Introduction
Cardiovascular diseases (CVD) remain the leading cause of mortality worldwide [
1], with atherosclerotic CVD (ASCVD) being the main cause of premature death in Europe and a major cause of disability and loss of productivity, with a huge global economic impact [
2].
Several risk factors are etiologic for ASCVD. Among the modifiable ones, elevated plasma low-density lipoprotein cholesterol (LDL-C) level is the most important [
3]. Many clinical trials have demonstrated that reducing LDL-C reduces risk for developing ASCVD and its clinical sequelae [
4]. In a meta-analysis of over 170,000 secondary prevention statin trial participants, the Cholesterol Treatment Trialists’ Collaboration showed that for every 1 mmol/L reduction of LDL-C (~ 40 mg/dL), cardiovascular (CV) events are reduced by approximately 20% [
5]. Hence, it has been estimated that every 1% reduction of LDL-C levels corresponds to a 1% reduction in CV events.
Currently, according to the severity of dyslipidemia and CV risk, treatment is based on lifestyle changes in dietary habits and physical activity coupled with pharmacological therapy [
6]. Lifestyle treatment for hypercholesterolemia includes an energy-balanced Mediterranean diet, low in saturated fat (< 7% of total energy), moderate or higher intensity physical activity (≥ 150 min/week), and weight loss (5–10% of body weight) for those who are overweight or obese. Exposure to active or passive tobacco smoking must be also avoided [
7]. LDL-C reductions with lifestyle improvements are usually in the range of 5 to 15%. If these reductions are maintained over a long period, this can result in meaningful CVD risk reduction [
9••]. For patients with hypertriglyceridemia, lifestyle interventions, including weight loss if overweight or obese (initially targeting loss of 5–10% of body weight in order to relieve insulin resistance), physical activity (≥ 150 min/week of moderate or higher intensity activity), and restriction of alcohol, simple sugars, or refined carbohydrate intakes, can help reduce triglyceride (TG) levels [
8].
Given the relatively small effect of lifestyle on improving cholesterol levels, the low level of adherence of patients to lifestyle changes long-term, and the need to reach low plasma LDL-C levels, there is a growing interest in natural compounds able to safely improve lipid patterns [
9••]. A number of lipid-lowering nutraceuticals have been identified and clinically tested; however, their efficacy and tolerability are variable. In this context, we review the efficacy and safety of the most studied lipid-modifying nutraceuticals and their association in order to drive their prescription towards the most evidence-based one.
According to their mechanism of action, lipid-lowering nutraceuticals can be classified into (i) inhibitors of intestinal cholesterol absorption, (ii) inhibitors of hepatic cholesterol synthesis, and (iii) enhancers of LDL-C excretion. In addition, there are many functional food/nutritional supplements with multiple or unclear mechanisms of action.
The effects of the most evidence-based cholesterol-lowering agents are summarized in Table
1.
See Table in link.
Inhibitors of Intestinal Cholesterol Absorption
Plant Sterols and Stanols
Plant sterols, present in almost all vegetable sources (in particular in vegetable oils, nuts, seeds, legumes, and fat spreads), are structurally similar to cholesterol. Plant sources contain also plant stanols. PS (plant sterols + stanols) average daily intake in a common diet is usually less than 500 mg [
10].
The main mechanism by which PS reduce LDL-C level is the decrease of intestinal absorption of exogenous cholesterol micelles in the gastrointestinal lumen interacting with the brush border membrane and substrate of the Niemann-Pick C1-Like 1 (NPC1L1) transporter [
11].
A large meta-analysis of 124 studies (201 strata) concluded that the PS are safe and that their LDL cholesterol-lowering effect continues to increase up to intakes of approximately 3 g/day with an average LDL-C reduction of 12% [
12]. Moreover, PS could have some impact also on TG but only in patients with high TG levels at baseline [
13]. A further meta-analysis of 15 randomized clinical trials (RCTs) involving a total of 500 participants showed that stanol- or sterol-enriched diets in combination with statins, compared with statins alone, produced significant reductions in LDL-C of 0.30 mmol/L [95% confidence interval (CI) − 0.35 to − 0.25], but no change in high-density lipoprotein cholesterol (HDL-C) or TG [
14].
Soluble Fibers
Dietary fiber is a term commonly used for a variety of substances of vegetable origin resistant to enzymatic digestion in the gastrointestinal tract. Some studies demonstrated the lipid-lowering properties of soluble fibers, including pectin, guar gum, mucilages, oats, and psyllium [
15•]. The lipid-lowering mechanisms of action of soluble fibers are different, including prolonged gastric emptying time, an increase of satiety, the inhibition of hepatic cholesterol synthesis, and an increase of fecal excretion of cholesterol and bile salts [
16]. The reduction of cholesterolemia obtained by soluble fibers is variable and dependent on the type of fiber, doses, subjects treated, study size, and different diets: 3 g soluble fiber from oats (3 servings of oatmeal, 28 g each) can decrease LDL cholesterol by approximately 0.13 mmol/L [
16]. However, the effect could be larger for oat-based fibers, psyllium, and glucomannan [
16].
β-Glucan
International guidelines for the management of dyslipidaemia suggest the consumption of 5–15 g/day (European guidelines) or 10–25 g/day (US guidelines) of soluble fibers derived from oats, rich in β-glucan to reduce blood cholesterol [
17,
18]. β-Glucan is a soluble fiber derived from the walls of different plant cells, bacteria, algae, fungi, and yeasts. β-Glucan has high viscosity, which confers lipid-lowering action. A meta-analysis of 17 RCTs with 916 patients showed that β-glucan consumption in hypercholesterolemic patients significantly reduced LDL-C (− 0.21 mmol/L [8.1 mg/dL] (95% CI: 0.27; − 0.14),
p < 0.00001). However, there were no significant differences in HDL-C and TG [
19]. In a recent trial, the addition of oat fibers to a Mediterranean diet induced an LDL-C reduction of 15.1% (95% CI: − 17.8 to − 5.9) [
20]. In 2010, the European Food Safety Authority (EFSA) confirmed that oat β-glucan is able to reduce plasma cholesterol levels; however, at least 3 g/day of β-glucan is necessary [
21].