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A daily glass of red wine associated with lifestyle changes independentlyimproves blood lipids in patients with carotid arteriosclerosis: results from arandomized controlled trial
Nutrition Journalvolume 12, Article number: 147 (2013)
Physical exercise and a Mediterranean diet improve serum lipid profile. Thepresent work studied whether red wine has an effect on top of alipid-lowering lifestyle in patients with carotid atherosclerosis.
A prospective randomised unblinded trial was performed from 2009 to 2011 in108 patients with carotid atherosclerosis, 65% of whom were already onstatin therapy with a low mean LDL of 104.9 mg/dl. Half of them wereadvised to follow a modified Mediterranean diet and to perform moderatephysical exercise during 30 min/day (lifestyle changes) for20 weeks. Within these two groups half of the patients were randomisedeither to avoid any alcohol or to drink 100 ml of red wine (women) or200 ml of red wine (men) daily.
LDL was significantly lowered by 7% in the lifestyle-changes group comparedto the no-lifestyle-changes group (p = 0.0296) after20 weeks. Lifestyle changes lowered the LDL/HDL ratio after20 weeks by 8% (p = 0.0242) and red wine independently by13% (p = 0.0049). The effect on LDL/HDL ratio after20 weeks was, however, more pronounced in the non-LC group. Totalcholesterol (−6%; p = 0.0238) and triglycerides(−13%; p = 0.0361) were lowered significantly by lifestylechanges after 20 weeks compared to the no-lifestyle-changes group.Lipoprotein (a) was not significantly affected by any intervention. Thegiven results are per ITT analysis.
Lifestyle changes including a modified Mediterranean diet and physicalexercise as well as a glass of red wine daily improve independently theLDL/HDL ratio in patients with carotid arteriosclerosis even though the vastmajority of them was already on statin therapy.
There is a huge body of evidence from observational and interventional studies thathigh serum total cholesterol, LDL cholesterol and lipoprotein(a) (Lp(a)) levels, aswell as low HDL-cholesterol levels are related to cerebral and cardiac vasculardiseases [1–8]. The role of triglycerides as an independent risk factor is lessconsistent as their level clusters with other risk factors [2, 9, 10].
Lifestyle changes (LC) including physical exercise and a Mediterranean diet improvelipid profile. Physical exercise mainly increases HDL and reduces triglycerides; LDLcould be affected [11, 12]. In an interventional trial a Mediterranean diet enriched with mixed nutsor extra-virgin olive oil decreased LDL cholesterol and triglycerides, and increasedHDL cholesterol . In their recent meta-analysis, Kastorini et al. found an increase in HDLand a decrease in triglycerides when comparing a Mediterranean diet withconventional diet . Some of the studies in this meta-analysis included red wine, others not.Three food items in particular have been shown to improve lipid profile: darkchocolate, tomatoes and walnuts, the latter two being frequently part of aMediterranean diet [15–20]. Light to moderate alcohol consumption (up to 1 drink daily for women and1 or 2 drinks daily for men) and possibly in particular red wine consumption isassociated with less cerebro- and cardiovascular diseases and an improved lipidprofile [21–26]. Regarding red wine consumption (and other food items) the question isstill open whether lifestyle associated with moderate red wine consumption or wineitself cause less cerebro-cardiovascular disease . Only in February 2013 the results of a large prospective randomisedtrial were published showing a benefit of mediterranean diet namely on stroke riskin comparison to a low-fat diet (relative risk reduction of 33%-46%) .
In the present prospective unblinded randomised controlled trial we assessed theeffect of a small amount of red wine and LC including the consumption of darkchocolate, tomatoes and walnuts associated with physical activity advice on lipidprofile in patients with arteriosclerosis documented by carotid ultrasound. Inparticular we studied whether the use of red wine on top of LC still results in anadditional lipid profile improvement. The present work is part of the ALVINA project(an acronym of “alimentation, vin et activitéphysique” which mean “nutrition, wine, and physical activity” inFrench), where also other parameters were studied.
122 patients were followed up to 20 weeks. The enrolled participants wereout-patients of the Neurology department of the Centre Hospitalier de Luxembourgand had undergone carotid and intracranial bitemporal color coded duplexsonography using an Antares system (Siemens Healthcare, 91052 Erlangen,Germany). Inclusion criteria were >30 years and the presence of plaquesor stenosis without hemodynamic compromise (i.e. <70%) in at least one commoncarotid artery, the carotid bifurcation, or the internal carotid artery. We usedthe Mannheim definition for plaques: It is defined as a focal structure thatencroaches into the arterial lumen of at least 0.5 mm or 50% of thesurrounding IMT value or demonstrates a thickness >1.5 mm as measuredfrom the media-adventitia interface to the intima-lumen interface . NASCET criteria were used to define high-grade stenosis [30, 31]. Exclusion criteria were a history of ocular or cerebral ischemiawithin the last 3 months, atrial fibrillation, or the incapacity to giveinformed consent.
This study was conducted according to the guidelines laid down in the Declarationof Helsinki and all procedures involving human subjects/patients were approvedby the national research ethics committee (200801/06) and notified to thenational commission on data protection in Luxemburg. Written informed consentwas obtained from all subjects. The trial was registered(http://www.clinicaltrials.gov, NCT01146132). The first patientwas included on June 4th 2009 and the last follow-up visit was on October 10th2011. The study was performed in Luxemburg.
The design of the study was a 2 × 2 factorial design. The patients wereattributed to groups of lifestyle in result of a randomization stratified forgender. Lots were drawn to generate the random allocation sequence. Block sizewas four. The intervention allocation was concealed in a non-transparentenvelope. Random allocation sequence was generated by an independent staffmember; patients were enrolled by the principal investigator; patients wereassigned to interventions by study nurse. The first group received no lifestylecounseling and the second one received lifestyle counseling at the beginning,after 1 week, after 2 weeks, after 3 weeks and after4 weeks. Within each lifestyle group patients were either randomly advisedto drink a glass of red wine a day (0.2 l for men and 0.1 l forwomen), or advised to avoid alcohol at all for the time of the study. The sortof red wine was at the participants’ discretion.
Figure 1 gives an overview of the study procedures.Only in the LC group, a dietician performed five sessions of 30 min each(baseline, after one week, after 2 weeks, after 3 weeks and after4 weeks) giving advice on healthy eating based on a modified Mediterraneandiet and physical exercise. In particular, 5 portions of fruit/vegetables perday, a diet low in absolute fat, a preference of vegetable oil (olive or canolaoil), whole grain products, poultry, low fat dairy products, a fat and a leanfish meal per week, a reduced consumption of red meat, and the avoidance ofpork, of ready-made meals, of sugar and of excessive salt intake wererecommended [32, 33]. A water intake of 1.5-2 l a day was recommended as well. Inaddition the regular consumption of one bar of dark chocolate (25 g,>70% of cacao), 1–2 tomatoes, and of 3–5 walnuts as well as atleast 30 min of moderate daily physical activity were recommended [32, 34, 35]. In the literature the quantities of dark chocolate, tomatoes, andwalnuts are higher [17, 20, 36, 37]; however we used quantities applicable in daily life over a longperiod. The control group (no LC) was seen at baseline, after 4 weeks andafter 20 weeks by a nurse and instructed not to change their eating andphysical activity habits. The patients allocated to the wine group (within theLC and the no-LC groups) underwent three short sessions of counseling concerningthe intake of red wine of their choice (0.2 l for men and 0.1 l forwomen) by the nurse [24, 38, 39].
All participants were initially seen by the dietician for a baseline assessmentof their nutrition habits over the last 2 working days and the last weekend dayusing the software Nutrilog Pro (Nutrilog SAS, Marans, France). The participantsin the lifestyle-changes group were reassessed at 4 weeks and at20 weeks using the same method. General anthropometrical data such asweight, height, body-mass index were recorded. Physical activity over the weekpreceding the clinical visit was assessed using a questionnaire. Physicalactivity was differentiated into light (no increase in respiration andsweating), moderate (increase in respiration, no sweating) and intense physicalactivity (increased respiration and sweating) [32, 34, 35]. Daily minutes of each exercise level were calculated. A scale (model763 1321009, Seca, Hamburg, Germany) was used to assess body weight and a meterto assess height. Fasting total cholesterol, LDL and HDL cholesterol,triglycerides, and Lp(a) at baseline, after 4 weeks and 20 weeks weremeasured from serum samples collected after a 12 hour fast. Totalcholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and Lp(a) wereassessed on a Modular P module (Roche, Basel, Switzerland). Total cholesterol,HDL-cholesterol, LDL-cholesterol and triglycerides were all determined byenzymatic colorimetric assays (all Roche, Basel, Switzerland). Animmunoturbidimetric assay (Roche, Basel, Switzerland) was used to measureLp(a).
The pre-defined primary endpoint of the study was a change in the ratio LDL/HDLcholesterol assessed at baseline and at 20 weeks. Secondary endpoints werechanges in the other above-mentioned blood parameters and body weight/BMI andthe above mentioned changes after 4 weeks. Extrapolated data from previousstudies allowed calculation of LDL/HDL ratio change between baseline and afterdiet or wine intake [25, 40, 41]. The extractions from the articles resulted in a 0.03 change in theno diet group with no wine, 0.1 in the diet group with no wine and the no dietgroup with wine, 0.48 in the diet group with wine. The standard deviation wasextrapolated to 0.02. Assuming an alpha risk of 0.025 (Bonferroni corrected fortwo comparisons) and a power of 0.9, the total sample size should be 88 to showa significant difference between groups by using a general linear modelincluding the diet and wine groups as well as their interaction. Allowing for15% of loss to follow-up, the sample size should finally be 100 patients.
The intent-to-treat analysis (ITT) included only patients who had attended thefirst and at least the 4 weeks visit. The per-protocol-analysis (PP)included ITT patients and excluded those who admitted not to have followed theinstructions or who did not present themselves at the 20-week visit. The ITTpopulation was the primary population. The groups (defined by LC and red wineintake) were compared for their baseline values. For continuous variables,normality was verified using the Shapiro-Wilk test. Where normally distributed,a two-sample t-test was used. Otherwise the Wilcoxon-Mann–Whitney test wasapplied. Dichotomous data was compared using a Pearson’s chi-squared test.In case expected cell frequencies were lower than 5, Fisher’s exact testwas applied. A general linear model with Tukey-Kramer adjustment for multiplecomparisons was used to assess the primary endpoints. The change valuerepresented the dependent value. Lifestyle group (conventional, LC), wine group(with wine, without wine) and the interaction between lifestyle and wine groupwere included in the model as independent variables as well as the baselinevalue as a covariate. In case where the normality assumption of the modelresiduals was violated, a non-parametric van-Elteren test was used withstratification for the other intervention (i.e. when comparing LC vs. no LC,stratification for wine group was used and vice versa). We looked for animbalance in statin treatment between the groups by the chi-square test atbaseline, after 4 weeks, and after 20 weeks. A p-value below 0.05 wasconsidered significant. All tests were two-tailed. All analyses were performedby using the SAS System v9.2 (SAS Institute, Cary, NC, USA).
108 patients, 36 women and 72 men aged from 37 to 83 years (mean64±9 years) were included in the ITT population (cf. Figure 2).
Among all baseline parameters (demographic, medical history, lipid profile,nutritional values and physical activity), no difference was found between groups(cf. Tables 1 and 2). There washomogeneity between the groups except for the fact that at baseline, subjects in theno-red-wine group consumed more lipids, proteins and mono-unsaturated fatty acidsand less red wine than subjects in the red-wine group. No serious adverse eventrelated to the intervention (LC or wine) was recorded.
The results for the primary endpoint and the secondary endpoints are presented inTable 3. Four weeks after beginning the intervention,LC and no-LC groups showed no significant differences in blood lipids. Significantdifferences were observable for HDL cholesterol (p = 0.0263) and LDL/HDLratio (p = 0.0293). After 20 weeks, LDL was significantly loweredby 7% in the lifestyle-changes group compared to the no-lifestyle-changes group(p = 0.0296). LC lowered the LDL/HDL ratio after 20 weeks by 8%(p = 0.0242) and red wine independently by 13% (p = 0.0049).Total cholesterol (−6%; p = 0.0238) and triglycerides(−13.2%; p = 0.0361) were lowered significantly by LC after20 weeks compared to the no-LC group. Interaction between LC and wine was notsignificant in any analysis of the outcomes with the general linear model.Consequently LC and wine can be considered as independent factors. Weight and BMIdid not change after 20 weeks; there was only a short effect after 4 weeksin the LC group (0.7%). Lp (a) was not affected by any intervention. No significantimbalance was found in statin use throughout the study. Results obtained on the PPpopulation were similar.
Our study demonstrates that in patients with carotid arteriosclerosis, both, LC andred wine have a beneficial effect on the LDL/HDL ratio after 20 weeks with an8% and 13% decrease, respectively when compared to their control groups. This effectis already present after 4 weeks in the red-wine intervention group. LDL issignificantly lowered in the LC group. HDL increased after 4 weeks in thered-wine group. HDL was hardly affected by LC. The effect of red wine on LDL/HDL wasindependent from the lifestyle changes, i.e. there was an additional benefit. Thisis a remarkable result as the majority of our patients (65%) were already on statintreatment and baseline LDL was already low (104.9 mg/dl). Therefore both,healthy diet and increased physical activity on the one hand and a glass of red wine(0.2 l/day for men and 0.1 l/day for women) on the other hand improve theratio of LDL and HDL in cerebrovascular patients. The effect on LDL/HDL ratio after20 weeks was, however, more pronounced in the non-LC group. This is probablydue to a ceiling effect. Our study is so far the largest prospective randomisedstudy using red wine. Total cholesterol (−6%) and triglycerides (−13%)were lowered by LC when compared to the non-LC group after 20 weeks, not after4 weeks. Lp(a) was not affected by any intervention.
The beneficial effect of Mediterranean diet on lipids is well documented. In theirrecent meta-analysis, Kastorini et al. found an increase in HDL of 1.17 mg/dland a decrease in triglycerides of 6.14 mg/dl when comparing a Mediterraneandiet with a conventional diet . Some of the studies included alcohol/red wine, others not. Our study isso far the first to document an additional effect of adding red wine to aMediterranean diet on blood lipids. Sola et al. investigated the effect of aMediterranean diet enriched in mixed nuts in 193 high cardiovascular risk subjectsafter 3 months . Compared with baseline, total cholesterol, LDL, the ratio LDL/HDL, andtriglycerides decreased significantly by 3.1%, 4.2%, 4.8%, and 6.2%, respectively.HDL increased by 1.8%. Regular physical exercise also has a beneficial effect onlipids, HDL is increased by about 8%, triglycerides are reduced by about 27% . LDL and total cholesterol are hardly affected. We included in our diet 3items known to alter positively lipid profile and generally accepted in the Europeanculture: dark chocolate, tomatoes and walnuts, the latter two being frequently partof a Mediterranean diet [15–20].
Previous studies have investigated the effect of LC and red wine on cholesterol.Avellone et al. investigated the effect of 250 ml of red wine daily oncholesterol in 48 subjects over 4 weeks. They found a 10% increase of HDL(significant) and a trend of a 7% decrease of LDL (not significant) with theintervention. LDL/HDL improved significantly by 14% . This number of 14% is comparable to the reduction of LDL/HDL by 13%found in the present study when comparing the results of the wine group to thenon-alcohol group. In their study, triglycerides decreased by 7%, and Lp(a) by 21%,however not significantly.
Coimbra et al. investigated 16 healthy adult subjects with isolatedhypercholesterolemia who had to drink 500 ml of red grape juice or 250 mlof red wine daily. There was no effect on LDL, HDL, triglycerides and Lp(a) after2 weeks (compared with baseline) . The duration of the study may have been too short; however in anotherstudy over 2 weeks, Rifler et al. investigated the effect of 250 ml of redwine daily in 33 patients post myocardial infarction [27, 43]. Both groups received a western prudent diet and performed adaptedexercise and physiotherapy. After 2 weeks the wine drinkers had a 5% decreasein total cholesterol and LDL, respectively, as compared to baseline, but a 16% and18% decrease in total cholesterol and LDL compared to the no-wine group.Triglycerides did not change. Although the data of the no-wine group compared tobaseline are not given in the article, this means that the no-wine group showed anincrease in LDL and total cholesterol, a finding also observed in our study. Apossible explanation for this phenomenon is that in our study and in the study byRifler et al. (in hospitalised patients) the no-wine group is as a matter of fact ano-alcohol or stop-alcohol group. Probably part of these subjects had consumedalcohol before the study and had to stop during the study.
In the literature there is conflicting evidence whether Lp(a) can be affected bylifestyle changes or not, like in our study. Lp(a) decreased after the regular dailyingestion of red wine with 30 g alcohol . In 2 other studies Lp(a) increased after alcohol withdrawal [45, 46]. In a postmenopausal women, no effect of two alcoholic drinks a day onLp(a) was observed . In a Norwegian study those who exercised increased their Lp(a) levelswith 15.4 (S.E. = 8.0) mg/l as compared to no exercise (P < 0.05).Also, dietary intervention tended to increase Lp(a), but the increase did not reachstatistical significance .
Our study did not address the intriguing question whether there is a particularlybeneficial effect of red wine over other forms of alcohol concerning the effect onblood lipids. Recent reviews suggest that regular consumption of small quantities ofany form of alcohol prevents cerebro-cardiovascular diseases rather than that thereis a particular benefit of red wine [21, 24, 49].
Potential limitations of our study are that the study size was modest, this was anopen trial, clinical benefit was not shown, and the intervention follow-up time wasrather short (20 weeks only). The strength of the study is the demonstration ofan additional beneficial effect of red wine on top of otherwise healthy lifestyle onblood lipids.
Lifestyle changes including a modified Mediterranean diet and physical exercise aswell as a glass of red wine daily improve independently from each other LDL/HDLratio in patients with carotid arteriosclerosis even though the vast majority wasalready on statin therapy. This may also translate in a reduction of future heartattacks and strokes. The exact molecules and mechanisms of the beneficial effect ofred wine on blood lipids can be deciphered in future studies.
Body mass index
High density lipoprotein
- Lp (a):
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We are very grateful to Mrs S. Spinelli (dietician) and to Prof. S. Senn(statistics) for their helpful comments.
Sources of funding
The Centre de Recherche Public-Santé mainly sponsored this study (rooms,personnel, technical devices and investigations). The Centre Hospitalier deLuxembourg authorised Prof. Droste and Dr. Gilson to spend part of their workingtime on this study and provided rooms and logistical and secretarialsupport.
The authors declare that they have no competing interests.
DWD, CI, MV, MM, MG, TV, GG, and AC developed the study design and organized itsperformance; TV, DWD, MM, and GG performed the data collection; NDB, CL, and AKperformed the data monitoring and administration; MV and TG performed thestatistical analyses; DWD wrote the manuscript; all were involved in datainterpretation and read and approved the final manuscript.