecubital vein, in order to evaluate: whole blood viscosity (WHV), plasma viscosity (PV), erythrocyte deformability (ED), in addition to lipid pattern, von Willebrand factor and fibrinogen. 
WHV, ED, and plasma viscosity were evaluated according to previously described method (6).
All patients underwent peripheral arterial tonometry (PAT) evaluation (Endopat, Endotech), accordingly to previously described method (7). According to the literature (8), RHI <1.50 is the value associated with a significantly higher risk of cardiovascular events. Venous blood samples withdrawal and endothelial function measurement were scheduled at baseline (T0) � before the treatment with nicotinic acid/laropiprant - and twelve months (T1) after.
Baseline characteristics of patients and results are shown in table 1.
We found a significant reduction in Lp(a) values at T1 (table 1), with a decrease of 32.3% from baseline levels. At T1 11 patients (23.9%) showed Lp(a) levels <500 mg/L.
Similarly, the levels of triglycerides, LDL-c, and fibrinogen levels were significantly decreased (table 1); HDL-c levels showed a significant increase (table 1). No significant difference in vWF levels was found (table 1). 
As regards endothelial function, PAT values were significantly decreased after treatment (2.13�0.81 vs 1.74�0.42, p=0.001), showing a worsening of endothelial function in 27 (58.6%) patients. A significantly higher number of patients had RHI<1.5 after the treatment [18 (39.1%) vs 8 (17.4%)].
Unexpectedly, blood rheology worsened as ED was impaired (p<0.0001) after 12 months, whereas WHV, plasma viscosity, and red cell aggregation did not show significant differences in comparison to baseline (table 1).
Interestingly patients with a worsening in microvascular reactivity in comparison to baseline showed a marked impairment in ED (0.3327�0.037 vs 0.3091�0.0351; p<0.0001) while others showed only a mild, even though significant, reduction (0.3347�0.0299 vs 0.3272�0.0235; p=0.044).
In this study we observed that nicotinic acid/laropiprant administration was associated with a worsening of ED and of endothelial function. Both these parameters have been associated with an increased vascular risk in healthy subjects and in patients with vascular disease.
This finding on vascular response and rheological pattern was observed despite the positive effect on the lipid profile, as confirmed by the modification of elevated triglycerides, low HDL cholesterol and elevated Lp(a) levels.
Furthermore, we have documented that these two parameters � EDI and microvascular reactivity - show a similar trend in response to 1-year treatment with nicotinic acid/laropiprant. This similar behaviour was previously reported in the PIVUS study in which endothelium-dependent vasodilation was positively associated with EDI, independently of traditional risk factors in elderly patients (9).  We have confirmed this datum in this clinical setting of high risk patients.
Nitric oxide (NO) is the possible link between vascular reactivity and erythrocyte behaviour. Indeed, a reduced vasodilatory response to ischemia is related to reduced NO availability which, in turn, worsens ED; moreover, erythrocyte themselves are able to produce NO. 
Regarding nicotinic acid/laropiprant, it was conceivable to hypothesize that a treatment associated with a better lipid profile should result in a better haemorheologic profile and possibly in a better endothelial function. Unexpectedly, we found a significant worsening of both these parameters. 
Present results do not allow to know if nicotinic acid or laropiprant is the drug responsible for these effects. Recently, Philpott et al found that Nicotinic acid ER do not improve endothelial or microvascular function after three months of treatment in patients with coronary artery disease (10).
We demonstrated that the addition of laropiprant to nicotinic acid is associated with a negative effect and a significant worsening of endothelial function. We might speculate that the addition of laropiprant to nicotinic acid is associated with this detrimental � not only neutral as for niacin ER alone � effect on endothelial function.
As regards ED, no previous data are available investigating the possible effect of niacin and/or laropiprant on these parameters.
Interestingly, the impairment in vasodilating endothelial function was not associated with increased prothrombotic potential of endothelial cells. This finding highlights a possible negative effect of laropiprant on peripheral vascular reactivity.
A limitation of the study is the lack of a �control group� of patients with elevated Lp(a) levels not on nicotinic acid/laropiprant, so that we cannot exclude an impairment of microvascular reactivity related to the elapsed time (one year).
In the light of the results of HPS2-THRIVE study, we may hypothesize that the addition of laropiprant to niacin might be responsible for these negative effects. In turn, these effects might explain, at least in part, the lack of a clinical net benefit of niacin/laropiprant in that trial.

Conflicts of interest
Dr Marcucci reported receiving honoraria for lectures from Daiichi Sankyo/Eli Lilly and Merck Sharp & Dohme. Dr Abbate reported receiving consulting fees from Eli Lilly; lecture fees from Instrumentation Laboratory and Sigma Tau; and research grant funding from Bayer, Boehringer Ingelheim, and Pfizer.

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Legend
Table 1. Baseline characteristics of study population.








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