Thomson

Lowering LDL-cholesterol through diet: potential role in thestatin eraEric Bruckert and David Rosenbaum Department of Endocrinology and Metabolism, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Assistance Publique- A healthy diet should be rich in vegetables and fruits, whole-grain, high-fiber foods, and fish and should contain a small amount of saturated and trans fats. In addition to these Correspondence to Pr Eric Bruckert, Unite´ de recommendations, some food ingredients such as plant sterol/stanol soy protein and Pre´vention Cardiovasculaire, Department ofEndocrinology and Metabolism, Groupe Hospitalier isoflavones may help reduce cholesterol levels. Increased dietary fiber intakes are Pitie´-Salpeˆtrie`re, Assistance Publique Hoˆpitaux de associated with significantly lower prevalence of cardiovascular disease and lower Paris, 83, boulevard de l’Hoˆpital, 75651 Paris Cedex13, France LDL-cholesterol concentration of about 5–10%. Beyond LDL-cholesterol lowering Tel: +33 1 42 17 78 49; fax: +33 1 42 17 79 63; effects, other benefits have been observed on hypertension, diabetes mellitus. In this review, we summarize the different dietary approaches proven to be associated Current Opinion in Lipidology 2011, 22:43–48 with LDL-cholesterol decrease. Nutritional interventions that do not exert significantLDL-cholesterol decrease have not been included in this review.
Recent findingsOn top of a ‘classical’ step 1 and step 2 diet, the cornerstone of dietaryrecommendations, recent findings confirm the deleterious effects of trans fatty acid orthe beneficial effects of sterols/stanols and nuts.
SummaryDietary recommendations may have an impressive impact on cardiovascular eventsbecause they can be implemented early in life and because the sum of the effect on LDL-cholesterol is far from being negligible: step 1 diet (À10%), dietary fibers (À5 toÀ10%), plant sterols/stanols (À10%), nut consumption (À8%), and soy protein (À3 toÀ10%).
Keywordscardiovascular diseases, cholesterol, diet, dietary fiber, omega-6, plant sterols,saturated fatty acid Curr Opin Lipidol 22:43–48ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins in coronary deaths was due to a 6% reduction in total cholesterol As a consequence, a long-term dietary High serum levels of low-density lipoprotein-cholesterol approach would be a unique opportunity to significantly (LDL-C) have been clearly linked to the risk of cardio- decrease CHD risk throughout a lifetime.
vascular disease (CVD). As a result of the high prevalenceof undesirable cholesterol levels, this risk factor may In this review, we summarize the different dietary inter- account for a large proportion of CVDs in European ventions able to decrease LDL-C. These interventions countries. Despite the rather short period of intervention can also be combined (when appropriate) with weight loss trials (usually <5 years), a 10% reduction in LDL-C either and increased physical activity with a further decrease with a dietary approach or with lipid lowering agents is LDL-C by up to 5%. When looked at individually, each associated with a 25% reduction of the incidence of cor- dietary recommendation has a rather small impact especi- onary artery disease Lifetime reductions in serum ally if long-term compliance is taken into account. How- LDL-C levels with adequate diet may therefore have a ever, when combined together in a comprehensive way, huge impact on CVD at population’s levels. Indeed, life- dietary changes may have a significant impact on LDL-C time reductions of LDL-C are associated with a dramatic and subsequently on CHD risk. Therefore, lifestyle decrease (À88%) in cardiovascular risk as shown in patients recommendations should be given as early as possible.
having a loss-of-function PCSK9 gene mutation Furthermore, a large study conducted in the US popu-lation demonstrated that a major decline (44%) of deaths from coronary heart disease (CHD) could be attributed to The National Cholesterol Education Program step 1 changes in risk factors. Interestingly, 24% of the decrease ( 30% of energy as total fat, <10% of energy as saturated 0957-9672 ß 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
fat, and < 300 mg cholesterol/day) and step 2 diets ( 30% in randomized controlled trials. Studies were included if of energy as total fat, <7% of energy as saturated fat, and they randomized participants to increased polyunsatu- <200 mg cholesterol/day) are the cornerstones of dietary rated fatty acid for at least 1 year without any concomitant recommendations in dyslipidemic patients.
major interventions, if they had an appropriate controlgroup and if they reported incidence of CHD. Eight trials Replacing dietary saturated fatty acid by polyunsaturated met inclusion criteria (13 614 participants with 1042 CHD fatty acid (mainly n À 6) is efficient in decreasing plasma events). Average weighted polyunsaturated fatty acid concentration of cholesterol In a meta-analysis of 72 consumption was 14.9% energy in intervention groups metabolic ward studies of solid food diets in healthy vs. 5.0% energy in controls. The overall pooled risk volunteers, Clarke et al. observed that replacement reduction was 19% [RR ¼ 0.81, 95% confidence interval of 5% calories as saturated fatty acid by polyunsaturated (CI) 0.70–0.95, P ¼ 0.008], corresponding to a 10% fatty acid led to a À0.39 mmol/l change in total blood reduced CHD risk (RR ¼ 0.90, 95% CI 0.83–0.97) for cholesterol. Similarly, replacing 6.4% of energy as satu- each 5% of polyunsaturated fatty acid energy increase.
rated fatty acid by n À 6 polyunsaturated fatty acid while Meta-regression identified study duration as an indepen- keeping total fat content at 30–33% of energy led to a dent determinant of risk reduction (P ¼ 0.017), with 22% decrease in plasma LDL-C (À0.63 mmol/l) studies of longer duration showing greater benefits.
Altogether, these data indicate that the highest level of In the Nurse’s Health Study, Hu et al. found that evidence in dietary recommendation is the replacement polyunsaturated fatty acid intake was inversely associated of saturated fatty acid by polyunsaturated fatty acid with CHD risk, with the highest quintile correspondingto a daily intake of 6.4% of energy. The authors con-cluded that replacing 5% of energy from saturated fatty acid with energy from monounsaturated and polyunsa- Increased dietary fiber intakes are associated with lower turated fatty acids would reduce CHD risk by 42% and prevalence of CVD in prospective studies Soluble would be more effective in preventing CHD than redu- fibers, when included within a saturated fat and choles- terol poor diet, lower LDL-C concentration of about5–10% in hypercholesterolemic and diabetic patients Trans fatty acids have been used in food manufacturing In a recent study in patients with mild-to-mod- for a long time partly because of their melting point at erate hypercholesterolemia, a 14 g daily administration of room temperature situated between saturated and unsa- Plantago ovata husk (Po-husk) during 8 weeks induced a turated fats which provides favorable texture and mouth mean reduction of 6.1% in LDL-C plasma concentration feel However, these fatty acids increase LDL-C and A significant lowering (16%) of plasma triglycerides decrease high-density lipoprotein-cholesterol (HDL-C).
was also observed. Additionally, Po-husk lowered the Furthermore, increasing epidemiologic and biochemical concentration of oxidized LDL in plasma; a commonly evidence suggest that trans fatty acid-rich diets are a used marker of oxidative damages involved in CHD.
significant risk factor for cardiovascular events Thus, Other fibers such as beta-glucan from barley and oat have the American Heart Association recommends limiting similar effects on LDL-C. Beyond LDL-C lowering, trans fats to less than 1% energy. As a result, step 1 fibers intake may also have other effects, such as and step 2 diets should also include a reduction of trans reduction of systolic blood pressure, decrease of body weight and better control of diabetes mellitus The results of these studies support the routine use of Whether some fatty acids might be associated with a soluble fibers in the recommended diets for adults with better risk factor profile is a matter of intensive research.
hypercholesterolemia. Patients can consume a variety of For example, stearic acid, when compared to other satu- soluble fibers, beta-glucan, psyllium, pectin, and guar rated fatty acids, lowered LDL-C but is neutral with respect to HDL-C In the opposite, in comparisonwith unsaturated fatty acids, stearic acid tends to raiseLDL-C, lower HDL-C, and increase the ratio of total cholesterol to HDL-C. However, it would premature and Plant sterols are plant compounds that have chemical difficult to implement these possible subtle differences structures similar to cholesterol. Absorption efficiency of between saturated fatty acids in clinical practice.
plant sterols in humans is considerably less than the oneof cholesterol Among the different plant sterols, the The most recent meta-analysis by Mozaffarian et al. most abundant are sitosterol, campesterol, and stigmas- systematically investigated and quantified the effects of terol. The daily dietary intake of plant sterols differs increased polyunsaturated fatty acid consumption, as a among populations and is low to efficiently decrease replacement for saturated fatty acid, on CHD endpoints Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lowering LDL-cholesterol through diet Bruckert and Rosenbaum A meta-analysis of randomized controlled trials in adults cholesterol as well as the LDL : HDL ratio. The exact was performed to establish a continuous dose–response underlying mechanisms remain to be established. Nuts relationship that would allow predicting the LDL-C have a unique fatty acid profile and feature a high lowering efficacy of different phytosterol doses  unsaturated to saturated fatty acid ratio. Additional Eighty-four trials including 141 trial arms were analyzed.
potential cardioprotective nutrients are found in nuts: The pooled LDL-C reduction was 0.34 mmol/l (95% CI: vegetable protein, fibers, alpha-tocopherol, folic acid, À0.36, À0.31) or 8.8% (95% CI: À9.4, À8.3) for a mean magnesium, copper, phytosterols and other phytochem- daily phytosterol dose of 2.15 g. Higher baseline LDL-C icals. Interestingly, adding nuts to diets does not seem to concentrations were associated with greater absolute be associated with weight gain, possibly due to the LDL-C reductions. No significant differences were increased satiety induced by nut consumption.
found between the dose–response curves establishedfor plant sterols vs. stanols, fat-based vs. nonfat-basedfood formats and dairy vs. nondairy foods. There was a strong tendency (P ¼ 0.054) toward a slightly lower effi- In 1995 Anderson et al. analyzed 38 controlled cacy of single vs. multiple daily intakes of phytosterols.
clinical studies among which 30 were conducted inhypercholesterolemic patients. Compared with animal Discussing the effect of plant sterols on atherosclerosis protein, a mean intake of 47 g/day of isolated or textured and CVD is beyond the scope of this review. Studies have soy protein resulted in a significant reduction in LDL-C raised the possibility of circulating plant sterols being (12.9%) and in triglycerides (10.5%) without significant a risk factor in the pathogenesis of atherosclerosis.
changes in HDL-C levels. Therefore, the Food and Drug Evidence supporting this hypothesis mainly comes from Administration approved a food-labelling health claim for observations in sitosterolemic patients, who hyperabsorb soy protein in the prevention of CHD. More recent plant sterols and may suffer premature atherosclerosis.
results found inconsistencies. Indeed, mean consumption of 50 g/day (ranging from approximately 25 to 133 g) of increased vascular risk linked to small increases in plasma isolated soy protein, lowered LDL-C levels by only 3% in plant sterol concentrations. However, other prospective comparison with milk or other proteins. The studies did and more recent large population-based studies did not not address possible mechanisms of the effects of soy confirm these earlier results. Furthermore, the potential protein intake Whether the changes were attribu- (and highly hypothetical) risk of plant sterol-enriched table to the soy protein per se, other soy-derived factors foods may be counterbalanced by the notable reduction (constitutive isoflavones), or both remained to be estab- lished. Altogether, these data suggest that soy protein/isoflavones are possible but uncertain components to use Among the therapeutic lifestyle changes aiming to reduce in the global strategy of dyslipidemic patients treatment.
CHD risk, plant stanol or sterol-enriched products con-sumption is now recommended to achieve the necessaryLDL-C lowering. Plant sterols and stanols are recom- mended by the American Heart Association and the As the use of soy protein, viscous dietary fibers and nuts European Food Safety Authority which stated that ‘a are supposed to enhance the cholesterol-lowering effec- clinically significant LDL-C lowering effect of about 9% tiveness of a diet, a dietary portfolio containing all of can be achieved by a daily intake of 2–2.4 g of phytos- these recommended food components known to decrease LDL-C was tested in hyperlipidemic adults in a random-ized controlled trial The study was conducted in46 healthy, hyperlipidemic adults. Participants were ran- domly assigned to undergo one of the three following Frequent nut consumption has been found to be protec- interventions on an outpatient basis for 1 month: a very tive against CHD in five large epidemiological studies saturated fat poor diet, based on milled whole-wheat A qualitative summary of the data from four of cereals and low-fat dairy foods (n ¼ 16; control group); these studies found an 8.3% reduction in risk of death the same diet plus a 20-mg lovastatin daily dose (n ¼ 14, from CHD for each weekly serving of nuts. Despite the statin group); or a diet rich in plant sterols (1.0 g/ fact that double-blind placebo-controlled studies are 1000 kcal), soy proteins (21.4 g/1000 kcal), viscous fibers impossible to conduct, more than 40 dietary intervention (9.8 g/1000 kcal), and almonds (14 g/1000 kcal) (n ¼ 16; studies have evaluated the effect of nut containing diets dietary portfolio group). The control, statin, and dietary on blood lipids. Even in the context of healthy diets, portfolio groups had mean (SE) decreases in LDL-C of these studies in healthy study participants or patients 8.0% (2.1%) (P ¼ 0.002), 30.9% (3.6%) (P < 0.001), and with moderate hypercholesterolemia have demonstrated 28.6% (3.2%) (P < 0.001), respectively. There were no that intake of different kinds of nuts lowers LDL-C, total significant differences in efficacy between the statin and Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
dietary portfolio treatments. Interestingly, this significant the false perception by both physicians and patients, that effect was confirmed in a longer 12-month study .
diet has poor efficacy; inappropriate evaluation of cardio- The main message for clinicians is that the different diet vascular risk; lack of time; and a demand of practical recommendations used in these studies are complemen- information. Obviously, proper information on efficacy tary (i.e., additive or synergistic) in their effect on serum and referring to a dietician should help provide practical LDL-C. A large study assessing the impact of such information expected by our patients.
strategy on atherosclerosis or cardiovascular events wouldbe most interesting.
Diet and lipid-lowering agentsGenerally speaking, both strategies should be combined when a statin prescription is recommended according to The term ‘Mediterranean diet’ is well understood but not local guidelines. All large intervention studies have been clearly defined because it is a comprehensive approach conducted in patients following a step 1 or step 2 diet which includes most of recommendations given in the even if the reality of adherence was poorly assessed. In step 1 and step 2 diets with an addition of higher fiber practice, there are few interactions between dietary intake through an increase in fruit and vegetable con- recommendation and statin use The most relevant sumption together with nuts. Detailed analysis of the one is the pharmacokinetic changes with statins metab- effect of this diet on risk factors and cardiovascular risk is olized by the cytochrome P450 with grapefruit juice.
beyond the scope of this manuscript. However, it is of Concomitant consumption of certain foods can lead to interest to mention the cumulative analysis among eight a modest reduction (in the case of fibers) or a slight cohorts (514 816 study participants and 33 576 deaths) increase (n À 3 fatty acids, phytosterols) of the statins’ evaluating overall mortality in relation to adherence to a Mediterranean diet. It showed that a two-point increasein the adherence score was significantly associated with areduced risk of mortality (pooled relative risk 0.91, 95% CI 0.89–0.94). Likewise, this analysis showed a beneficial role for greater adherence to a Mediterranean diet on Both eicospentenoic and docohexenoic acids, the marine cardiovascular mortality (pooled relative risk 0.91, 95% omega-3 polyunsaturated fatty acids have been exten- CI 0.87–0.95). Another systematic review was made with sively studied to assess their role in prevention of CVD.
35 different intervention studies The Mediterra- These studies were stimulated by early observation that nean diet showed favorable effects on lipoprotein levels, the Greenland Inuit population had low risk of CHD.
endothelium vasodilatation, insulin resistance, metabolic These products have pleiotropic effects on the cardio- syndrome, antioxidant capacity, myocardial and cardio- vascular system with little if any risk of adverse events vascular mortality. The Mediterranean diet has also favorable effects on obesity and type 2 diabetes. Bothepidemiological and interventional studies have revealed Meta-analyses of randomized controlled studies failed to a protective effect of the Mediterranean diet against mild achieve a straightforward conclusion regarding the effect chronic inflammation and its metabolic complications on reduction of events possibly due to quality hetero- As a consequence, this popular way of explaining geneity in studies included. The most recent one to the patient what a healthy diet might be is an attractive included 29 trials with 35 144 subjects. It showed that tool in current practice. A difficult question is whether omega-3 fatty acid intake was not associated with a this diet should include more omega-6 fatty acid (confer statistically significant decrease of mortality (RR 0.88; paragraph on step 1 and step 2 diet) or be more ‘olive 95% CI 0.64–1.03) in high-risk patients There is, however, strong indication for a reduction in coronaryevents and sudden coronary death mostly in secondaryprevention The impact of omega-3 fatty acid in primary prevention remains to be established although a As shown above, the goal of reducing cholesterol and reduction of event was observed in the JELIS trial improving risk factors in hypercholesterolemic patients Altogether, these data do not support wide utilization of can be reached through improvement, even subtle, of high-dose omega-3 food supplement to prevent cardio- food habits. However, patients’ adherence and compli- ance to dietetic prescription are essential to ‘make itwork’ but difficult to obtain. To improve adherence, In this context, a large randomized placebo-controlled physicians should identify possible barriers and seek study tested the effect of 400 mg of eicospentenoic and for adequate levers to overcome these barriers. Several docohexenoic acids or 2 g of alpha linolenic fatty acid or barriers to adherence have been identified among which: both in 4837 patients who had a myocardial infarction Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Lowering LDL-cholesterol through diet Bruckert and Rosenbaum The study failed to achieve a significant reduction Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths fromcoronary disease, 1980–2000. N Engl J Med 2007; 356:2388–2398.
in the primary event. Importantly, this recent study Czernichow S, Thomas D, Bruckert E. n À 6 fatty acids and cardiovascular included patients with the state-of-the-heart treatment health: a review of the evidence for dietary intake recommendations. Br J Nutr of their medical condition. This well conducted and A recent review discussing the pleiotropic effect of omega-6 fatty acids and their recent study does not support wide utilization of low- potential impact on cardiovascular disease. The review discusses what could be dose supplement to prevent cardiovascular events in the ideal level of omega-6 in the diet.
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10 Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review Unlike food supplement, such intake usually replaces and meta-analysis of randomized controlled trials. PLoS Med 2010; meat consumption and is associated with a reduction in This is the most recent meta-analysis showing an interesting consistency between randomized controlled trials and observational studies for the impact of differentfatty acids on cardiovascular disease.
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with other changes in lifestyle such as smoking cessation, 14 Sola` R, Bruckert E, Valls RM, et al. Soluble fiber (Plantago ovata husk) increased physical activity and weight loss when appro- reduces plasma low-density lipoprotein (LDL) cholesterol, triglycerides, in-sulin, oxidised LDL and systolic blood pressure in hypercholesterolaemic priate. In practice, the recommendations provided by patients: a randomised trial. Atherosclerosis 2010; 211:630 –637.
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D.R. declared the following conflict of interest: travelling grants and This is one of the most recent meta-analysis on the effect of plant sterol and stanol payment of registration fees from Daichii-Sankyo, Menarini, Novartis, on lipid parameters. It shows that there are no differences between stanol and Sanofi-Aventis, and lecture fees from Diadexus, Ipsen and MSD.
E.B. declared the following conflict of interest: fees for presentations 19 Sabate´ J, Oda K, Ros E. Nut consumption and blood lipid levels: a pooled and participation to boards: Merck, Pfizer, Astra Zeneca, Abott, analysis of 25 intervention trials. Arch Intern Med 2010; 170:821 –827.
This is a well updated review on the effect of nuts on lipid parameters.
California Almond Board, Unilever, Danone, Sanofi-Avantis, MSD,Shering Plough, Genfit, AMT and NovoNordisk.
20 Banel DK, Hu FB. Effects of walnut consumption on blood lipids and other cardiovascular risk factors: a meta-analysis and systematic review. Am J ClinNutr 2009; 90:56–63.
21 Anderson JW, Johnstone BM, Cook N. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995; 333:276 –282.
Papers of particular interest, published within the annual period of review, havebeen highlighted as: 22 Xiao CW. Health effects of soy protein and isoflavones in humans. J Nutr 23 Taku K, Umegaki K, Sato Y, et al. Soy isoflavones lower serum total and LDL Additional references related to this topic can also be found in the Current cholesterol in humans: a meta-analysis of 11 randomized controlled trials. Am World Literature section in this issue (p. 64).
Law MR, Wald NJ, Thompson SG. By how much and how quickly does 24 Jenkins DJ, Kendall CW, Marchie A, et al. Effects of a dietary portfolio of reduction in serum cholesterol concentration lower risk of ischaemic heart cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, 25 Jenkins DJ, Kendall CW, Marchie A, et al. Direct comparison of a dietary low LDL, and protection against coronary heart disease. N Engl J Med 2006; portfolio of cholesterol-lowering foods with a statin in hypercholesterolemic participants. Am J Clin Nutr 2005; 81:380–387.
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26 Jenkins DJ, Kendall CW, Faulkner DA, et al. Assessment of the longer-term 32 Filion KB, El Khoury F, Bielinski M, et al. Omega-3 fatty acids in high-risk effects of a dietary portfolio of cholesterol-lowering foods in hypercholester- cardiovascular patients: a meta-analysis of randomized controlled trials. BMC olemia. Am J Clin Nutr 2006; 83:582–591.
This is a recent meta-analysis in at-risk patients.
27 Sofi F, Cesari F, Abbate R, et al. Adherence to Mediterranean diet and health status: meta-analysis. BMJ 2008; 337:a1344.
33 Yokoyama M, Origasa H, Matsuzaki M, et al., Japan EPA Lipid Intervention 28 Giugliano D, Esposito K. Mediterranean diet and metabolic diseases. Curr Study (JELIS) Investigators. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a rando- 29 Esposito K, Ciotola M, Giugliano D. Mediterranean diet, endothelial function mised open-label, blinded endpoint analysis. Lancet 2007; 369:1090 – and vascular inflammatory markers. Public Health Nutr 2006; 9 (8A):1073– 30 Vaquero MP, Sa´nchez Muniz FJ, Jime´nez Redondo S, et al. Major diet-drug 34 Leo´n H, Shibata MC, Sivakumaran S, et al. Effect of fish oil on arrhythmias and interactions affecting the kinetic characteristics and hypolipidaemic proper- mortality: systematic review. BMJ 2008; 337:a2931.
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This is a comprehensive and updated review of possible interactions between food 35 Kromhout D, Giltay EJ, Geleijnse JM for the Alpha Omega Trial Group. n-3 fatty acids and cardiovascular events after myocardial infarction. New Engl J 31 Saravanan P, Davidson NC, Schmidt EB, Calder PC. Cardiovascular effects of marine omega-3 fatty acids. Lancet 2010; 376:540 –550.
This is the study that analyzed four groups of patients (placebo, 400 mg/day This is a well updated review on the effect of marine omega-3 fatty acids on the eicospentenoic and docohexenoic acids, 2 g/day alpha linolenic acid and both) cardiovascular system. The review assesses uncertainties about the efficacy on failed to achieve a significant reduction in the primary event. Importantly this trial top of a well conducted treatment including all drugs that were proven to be included patients with the state-of-the-heart treatment of their medical condition efficacious in reducing coronary events.
(postmyocardial infarction and risk factors).
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