* A Consensutives on behalf

* Correspondþ39 02 7600 3

E-mail addr

0939-4753/$ -doi:10.1016/j.

Nutrition, Metabolism & Cardiovascular Diseases (2008) 18, S1eS16

www.elsevier.com/locate/nmcd

CONSENSUS DOCUMENT

Non-pharmacological control of plasmacholesterol levels*

Andrea Poli a,*, Franca Marangoni a, Rodolfo Paoletti a,Elmo Mannarino b, Graziana Lupattelli b, Alberto Notarbartolo b,Paolo Aureli c, Franco Bernini d, Arrigo Cicero d, Antonio Gaddi d,Alberico Catapano e, Claudio Cricelli f, Marinella Gattone g,Walter Marrocco h, Marisa Porrini i, Roberto Stella j, Alfredo Vanotti k,Massimo Volpe l, Roberto Volpe m, Carlo Cannella n, Alessandro Pinto n,Eugenio Del Toma o, Carlo La Vecchia p, Alessandra Tavani p,Enzo Manzato q, Gabriele Riccardi r, Cesare Sirtori s, Alberto Zambon t

a Nutrition Foundation of Italy, Italyb Italian Society for the Study of Atherosclerosis (SISA), Italyc National Italian Institute of Health (ISS), Italyd Study Group for Dismetabolic Diseases and Atherosclerosise Italian Society for Clinical and Experimental Therapy (SITeCS), Italy,f Italian Society of General Medicine (SIMG), Italyg Italian National Association of Hospital Cardiologists (ANMCO), Italyh Italian Federation of General Medicine Doctors (FIMMG), Italyi Italian Society of Human Nutrition (SINU), Italyj National Society of Medical Education (SNAMID), Italyk Italian Association of Dietetics (ADI), Italyl Italian Society of Cardiology (SIC) and Italian Society for Cardiovascular Prevention (SIPREC), Italym Italian National Research Council (CNR), Italyn Sapienza University of Rome, Italyo Past President of ADI, Roma, Italyp Mario Negri Pharmacological Research Institute, Italyq University of Padova, Italy

s document prepared by a panel convened by the Nutrition Foundation of Italy (NFI). This panel included representa-of the Scientific Societies and Institutions given in brackets (first list), as well as experts in the field (second list).

ing author. Nutrition Foundation of Italy, Viale Tunisia, 38, 20124 Milan, Italy. Tel.: þ39 02 7600 6271/7639 9532; fax:514.ess: poli@nutrition-foundation.it (A. Poli).

see front matter ª 2007 Elsevier B.V. All rights reserved.numecd.2007.10.004

2 A. Poli et al.

r University of Naples, Italys University of Milan, Italyt University of Padova, Italy

Received 27 June 2007; received in revised form 24 October 2007; accepted 25 October 2007

KEYWORDSCholesterol;Dietary intervention;Prevention;Cardiovasculardiseases;LDL cholesterol;HDL cholesterol

Abstract The importance of non-pharmacological control of plasma cholesterollevels in the population is increasing, along with the number of subjects whoseplasma lipid levels are non-optimal, or frankly elevated, according to internationalguidelines. In this context, a panel of experts, organized and coordinated by theNutrition Foundation of Italy, has evaluated the nutritional and lifestyle interven-tions to be adopted in the control of plasma cholesterol levels (and specificallyof LDL cholesterol levels). This Consensus document summarizes the view of thepanel on this topic, with the aim to provide an updated support to clinicians andother health professionals involved in cardiovascular prevention.ª 2007 Elsevier B.V. All rights reserved.

Several ecological and epidemiological studieshave proved that elevated plasma levels of totaland, in particular, low-density lipoprotein (LDL)cholesterol are associated with an increased riskof coronary and, in general, cardiovascularevents [1]. More recently, many controlledstudies undertaken with dietary or pharmacolog-ical interventions have demonstrated thatreduced plasma levels of total and LDL choles-terol (LDL-C) result in a decreased incidence ofsuch events. The risk reduction is strongly re-lated to the magnitude of the decline in LDL-C.In general, a 1% decrease in plasma levels of to-tal or LDL-C is followed, on average, by a 1%risk-reduction. Moreover, the effect on cardio-vascular risk appears to be independent of themethods used to achieve a lower plasma choles-terol level [2].

The large majority of epidemiological studieshave also demonstrated that elevated plasmatriacylglycerol (triglyceride) and/or reducedplasma high-density lipoprotein (HDL) cholesterolconcentrations are associated with increased car-diovascular risk. However, the results of pharma-cological intervention trials to modify theseparameters have been equivocal and there is noconsensus, from the preventive point of view, onthe appropriateness of this approach in the generalpopulation.

Conversely, the various lifestyle and dietaryinterventions that affect plasma HDL cholesterol(HDL-C) and triglyceride levels are usually consid-ered effective in cardiovascular risk reduction.This probably results from:

a. the low risk associated with dietary and life-style interventions;

b. the fact that many of the interventions that re-duce plasma triglyceride levels and increaseplasma HDL cholesterol levels have additionalfavorable effects (e.g., on weight manage-ment, systemic inflammation, and insulin sen-sitivity), and, hence, are worth implementingin the general population and in individuals.

Yet, it is necessary to establish clear prioritiesamong the different lipid-lowering interventions,and to focus prevention on the reduction of totaland plasma LDL cholesterol levels. This is espe-cially required because health-care providersfrequently misunderstand what the results ofepidemiological studies show, as opposed to thoseof intervention trials.

With this in mind, the Nutrition Foundation ofItaly (NFI) organized and coordinated a panel ofexperts who examined the information regardingthe nutritional and lifestyle control of cholester-olemia. The goal is to provide clinicians and otherhealth professionals involved in cardiovascularprevention with an up-to-date review of the avail-able evidence.

This statement has been formulated accordingto the following procedure:

a) agreement on the outline;b) writing of individual chapters by selected panel

members and peer review of these by otherpanel members;

c) summary of the outcomes;

Non-pharmacological control of plasma cholesterol 3

d) revision by all of the panel members;e) revision by an external expert.

This paper focuses on the effects on total andplasma LDL cholesterol levels, along with those onother lipid parameters, of interventions to:

a) modify the pattern of consumption of dietaryfatty acids;

b) reduce the dietary intake of cholesterol;c) modify the pattern of consumption of carbohy-

drates and fiber;d) change the proportional intake of other micro-

and macronutrients;e) manage weight;f) supplement with phytosterol-enriched foods or

soy protein;g) take regular exercise.

These interventions will also be evaluated inlight of their incorporation into the average Med-iterranean (Italian) diet. Specific conditions (e.g.,the menopause) in which such interventions mightbe detrimental (e.g., through an increase in therisk of osteoporosis), are also discussed.

Dietary fatty acids and cholesterolemia

Correlations between fatty acid intake and cho-lesterolemia were described in the second half ofthe twentieth century, when the Seven CountriesStudy by Keys and colleagues demonstrated howtotal plasma cholesterol levels increases togetherwith the proportion of fat in the diet. Severalsubsequent studies that examined the effects ofindividual fatty acids on both total plasma cho-lesterol levels and the different lipoprotein sub-classes, namely LDL and HDL, improved ourunderstanding of this correlation [3]. Several ep-idemiological and interventional studies exam-ined the effects of dietary fatty acids onlipoprotein metabolism and cholesterol trans-port. Overall, the available data suggest that,when isocalorically substituted for nutrientswith neutral effects on cholesterolemia (such ascarbohydrates), saturated and trans fatty acidstend to increase total and plasma LDL cholesterollevels. Conversely, polyunsaturated, cis fattyacids (namely, those of the n-6 series such as li-noleic acid) induce the opposite effects. Mono-unsaturates, such as oleic acid, also reduce totaland plasma LDL cholesterol levels, although toa lesser extent than do n-6 polyunsaturates. Theeffects of fatty acids on plasma HDL cholesterollevels are [2]:

a) an increase after saturates intake;b) an increase (to a lesser degree) after monoun-

saturate consumption;c) no change after polyunsaturates;d) a decrease after trans ingestion.

In terms of fat content, it is important to basefood choices on up-to-date composition tables,since changes in the fatty acid composition ofseveral food items (e.g., meat) as a consequenceof new diets for animals and new food-processingtechniques are sometimes relevant. As an exam-ple, pork meat is nowadays lower in saturated andtotal fats, but higher in mono- and polyunsatu-rated fatty acids (PUFAs), as compared with40 years ago.

Saturated fatty acids

The substitution of a percentage of dietary carbo-hydrates with an isocaloric portion of saturatedfatty acids (mostly found in red meat, sausage,dairy products, such as butter and cheese, andsome tropical oils, such as coconut and palm)increases total plasma cholesterol levels [2]. Ingeneral, saturated fatty acids increase both totaland HDL-C levels; hence, they tend not to modifysignificantly, or to only slightly worsen, their ratio.On the other hand, preliminary data suggest that,from a functional point of view, HDL associatedwith an increased consumption of saturates mightbe less active than native HDL, but the evidenceon this issue is still not conclusive [4].

In particular, the response of cholesterolemiaand its subfractions to fatty acids of differentchain lengths appears to be diverse. For example,saturated fatty acids with eight to ten carbonatoms (caprylic and capric acids) increase plasmaLDL cholesterol levels but do not affect HDL levels.The greatest hypercholesterolemic effect is attrib-uted to fatty acids with 12e16 carbon atoms.However, as lauric, myristic, and palmitic acids(12, 14, and 16 carbon atoms, respectively) areconcomitantly present in most food items, it isdifficult to ascertain their individual effects [5].

A recent meta-analysis that compared theeffects of these three fatty acids when they aresubstituted isocalorically for carbohydrates indi-cates that, as the number of carbon atoms in-creases, the hypercholesterolemic effect on boththe LDL and HDL fractions tapers off. Lauric acidappears to exert a more prominent effect on HDLthan on plasma LDL cholesterol levels; stearicacid, quantitatively the second fatty acid of thediet, reduces plasma LDL cholesterol levels, as

4 A. Poli et al.

does oleic acid when substituted for lauric, myr-istic, palmitic, or trans fatty acids [6]. It is inter-esting that stearic acid can be converted intooleate in vivo. The results of several observationaland intervention studies on the role of stearic acidon plasma HDL cholesterol levels (which some-times is reduced, but is often unchanged) are stillequivocal. Variations of plasma LDL cholesterollevels are negligible when stearic acid is isocalori-cally substituted for carbohydrates [7].

Most international guidelines suggest that toimprove cholesterol levels saturated fat intakeshould be lower than 10% of the total caloricintake [8]. Reasonably, the optimal intake of satu-rated fatty acids could be 7e10% of total calories;interestingly, in Italy the consumption of suchfatty acids is, on average, 10.4% of total calories[Istituto Nazionale di Ricerca per gli Alimenti e laNutrizione (INRAN), unpublished data].

Monounsaturated fatty acids

According to the majority of published studies,oleic acid [mostly found in olive oil, in somevariants of sunflower and safflower oils (called‘high oleic’) and in the Canadian rapeseed oilversion (canola), as well as in some animal prod-ucts such as lard] does not significantly influencetotal plasma cholesterol levels. This is also thecase for other monounsaturated fatty acids (MU-FAs). Indeed, monounsaturate consumption is notused in any of the equations to calculate thechanges in cholesterolemia associated with spe-cific fatty acid intake, such as those proposed byHegsted et al. [9] and Keys [10]. This neutral effectof oleate seems to result from a concomitant in-crease of plasma HDL cholesterol levels and a mod-est reduction of plasma LDL cholesterol levels,which thus increases the HDL/LDL ratio, which isinversely related to cardiovascular risk.

According to two studies performed by Grundyet al. [11] and by Mensink et al. [6] in the late1980s, a diet very rich in monounsaturates (24and 28% of total calories, respectively) and poorin saturates decreases plasma LDL cholesterollevels to an extent similar to that obtained witha low-fat, high-carbohydrate diet.

The global effect of monounsaturates on thelipid profile might explain, at least in part, theresults of the epidemiological studies and of theobservations by Key (in the 1970s) that the Medi-terranean diet, rich in mono-unsaturates, is asso-ciated with decreased cardiovascular risk.However, it is interesting that studies carried outin North American countries (where the main

source of mono-unsaturates is not olive oil but,rather, other oils or animal products) often failedto observe a protective effect of monounsatu-rates. For example, in the Nurses’ Health Studythe correlation between monounsaturate intakeand cardiovascular morbidity was negligible at thefirst follow-up and modest at the second [12].

This discrepancy might be explained if, inaddition to oleic acid, the minor components ofolive oil contribute to the protective effect ob-served in the Mediterranean countries. However,this issue has not been resolved as yet.

Based on the available data, the Adult Treat-ment Panel III (ATP-III) in 2001 recommended theproportion of mono-unsaturates be raised from10% to 15% in the optimal diet for cholesterolemiacontrol [8]. Similar levels of monounsaturate con-sumption are also included in the European Ath-erosclerosis Society (EAS), European Society ofCardiology (ESC), and European Society of Hyper-tension (ESH) guidelines. The average consumptionof mono-unsaturates in Italy fluctuates between 18and 20% of total fatty acids.

Polyunsaturated fatty acids of then-6 series

PUFAs of the n-6 series (which occur widely infood, essentially as linoleic acid, and in particularin some seed oils, such as corn, sunflower, andsoybean oils) induce a documented cholesterol-lowering effect. This is about half the hypercho-lesterolemic activity of saturates according toequations such as that of Hegsted et al. [9]. Thiseffect of n-6 polyunsaturates was first noted inthe 1950s, during early studies to assess the ef-fects of fatty acids upon cholesterolemia. In gen-eral, a 1% increase of n-6 polyunsaturatesingested with the diet leads to a mean reductionof total plasma cholesterol levels of approximately1 mg/dl [13].

Linoleic acid (the 18-carbon precursor of the n-6series) is thus generally considered as hypocholes-terolemic, especially when compared with oleateor saturates. This fatty acid, unlike monounsatu-rates, does not have significant effects on plasmaHDL cholesterol levels. The ability of linoleic acidto affect LDL-C might arise from an increasedexpression of such lipoproteins’ receptors in theliver [14].

These data are indirectly confirmed by theobservation that consumption of polyunsaturatesof the n-6 series is associated with a significantreduction of cardiovascular risk in mostepidemiological studies and in some controlled

Non-pharmacological control of plasma cholesterol 5

intervention trials. In the Nurses’ Health Study, therisk for women in the highest quintile of consump-tion is reduced by 30%, as compared with women inthe lowest quintile [15].

Based on these data, in 2001 the US ATP-IIIrecommended an optimal intake of total polyun-saturates (n-6 þ n-3) up to 10% of the total caloriesfor cholesterolemia control. This amount includesapproximately 2 g (i.e., 1% of total calories) of n-3 fatty acids. It should be stressed that, accordingto recent studies, polyunsaturates consumption inItaly is much lower, at 3e6% of total calories [16].

Polyunsaturated fatty acids of then-3 series

The n-3 fatty acids are found in nuts and vegeta-bles as alpha-linolenic acid (ALA) and in marineproducts as eicosapentaenoic acid (EPA), anddocosahexaenoic acid (DHA). Their intake mainlyaffects triglyceride-rich lipoproteins [very lowdensity lipoproteins (VLDLs)], whose synthesisand hepatic excretion are reduced. Consequently,n-3 fatty acid intake tends to decrease plasmatriglyceride levels. This effect is more pronouncedin patients with elevated basal plasma triglyceridelevels and can be accompanied by an increase inplasma LDL cholesterol levels, usually of lowermagnitude [17]. The effects n-3 fatty acids have onVLDL metabolism, which occur through differentmechanisms, include the reduction of VLDL secre-tion and triglyceride transport, with the formationof smaller VLDLs and, likely, an increased VLDLclearance. The main mechanism of action is thereduced availability of fatty acids for incorpora-tion into triglycerides because of the increasedbeta-oxidation, reduced synthesis through the in-hibition of key enzymes, and the modulation ofmembrane composition.

Some studies showed a positive effect of n-3fatty acids, such as fish oil, on plasma HDLcholesterol levels, namely via increased HDL2

(larger and richer in cholesterol) and reducedHDL3 levels. However, the results are not consis-tent and other studies reported limited or no ef-fects of n-3 fatty acids on these parameters [18].

Similarly, most studies concur that the effectsof n-3 fatty acids on total and plasma LDL choles-terol levels are negligible. Qualitatively, supple-mentation with EPA and DHA leads to theformation of larger (hence less atherogenic)LDLs, possibly through the inhibition of cholesterylester transfer protein (CETP) [19].

Some authors propose the assessment of n-3 andn-6 fatty acid intake not only in absolute terms,

but also as a ratio between these two fatty acidclasses. The rationale lies in the inhibitory activityof n-6 (when in very high proportion) on n-3metabolism and the proposed pro-inflammatoryenvironment that results. However, the availabledata do not support a significant correlationbetween a high n-6 to n-3 ratio and inflammatorymarkers; a role for the n-6 to n-3 ratio in thecontrol of cholesterolemia has also not beenconvincingly demonstrated.

Unsaturated fatty acids with transconformation

Nearly absent in vegetables (in which double bondsalways have a cis conformation), trans fatty acidscan be found in limited amounts (usually <5% oftotal fat) in dairy products and in meats from rumi-nants. However, the major sources of trans fattyacids in Western countries are the ‘partially hydro-genated fatty acids’ of industrial origin. Markedamounts of trans fatty acids are formed whenoils are solidified to produce margarine [20]. Indus-trially derived trans fatty acids tend to increasetotal and plasma LDL cholesterol levels, and re-duce plasma HDL concentrations. Quantitatively,trans fatty acids increase plasma LDL cholesterollevels by 1.2 mg/dl and reduce HDL levels by0.6 mg/dl for each 1% increase in their consump-tion as isocaloric substitution for carbohydrates.

The effects of trans fatty acids are thought tooccur through their inhibitory effects towardperoxisome proliferator activated receptor (PPAR)alpha, a nuclear receptor that controls the tran-scription of genes which code for a number of apo-proteins and enzymes (e.g., lipases), involved inmultiple aspects of lipid metabolism [20].

Moreover, trans fatty acids appear to inducea potentially deleterious pro-inflammatory activ-ity. The metabolic effects of trans fatty acids pro-duced by ruminants, and found in milk and dairyproducts, are understood less well.

Evidence from prospective studies indicatesthat the increased consumption of trans fattyacids of industrial origin increases the risk of car-diovascular disease. In the Nurses’ Health Study,women in the highest quintile of consumptionhad a risk of fatal and non-fatal events that was50% higher at the first follow-up and 33% higherat the subsequent follow-up [15].

Most recent margarines (usually softer andeasier to spread) have low or negligible concen-trations of trans fatty acids, whereas the ‘oldgeneration’ harder margarines used to containup to 40% of these compounds. Fat that is

6 A. Poli et al.

trans-rich is still employed in several pastry andbakery products, especially those of artisanmanufacture, because of their low cost, highstability, and favorable technological features.A recent statement of the American Heart Associ-ation (AMA) suggests that the total intake of transfatty acids should not exceed 1% of the total ca-loric intake (i.e., 2e2.5 g/day). In 2002, the Insti-tute of Medicine in the USA stated that transintake should be as low as possible, since no im-portant physiological role is known for these fattyacids.

Key points

A lipid intake of 30e35% of total calories isprobably adequate to control total and plasmaLDL cholesterol levels in Western countries,and specifically in Italy. Based on the nutri-tional habits in Italy and other Mediterraneancountries, it is advisable to use mainly extravirgin olive oil as the dietary fat of choice,even though its effects on total and plasmaLDL cholesterol levels are modest. Saturatesintake should be limited to 7e10%, while transintake should be limited to those from dairyproducts only. The use of seed oils rich in n-6 polyunsaturates improves total and plasmaLDL cholesterol levels; consequently, polyun-saturates can contribute up to 7e10% of totalcalories, including 1% of n-3 polyunsaturates(which do not modify total and plasma LDLcholesterol levels).

Key points

The most recent evidence puts a new perspec-tive on the role of dietary cholesterol in cho-lesterolemia management. Even if it mayseem advisable not to exceed a daily choles-terol intake of 300 mg, it is unwise to reducedramatically or eliminate cholesterol-richfoods such as eggs.

Dietary cholesterol and cholesterolemia

The exact roles and contributions of dietarycholesterol to cholesterolemia and atherogenesisare still debated. Indeed, it has been proved thatdietary cholesterol increases plasma LDL choles-terol levels; however, this effect is much lessprominent than that of saturated or trans fattyacids. Finally, whether the intake of dietarycholesterol affects cardiovascular risk is still un-certain [2].

Cholesterol is only present in animal-derivedfood items. For instance, high cholesterol levelsare found in bovine liver, brain and tripe, in eggs,and in crustaceans. Bread, pasta, rice, and vege-table oils are devoid of cholesterol. Of course,food items that contain eggs and butter alsocontain cholesterol.

A meta-analysis of 395 studies, carried out todetermine the influence of exogenous cholesterolon plasma lipids, found that a decrease of 200 mg/day in cholesterol consumption leads to a 5 mg/dldecrease in total plasma cholesterol levels and, inparticular, to a 3.8 mg/dl decrease in plasma LDLcholesterol levels [3]. Patients with mixed hyperli-poproteinemia appear to be more sensitive to ex-ogenous cholesterol than patients with isolatedhypercholesterolemia. After a cholesterol-richdiet (e.g., with elevated egg consumption), in-creases in plasma LDL cholesterol levels aresmaller in insulin-resistant patients than in thosewho are not resistant to insulin. This differencemight result from the reduced cholesterol absorp-tion in the former, who behave as ‘cholesterolsynthesizers’.

The wide inter-individual variability of choles-terol absorption (from w30 to w80%) and thecontribution of biliary cholesterol (w1 g/day),which is greater in absolute terms and non-modifi-able, also make it difficult to determine the exactcontribution of dietary cholesterol to its circulat-ing concentrations. This inter-individual variabilityis likely a consequence of specific genetic polymor-phisms that can affect the plasma lipid profile inresponse to diet. Carriers of the e4 allele ofapoE, as an example, respond better to dietarycholesterol restriction in terms of LDL-C reductionand increase in plasma HDL cholesterol levels [21].

The AHA guidelines prudently recommend lim-iting cholesterol intake to less than 300 mg/day inthe general population and to less than 200 mg/day in hypercholesterolemic, diabetic, or cardio-vascular patients. Other health authorities, suchas those of Canada, recommend a saturated fat in-take of less than 10% of total calories, but do notintentionally indicate an upper limit of cholesterolintake.

Nonetheless, limiting dietary cholesterol intakemakes sense, even though some cholesterol-richfoods, such as eggs, are of important nutritionalvalue.

Non-pharmacological control of plasma cholesterol 7

Carbohydrate and dietary fiber

Several reports demonstrate that substituting sat-urated and trans fatty acids with carbohydratesleads to a reduction of total and plasma LDL cho-lesterol levels. However, increasing carbohydratedietary intake can bring about deleterious effectson plasma lipids, such as increased plasma triglyc-eride levels e which might be an independent riskfactor for cardiovascular disease e and increasedconcentrations of small, dense LDLs, along withdecreased plasma HDL cholesterol levels [2]. A re-cent meta-analysis performed on 60 controlled tri-als concludes that increased carbohydrateconsumption, as isocaloric substitution for fat, isassociated with a decrease in plasma HDL choles-terol levels [22].

Several lines of evidence differentiate theeffects on lipid metabolism of mono- and disac-charides from those of polysaccharides. Simplesugars, namely sucrose and fructose, may increaseplasma triglyceride concentrations; high sucroseintake has also been associated with decreasedplasma HDL cholesterol levels. This latter effect isexplained by the increase in plasma triglycerideconcentrations, because the enrichment of HDLwith triglycerides enhances their catabolism. Con-versely, mono- and disaccharides do not signifi-cantly affect plasma LDL cholesterol levels [23].

Currently, the glycemic index (GI, the relativeglycemic response to a food compared with whitebread or pure glucose) and the glycemic load (GL,which also takes into account the amount ofcarbohydrate consumed) of a food item are consid-ered the most functionally relevant parameters ofcarbohydrates and of carbohydrate-rich foods [24].

It is known that the blunting of postprandialglycemia and insulinemia associated with theconsumption of low-GI food ameliorates insulinsensitivity and reduces the hepatic synthesis andsecretion of triglycerides, which leads to lowerconcentrations of triglyceride-rich lipoproteinsand increased plasma HDL cholesterol levels [25].

Several studies have demonstrated that thesubstitution of saturated fat with low-GI carbohy-drates does not lead to the increased plasmatriglyceride levels and reduced plasma HDL cho-lesterol levels usually associated with a diet rich inhigh-GI carbohydrates [26].

Two cross-sectional studies [27,28] have alsodemonstrated that plasma HDL cholesterol levelsis inversely correlated with the average GI ofa usual diet. Low-GI diets e often rich in soluble fi-bers e also induce a modest, though reproducible,hypocholesterolemic effect.

International guidelines advise that total carbo-hydrates make up for 50e60% of total calories;simple carbohydrates should not exceed 10% of thedaily caloric intake. However, if fatty acids withfavorable effects on plasma lipids (MUFAs andPUFAs) are selected, even diets with less than50% carbohydrates may induce a positive effect onplasma cholesterol levels.

Dietary fiber also induces notable effects onplasma lipids and lipoproteins. This effect is morepronounced for soluble or gel-forming fibers (i.e.,pectins, gum, beta-glucans, mucilages, and hemi-cellulose) for which the dietary sources are ce-reals, such as barley and oat, and legumes. Theconsumption of 5e10 g/day of soluble fiber, suchas beta-glucans, glucomannan, guar, and psyllium,reduces plasma LDL cholesterol levels by w5% [8].A meta-analysis [29] concluded that each gram ofsoluble fiber reduces total plasma cholesterollevels by w2 mg/dl and plasma LDL cholesterollevels by w2.5 mg/dl, with small variations dueto study groups and doses. Fiber reduces choles-terol absorption by the ileum and increases fecalexcretion. For psyllium (but not other fiber types),partial impairment of the enterohepatic circula-tion of bile salts has also been demonstrated.

The US Food and Drug Administration (FDA)allowed the claim of a ‘reduction of cardiovascularrisk’ (within a low-cholesterol and saturated fatdiet) for psyllium extracted from Plantago psyl-lium and, more recently, for beta-glucans of oatand barley.

By contrast, soluble fiber does not inducesignificant effects on plasma concentrations oftriglycerides and HDL-C.

A Cochrane Collaboration review [30] recentlyanalyzed the randomized trials that specifically as-sessed the effects of whole cereals (the majorsource of soluble fibers) on lipid risk factors forcardiovascular disease. In particular, eight studiesthat examined the effects of oat and its deriva-tives on lipid profile clearly indicated their effec-tiveness in reducing plasma LDL cholesterollevels. No variations of plasma triglyceride levelsand plasma HDL cholesterol levels were observed.

In general, studies carried out with carbohy-drate- and fiber-rich diets showed that these alsoled to modest reductions of body weight, probablythrough the satiating effects of bulky food withlow caloric load. The reduction of body weightalong with the effects of fibers might partlyexplain the less atherogenic profile associatedwith this kind of diet.

The most recent international guidelines [ATP-III [8], AHA 2006 [31]] recommend an increased

8 A. Poli et al.

consumption of fiber-rich food to achieve a dailyintake of 30 g.

Some guidelines suggested that such a targetamount could be reached using fiber supplementsin doses that range from 5 to 10 g/day. However,at present there is no evidence that supplementsprovide the same effects as whole foods. Basedon current data, consumption of the latter (includ-ing whole grains, which may favorably affectcardiovascular heart disease (CHD) risk via addi-tional biological mechanisms) is preferable overthe use of the former or of purified fiber.

Key points

Absorbable dietary carbohydrates do not playa major role in the control of total and plasmaLDL cholesterol levels, even though they canreduce the levels of these when they replacehypercholesterolemic fat, namely saturatedand trans fatty acids.On the other hand, low-GI foods may help toameliorate, though to a limited extent,plasma HDL cholesterol levels and to reduceplasma triglyceride levels.A daily fiber intake of 25e30 g may play a sig-nificant hypocholesterolemic role; soluble andgel-forming fiber is more effective than non-soluble fiber, and increasing its intake by5 g/day can reduce total and plasma LDL cho-lesterol levels.

Key points

A moderate ethanol intake (<40 g/day in menand <25 g/day in women) increases plasmaHDL-C levels.Dietary protein does not appear to induce sig-nificant effects on plasma total cholesterol orfractions thereof.Calcium (and possibly magnesium) and garlicsupplements may help to lower plasma choles-terol, but published data conflict.Vitamins, other minerals, and soy lecithin donot significantly affect plasma total or LDL-Clevels.

Interventions on other macro- andmicronutrients

Few other nutrients appear to induce a discernibleeffect on lipoprotein patterns.

Ethanol consumption at doses that may be re-garded as ‘moderate’ (�30e40 g/day in men,�15e25 g/day in women) is associated with signif-icantly higher HDL cholesterol levels than thosefound in non-drinkers. This effect is seen on bothmain HDL subfractions (HDL2 and HDL3) and maybe directly elicited by ethanol through increasedsynthesis of apolipoprotein A-1 (apoA-I), the majorapolipoprotein present in HDL [32].

High ethanol intake may sometimes increaseplasma triglyceride levels, in particular in subjectsalready hypertriglyceridemic at baseline, but onaverage the effect of moderate ethanol doses onplasma triglyceride levels is not significant [33].

The action of ethanol on HDL lipoproteins mayaccount for about half of the reduction in coronary

and cardiovascular risk associated with moderateethanol consumption in observational studies [34].

The effect of dietary protein on cholesterollevels appears to be modest [2]. Although vegeta-ble protein is traditionally believed to reduce cho-lesterolemia when substituted for animal protein,it is difficult to assess the effect of vegetable pro-tein independently from that of other vegetablecomponents with established cholesterol-loweringaction, such as fiber. Likewise, it is difficult todissect the individual contribution of vegetableprotein because its consumption substitutes fornutrients (i.e., animal fat) known to increase totaland LDL-C levels. In the OmniHeart study, how-ever, partially substituting protein for carbohy-drates led to modest but statistically significantbeneficial changes in plasma total and LDL-C, aswell as in triglyceride levels [35].

Specific data are available for soy protein asdiscussed below.

Some studies suggest a possible effect of garlicon total and LDL-C values, but literature reportsare inconsistent [36]. Similarly, other reports high-light a beneficial effect of calcium (and possiblymagnesium) on cholesterolemia, likely to be be-cause of the ability of these bivalent cations tobind fatty acids, triglycerides, and cholesterol inthe gut, and thereby limit their absorption [37].

In contrast, vitamins, other minerals, soy lecithinand the like have no significant influence on plasmatotal cholesterol and, in particular, on LDL-C [38].

Body weight changes andcholesterolemia

Obesity is involved in the development of a numberof chronic degenerative diseases and leads to

Key points

In most available studies, body-weight controlcan reduce significantly, albeit not dramati-cally, plasma total and LDL-C levels, especiallyin obese subjects. In addition, a decline intriglycerides is usually observed; HDL-C levelstend to rise on sustained weight loss.

Non-pharmacological control of plasma cholesterol 9

increased cardiovascular risk through multiplemechanisms. In this regard, the most recentstudies have turned the spotlight on abdominalobesity, often associated with atherogenic dyslipi-demia (low HDL-C and elevated plasma triglycer-ide levels, along with hyperinsulinemia andarterial hypertension).

The same alterations in plasma lipid profile,however, occur in overweight or obese patients asdefined by body mass index (BMI) criteria. Accord-ingly, the correlation between BMI and LDL-Cvalues is rarely significant in observational studies,whereas the positive correlation between BMI andtriglycerides and the negative correlation withHDL-C generally reach statistical significance,even in multivariate analysis.

Studies that examined the effects of weight losson plasma total cholesterol or lipid patterns in-dicate that weight loss is basically associated witha modest, yet statistically significant, decrease inplasma total and LDL-C levels, whereas the effectson triglycerides are usually more pronounced.Changes in HDL-C are diverse [39].

The conclusions of a systematic review thatencompassed 70 studies designed to induceweight reduction and detect changes in plasmalipid levels indicated that weight loss per se (aver-aging 16 kg or 16% from baseline weight) is associ-ated with a mean decrease in plasma totalcholesterol of about 30 mg/dl, with LDL andVLDL cholesterol dropping in equal proportions[40]. Overall, significant correlations are foundbetween weight reduction and decreased plasmatotal cholesterol, LDL-C, VLDL cholesterol, andtriglyceride concentrations. For every kilogramdecrease in body weight, total and LDL-C levelsare reduced by 2 mg/dl and 0.8 mg/dl, respec-tively. Furthermore, a 0.3 mg/dl reduction inHDL-C occurs for subjects who actively loseweight, whereas a 0.4 mg/dl increase occurs forsubjects at a stabilized weight. A more recentmeta-analysis showed that a drop in LDL-C con-centration for every 10 kg of weight loss amountsto 8.8 mg/dl in grossly overweight/obese sub-jects, which substantially confirms the above con-clusions [41]. Furthermore, weight loss is knownto lower cardiovascular risk through additionalmechanisms (such as improved glycemic andblood pressure control).

Not all the studies, however, are consistent.Data from the Swedish Obese Subjects (SOS) studyindicate that an average weight loss of 33% at twoyears after bariatric surgery decreased plasmatriglyceride concentrations and increased plasmaHDL-C concentrations without affecting plasmatotal cholesterol [42].

Improvements in HDL-C and in plasma triglycer-ide levels tend to be greater in overweight orobese subjects on low-carbohydrate diet, whereaschanges in LDL-C levels were more favorable insubjects on low-fat diets [43].

Physical activity and cholesterolemiccontrol

The findings from epidemiological observationsclearly indicate that physical inactivity remarkablyincreases the odds of many chronic degenerativediseases, including cardiovascular disease. Regularphysical activity is beneficial for many risk factorsof the above clinical conditions as it improves theplasma lipid profile and also aids, for instance,overweight and hypertension control [44]. How-ever, a sedentary lifestyle (a good proxy for whichmay be the time spent watching television) is alsoa strong marker of a poor lipid profile, indepen-dent of the person’s physical activity [45]. Obser-vational studies indicate that the impact ofphysical activity on lipid fractions is greatest forHDL-C, which tends to increase, and for triglycer-ides, which tend to fall in active individuals ascompared with inactive controls. The increase inHDL-C levels observed in active with respect tosedentary subjects varies from 9 to 50% and tri-glyceride reduction ranges from 19 to 50% [46].

By contrast, changes in plasma total and LDL-Cvalues are less consistent and wane in manystudies after adjusting for other lifestyle compo-nents (dietary habits, smoking, and alcohol con-sumption among others) using multivariateanalysis.

Most observational studies show a close relation-ship between total ‘amount’ of physical activityand the resultant changes in plasma lipid profiles.Significant concentration changes in plasma lipid,however, may not be achieved until a distinctthreshold is met. This threshold is not clear-cutand varies across different studies from 700 to

10 A. Poli et al.

2000 kcal/week (which corresponds to about 11e32 km/week of brisk walking or jogging), with fur-ther benefits likely to occur above 3000 kcal/week [47,48]. Aerobic physical activity, such aswalking, jogging, cycling, or swimming, with totalenergy expenditure of 1500e2200 kcal/week(which corresponds to about 24e32 km of briskwalking or jogging per week) may increase plasmaHDL-C levels by 3.5e6 mg/dl and lower plasma tri-glyceride levels by 7e20 mg/dl. A further 16 km/week would trigger an additional 3 mg/dl increasein plasma HDL-C levels and an additional 3e8 mg/dl drop in plasma triglyceride concentrations.

A similar scenario emerges from a review ofsome 100 prospective intervention studies per-formed between 1974 and 1999. These studiesincluded exercise interventions based on aerobicactivity, usually cycling, walking, or running, withintensities >60% of maximum heart rate or VO2 inan ergometric test.

Exercise training was reported to alter total andLDL-C levels in just over25% of the studies and inducereductions, if any, of 4e7%. Plasma HDL-C rose by 2e8 mg/dl (w5e20%), whereas plasma triglyceridelevels decreased by 5e38 mg/dl (w5e20%). Theseeffects were more pronounced in males and inpreviously sedentary individuals. Conversely, resis-tance exercise programs do not significantly modifyplasma lipids [46], but may increase lean musclemass and insulin sensitivity, and reduce the gain inwaist circumference associated with aging [49].

A prospective, randomized study compared theeffect of three training programs of exercise: largeamount of high intensity; large amount of moder-ate intensity; and small amount of moderateintensity. At the end of the program, exercisetraining increased the size and concentration ofHDL particles and decreased plasma triglycerides,but had no significant effect on the total or LDL-Cconcentrations. The high-intensity, high-amountexercise group showed the most improvement inlipid profiles [50].

Key points

Regular aerobic physical activity generally in-duces an increase in plasma HDL-C and a de-crease in plasma triglyceride levels, whereasthe effects on total and LDL-C are inconsistentand generally modest. This effect is, to someextent, dose-dependent and the efficacythreshold is set at 1500 kcal/week (equivalentto about 24 km of brisk walking or jogging perweek).

Interventions to enhance thecholesterol-lowering actionof an appropriate diet

Interventions on dietary macronutrients (essen-tially lipids) typically induce decreases in plasmatotal and LDL-C levels that range from 5 to 10%. Ifthis does not lower plasma cholesterol to thetarget values in individuals according to their risklevel, in the absence of compelling indications forhypolipidemic pharmacological treatment it ispossible to use strategies that boost the choles-terol-lowering action of the above dietary ap-proaches. Implementing such interventions is notintended to replace the dietary interventions de-scribed above, which should be continued. These‘additional’ strategies may sometimes be per-ceived by the lay public as possible ‘shortcuts’ toavoid a change in dietary habits (or to avoidcompliance with such changes in the long term).Physicians and health-care professionals shouldprovide adequate counseling and recommend theiruse only if targeted common dietary modificationsfail to attain anticipated goals.

In this context, controlled studies have beenperformed mainly with plant sterols and soy pro-tein. The consumption of foods enriched in plantsterols or soy protein requires sustained adherenceto ensure plasma cholesterol levels do not returnto baseline.

Phytosterol-enriched food productsand plasma cholesterol control

Phytosterols (or plant sterols and stanols) arehydrophobic molecules that are structurally re-lated to cholesterol. They occur naturally invegetable oils and, in smaller amounts, in vegeta-bles, fresh fruits, chestnuts, grains, and legumes.The dietary intake of plant sterols does not usuallyexceed 250e300 mg/day in Northern Europeancountries, whereas it appears to be higher (up to500e600 mg/day) in Mediterranean countries [51].

Plasma total phytosterol levels in humans arevery low, in the range from 1 to 2 mg/dl. Despitetheir significant initial absorption from the intesti-nal tract via the same efficient pathway that medi-ates cholesterol absorption, phytosterols arealmost completely returned to the intestinal lu-men through specific transporters. As a result,their net absorption is much lower than that ofcholesterol (0.02e3.5% vs 35e70%) [52].

The interest in phytosterols lies in their abilityto compete with cholesterol for intestinal

Key points

Incorporation of food products that contain 2 gof phytosterols into the diet reduces plasma to-tal and LDL-C levels by about 10% without sig-n ificant effects on plasma HDL-C andtriglycerides. Their consumption should belinked to the principal meal(s) and be contin-ued for a long time.

Non-pharmacological control of plasma cholesterol 11

absorption, through their interference with biliaryand food-derived cholesterol for micelle formationin the gut. The ability of phytosterols to modulatedietary cholesterol absorption entails a decreasein plasma cholesterol levels, in particular the LDL-bound fraction, through a partially dose-depen-dent mechanism [53].

The correlation between use of different dosesof phytosterols and the reduction of plasma LDL-Clevels was examined in several studies publishedbetween 1998 and 2006, as well as in one meta-analysis [54]. Available data suggest that plasmaLDL-C reductions increase with phytosterol doses,at least in the range from 0.7 to 2.0e2.5 g/day;the use of higher doses provides no additional ben-efits in terms of plasma cholesterol reduction andis therefore not advisable.

Based on recent data, food matrices do notappear to affect significantly the cholesterol-low-ering efficacy of phytosterols at equivalent doses.Phytosterols do not appear to be more effective ifingested in several daily doses during meals,whereas linking the time of ingestion to a principalmeal is markedly more effective than consumptionnot linked to meals [55].

Long-term efficacy studies have shown that thecholesterol-lowering effect of phytosterols usuallybecomes apparent after three weeks and is sus-tained upon regular consumption. Furthermore,their effect on the lipid profile is additive to thatof lipid-lowering diets and does not change insubjects treated with statins and/or fibrates,which thereby reduces the plasma LDL-C levelsachieved with pharmacological treatment by a fur-ther 8e10%.

A relevant issue in the use of phytosterols,which is necessarily chronic, is their long-termsafety. A number of studies have shown thatchanges in the plasma levels of several lipophilicvitamins and nutritional or non-nutritional factorsare insignificant. By contrast, a 7e17% decline inthe plasma levels of b-carotene after adjustmentfor LDL reduction was observed for as yet unclearreasons, although this may be controlled by in-creasing the intake of fresh high-carotenoid vege-tables [56].

Based on the elevated coronary disease risk inthe very few patients with phytosterolemia causedby mutations in the ABC G5/G8 transporters, someauthors have raised the possibility that the modestincrease in the plasma concentration of phytos-terols in subjects treated with 2 g/day thereof maybe atherogenic. The three published case-controlstudies that compare subjects with and withouta history of coronary disease, however, are notconsistent (the risk increased in one study,

remained unchanged in the second, and decreasedin the third) and, therefore, do not support this hy-pothesis [57].

Based on the available information, it is thusreasonable to concur with the NCEP ATP-III guide-lines published in 2001 [58], which recommenda daily intake of 2 g/day of phytosterols and/orphytostanols to achieve an additional plasmaLDL-C reduction when dietary interventions arenot successful. Similar recommendations were in-corporated in the Australian guidelines for lipidcontrol and the Finnish Medical Society guidelinesin 2004.

Soy protein

Soy-derived protein displayed significant choles-terol-lowering activity in clinical studies that in-volved patients with different forms ofhypercholesterolemia. A meta-analysis in 1995[59] reported that soy protein, when partially orfully substituted for dietary animal protein, in-duced a mean decrease of 23 mg/dl in plasma totalcholesterol concentrations and of 22 mg/dl in LDL-C concentrations. The observed reduction was re-lated to the initial plasma cholesterol concentra-tions, that is it was greater in subjects withestablished hypercholesterolemia and minor ornegligible in those with baseline cholesterolemiabelow 230 mg/dl. This set of data has been recon-firmed by a new meta-analysis published recently[60].

Based on the available scientific evidence, in1999 the US FDA released a claim that a dailydietary supplementation with four soy-proteinservings (6.25 g each) may significantly reducethe risk of cardiovascular disease [61]. At thesedoses, the average fall in plasma cholesterol levelsis about 10%, depending on the baseline cholester-olemia (as noted above) and is mostly accountedfor by the reduction in LDL-C, whereas HDL-Cand plasma triglyceride levels are essentially un-changed after treatment.

12 A. Poli et al.

The most effective cholesterol-lowering soycomponent is almost certainly protein, whereasisoflavones do not appear to contribute signifi-cantly to the effects on lipid metabolism. Thecholesterol-lowering effect may be attributable tothe ability of soy protein to upregulate theexpression of apo-B receptors [62,63].

Based on early preclinical studies, Lupinus albusprotein may also provide an interesting option todevelop cholesterol-lowering foods [64].

Key points

Including 25 g of soy protein in the diet asa partial replacement of animal protein re-duces plasma total and LDL-C concentrations.The beneficial effects are proportionallygreater in subjects with hypercholesterolemia;no significant effects are observed on HDL-Cand plasma triglyceride levels.

Key points

In women, the diet should be targeted notonly at coronary risk reduction through plasmacholesterol control, but also at the preventionof osteoporosis. Both aims can be achievedthrough foods with low fat and adequate cal-cium content, optimal vitamin D intake, andregular physical activity.

Simultaneous prevention of coronaryheart disease and osteoporosis inpostmenopausal woman

Appropriate assessment of the dietary lipid intakeis also important to meet an adequate dailycalcium requirement. Milk and dairy products(yogurt, cheese, and ice cream) represent themajor source of calcium. This issue is crucial, inparticular for women who need to prevent osteo-porosis and its complications as well as to preventcoronary heart disease through the control ofplasma cholesterol levels.

Daily calcium requirements vary throughout anindividual’s lifetime and rise from 1200 mg/day infertile women to 1500 mg/day in postmenopausalwomen. However, epidemiological studies, whichinclude some from Italy, reported a low averagecalcium intake in the daily diet [65].

Although women should be advised to increasetheir calcium intake and consider primarily milkand dairy products for this purpose, it is importantto take into account that these foods (especiallycheese) may contain large amounts of saturatedfat and may therefore worsen the cardiovascularrisk profile, particularly plasma total and LDL-Clevels. Dietary prevention of osteoporosis shouldfocus not only on calcium intake, but also onreducing animal protein and increasing the amountof basic foods that are able to buffer excess acid inplasma, which in turn stimulates bone calciummobilization [66].

It is therefore advisable to adopt a diet withadequate calcium content while at the same timelimiting the total lipid intake. However, adequatecalcium levels may be found in low-fat foods suchas skimmed or partially skimmed milk and low-fatyogurts (which contain slightly larger calciumamounts than whole milk and yogurt). They arealso found in specific dairy products (cottagecheese, ricotta cheese from cow’s and sheep’smilk), in specific types of fish and shellfish(anchovies, squid, octopus, horse mackerel, mus-sels, striped sea bream), and in specific vegeta-bles and seeds (rocket, green chicory, mustardgreens, endive). Calcium from all these foods,unlike that found in grains, beans, and othervegetables, is readily absorbed because of thelow oxalate and phthalate content. A remarkableamount of calcium may also be obtained frommineral waters that contain at least 150e200 mgcalcium per liter [67].

It should be recalled, however, that calciumabsorption occurs only partially (by an estimated8e23%) through passive diffusion, which is relatedto dietary calcium intake. In contrast, the majorpathway of calcium absorption is dependent onvitamin D. Daily sunlight exposure usually providesadequate vitamin D supply; however, vitamin D isalso present in some low-fat (i.e., mushrooms) andmedium-fat foods, such as eggs and, in particular,some types of fish (i.e., anchovies, herring,salmon, sardines, dripped olive-oil tuna). In thesefish types, vitamin D levels range from 5 to 19 mgper 100 g edible parts.

Thus, a balanced diet combined with ade-quate sunlight exposure and physical activity(the latter is also relevant to osteoporosis pre-vention), can improve outcomes not only inpatients with hypercholesterolemia and othercardiovascular risk factors, including obesity,diabetes and arterial hypertension, but also inthose with hallmarks of osteopenia or establishedosteoporosis.

Key points

A Mediterranean-like diet seems to influencethe cardiovascular risk positively, probablyvia mechanisms not entirely explained by theeffects on the plasma lipid profile.The effect of such a dietary model on choles-terol levels can be enhanced, whenever nec-essary, by specific interventions or the use offortified foods.

Non-pharmacological control of plasma cholesterol 13

The Mediterranean diet and plasmacholesterol control

In 1993, the International Conference on the Dietof the Mediterranean [68,69] summarized the keyelements of this diet at follows:

1) abundant plant foods (fruits, vegetables, breads,other forms of cereals, beans, nuts, and seeds);

2) minimally processed, seasonally fresh, and lo-cally grown foods;

3) fresh fruits as the typical daily dessert withsweets based on nuts, olive oil, and concen-trated sugars or honey during feast days;

4) olive oil as the principal source of dietary lipids;5) dairy products (mainly cheese and yogurt) in

low-to-moderate amounts;6) fewer than four eggs per week;7) red meat in low frequency and amounts;8) fish and poultry in low-to-moderate amounts;9) wine in low-to-moderate amounts, generally

with meals.

However, countries around the Mediterraneanbasin have different dietary patterns, even thoughthe current process of globalization and lifestylemodification is slowly altering the dietary habits ofeach country. Thus, there is no uniform ‘Mediter-ranean diet’ and, indeed, the term ‘Mediterraneandiet’ may be considered a misnomer. It refersspecifically to the dietary pattern observed in theearly 1960s in areas of Southern Italy and Greeceand on the island of Crete. This diet is preciselyassociated with these traditionally olive-growingareas. Indeed, the use of olive oil as the major andoften exclusive fat source is unique to the Medi-terranean area. From the nutritional viewpoint,the use of olive oil (which was recently granted anFDA health claim of cardioprotective activity) en-ables the intake of saturated fatty acids (exceptshort-chain ones from dairy products) to be limitedas they can be replaced with monounsaturates suchas oleic acid. Consumption of n-6 PUFAs is also low.

The Mediterranean nutritional pattern also in-cludes a high intake of fiber and ‘functional’phytochemicals from plant foods, among whichphytosterols (from seed oils and cereals) are ofparticular importance and of which, on average,400 mg/day are consumed. The Mediterranean dietfeatures most of the indications for plasma choles-terol control outlined in this paper, with someexceptions. Actually, this diet only includes a low-to-moderate amount of n-6 PUFAs, mostly fromseed oil (soy, sunflower, corn, rapeseed, peanut,and sesame), that can contribute to the control of

total and plasma LDL cholesterol levels. Moreover,the Mediterranean diet provides a rather high per-centage (25e35%) of calories from fat, in contrastto most nutritional guidelines (�30% of daily calo-ries). However, a moderate increase of caloriesfrom fat, if derived from MUFAs, is considered fa-vorable by most investigators and some authorita-tive guidelines. The increase in MUFA can alsopositively influence health-related parametersother than the lipid profile, such as insulin sensitiv-ity. A shift of w10% of calories from carbohydratesto calories from MUFAs is currently adopted as die-tary therapy for the metabolic syndrome and type IIdiabetes, as it reduces plasma triglyceride levelswithout influencing plasma HDL cholesterol levels.

Several studies support the positive effects of theMediterranean regimen on plasma lipid profile (re-duction of total and plasma LDL cholesterol levels,plasma triglyceride levels, and apo-B and VLDLconcentrations, and an increase in plasma HDLcholesterol levels). This effect is associated withincreased plasma antioxidant capacity, improvedendothelial function, reduced insulin resistance,and reduced incidence of the metabolic syndrome.In general, the Mediterranean diet reduces the risk ofCHD, an effect that is not completely explained by itsaction on the lipid profile and is, in part, attributableto further non-lipid pathways [69e71]. Additionalstudies built on evidence-based methodologies arenecessary to draw conclusions, in particular todiscern the individual effects of dietary componentsfrom those of the diet as a whole.

In conclusion, the Mediterranean diet can rep-resent, in Italy, the most appropriate base fora nutritional strategy aimed to prevent cardiovas-cular diseases. In specific cases its effects on totaland plasma LDL cholesterol levels may be aug-mented via selective adjustments of the lipidintake or through ad hoc supplementation withfunctional foods, implemented whenever possibleon the grounds of personal diet characteristics. Ex-cept for specific cases, such interventions shouldprecede any pharmacological action.

14 A. Poli et al.

Grading of evidence

The levels of evidences and the grades ofrecommendation regarding the lipid effect ofthe main dietary and life-style interventionsdescribed in this paper, prepared accordingto the SIGN protocol [72], are summarized inTable 1.

Table 1 Levels of evidence and grades of recom-mendation regarding the lipid effect of some of thenutritional and life-style interventions examined inthe paper

Dietary recommendation Grading SIGN

Diminution in saturated fatty acidsintake reduces total and LDLcholesterol

A, 1þ

Increased n-6 PUFA intakedecreases total and LDLcholesterol

A, 1þ

Trans-unsaturated fatty acidsintake diminution decreases totaland LDL cholesterol and increasesHDL cholesterol

B, 2þþ

Dietary cholesterol intakereduction decreases total andLDL cholesterol

B, 2þþ

Low GI foods intake increases HDLcholesterol

B, 2þ

High fiber diets decrease total andLDL cholesterol levels

A, 1þ

Weight reduction slightly reducestotal and LDL cholesterol inoverweight/obese patients

A, 1þ

Physical activity improves HDLcholesterol levels

A, 1þ

Phytosterols daily use reduces totaland LDL cholesterol

A, 1þþ

Soy protein substitution for animalprotein reduces total and LDLcholesterol

A, 1þ

Levels of evidence: 1þþ, high quality meta analyses, sys-tematic reviews of RCTs, or RCTs with a very low risk ofbias; 1þ, well conducted meta analyses, systematicreviews of RCTs, or RCTs with a low risk of bias. Gradesof recommendation: (A) At least one meta analysis,systematic review, or RCT rated as 1þþ, and directlyapplicable to the target population; or A systematicreview of RCTs or a body of evidence consisting princi-pally of studies rated as 1þ, directly applicable to thetarget population, and demonstrating overall consistencyof results. (B) A body of evidence including studies ratedas 2þþ, directly applicable to the target population,and demonstrating overall consistency of results; orExtrapolated evidence from studies rated as 1þþor 1þ.

Acknowledgments

Eric Rimm (Boston, USA), Andrea Cignarella (Mi-lano) and Francesco Visioli (Paris) are gratefullyacknowledged for their contribution and helpfuldiscussion.

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