High Blood Press Cardiovasc Prev (2016) 23:381–386 DOI 10.1007/s40292-016-0168-x
ORIGINAL ARTICLE
Effects of a Novel Fixed Combination of Nutraceuticals on Serum Uric Acid Concentrations and the Lipid Profile in Asymptomatic Hyperuricemic Patients Results from the PICONZ-UA Study Francesco Rozza1,2 • Valentina Trimarco1,3 • Raffaele Izzo1,4 • Davide Grassi5 Claudio Ferri5
•
Received: 15 July 2016 / Accepted: 5 September 2016 / Published online: 19 September 2016 Ó Springer International Publishing Switzerland 2016
Abstract Introduction Asymptomatic hyperuricemia is not a current indication for therapy as the definite role of serum uric acid elevation as a cardiovascular risk factor is extremely likely but still controversial. Aim We designed a double blind, placebo-controlled, randomized study to assess the effects of a combination of nutraceuticals (ZinutriKÒ, containing a fixed combination of kampferol, baicalin, caffeine, and rutin) on serum uric acid levels, lipid variables and the global cardiovascular risk profile. Methods Sixteen individuals (mean age 59.0 ± 11.9 years, 4 women) with asymptomatic hyperuricemia completed the study. Results ZinutriKÒ treatment (4 weeks) reduced serum uric acid concentrations (from 7.9 ? 0.9 to 7.0 ? 0.7 mg/dL) when compared to both baseline and placebo (p \ 0.006 and p \ 0.001, respectively). Compared to both placebo and baseline, the same fixed combination of nutraceuticals also reduced circulating LDL cholesterol and increased HDL cholesterol concentrations within 4 weeks (p \ 0.001 & Raffaele Izzo
[email protected] 1
Hypertension Research Center (CIRIAPA), Federico II University, Naples, Italy
2
Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy
3
Department of Neurosciences, Federico II University, Naples, Italy
4
Department of Translational Medical Sciences, Federico II University, Via S. Pansini 5, Building 2, Naples 80131, Italy
5
Department of Medicine, Life and Environmental Sciences, L’Aquila University, Coppito, Italy
or less), thereby improving the Framingham risk score (p \ 0.001 or less). Neither minor nor major side effects were observed. Conclusions This study represents the first demonstration that a short-term therapy with a fixed combination of different natural substances can significantly reduce serum uric acid concentrations in asymptomatic hyperuricemic patients, with no side effects and a significant improvement in the lipid pattern and then in the global cardiovascular risk profile. Keywords Hyperuricemia Nutraceuticals Hyperlipidemia
1 Introduction Prevalence and incidence rates of hypertension, diabetes mellitus, chronic kidney disease, coronary heart disease and/or stroke directly correlate with serum uric acid levels [1, 2]. Despite of this, asymptomatic hyperuricemia is not a current indication for therapy [3] as the definite role of serum uric acid elevation as a cardiovascular risk factor is still controversial. Causal odds ratios were not significant for any of the above conditions when calculated using the genetic risk score derived from uric acid-regulating single nucleotide polymorphisms [4–6]. Similarly, reductions in serum uric acid levels obtained in hyperuricemic patients by prolonged xanthine oxidase inhibition did not predict the risk of all-cause death and/or cardiovascular events [7]. In contrast, a significant association between serum acid concentrations, cardiovascular mortality and sudden cardiac death has been described in the Ludwigshafen Risk and Cardiovascular Health study [8]. In the same population Kleber et al. [6] found that causal hazard ratios
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corresponding to each 1 mg/dl increase in uric acid were significant for cardiovascular death and sudden cardiac death. Thus, the current knowledge seems to indicate that hyperuricemia—even of a mild degree—is combined to increased cardiovascular and/or renal events but the protective role of serum uric acid reduction in gouty and nongouty patients is still debated [7, 9, 10]. In this contest, westernized diets are usually rich in uric acid-raising components [1, 2, 11]. Concordantly, such diets are combined to marked and progressive increments in serum uric acid concentrations. On the opposite hand, ‘‘healthy’’, ‘‘Mediterranean-like’’ diets can significantly reduce serum uric acid levels, as demonstrated by the very low serum uric acid concentrations that have been described in primates and humans eating such diets [12]. Thus, whatever the role of uric acid, adoption of a correct daily diet is expected to nullify its potential impact on the cardiovascular apparatus by normalizing its circulating concentrations [12]. Unfortunately, dietary changes are often not recommended and/or recommended but characterized by poor adherence and persistence. Thus, an alternative therapeutic strategy against mild to moderate hyperuricemia might be found in nutraceuticals. However, to the best of our knowledge nutraceuticals have been never tested in randomized placebo-controlled studies conducted in asymptomatic hyperuricemic patients. To address this topic, we designed this Pilot, double blind, placebo-controlled, cross-over, randomIzed study to assess the effects of a COmbination of Nutraceuticals (ZinutriKÒ, Akademy Pharma) on serum Uric Acid concentration (PICONZ-UA Study). In this regard, ZinutriKÒ is a combination of kaempferol (a polyphenol present in Ginkgo Biloba), baicalin (extract of Scutellaria Baicalensis root), dry extract of green coffee seed and rutin. As is known, polyphenols from tea have been demonstrated to reduce serum uric acid concentrations [13]. Kaempferol is able to block the enzyme NADPH oxidase [14] and might therefore reduce the negative impact of uric acid on oxidant generation [2]. Concordantly, both kaempferol and rutin have been recently reported to inhibit xanthine oxidase and simultaneously blunt Fe?? -induced lipid peroxidation [15]. In a similar way, while kaempferol directly inhibits oxidant generation [16] baicalin, one of the principal components of Scutellaria Baicalensis, manifests with a significant scavenging capacity [17]. Thus, also baicalin is expected to reduce the negative cardiovascular impact of hyperuricemia. On the other hand, the same nutraceutical [17] and polyphenols from tea [13] are also known to ameliorate the lipid pattern and might, in turn, simultaneously reduce the global cardiovascular risk. Thus, we also analyzed eventual changes in the lipid pattern and the Framingham risk score (FRS) [18].
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2 Patients and Methods Participants to the PICONZ-UA study were recruited in our institution in Naples among individuals of both genders with no personal history of any kind of medical, neurological, or psychiatric disorders but with serum uric acid concentrations [6 mg/dL on at least two occasions within the last 12 months. Age was requested to be[18 and\80 years. Participants were not requested to have normal sitting systolic (SBP)/diastolic (DBP) blood pressure levels, i.e. less than 140/90 mmHg. The body mass index was requested to be [19 and\30 kg/m2, serum creatinine level\1.1 mg/dL for both genders. Fasting glucose was requested to be\125 mg/ dL with a glycated haemoglobin level\6.5 %. Serum LDL concentration was requested to be\160 mg/dL at fast, serum triglyceride concentration \200 mg/dL at fast. Individuals reporting not only chronic/acute diseases, but also any kind of metabolic abnormality or major cardiovascular risk factor, or both, as well as any type of medication or dietary supplement intolerance were excluded from the PICONZ-UA study. Current smokers and habitual consumers of nutraceuticals and/or supplements were also screened out. To further avoid confounding factors, daily intense sporting activities ([10 h/week), weight change ([10 % body weight) within the last 6 months and participation in another study 3 months before entering the study were also considered as exclusion criteria. The primary endpoint was pre-defined as the observed changes in serum uric acid concentration after 4 week (active versus placebo arms). The secondary endpoint was represented by the observed changes in circulating lipids. All participants gave their written informed consent. The PICONZ-UA study has been approved by the University of Naples Ethics Committee.
3 Protocol After the screening visit and recruitment, participants were given dietary counseling, according to their clinical profile and individual preferences, and then randomized to receive either oral placebo or ZinutriKÒ for 4 weeks, in double blind. At the end of this period, participants were switched from placebo or ZinutriKÒ to either ZinutriKÒ or placebo for additional 4 weeks, again in double blind, according to a cross-over design, i.e. patients starting on placebo were switched to ZinutriKÒ and vice versa. At entry and then at the end of the two study periods, SBP and DBP levels, resting heart rate, serum uric acid levels, the lipid profile, fasting glucose concentrations and FRS were also assessed.
Effects of a Novel Fixed Combination of Nutraceuticals on Serum Uric
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3.1 Measurements and Definitions
3.3 Statistical Analysis
Serum uric acid and plasma lipid concentrations were measured by standard laboratory methods. LDL cholesterol concentration was not measured but calculated according to the well recognized Friedewald formula. All measurements were performed by technicians who did not take any part in planning the current study and were totally unaware of its design and purpose in the central laboratory of our institution in Naples. SBP and DBP were measured by standard sphygmomanometer after 5 min in the sitting position, according to the guidelines of the European Society of Hypertension/ European Society of Cardiology [19] by a physician who was totally unaware of the PICONZ-UA study design, purpose, and results. BP measurements were made in all participants in a comfortable room of our institution, i.e. the Hypertension Research Center, in Naples, before blood samplings. The 10-year risk of coronary heart disease (CHD) was also calculated using the FRS, i.e. including age, genderspecific cholesterol, HDL cholesterol, SBP and cigarette smoking [18].
Data were analysed using SPSS (version 23.0; SPSS, Chicago, IL, USA) and expressed as mean ± SD. All variables deviating from normal distribution were log transformed before parametric statistics were calculated. Differences in the considered variables among baseline, placebo and NUT treatment were determined using single group ANOVA for repeated measures with deviation contrast from baseline for trend analysis and Bonferroni adjustment for the single main effects. Sample power (17 observations) was determined for a-error B0.05 and power = 0.8, assuming an average correlation between sequential measures of 0.7. Significance was set at p \ 0.05.
3.2 ZinutriKÒ Components ZinutriKÒ is a fixed combination of nutraceuticals. Each pill contains: dry extract of Ginkgo Biloba leaf (250 mg; kampferol = 10 mg); dry extract of Scutellaria Baicalensis root (166,667 mg; baicalin = 50 mg); dry extract of green coffee seed (100 mg, chlorogenic acid = 10 mg, caffein = 4.5 mg); and rutin (50 mg). Each of the components has a purity consistent with the European Pharmacopoeia requirements (https://www. edqm.eu/en).
4 Results Seventeen individuals were initially enrolled but only 16 patients (mean age 59.0 ± 11.9 years, 4 women) completed the study, since one patient withdrew his consent to participate during the placebo period. Baseline demographic and clinical characteristics of the study population before and after ZinutriKÒ/placebo treatments are reported in Table 1. No patient took any drug except the study treatment. As expected, neither major nor minor adverse events were reported. With regard the primary endpoint, ZinutriKÒ treatment reduced serum uric acid concentrations when compared to both baseline levels and placebo (Fig. 1). As regard the secondary endpoint, ZinutriKÒ treatment significantly decreased serum LDL and increased serum HDL levels (Table 1). In particular, we observed a significant reduction in both circulating total (mean = -36 mg/dl) and LDL
Table 1 Characteristics of the study population at baseline and after ZinutriKÒ/placebo treatments (4 weeks in both cases) Baseline (n = 16)
Placebo (n = 16)
ZinutriKÒ (n = 16)
p\ (placebo vs baseline)
p\ (ZinutriKÒ vs baseline)
p\ (ZinutriKÒ vs placebo)
BMI (kg/m2)
27.9 ± 4.4
27.8 ± 4.3
27.9 ± 4.3
NS
NS
NS
SBP (mmHg)
135.1 ± 16.1
135.3 ± 17.0
133.4 ± 17.7
NS
NS
NS
DBP (mmHg) Total cholesterol (mg/dl)
78.4 ± 7.9 212.2 ± 29.4
78.7 ± 7.5 212.0 ± 30.5
79.1 ± 8.6 176.9 ± 31.0
NS NS
NS 0.0001
NS 0.0001
HDL cholesterol (mg/dl)
46.7 ± 11.4
47.2 ± 11.3
51.7 ± 10.3
NS
0.0001
0.0001
LDL cholesterol (mg/dl)
129.7 ± 37.2
128.8 ± 38.7
94.3 ± 29.5
NS
0.0001
0.001
Triglycerides (mg/dl)
178.6 ± 79.1
179.7 ± 81.2
154.2 ± 74.6
NS
NS
NS
Uric acid (mg/dl)
7.9 ± 0.9
7.9 ± 1.0
7.0 ± 0.7
NS
0.006
0.001
Framingham Risk score
9.5 ± 5.6
9.6 ± 5.9
7.0 ± 4.9
NS
0.001
0.0001
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, HDL high density lipoprotein, LDL low density lipoprotein
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p < 0 .0 0 0 1
p < 0 .0 0 1 p < 0 .0 0 6
10
p < 0 .0 0 1
18
12
6
FRS
Uric Acid (mg / dl)
8
4 6
2
0
0 Base line
PL
NUT
Fig. 1 Changes in serum uric acid (mean ? SD) concentrations induced by 4 week placebo (PL) or ZinutriKÒ (NUT) treatments in asymptomatic hyperuricemic individuals
cholesterol concentrations (mean = -35 mg/dl), mirrored by a significant increase in serum HDL cholesterol levels (?5 mg/dl) after treatment with ZinutriKÒ. In contrast, no statistical differences were detected after placebo treatment. Concordant to the observed changes in the lipid pattern, the FRS was positively influenced by ZinutriKÒ but not placebo treatments (Fig. 2). Changes in serum uric acid levels and Framingham Risk Score were not correlated. Similarly, we did not find significant correlations between individual changes in serum uric acid and either LDL or HDL concentrations. As far as other evaluated variables are concerned, we observed no changes in either SBP or DPB levels at the end of either the active or the placebo treatment. Also other variables, i.e. body weight etc., were poorly or not influenced by placebo and/or ZinutriKÒ treatments.
5 Discussion To our knowledge, the PICONZ-UA study represents the first demonstration that a short-term therapy with a fixed combination of three different natural substances can significantly reduce serum uric acid concentration in asymptomatic hyperuricemic patients, with no side effects and a significant improvement in the lipid profile. A modest minority of individuals with sustained hyperuricemia develops gout as a clinical disease [2].Thus, despite of the fact that cardiovascular/renal morbidity and
Base line
PL
NUT
Fig. 2 Changes in the Framingham risk score (FRS) (mean ? SD) induced by either placebo (PL) or ZinutriKÒ (NUT) treatments (4 weeks in both cases) in 16 individuals with asymptomatic hyperuricemia
mortality seem directly related to the circulating level of uric acid [2], asymptomatic hyperuricemia, i.e. an uric acid levels [6 mg/dL, is neither considered a disease state nor represents an accepted indication for uric acid lowering treatment [3]. Accordingly, both the range and the upper limit of normality for serum uric acid level are still argument of debate [1, 2]. Recently, many vegetables, fruits and herbs have been identified as protective agents against metabolic and cardiovascular diseases [2, 3, 20, 21]. Some of these agents have been also reported to lower serum uric acid levels. In particular, animal experiments have demonstrated that the oral administration of green tea, likely due to its high polyphenol content, is able to reduce serum uric acid, triglycerides, total cholesterol and non esterified fatty acid levels in rats receiving an high fructose diet [13]. Further, when exceeding the level of about 5 mg/dL circulating uric acid can switch its natural antioxidant action to a pro-oxidant one, due to either the direct de novo oxidant production that occurs during its production/degradation process or by its ability to stimulate NADPH oxidase [22, 23]. Concordantly, even very modest increments in serum uric acid concentrations are combined in humans to the progressive appearance of the components of the metabolic syndrome [23]. In keeping to this, although not combined to reductions in cardiovascular events and/or allcause death [7], prolonged xanthine oxidase inhibition was found to be combined to significant reductions in SBP and
Effects of a Novel Fixed Combination of Nutraceuticals on Serum Uric
DBP levels [24]. Thus, although we found no significant changes in BP levels after active treatment but assuming our study was a short term and not a long term one, and waiting for the ad hoc trials aiming to demonstrate that the selective inhibition of xanthine oxidase operated by febuxostat is also able to reduce cardiovascular, cerebrovascular and renal events [25], it sounds reasonable to individuate appropriate preventive strategies aiming to blunt the negative impact on uric acid on the cardiometabolic risk profile. In this context, ZinutriKÒ contains kaempferol, a polyphenol present in many compounds such as Ginkgo Biloba, which is to day the most frequently prescribed herbal preparation in Germany [26] and one of the most commonly used over-the-counter herbal preparation in the United States [27]. Kaempferol possesses the ability to block the enzyme NADPH oxidase [16] and might therefore reduce the negative impact of uric acid on oxidant generation. In addition, ZynutriKÒ contains the dried root of Scutellaria Baicalensis, one of the most important crude drugs in traditional Chinese and Japanese medicine, titrated in baicalin, that displays a significant scavenging capacity [17]. Thus, ZynutriK might simultaneously reduce uric acid generation and counteract the pro-oxidant activity exerted by even mildly elevated uric acid concentrations. Due to these complex interactions between the different components, we decided to perform this randomized, double blind, placebo-controlled, pilot study to investigate whether or not their oral administration as a single pill prepared in fixed combination was able to reduce serum uric acid concentrations and improve the lipid metabolic profile. Our results clearly supported the starting hypothesis, indicating the reduction in serum uric acid concentration within 4 weeks of ZinutriKÒ therapy. Of note, the same nutraceutical was also able to induce reciprocal changes in LDL-HDL cholesterol levels, i.e. decrement in LDL with increment in HDL. Thus, also the whole FRS was positively influenced by ZinutriKÒ treatment. In particular, we arbitrarily decided to use the Framingham risk score and not the SCORE since the first estimates the risk for CHD and not for cardiovascular death. Nevertheless, since the lipid pattern is a fundamental component of all of the cardiovascular risk scoring systems it is extremely likely that similar positive changes would have been observed also with other risk calculations. In this regard, we were not able to find significant correlations between the individual changes in serum uric acid and either LDL or HDL concentrations. However, the lack of significance between changes in the two variables, i.e. uric acid and the lipid pattern, merely reflects the small number of evaluated patients and deserves a further evaluation in a larger population.
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6 Conclusions We are obviously well aware that the current clinical study does not demonstrate that ZinutriKÒ is able to reduce the negative suggested impact of uric acid on cardiovascular outcomes and/or to exert favourable cardiovascular effects in the long run. In particular, a strong limitation of the PICONZ-UA study is represented by the small sample size and the short observational period. Both of these limitations imply the remarkable changes we have observed in serum uric acid, LDL and HDL concentrations might become unapparent under different study conditions. Thus, further studies in larger populations, in various patient settings and with a prolonged follow up are needed to confirm our results. Nevertheless, the negative impact of increased LDL concentrations on all-cause and cardiovascular death is not debated [3]. Further, although asymptomatic hyperuricemia, i.e. with no urate deposit and/or no renal disease [28], is not an indication for any given specific therapy, the excellent safety and tolerability profiles manifested by ZinutriKÒ support its use to potentiate the positive effects of lifestyle modifications, i.e. dietary, in asymptomatic subjects having a serum uric acid concentration [6 mg/dL. This approach is also expected to significantly reduce the cost of asymptomatic hyperuricemia in the general population [29], being both the number of all-cause hospitalizions and total health cost clearly and directly correlated to the circulating levels of uric acid. Compliance with Ethical Standards Conflict of interest The authors declare that they have no conflict of interest. Research involving human participants and/or animals This article does not contain any studies with human participants or animals performed by any of the authors. Informed Consent Written informed consent was obtained from each subject.
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