Current Atherosclerosis Reports (2021) 23: 68

https://doi.org/10.1007/s11883-021-00964-x

CARDIOVASCULAR DISEASE AND STROKE (J. A. UNDERBERG AND J. NEWMAN,

SECTION EDITORS)

Phytosterols and Cardiovascular Disease

Umidakhon Makhmudova1 · P. Christian Schulze1 · Dieter Lütjohann2 · Oliver Weingärtner1

Accepted: 27 July 2021 / Published online: 1 September 2021

© The Author(s) 2021

Abstract
Purpose of Review Coronary heart disease is the leading cause of mortality worldwide. Elevated blood cholesterol levels are
not only the major but also the best modifiable cardiovascular risk factor. Lifestyle modifications which include a healthy
diet are the cornerstone of lipid-lowering therapy. So-called functional foods supplemented with plant sterols lower blood
cholesterol levels by about 10–15%.
Recent Findings In the recent revision of the ESC/EAS dyslipidemia guideline 2019, plant sterols are recommended for
the first time as an adjunct to lifestyle modification to lower blood cholesterol levels. However, the German Cardiac Society
(DGK) is more critical of food supplementation with plant sterols and calls for randomized controlled trials investigating
hard cardiovascular outcomes. An increasing body of evidence suggests that plant sterols per se are atherogenic.
Summary This review discusses this controversy based on findings from in vitro and in vivo studies, clinical trials, and
genetic evidence.

Keywords Cholesterol metabolism · Phytosterols · ABCG5/G8 · NPC1L1 · Atherosclerosis

Introduction disease (CHD) [2]. LDL-C reduction decreases the risk for
CHD and major coronary events [3]. Therefore, LDL-C
According to the World Health Organization (WHO, 2017), reduction is the central goal of the recently revised ESC/
17.9 million humans die each year from cardiovascular dis- EAS guidelines for the management of dyslipidemias: lipid
eases, which accounts for a third of all deaths worldwide modification to reduce cardiovascular risk and many other
[1]. The most common manifestation among cardiovascu- international guidelines such as the National Lipid Associa-
lar diseases is coronary heart disease (CHD). Low-density tion (NLA) [4], USA, the National Institute for Health and
lipoprotein (LDL-C) levels correlate with coronary heart Care Excellence (NICE) [5], and the American College of
Cardiology/American Heart Association (ACC/AHA) [6]
to name only a few. Of note, the ESC/EAS dyslipidemia
This article is part of the Topical Collection on Cardiovascular guidelines included in the revised version of 2019 for the
Disease and Stroke first time that plant sterols (phytosterols) are a recommended
* Oliver Weingärtner
therapeutic strategy to lower blood cholesterol levels. The
[email protected] ESC/EAS joint guidelines recommend 2 g phytosterol sup-
Umidakhon Makhmudova
plementation in individuals with high cholesterol levels at
[email protected] intermediate and low cardiovascular risk; in those who do
P. Christian Schulze
not qualify for pharmacotherapy, in high- and very-high-
[email protected] risk patients on top of pharmacotherapy who fail to achieve
Dieter Lütjohann
LDL-C-goals or who cannot be treated with statins, and in
[email protected] individuals with familial hypercholesterolemia [7••]. The
American Heart Association, on the other hand, restricts the
1
Klinik Für Innere Medizin I, Universitätsklinikum Jena, Am use of phytosterols to patients with familial hypercholester-
Klinikum 1, 07747 Jena, Germany
olemia and for secondary prevention and emphasizes that
2
Institut für klinische Chemie und klinische Pharmakologie, more information is required to recommend plant sterols in
Universitätsklinikum Bonn, Bonn, Germany

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the general population [6]. The National Institute for Health Plant Sterol Biochemistry and Physiology
and Care (NICE) in the United Kingdom recommends that
anyone with increased risk of CHD not use plant sterols or Both cholesterol and phytosterols belong to the family of
plant stanols as part of their cholesterol-lowering strategy triterpenes. They have a tetracyclic ring and carbon-linked
[8]. Likewise, the German Federal Institute for Risk Assess- side chain. Plant sterols differ from cholesterol by struc-
ment (BfR) does not recommend the use of plant sterol- tural modification within the side chain in position C24.
enriched foods and pushes that no more market approval Plant stanols are saturated sterols with a double-bind at the
should be awarded to phytosterol-enriched functional foods C5-atom in the B-ring [11]. The most common plant sterols
[9]. Finally, the Germany Cardiac Society (DGK) calls for in the diet are campesterol and β-sitosterol (they constitute
randomized, controlled trials investigating hard cardiovas- about 65% and 30%, respectively) and the most common
cular outcomes for foods that are supplemented with plant stanols are 5α-saturated stanols (generally plants have very
sterols and criticizes the recently revised ESC/EAS recom- little amounts of stanols) [11].
mendation [10•]. This review summarizes the current evi- Cholesterol and phytosterols are absorbed in the small
dence on plant sterols and cardiovascular risk. intestine (Fig. 1). They are solubilized and incorporated into
micelles and absorbed via a specific carrier — Niemann-
Pick C1-like protein 1 (NPC1L1) [12]. The heterodimer
ATP binding cassette transporter G5 and G8 (ABCG5/8)
secretes phytosterols and small amounts of cholesterol
back into the intestinal lumen [13, 14]. The same processes

Fig. 1  Cholesterol and plant sterol metabolism. Cholesterol (C) and pool of sterols consists of endogenously synthesized C and dietary C/
plant sterols (PS) from the diet are incorporated into micelles in PS. Also in the hepatocyte, NPC1L1 absorbs sterols and ABCG5/8
the small intestine and are transported to the enterocyte mucosa via secretes them into the bile. Part of cholesterol is converted into bile
the sterol transporter Niemann-Pick C1-like 1 protein (NPC1L1). acids (BA) which are transported in free and conjugated form by spe-
Free PS and “excess” C are secreted back into the lumen by the cific BA transporters into the bile. In the liver, very low-density cho-
ABCG5/ABCG8 heterodimer tandem transporter. Esterified choles- lesterol (VLDL) is formed from C, lipoproteins (containing mostly
terol and plant sterols are transported in chylomicrons, secreted into apoB100), and tryglycerides. In the bloodstream, VLDL is converted
the lymph, converted to chylomicron remnants, and taken up in the to intermediate-density cholesterol (IDL) and low-density cholesterol
liver, whereas small amounts of free C/PS leave the enterocyte via (LDL). LDL is the main carrier of cholesterol in the bloodstream.
apoA-containing HDL. Chylomicron remnants also contribute to ath- Both C and PS accumulate in the arterial wall and are associated with
erosclerotic plaque formation in the arterial wall. Thus, the hepatic cardiovascular events

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occur in the hepatocyte, where both NPC1L1 and ABCG5/8 also speculated that sitosterol possibly inhibits the caspase
are expressed. As a result of this selection, which can be pathway in macrophages, since in their model, sitosterol
interpreted as a “defense mechanism” against phytosterols, induces necrosis, but not cell-programmed apoptosis [22].
plasma plant sterol concentration is 1000-fold lower than
plasma cholesterol levels. In Vivo Studies

Animal studies demonstrate that a diet supplementation with

Plant Sterols in Nutrition and Nutraceuticals phytosterols reduces serum cholesterol levels and athero-
sclerotic lesions [24–27]. However, there are also studies
Phytosterols are part of plant foods, mainly in unrefined that demonstrate negative vascular effects. In ­apoE−/− mice
vegetable oils, grains, nuts, and olive oil. A typical western on a western-type, we found that lipid-lowering with a
diet contains equal amounts (approximately 400 mg) of both plant sterol-enriched diet compared to ezetimibe treatment
plant sterols and cholesterol each day. Unlike cholesterol, resulted in twice as much atherosclerotic lesion formation
phytosterols are not synthesized in humans, phytosterols [28]. This result is of particular interest since both options
have no function in human organism and diet is their only of inhibition of cholesterol absorption resulted in compara-
source. ble serum cholesterol levels of 400 mg/dl. Similar results
Cytellin — the first plant sterol product — was intro- were obtained in ­apoE−/− mice on a regular diet without
duced to the market in the late 50 s. Due to its low pal- cholesterol supplementation. Mice which were on a plant
atability and poor bioavailability, it was withdrawn in the sterol-enriched diet demonstrated twice as much athero-
1985 [15]. In the mid-1990s, a margarine enriched with sclerotic lesions, compared to those treated with ezetimibe,
phytosterols — the first phytosterol containing functional even though serum cholesterol levels in both groups were
food — was launched. Phytosterol-enriched low-fat milk 200 mg/dl. Moreover, wild-type mice supplemented with
and in margarines resulted in a 10–15% LDL-C reduction phytosterol-enriched food had increased cerebral lesion size
[16], whereas fortified cereals reduce LDL-C by 5.4% [17]. after cerebral ischemia and impaired endothelial-dependent
Up to date, different food products enriched with phytoster- vasorelaxation compared to mice on normal chow. Further,
ols are available: milk, soy, yoghurt products; soy and fruit Chen et al. reported an elevation of blood pressure in rats
drinks; cereal; sausage etc. More than 300 million USD are fed with phytosterol-enriched food [29].
spent annually on functional food enriched with phytosterols Plat and colleagues investigated oxidized phytoster-
worldwide [18]. ols. They fed LDL-r−/− mice with control diet, oxysterol-
enriched, and oxyphytosterol-enriched diet. The latter
resulted in significant increase of oxyphytosterol amounts
Plant Sterols and Cardiovascular Risk in atherosclerotic lesions compared to control and oxys-
terol-enriched diet. The proportion of severe atherosclerotic
In Vitro Studies lesions was significantly higher on an oxysterol- and oxy-
phytosterol-enriched diet [30]. They concluded that oxidized
Phytosterol cellular uptake was studied in HepG2 and phytosterols may contribute to the severity of atherosclerotic
CaCo-2 cell lines. In both cell lines, incubation with phy- lesions. Although, in normal diet, only very small amounts
tosterols resulted in the reduction of cellular cholesterol of oxidized phytosterol can be found, they are elevated in the
levels [19, 20]. Cytotoxic effects of phytosterols on human plasma of patients with sitosterolemia and small amounts
endothelial cells have been reported by Boberg and col- can even be found in the plasma of healthy individuals [31].
leagues. They incubated human endothelial vein cells Yu and colleagues generated ABCG5/8 knockout mice to
(HUVEC) with sitosterol for 72 h, which resulted in con- elucidate the role of these genes. They observed a ~ 30-fold
traction of HUVEC and increase of intracellular lactate increase in sitosterol concentration in these mice on chow
dehydrogenase [21]. In another study, Bao and colleagues diet [32]. When dietary cholesterol content was increased,
reported a sitosterol-induced necrotic death in macrophages, plasma phytosterol levels fell by ~ 50% (both in wild-type
derived from mice [22]. The lesional necrosis of atheroscle- and ABCG5/8 knockout mice). Besides, liver and plasma
rotic plaque mainly consists of macrophages; therefore, the cholesterol levels were decreased by 50% on chow diet,
authors hypothesized that sitosterol-induced accelerated containing only very small amounts of cholesterol. Fur-
macrophage death leads to plaque necrosis, to plaque rup- ther analysis of knockout mice by Yu et al. and McDaniel
ture, and eventually to cardiovascular events. They sup- et al. demonstrated that these mice had a normal phenotype
ported this hypothesis by findings from a previous study in comparable with that of wild-type mice. When fed with a
which they demonstrated a decrease in lesional macrophages high-phytosterol diet, they failed to gain weight, developed
resulting in a decrease of plaque necrosis in vivo [23]. They hepatosplenomegaly, and died prematurely. On a regular

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diet, they accumulated phytosterols in different tissues and and established CVD [45]. Glueck et al. analyzed phytos-
organs and developed complex cardiac lesions [32, 33]. terol levels in 595 hypercholesterolemic subjects and its rela-
tion to the incidence of coronary heart disease in those indi-
Human Studies viduals and their first-degree relatives. They found a weak
correlation between phytosterol and cholesterol plasma lev-
Case Reports els and a positive correlation between the phytosterol con-
centrations and personal or family history of coronary heart
Abnormally high levels of phytosterols are found in patients disease [46]. Sudhop et al. also demonstrated a correlation
with sitosterolemia. Sitosterolemia is a rare genetic disorder, between sitosterol, campesterol, sitosterol/cholesterol ratio,
caused by mutations in ABCG5 or ABCG8 located in chro- and campesterol/cholesterol ratio in individuals admitted to
mosome 2 resulting in increased plasma phytosterol levels hospital for elective coronary artery bypass grafting [47].
(not mainly sitosterol but also campesterol, stigmasterol, On the other hand, there are case–control studies that
and avenisterols). In 1974, two sisters were diagnosed with show no effect on cardiovascular risk or a negative correla-
this rare disease presenting with xanthomatas (a deposition tion of plasma phytosterol levels and cardiovascular disease.
of phytosterols and cholesterol in different organs, mainly The prospective EPIC-Norfolk population study did not
in extensor areas) and elevated phytosterol plasma levels find any significant difference between those with coronary
[34]. The causal genetic mutation on ABCG5/8 was dis- heart disease and healthy controls [48]. Similarly, the CORA
covered only several years later in 2001 [13]. The clinical study could not find any association between phytosterols
phenotype of sitosterolemia is very heterogenic — from and coronary heart disease [49].
asymptomatic to fatal cases as consequence of premature
coronary heart disease. These patients are often character- Cohort Studies and Randomized Clinical Trials
ized by xanthomas, severe coronary heart disease, aortic
stenosis, and early cardiovascular death. Some patients LURIC (Ludwigshafen Risk and Cardiovascular Health
present with hematologic disorders, such as stomatocytic Study) — a prospective cohort study with a total of 3,316
hemolysis and macrothrombocytopenia [35]. The youngest participants — demonstrated that plasma phytosterol levels
patient diagnosed with sitosterolemia — a 2-year-old girl — were predictors of all-cause and cardiovascular mortality
had elevated LDL-C levels and tuberous and intertriginous [50]. Another cohort study — MONIKA/KORA — dem-
xanthomas [36]. In another case, a 5-year-old girl died due onstrated that in healthy men 35–64 years of age, higher
to severe coronary three-vessel disease [37]. The discov- phytosterol levels correlated with occurrence of myocar-
ery of this rare disease has raised the interest in plant sterol dial infarction during 10-year follow-up [51]. On the other
physiology and its potential damaging effects on the human hand, a 22-year follow-up study of 232 men at high car-
organism. diovascular risk demonstrated that higher plant sterol levels
are correlated with lower long-term mortality [52]. Most
Case–Control and Retrospective Cohort Studies importantly, in patients admitted for coronary angiogra-
phy for suspected coronary artery disease, we found that
A meta-analysis of randomized clinical trials on lipid- 7α-hydroxycampesterol and their ratios to cholesterol were
lowering efficacy of plant sterols demonstrated that plant associated with cardiovascular events during a 5-year fol-
sterols reduce LDL-C levels by 17%. However, there is a low-up period [53•]. All the above-mentioned studies are
great inter-individual variability [38••] and some studies prospective cohort studies. Unfortunately, to date, there is no
have not found any LDL-C lowering effect of plant sterols prospective, placebo-controlled, randomized trial to address
at all [39, 40]. the impact of phytosterol diet supplementation on hard car-
In a case–control study in females with documented coro- diovascular outcomes.
nary artery disease vs. healthy controls, elevated ratios of
phytosterols to cholesterol were associated with increased Meta‑analysis of Case–Control, Cross‑Sectional, and Cohort
cardiovascular risk [41]. Similar results were observed in Studies
men in the PROCAM (Prospective Cardiovascular Münster)
study [42]. Our group demonstrated that among patients A meta-analysis based on data from 17 studies (4 case–con-
undergoing aortic valve replacement, those with a positive trol, 3 cohort, 5 cross-sectional, and 5 nested case–control)
history of cardiovascular disease had an increased campes- evaluated the effect of phytosterol plasma levels on cardio-
terol-to-lathosterol ratio in plasma and aortic valve cusps vascular risk. The authors of this meta-analysis concluded
[43]. Correlation of enhanced phytosterol levels/ratio to cho- that plasma phytosterol levels are not associated with car-
lesterol with cardiovascular risk and coronary heart disease diovascular risk. However, the results of this meta-analy-
was also reported in patients without diabetes history [44] sis are to be interpreted with caution. First, there are no

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standardized methods of phytosterol measurements, hence variants resulted in twofold increase of cardiovascular risk,
results from different laboratories may differ largely. Second, whereas a 1 mmol/L non-HDL cholesterol increase for genes
not all studies were appropriately adjusted to potential con- that affect only non-HDL cholesterol, but have no impact on
founding variables. Finally, of 59 initially selected publica- plant sterol metabolism, such as PCSK9, apoB, HMG-CoA
tions, only 17 were included in the meta-analysis — another reductase, and LDL receptor, was associated with a 1.5-fold
41 were excluded because no explicit phytosterol exposure increase of cardiovascular risk. The authors concluded that
levels were reported or they did not meet inclusion criteria non-HDL cholesterol can only explain around 60% of the
of this meta-analysis [54]. increase in cardiovascular risk and the remaining 40% must
be due to other mechanisms. ABCG5/8 and NPC1L1 are
Genetic Studies not associated with other conventional cardiovascular risk
factors. In contrast, ABCG5/8 and NPC1L1 variants have
Plasma sterol concentrations are regulated by ABCG5/8 and a consistent close relationship to plant sterols — making
NPL1C1. NPL1C1, which is expressed on the apical surface elevated plant sterol levels a plausible explanation for the
of enterocytes, is responsible for the intestinal absorption of excess CAD risk. The authors, therefore, concluded that
both cholesterol and plant sterols [55], whereas ABCG5/8 dietary sterols such as plant sterols may contribute directly
reduces dietary sterol concentration in the plasma by pump- to atherogenesis, raising questions about the safety of sup-
ing plant sterols and “excess” cholesterol back into the plementing food with phytosterols for the purpose of cardio-
intestinal lumen [13]. Teupser et al. identified three variants vascular risk reduction.
of ABCG8 and ABO blood group locus, associated with
increased plasma phytosterol concentration in humans.
Around 10% of the variability in serum phytosterol levels Safety Concerns Beyond the Cardiovascular
in the normal population could be explained by these three System
variants. Teupser and colleagues conducted a meta-analysis
of 11 different studies comprising over 13,000 cases with Besides proatherogenic effects, there are other safety con-
coronary heart disease and controls, and showed a positive cerns regarding phytosterols. As early as 2000, Ratnayake
correlation between those three alleles, serum phytosterol and colleagues found that vegetable oil rich in phytosterols
levels, and higher probability of coronary heart disease [56]. makes red blood cells more rigid and less flexible and results
As early as 2010, Teupser and colleagues came to the con- in significant shortening of the lifespan of rats [59]. This
clusion that genetic variants that increase plasma plant sterol finding leads to the ban of any phytosterol-enriched foods
levels are associated with CAD. in Canada in 2003 [60].
A genome-wide study including sequence data of a total Another concern coming from in vivo studies is the nega-
of 91,002 participants who were of European, African, or tive impact of phytosterols on hormonal status and the repro-
South Asian ancestry identified 15 distinct NPC1L1 inacti- ductive system of male and female rats [61, 62] and goldfish
vating mutations. Approximately 1 of 650 persons was a het- [63]. However, this finding could not be proven in humans.
erozygous carrier for one of these mutations. Even though In 185 healthy volunteers, phytosterol consumption (1.6 g/
heterozygous carriers of NPC1L1 inactivating mutations had day) for 1 year did not affect the reproductive hormone levels
a mean LDL-C level that was only 12 mg/dl lower than that in both male and female participants [64].
of non-carriers, carrier status was associated with a relative Further, there is concern that phytosterols can interfere
risk reduction for CAD of 53%. The authors concluded that with the absorption of several fat-soluble vitamins — such
the genetic inhibition of NPC1L1 may also lower the risk of as tocoferol and β-carotene [64, 65]. The Scientific Com-
coronary heart disease by reducing the absorption of plant mittee on Food of the European Commission has significant
sterols [57]. safety issues and recommends the use of natural sources of
Only recently, Helgadottir and colleagues [58••] reported β-carotene to compensate for the reduction of β-carotenes
a large genetic study from Iceland, Denmark, and the UK, caused by long-term consumption of phytosterol-enriched
with 85,544 cases and 648,442 controls. They determined foods [66].
a genetic risk score (GRS) for ABCG5/8 and NPC1L1 —
lipid genes which are involved in plant sterol metabolism
— and lipid genes, which are not involved in the plant sterol Conclusions
metabolism — such as PCSK9, apoB, HMG-CoA reductase,
and LDL receptor. They identified variants of ABCG5/8 and The revised ESC/EAS guidelines for the management of
NPC1L1, associated with a significant impact on non-HDL dyslipidemias included for the first time a recommenda-
cholesterol and phytosterol levels. A predicted 1 mmol/L tion for plant sterols as part of lifestyle changes to reduce
increase in non-HDL cholesterol for ABCG5/8 and NPC1L1 serum cholesterol levels. Recent genetic evidence suggests

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that plant sterols “per se” are atherogenic. These findings 7.•• Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guide-
support the call for randomized controlled trials with hard lines for the management of dyslipidaemias: lipid modification
to reduce cardiovascular risk: the Task Force for the manage-
cardiovascular outcomes prior to a general recommendation ment of dyslipidaemias of the European Society of Cardiol-
for plant sterols to lower serum cholesterol levels, as reiter- ogy (ESC) and European Atherosclerosis Society (EAS). Eur
ated only recently by the German Cardiac Society (DGK). Heart J. 2020;41:111–88. The revised ESC/EAS dyslipidemia
guideline which included for the first time plant sterols as an
option to lower blood cholesterol levels.
Funding Open Access funding enabled and organized by Projekt DEAL. 8. Cardiovascular disease: risk assessment and reduction, including
lipid modification. National Institute for Health and Care Excel-
lence (UK), London; 2016.
Declarations 9. Bundesinstitut für Risikobewertung. Menschen mit normalen
Cholesterinwerten sollten auf den Verzehr von Lebensmitteln
Human and Animal Rights and Informed Consent This article does not mit zugesetzten Pflanzensterinen verzichten. 2008. https://m ​ obil.​
contain any studies with human or animal subjects performed by any bfr.​bund.​de/​cm/​343/​mensc​hen_​mit_​norma​len_​chole​steri​nwert​
of the authors. en.​pdf.
10.• Kommission für Klinische Kardiovaskuläre Medizin der
Conflict of Interest Oliver Weingärtner reports honoraria from Amgen, DGK, Weingärtner O, Landmesser U, März W, Katzmann JL,
Novartis, Hexal, Fresenius, Sanofi-Aventis, Pfizer, and Akcea Thera- Laufs U. Kommentar zu den Leitlinien (2019) der ESC/EAS
peutics. The other authors declare that they have no conflict of interest. zur Diagnostik und Therapie der Dyslipidämien. Kardiologe.
2020;14:256–66. This review is the comment of the German
Society of Cardiology (DGK) on the ESC/EAS dyslipidemia
Open Access This article is licensed under a Creative Commons Attri- guidelines 2020 which calls for cardiovascular outcome
bution 4.0 International License, which permits use, sharing, adapta- studies prior to recommending plant sterols as a dietary
tion, distribution and reproduction in any medium or format, as long supplement.
as you give appropriate credit to the original author(s) and the source, 11. Valitova JN, Sulkarnayeva AG, Minibayeva FV. Plant sterols:
provide a link to the Creative Commons licence, and indicate if changes diversity, biosynthesis, and physiological functions. Biochem-
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otherwise in a credit line to the material. If material is not included in (NPC1L1) is the intestinal phytosterol and cholesterol trans-
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