Dietary management of dyslipidaemias. Is there any evidence for cardiovascular benefit?

Maturitas 108 (2018) 45–52

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Review

Dietary management of dyslipidaemias. Is there any evidence for cardiovascular benefit?

T

⁎

Panagiotis Anagnostisa, , Stavroula A. Paschoub, Dimitrios G. Goulisa, Vasilios G. Athyrosc, Asterios Karagiannisc a

Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Greece Division of Endocrinology and Diabetes, “Aghia Sophia” Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece c Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece b

A R T I C L E I N F O

A B S T R A C T

Keywords: Dyslipidaemia Hypercholesterolaemia Hypertriglyceridaemia Mediterranean diet Sterols Red yeast rice

Specific dietary strategies are the mainstay of management in most cases of dyslipidaemia, prior to or simultaneously with the initiation of a lipid-lowering agent. The exact approach differs according to the type of dyslipidaemia. In particular, a reduction in carbohydrates (mainly foods with a high glycaemic index) and their substitution with mono- and polyunsaturated fatty acids is the main strategy in patients with high levels of triglycerides (Tg) and/or low levels of high-density lipoprotein cholesterol (HDL-c). A reduction in saturated and trans fatty acids, combined with an increased intake of specific dietary components, such as plant sterols, soy protein and red yeast rice, constitutes the more efficacious dietary approach in cases where levels of total cholesterol and low-density lipoprotein cholesterol (LDL-c) are elevated. A reduction in excessive body weight is beneficial in every type of dyslipidaemia, whereas increased physical activity is mostly effective in cases with low HDL-c and high Tg levels. With respect to the potential cardiovascular benefit of these dietary interventions, there is currently evidence for the Mediterranean diet. Potential benefit may derive also from single dietary components of that diet, such as legumes, fruits, vegetables, nuts and omega-3 fatty acids, although to a lesser extent than with that general dietary pattern. The purpose of this review is to outline current knowledge regarding the recommended specific dietary pattern according to the type of dyslipidaemia and the evidence for the potential cardiovascular benefits of such approaches.

1. Introduction Dyslipidaemia is a well-established and prominent cause of cardiovascular morbidity and mortality worldwide [1–3]. This term is used to describe a composite of disorders in lipid metabolism, including high concentrations of low-density lipoprotein cholesterol (LDL-c) and/or triglycerides (Tg) and/or low concentrations of high-density lipoprotein cholesterol (HDL-c), either as mixed or pure disorders. Dyslipidaemias are generally classified into primary and secondary disorders. Primary dyslipidemias are mainly genetically determined and are further subdivided into hyperchylomicroneamia, familial hypercholesterolaemia (FH), mixed hyperlipidaemia, familial hypertriglyceridaemia and familial reduction in HDL-c levels [2]. A dyslipidaemia is characterized as “secondary”, when a specific disease [such as diabetes mellitus (DM), hypothyroidism, Cushing’s syndrome, acromegaly, chronic kidney disease (CKD) or nephrotic syndrome, human immunodeficiency virus (HIV) infection, cirrhosis and alcohol abuse] or drug (such as estrogen

and oral contraceptives, androgen, tamoxifene, progestagen, corticosteroids, cyclosporine, β-blockers, thiazide diuretics) is implicated in its pathogenesis [1–3]. Except for the cases of elevated Tg (> 500 mg/dl), the main target should be LDL-c. This target is set after categorizing the patient according to his/her 10-year risk of cardiovascular death, according to the recent European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) guidelines for the management of dyslipidaemias [1] and national societies, such as the Hellenic Atherosclerosis Society [2]. In “low” (when the calculated SCORE is < 1% for 10-year risk of fatal CVD) and “moderate risk” (when the SCORE is ≥1% and < 5%) individuals, the LDL-c goal is < 115 mg/dl. In “high risk” patients [when the calculated SCORE is ≥5% and < 10% or single risk factors are markedly elevated, such as in FH or CKD] the LDL-c target is < 100 mg/dl, whereas an LDL-c goal < 70 mg/dl is recommended for very high risk patients, such as those with established coronary heart disease (CHD) or CHD equivalents, such as type 2 DM

⁎ Corresponding author at: Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki Sarantaporou 10, 54640, Thessaloniki, Greece. E-mail address: [email protected] (P. Anagnostis).

https://doi.org/10.1016/j.maturitas.2017.11.011 Received 29 October 2017; Received in revised form 9 November 2017; Accepted 13 November 2017 0378-5122/ © 2017 Elsevier B.V. All rights reserved.

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Afterwards, the patient’s lipid profile should be categorized according to the classification used for primary dyslipidaemias, as described before. General and well-balanced rules include a reduction of initial body weight by 5–10% (in overweight and obese patients) with a comprehensive lifestyle intervention, which leads to amelioration in most of CVD risk factors [5]. According to expert guidelines, this is achieved generally by adopting an energy deficit of 500–750 kcal/d or 30% of daily calorie intake (which is usually translated to 1200 to 1500 kcal/d for women and 1500 to 1800 kcal/d for men) [5]. After the maximum weight loss is achieved at six months, this is usually followed by a plateau and gradual regain over time. To avoid this phenomenon, further strategies, such as frequent self-weighing, consumption of a reduced calorie diet and physical activity of at least 200 min/week are suggested [5]. Various dietary patterns have been proposed for weight loss. Debate still exists with regard to the most efficacious strategy on weight loss, comparing low fat (LF) with low carbohydrate (LC) diets. Many studies have been published on this concept retrieving conflicting results. A recent meta-analysis of randomized-controlled trials (RCTs) showed that LC diets lead to a greater reduction in body weight [weighted mean difference (WMD): −2.17 kg; 95% Confidence Interval (CI): −3.36, −0.99] compared with LF diets [6]. However, two older meta-analyses of RCTs showed that the preponderance in body weight by LC diets was evident only at six months (WMD: −3.3 kg; 95% CI: −5.3–−1.4 kg) [7] and −4.02 (95% CI: −4.54–−3.49) kg [8]. LC was equally effective with LF diet after one year (WMD: −1.05 kg; 95% CI: −2.09–−0.01 kg) [8] and −1.0 kg; 95% CI: −3.5–1.5 kg) [7]. Another general rule is to reduce saturated fat acids (SFA) to < 10% of daily calorie consumption and to avoid trans-fatty acids (TFA). Reduction of SFA intake is associated with a reduction in CVD events by 17% [risk ratio (RR): 0.83; 95% CI: 0.72, 0.96], including mainly the risk of fatal and non-fatal myocardial infarction (MI) (RR: 0.90; 95% CI: 0.80, 1.01), but without effect on all-cause or CVD mortality. Notably, this benefit is evident when SFA are substituted by poly-unsaturated (PUFA) [9]. Mono-unsaturated fatty acids (MUFA) and PUFA should constitute at least 10% of daily energy intake. Furthermore, cholesterol intake should be restricted to < 300 mg/d [1–3]. TFA are unsaturated fatty acids, the structure of which is characterized by the presence of at least one unsaturated, non-conjugated double bond located in the trans (rather than the usual cis) configuration [10]. They are found in foods containing hydrogenated oils, such as baked goods, snacks (potato, corn and tortilla chips), fried foods, creamer and margarine. TFA seem to adversely affect cardiovascular health, via their detrimental effect on lipid profile, insulin sensitivity, systemic inflammation and endothelial dysfunction [10]. If TFA are preferred instead of carbohydrates or SFA, this leads to a 24% and 20% higher risk for MI and CHD death, respectively, for every 2% of isocalorically daily intake [10]. This CVD risk is stronger with trans-18:1 (produced by light hydrogenation or deodorization) isomers than trans16:1 isomers and with industrial TFA, compared with ruminant ones [10,11]. It is recommended that TFA should not exceed 1% of total calorie intake [1–3]. Higher TFA intake (≥1% of energy) is associated with both increased CHD (HR: 1.28, 95% CI: 1.09–1.50) and all-cause mortality (HR: 1.34, 95% CI: 1.16–1.56) [11]. Carbohydrates [1–3] should account for 45–50% of the total calorie intake, mainly deriving from whole grain food (25–40 g/d, including at least 7–13 g of soluble fibre) [1–3]. Smoking cessation and modest alcohol consumption (two units/d for men and one unit/d for women) are also encouraged, as a part of a lifestyle intervention to reduce CVD risk [1–3].

(T2DM) [1,2]. Recent guidelines released by the American Association of Clinical Endocrinologists (AACE) identify an additional CVD risk category, termed “extreme risk”, which includes those with progressive atherosclerotic CVD (unstable angina in patients after achieving an LDL-c < 70 mg/dl), premature CVD (males < 55 yrs, females < 65 yrs) or established CVD in patients with DM, CKD or heterogyzous FH. The LDL-c target for this category is < 55 mg/dl [3]. Additional target, especially in high-risk patients, is non-HDL-c levels. The calculation formula for the latter is by adding 30 mg/dl to the LDL-c target [1–3]. The approach to the patient’s CVD risk according to a specific LDL-c target has been adopted by most scientific societies. On the contrary, the American College of Cardiology/American Heart Association (ACC/ AHA) guidelines propose a ≥50% reduction in LDL-c in high CVD risk patients (recommending high-intensity statin therapy) or a 30–50% reduction in LDL-c in those with moderate CVD risk (recommending moderate-intensity statins) [4]. This approach could significantly expand the number of patients receiving statins if implemented in the European population (nearly all men and two-thirds of women older than 65 years) [5]. It also leads to suboptimal treatment of patients in specific categories, such as those with FH [4]. Epidemiological evidence shows improvement in total cholesterol (TC) and LDL-c concentrations in the general population, mainly due to the increased use of lipid-lowering agents (statins). However, there still remains a significant proportion with lipid profile above targets, mainly attributed to the dietary pattern [3]. Although total CVD risk reduction should be individualized, lifestyle intervention remains the first-line approach, before initiation of lipid-lowering treatment in all risk categories, except for very high risk patients with LDL-c concentrations > 70 mg/dl [2]. It is also the most cost-effective option for CVD risk reduction [3]. However, a general dietary pattern does not fit all categories of dyslipidemias and, thus, a tailored approach is suggested. Except for the well-recognized benefits of the Mediterranean diet and its individual components, there is also evidence for specific functional foods, such as plant sterols or stanols. What is of outmost importance, is whether these approaches confer an independent benefit on CVD risk reduction [1,2]. The purpose of this narrative review was to provide current knowledge regarding the dietary approach and management according to the type of dyslipidaemia and, more remarkably, the existing evidence for cardiovascular benefit of each approach. 2. Methods We searched PubMed for English language publications until September 2017, under the following terms: “diet” OR “dietary” AND (“dyslipidaemia” OR “dyslipidaemias” OR “hyperlipidaemia” OR “hyperlipidaemias” “hypercholesterolaemia” OR “hypertriglyceridaemia” OR ““dyslipidemia” OR “dyslipidemias” OR “hyperlipidemia” OR “hyperlipidemias” “hypercholesterolemia” OR “hypertriglyceridemia”] AND (“cardiovascular disease” OR “cardiovascular death” OR “cardiovascular events” OR “cardiovascular mortality” OR “cardiovascular morbidity”). Additionally, we included references from the reviewed articles in order to widen our search. On the top, a manual search of key journals and abstracts from the major annual meetings in the field of Endocrinology and Lipidiology was conducted. Special attention was paid to guidelines or original papers focusing on the management of patients with dyslipidaemias. This review collected, analyzed and qualitatively re-synthesized information regarding: (1) the classification of dyslipidaemias, (2) the general dietary approach (3) the dietary management according to the type of dyslipidaemia, (4) the cardiovascular benefit of the Mediterranean diet and its components separately.

4. Dietary management according to the type of dyslipidaemia

3. General dietary approach to the patient with dyslipidaemia

4.1. Hypertriglyceridaemia

The first step is to exclude secondary causes of dyslipidaemias.

High Tg concentrations have been independently associated with 46

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may be more beneficial in patients with T2DM [26]. The third effective strategy in the management of hypertriglyceridaemia is the increased daily intake of omega-3 FA [eicosapentaenoic (EPA) and docosahexaenoic (DHA)], which are mainly found in fish oils and nuts, and, more importantly, the substitution on SFA by MUFA and PUFA [1–3,14]. The main underlying mechanisms for their actions are: reduced synthesis of very-low density lipoprotein (VLDL) in the liver, since they constitute inadequate substrates for Tg synthesis, increase in phospholipoid levels, inhibition of esterification of other fatty acids and increased β-oxidation in the liver. Furthermore, omega-3 FA inhibit calcium and sodium cation entry into myocardial cells, which is responsible for their anti-arrhythmic effect [27]. Daily intake of 3–4 g of omega-3 FA (either as fish oil supplements or prescription ethyl esters) reduces serum Tg by 20–50%, depending on baseline concentrations [27]. A systematic review showed a mean reduction in Tg levels by 22.4% with DHA compared with 15.6% with EPA. DHA also increases HDL-c to greater extent than EPA (7.3% versus 1.4% respectively), but also LDL-c (2.6% versus −0.7%, respectively [28]. The higher the baseline LDL-c levels, the greater the increase with omega-3-FA [28].

CVD in population-based prospective cohort studies, as well as intervention trials, although this association is less robust compared with the one observed between TC or LDL-c and CVD (mainly CHD) mortality [12,13]. The main strategies to reduce high Tg-rich lipoprotein concentrations are the reduction of excessive weight, alcohol consumption and total amount of dietary carbohydrates, especially the proportion of mono- and disaccharides. It is also recommended to increase consumption of omega-3 fatty acids (FA), to substitute SFA with MUFA and PUFA and to increase physical activity (at least 30 min, ≥5 d/week) [1–3,14]. In general, total daily fat is recommended to comprise the 25–35% of daily energy intake in cases of borderline and 30–35% of cases of high and very high Tg concentrations, with SFA limited to 7% and 5%, respectively. In all cases of hypertriglyceridaemia, MUFA and PUFA intake is advised to be at 10–20% of daily calorie intake [14]. According to the AHA, a weight loss of up to 5% is recommended for borderline hypertriglyceridaemia (defined as non-fasting Tg concentrations of 150–199 mg/dl), whereas a weight loss of 5–10% would be more beneficial for high (200–499 mg/dl) or very high (> 500 mg/ dl) Tg levels [14]. A weight loss of 5–10% is adequate to cause a 20% reduction in Tg [15]. It is also estimated that with a 3-kg loss of body weight, the weighted mean reduction in Tg is estimated at ∼15 mg/dl [5]. The dietary pattern of choice for reducing Tg levels is LC diet, which seems to be more efficacious than LF in weight loss at six months (but not at 12 months), as mentioned above. Meta-analyses of RCTs have shown a greater reduction in Tg with LC compared with LF diet (WMD: −22.1 mg/dl; 95% CI: −32.7, −0.13.3), but a greater increase in LDLc concentrations (WMD: 6.18 mg/dl; 95% CI: 0.11, 12.8) [7,8]. In this regard, the Mediterranean dietary pattern [which is low in SFA (8%) and enriched in MUFA (12%) and PUFA (8%), as well as, in dietary fiber] predominates in reducing Tg, compared with LF diets [such as the Dietary Approaches to Stop Hypertension (DASH) diet, which is also high in dietary fiber ( > 30 g/d) and provides 27% of calories from total fat] [14,16,17]. Carbohydrates should constitute the 50–55% and 45–50% of total daily energy intake in cases of high (200–499 mg/dl) and very high ( > 500 mg/dl) Tg concentrations. The proportion of added sugars should be restricted to 5–10% and 10% and the protein intake should be increased to 15–20% and 20%, respectively [14]. Daily fructose consumption should also be restricted to < 100 g in cases of borderline hypertriglyceridaemia, to 50–100 g and < 50 g in cases of high and very high Tg concentrations, respectively, as defined above [14,18]. A meta-analysis has shown that a daily intake of up to 90 g of fructose is beneficial in reducing HbA1c, with no significant changes in body weight. Moreover, daily intakes of ≤50 g and ≤100 g are safe for postprandial and fasting Tg levels, respectively. Higher intakes increase Tg in a dose-dependent manner, especially if sucrose or starch are replaced by fructose [19]. Fructose, despite its low glycaemic index (GI), has detrimental effect on insulin sensitivity, if it is consumed in high amounts, whereas it is beneficial in modest daily intakes [20,21]. Low GI diets, especially with daily carbohydrate restriction to 45–50% of energy intake are more efficacious on lowering Tg (without any effect on TC) levels, compared with conventional diets (55–60% of energy from carbohydrates and energy restriction to 250–500 kcal/d) [22,23]. They may be also beneficial on other CVD risk factors, such as plasminogen activator inhibitor-1 (PAI-1) concentrations [20]. However, whether the effect of low GI on maintenance of weight loss after 12 months is greater than that of high GI remains controversial [22,23]. A very recent Cochrane meta-analysis of 21 RCTs (n = 2538 participants) assessed the effect of implementation of GI diet on total and CVD mortality, CVD events and cardiovascular risk factors. No effect of GI was found on all these parameters [24]. In general, whole grain intake is encouraged, although another recent meta-analysis did not show significant reduction in Tg concentrations (in contrast to TC and LDL-c) compared with non-whole grain consumption (WMD: −3.54 mg/dl; 95% CI: −7.08, 0.88; p = 0.10) [25]. However, this dietary approach

4.2. Hypercholesterolaemia Except for the cases of high (such as those with FH) and very high CVD risk (with baseline LDL-c levels of ≥100 mg/dl and ≥70 mg/dl, respectively, in which a combination with statin is recommended), lifestyle intervention is recommended as the first-line approach in all other cases with increased TC and LDL-c levels, prior to lipid-lowering therapy. The dietary strategy includes primarily the reduction in SFA and TFA and, secondarily, reduction in body weight and increased consumption of dietary fibre and supplementary food compounds, such as phytosterols and red rice, and, to a lesser extent, increase in physical activity [1–3]. As mentioned above, daily TFA intake should not exceed 1% of total energy intake [1–3]. Of note, TFA from natural sources up to 4.19% of daily intake do not seem to have any effect on plasma lipids [29]. Notably, not all SFA are atherogenic, in terms of TC and LDL-c increase. Stearic acid in contrast to other SFA (such as myristic and palmitic fatty acids) and TFA, reduces LDL-c [30]. Lauric acid increases TC, but mainly due to its dual effect on LDL-c and HDL-c. In general, replacement of TFA and SFA by cis-unsaturated fatty acids (but not carbohydrates) confers the most cardioprotective effect, since it effectively reduces TC/HDL-c ratio [30,31]. It has been estimated that 1% energy replacement of TFA with SFA, MUFA or PUFA, is translated to a decrease in TC/HDL-c ratio by 0.31, 0.54 and 0.67, respectively [31]. However, whether intake of SFA is associated with increased CVD risk is a matter of debate, since meta-analyses have yielded conflicting results [9,32] (Table 1). A weight loss of 5–10% is adequate to cause approximately a 15% reduction in LDL-c concentrations [15]. It is estimated that for 10 kg weight loss, a reduction of 8.9 mg/dl may be achieved in obese and overweight subjects [33]. Moreover, increased consumption of wholegrain foods, especially when comprising oat, is also efficacious [1]. A recent meta-analysis of RCTs showed a WMD of −4.64 mg/dl (95% CI: −7.34, −1.93) in TC and −3.48 mg/dl (95% CI: −5.8, −1.16) in LDLc by whole-grain compared with non-whole grain diets [25]. An older meta-analysis showed a decrease in TC by −1.74 mg/dl (95% CI: −2.088, −1.35)] and in LDL-c levels by −2.2 mg/dl (95% CI: −2.70, −1.70) per g of soluble fiber, regardless of the dietary sourse (oat, psyllium or pectin) [34]. Larger reductions may be observed in subjects with higher baseline TC levels (≥228 mg/dl, especially with ≥3 g of soluble fiber per day) [35]. In a similar way, increased daily intake of soy isoflavones significantly decreases serum TC and LDL-c. In particular, compared with isoflavone-depleted soy protein, isoflavone enriched soy protein causes a greater decrease in TC by 3.86 mg/dl (−1.77%) and LDL-c by 5 mg/dl (−3.58%), an effect that is evident only in hypercholesterolaemic, but not in normocholesterolaemic, subjects [36]. Another meta-analysis of RCTs, has shown greater 47

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4.3. Low HDL-C

Table 1 Lifestyle recommendations according to the type of dyslipidaemia.

The most effective strategy to increase HDL-c is the increase in physical activity and reduction in TFA intake. To a lesser extent, reduction in excessive body weight, substitution of dietary carbohydrate with PUFA, MUFA and SFA, as well as modest alcohol consumption, further contribute in HDL-c increase [1,10,44]. A 5–8 kg weight loss may increase HDL-c by 2–3 mg/dl [5]. Alternatively, a weight loss of 5–10% is adequate to cause an 8% to 10% increase in HDL-c [13]. A LC diet and the replacement of carbohydrates by unsaturated fat are associated with an increase in HDL-c concentrations by 7–12% [44]. LC exerts a greater effect on HDL-c levels than LF dietary pattern (WMD: 4.6 mg/dl, 95% CI 1.5, 8.1) [7]. Whole grain intake, plant sterols and red yeast rice do not have any effect on HDL-c concentrations [25,40,43]. Slight increases in HDL-c levels may be seen with soy protein (1.16 ± 0.38 mg/dl with 52 mg soy-associated isoflavones) [38] (Table 1).

Hypertriglyceridaemia 1. Loss of excessive body weight (5–10%) 2. Reduction of alcohol consumption 3. Reduction of the proportion of daily carbohydrate consumption (45–55%) 4. Reduction of the proportion of mono- and disaccharides consumption 5. Increase of omega-3 fatty acids consumption (3–4 g/d) 6. Increase of physical activity (at least 30 min, ≥5 days/week) 7. Substitution of saturated fat with mono- or polyunsaturated fat Hypercholesterolaemia 1. Reduction of the proportion of daily saturated fat ( < 10%) and trans fat ( < 1%) consumption 2. Loss of excessive body weight (5–10%) 3. Increase of dietary fibre (whole grain, oat) consumption 4. Increased intake of plant sterols or stanols (2–4 g/d) 5. Red yeast red rice supplements 6. Increase of physical activity (at least 30 min, ≥5 days/week) 7. Isoflavone enriched soy protein consumption Low HDL-c 1.Increase of physical activity (at least 30 min, ≥5 days/week) 2. Reduction of trans fat consumption ( < 1%) 3. Loss of excessive body weight (5–10%) 4. Reduction of dietary carbohydrate intake and their substitution with mono- or polyunsaturated fat 5. Modest alcohol consumption 6. Smoking cessation 7. Reduction of mono- and disaccharide consumption and substitution by lowglycemic index carbohydrates (high fibre, whole grain foods)

5. Evidence for possible cardiovascular benefit The crucial point with respect to the dietary management of dyslipidaemias is whether this is accompanied by a reduction in CVD risk. Data from existing studies have been sometimes conflicting. The sample size of many of them is small from an epidemiological point of view, while their duration is usually short for such clinical outcomes. There is also a difficulty in estimating the effect of single nutritional components compared with changes in overall dietary patterns [45,46]. Despite the above problems, evidence for a possible CVD benefit after dietary interventions indeed exists in the literature and will be discussed.

*Recommendations are listed according to the magnitude of the effect for each type of dyslipidaemia.

decreases in TC and LDL-c [-8.5 mg/dl (−3.77%) and 8.1 mg/dl (−5.25%), respectively] [37]. However, a dose-response relation between soy-associated isoflavones and changes in LDL-c cannot be supported [38]. Further effective strategy in reduction of TC and LDL-c concentrations is the consumption of specific food supplements, such as plant sterols (β-sitosterol, campesterol and stigmasterol) and red yeast rice. Sterols are cholesterol-like molecules derived from all plant foods and act by inhibiting intestinal cholesterol absorption. Stanols, including sitostanol and campestanol, are saturated sterols acting in a similar way and without difference with sterols regarding their magnitude of cholesterol reduction or whether they are consumed, either by enriched foods or tablets [39]. The effect on TC and LDL-c differs according to the dose, ranging from 4.9 and 6.7%, 5.9% and 8.5% and 6.8 and 9.9%, with 0.8, 1.6 and 3.24 g of plant sterols/d, respectively [40]. Cholesterol-lowering effects of phytosterols also differ according to the food matrix that contains them, being almost three times in low-fat meat (8.9% and 15.9% for TC and LDL-c, respectively) than in bread and cereal (6.5 and 5.4% reduction in LDL-c, respectively) [41]. According to the recent ESC/EAS guidelines, a daily consumption of ≥2 g of sterols is recommended in patients with hypercholesterolaemia at lowmoderate CVD risk, in those at high or very high CVD risk inadequately controlled or intolerant to statins and in adults and children with FH [1]. Red yeast rice contains a substance called monacolin K (lovastatin), which acts by inhibiting 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the pathway of cholesterol synthesis, in the same way as statins. It is found in many Chinese herbal products. Most studies have tested doses of 200–3600 mg/d (corresponding to 2–6.1 mg/d of lovastatin), which lead to reductions in LDL-c of 10–33% [42,43]. A meta-analysis showed a WMD of −37.5 mg/dl (95% CI: −43.69, −30.93) mg/dl in TC, of −33.64 mg/dl (95% CI: −39.82, −27.45) in LDL-c and of −20.37 mg/dl (95% CI: −27.45, −12.40) in Tg [43]. In patients with statin intolerance, the vast majority tolerates red yeast rice and more than half can achieve their LDL-c goals [42].

5.1. Mediterranean diet Μediterranean diet represents the traditional eating habit of populations bordering the Mediterranean Sea during the 1960s, mainly Greeks and Italians. The frequent and high consumption of plant-based foods is the main characteristic of this dietary pattern, while olive oil is the principal source of fat. Fish, dairy products and poultry follow, while consumption of red or processed meat is very low. Μediterranean diet is completed with moderate consumption of wine with meals and use of herbs and spices instead of salt [47]. The Prevención con Dieta Mediterránea (PREDIMED) trial [17] investigated the effect of Mediterranean diet on CVD events in patients with T2DM, without CVD at the time of enrollment. A total of 7447 individuals were enrolled to three of the following diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts and a LF diet. Participants were followed for a median of 4.8 years in total and there was a 30% reduction in the risk for CVD clinical events (acute MI, stroke or death from other cardiovascular causes) in the groups of patients assigned to Mediterranean diet with olive oil and nuts (HR: 0.70; 95% CI: 0.53, 0.91) and 0.70 (95% CI: 0.53, 0.91), respectively, compared with the LF group [17]. Another interventional trial, which followed newly-diagnosed patients with T2DM for eight years, revealed that the rate of regression in the intima-media thickness of the carotid artery was about 50% higher, while the rate of progression 50% lower in the group assigned to the Mediterranean diet (n = 108) as compared with a group of patients assigned to a low-fat diet (n = 107) [48]. The beneficial effects of the Mediterranean diet had already been implied by a previous population-based, prospective study, which followed 22,043 Greek adults for 44 months. High degree adherence to the traditional Mediterranean diet was associated with significant reduction in deaths due to CHD (adjusted HR: 0.67; 95% CI: 0.47, 0.94). Cancer-related and all-cause mortality were also reduced (adjusted HR: 0.76; 95% CI: 0.59, 0.98 and 0.75; 95% CI: 0.64, 0.87, respectively) [49]. The mechanisms by which Mediterranean diet exerts these cardiovascular benefits have not been fully elucidated yet. Of course, they 48

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analysis of 16 prospective cohort studies, including 833,234 participants in total, who were followed for 4.6–26 years, provided further strong evidence [65]. One serving per day of fruit and vegetables reduced the overall mortality by 6% and 5%, respectively. A significant inverse association was observed specifically for CVD mortality, with a decrease by 4% for each additional serving per day and a threshold of around five servings per day, after which, the risk did not reduce further [65]. The fact of this threshold, along with the non-significant differences in risk of mortality between vegetarians and non-vegetarians in another British study [66], highlights the importance of fruit and vegetable consumption as a part of an overall balanced healthy diet [48].

seem to be multifactorial both from a clinical and a pathophysiological point of view. From a clinical point of view, this diet pattern ameliorates a variety of risk factors that contribute in the manifestation of cardiovascular disease. Two RCTs in patients with metabolic syndrome (follow-up time of two to five years) resulted in possible reversal of the syndrome [16,50]. Various meta-analyses have also reported a better glycaemic control when the Mediterranean diet is adopted, as it is reflected by a reduction in HbA1c levels (by 0.30-0.47%) in patients with T2DM [51–55]. One of these meta-analyses [55] showed also that adherence to this dietary pattern can lead to body weight reduction, as well as, to a reduction in TC levels. Another large meta-analysis with 534,906 individuals in total from 50 studies, some of whom with T2DM, provided strong evidence that the Mediterranean diet exerts multiple contemporary beneficial metabolic effects, including decrease in waist circumference (by 0.42 cm), increase in HDL-c levels (by 1.17 mg/dl) and a decrease in Tg levels (by 6.14 mg/dl), systolic (by 2.35 mm Hg) and diastolic blood pressure (by 1.58 mm Hg) [55]. From a pathophysiological point of view, these benefits are considered to derive mostly by an improved balance between anti-inflammatory and anti-oxidative nutrients (vitamins, minerals, fibers and polyphenols) compared with pro-inflammatory nutrients (sugars, fatty acids, starches) [56]. A systematic review and meta-analysis, including 17 RCTs and 2300 adult subjects in total, provided evidence that the Mediterranean diet decreases circulating levels of inflammation markers, such as C-reactive protein (CRP), interleukin-6 and adhesion molecules [57]. Same findings have been reported in interventional trials including patients with metabolic syndrome or T2DM [58,59]. The anti-oxidant and anti-inflammatory effects of the Mediterranean diet could offer plausible explanations to the beneficial clinical findings, that are not only restricted in the field of CVD but are also expanded into a number of disorders associated with chronic inflammation, such as metabolic syndrome, obesity, diabetes, atherosclerosis, cancer, pulmonary diseases and cognitive problems [60]. If these antioxidant, anti-inflammatory and consequently clinical effects of the Mediterranean diet are the result of the overall dietary pattern or the sum of effects of individual nutritional components has been questioned in the literature. We will therefore comprehensively present data regarding specific isolated nutrients that have been considered as possible therapeutic tools for the management of dyslipidaemia and exert probable CVD benefits.

5.4. Nuts Nuts constitute a unique kind of food, very rich in unsaturated fatty acids, vitamins, phenols, fibers and minerals. Nut consumption has been associated with beneficial effects on multiple CVD risk factors, such as LDL-c [67], endothelial dysfunction [68], visceral adiposity [69], hyperglycaemia [70] and insulin resistance [71]. Furthermore, various meta-analyses have provided evidence that higher consumption of nuts is associated with reduced risk of CHD and hypertension [72–76]. A recent meta-analysis, including 354,933 participants, showed that one serving of nuts per week and per day may result in 7% and 39% decrease in CVD mortality, respectively, driven primarily by a decrease in CHD rather than stroke deaths [77]. Increased nut consumption is also associated with a decreased cancer mortality (by 14%, with no proven dose-effect), as well as, with a decreased all-cause mortality by 4% and 27% with one serving per week and one serving per day of nuts, respectively [77]. 5.5. Omega-3 FA A large systematic review and meta-analysis, focusing on evidence from RCTs and large prospective studies in humans, has provided evidence that modest consumption of fish (one to two servings per week), especially of species high in omega-3 FA content, reduces the risk of coronary death by 36%, as well as, total mortality by 17% in the general adult population [78]. An earlier RCT assessed the benefit of omega-3 FA supplementation on mortality in 11,323 survivals after a recent MI. One gram of omega-3 FA per day resulted in a significantly early decrease in mortality after three months of treatment (by 41%), while a similar significant pattern was shown after six to eight months of treatment specifically for CVD and CHD deaths [79]. Another randomized, double-blind, placebo-controlled trial in patients with heart failure proved that treatment with 1 g of n-3 FA per day can provide a small benefit in terms of mortality (decrease by 4.5%) and hospital admissions due to CVD reasons (decrease by 8%) [80]. During the same time period, 18,645 patients with dyslipidaemia were recruited in Japan and were randomly assigned to receive either 1800 mg of EPA daily with statin or statin alone [81]. They were followed for 4.6 years and it was shown that in patients with a history of CHD, the major coronary events were reduced by 19% in the group receiving EPA (vs 10.7% in the placebo group), whereas no difference was found in patients with no history of CHD. Sudden cardiac and coronary death did not differ between the two therapy groups [81]. The most recent double blinded trial, the ORIGIN (Outcome Reduction with an Initial Glargine Intervention) study, which randomly assigned 12,536 high CVD risk patients with dysglycaemia (impaired fasting glucose, impaired glucose tolerance or diabetes), did not show any significant reduction in the rate of CVD events after daily supplementation with 1 g of omega-3 FA compared with placebo [82].

5.2. Legumes Strong evidence regarding the beneficial effects of legume consumption on cardiovascular health has derived from the NHANES I (First National Health and Nutrition Examination Survey) Epidemiologic Follow-up Study, conducted in the USA [61]. A total of 9632 men and women, free of CVD at the time of enrollment, were prospectively followed for 19 years. Frequency of legume intake was estimated using a 3-month questionnaire, while the incidence of CVD events was obtained from medical records and death certificates. Legume consumption for four times or more per week was associated with a reduction by 22% of the risk for CHD and by 11% for CVD in total, as compared with legume consumption less than once a week [61]. 5.3. Fruits and vegetables Growing evidence from epidemiological studies over the past decades has shown that fruit and vegetable consumption is related to lower mortality, including mortality from CVD [48,62–64]. Data form the NHANES I Epidemiologic Follow-up Study cohort very early showed an inverse association of fruit and vegetable intake (≥3 times per day compared with < 1 time per day) with the risk of CVD (27% lower stroke incidence, 42% lower stroke mortality, 24% lower ischemic heart disease mortality, 27% lower CVD mortality) and all-cause mortality (15% lower) in the general US population [62]. A recent meta-

5.6. Red yeast rice Red yeast rice does not represent a traditional element of the 49

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Mediterranean diet, but it is usually met as a part of the dietary patterns followed by Asian people, for whom data regarding the efficacy of lipidlowering therapies in the reduction of CVD rates are rather missing in the literature. An important multicenter study investigated the effects of Xuezhikang, a partially purified extract of the red yeast rice, in 5000 Chinese patients who experienced a previous MI and were randomly assigned either to placebo or Xuezhikang daily for an average of 4.5 years. Treatment with Xuezhikang not only improved lipid profile, but it also significantly decreased the risk for non-fatal MI and death from CHD by 45%, as well as CVD and total mortality by 30% and 33%, respectively [83]. A systematic review including data from 22 RCTs indicated also a beneficial effect of Xuezhikang on the incidence of allcause deaths, CHD deaths and MI [84].

[3]

[4]

[5]

[6]

6. Conclusions

[7]

Dietary strategies are the mainstay in the management of dyslipidaemias. This approach differs according to the type of dyslipidaemia. In general, LC (low GI) diets are beneficial in reducing TG and increasing HDL-c, whereas diets low in SFA and TFA are more beneficial in cases of high TC and LDL-c levels. Reduction in excessive body weight is beneficial in every type of dyslipidaemia. Increased physical activity is beneficial for low HDL-c and high Tg levels. Specific dietary compounds, such as plant sterols and red yeast rice are suggested for cases of hypercholesterolaemia. With respect to the potential CVD benefit by dietary interventions, we should note that during the last few decades nutritional scientists have generally shifted their interest from isolated nutrients to diet patterns as a whole. This is very obvious indeed in the 2015–2020 Dietary Guidelines for Americans, where the importance of overall healthy eating diets is highlighted [85]. CVD is the result of multiple and various risk factors, including excessive body weight, lipoprotein concentrations and function, blood pressure, glucose metabolism, insulin homeostasis, inflammation, oxidative stress and endothelial dysregulation [45,86]. Therefore, a possible CVD benefit could not derive from focusing on single components of foods. The combination of healthy nutrients in habitually followed dietary patterns can produce synergistic effects that are very important for cardiovascular health.

[8]

[9]

[10] [11]

[12]

[13]

[14]

[15]

Contributors

[16]

Panagiotis Anagnostis designed the study, searched the literature, extracted and analyzed the data and wrote the first draft of the paper. Stavroula A. Paschou searched the literature, extracted and analyzed the data and wrote the first draft of the paper. Dimitrios G. Goulis, Vasilios G. Athyros and Asterios Karagiannis reviewed the manuscript and provided critical scientific input.

[17]

[18]

[19]

Conflict of interest [20]

The authors declare that they have no conflict of interest.

[21]

Funding

[22]

No funding was received for the writing of this narrative review.

[23]

Provenance and peer review This article has undergone peer review.

[24]

References

[25]

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