Received: 1 November 2017
Accepted: 7 December 2018
Dietary natural products as emerging lipoprotein(a)‐lowering
Amir Abbas Momtazi‐Borojeni
Khalid Al Rasadi
Department of Medical Biotechnology,
Nanotechnology Research Center, Faculty of
Medicine, Mashhad University of Medical
Sciences, Mashhad, Iran
Second Propedeutic Department of Internal
Medicine, Medical School, Aristotle University
of Thessaloniki, Hippocration Hospital,
Unit of Internal Medicine, Angiology and
Arteriosclerosis Diseases, Department of
Medicine, University of Perugia, Perugia, Italy
Department of Hypertension, WAM
University Hospital in Lodz, Medical
University of Lodz, Lodz, Poland
Polish Mother’s Memorial Hospital Research
Institute, Lodz, Poland
Department of Clinical Biochemistry, Sultan
Qaboos University Hospital, Muscat, Oman
Biotechnology Research Center,
Pharmaceutical Technology Institute,
Mashhad University of Medical Sciences,
Neurogenic Inflammation Research Center,
Mashhad University of Medical Sciences,
School of Pharmacy, Mashhad University of
Medical Sciences, Mashhad, Iran
Amirhossein Sahebkar, Pharm.D., Ph.D.,
Department of Medical Biotechnology, School of
Medicine, Mashhad University of Medical
Sciences, Mashhad, P.O. Box: 91779‐48564, Iran.
Elevated plasma lipoprotein(a) (Lp(a)) levels are associated with an increased risk of
cardiovascular disease (CVD). Hitherto, niacin has been the drug of choice to reduce
elevated Lp(a) levels in hyperlipidemic patients but its efficacy in reducing CVD outcomes
has been seriously questioned by recent clinical trials. Additional drugs may reduce to
some extent plasma Lp(a) levels but the lack of a specific therapeutic indication for Lp(a)‐
lowering limits profoundly reduce their use. An attractive therapeutic option is natural
products. In several preclinical and clinical studies as well as meta‐analyses, natural
products, including L‐carnitine, coenzyme Q
, and xuezhikang were shown to significantly
decrease Lp(a) levels in patients with Lp(a) hyperlipoproteinemia. Other natural products,
such as pectin, Ginkgo biloba,flaxseed,redwine,resveratrolandcurcuminoidscanalso
reduce elevated Lp(a) concentrations but to a lesser degree. In conclusion, aforemen-
tioned natural products may represent promising therapeutic agents for Lp(a) lowering.
cardiovascular disease, coenzyme Q10, L‐carnitine, lipoprotein(a), natural products, nutraceu-
Lipoprotein(a) (Lp(a)), first discovered by Berg (1963), is a cholesterol‐rich
low‐density lipoprotein (LDL)‐like particle (Berg et al., 1997), with a
diameter up to 25 nm and density higher than LDL (Krempler, Kostner,
Bolzano, & Sandhofer, 1980). Lp(a) is known to exert atherogenic and
prothrombotic properties (Marcovina,Koschinsky,Albers,&Skarlatos,
2003; Ellis, Boffa, Sahebkar, Koschinsky, & Watts, 2017; Pirro, Bianconi,
et al., 2017; Ferretti, Bacchetti, Johnston, et al., 2018). This lipoprotein is
mainly synthesized in hepatocytes and includes a central LDL‐like
lipoprotein core containing a single molecule of apolipoprotein B (apoB)
covalently bound, in a 1:1 molar ratio, to glycoprotein apolipoprotein(a)
(apo(a)) by a disulfide bridge between cysteine residues of apo(a)
(Cys4057) and apoB100 (Cys4326). The presence of apo(a) represents
J Cell Physiol. 2019;1–14. wileyonlinelibrary.com/journal/jcp © 2019 Wiley Periodicals, Inc.
the major structural difference between Lp(a) and LDL, leading to diverse
physical and chemical properties (Clarke et al., 2009; Marcovina et al.,
2003; Siekmeier et al., 2010).
POPULATION, GENETIC VARIANTS,
AND LP(A) LEVELS
Plasma Lp(a) level is mostly hereditary and highly heterogeneous
between various individuals (Banach, 2016; Kotani, Serban, Penson,
Lippi, & Banach, 2016; Lanktree, Anand, Yusuf, & Hegele, 2010;
Tsimikas, 2017). Distribution of Lp(a) concentrations in different
populations is ethnic group‐specific (Lanktree et al., 2010). African
descendants have elevated plasma Lp(a) concentrations compared
with Asians and Caucasians (Berglund & Ramakrishnan, 2004). In the
general population, plasma Lp(a) levels can vary over 1,000‐fold,
ranging from <0.1 to >100 mg/dl (Boerwinkle et al., 1992). In this
context, although multiple acquired factors may have some influence
on plasma Lp(a) levels (Pirro, Bianconi, et al., 2017), dietary or other
lifestyle interventions have only a little impact, whereas genetic
variations mainly limited to the LPA gene, (the gene encoding apo(a)),
are believed to play a major role (Boerwinkle et al., 1992).
Single nucleotide polymorphisms (SNPs) in the LPA gene are strongly
associated with plasma Lp(a) levels (Clarke et al., 2009; Helgadottir et al.,
2012; Kamstrup, Tybjærg‐Hansen, Steffensen, & Nordestgaard, 2009).
The Precocious Coronary Artery Disease (PROCARDIS) study revealed
that two apo(a) SNPs accounted for 36% of the variation in Lp(a) levels
among European descendants (Clarke et al., 2009).
Allele size in the LPA gene is the other genetic factor that defines
plasma Lp(a) concentrations. Both the levels and atherogenicity of Lp(a),
evaluated by study of the carotid stenosis incidence, were found to be
influenced by genetic variants in the LPA gene, resulting in 30 different
isoforms of apo(a) (Kronenberg et al., 1999; Marcovina et al., 1996;
Sandholzer et al., 1991). The isoforms stem from variation in repeat
number of kringle IV type 2 (KIV‐2) domain, which is a highly
glycosylated repetitive domain in apo(a) structure. In general, proteins
with lower molecular weight are more efficiently synthesized and less
efficiently degraded than larger proteins. Therefore, apo(a) isoforms with
smallernumberofKIV‐2 repetitions have smaller sequences and are
associated with higher plasma Lp(a) levels and potentially more
atherothrombogenic activity (Kronenberg et al., 1999). The most
frequently used method to quantify plasma levels of Lp(a) is enzyme
immunoassay (enzyme‐linked immunosorbent assay) involving antibodies
that interact with the kringle region of apo(a) subunit. However, because
of the wide heterogeneity in apo(a) size, measurement of Lp(a) via
immunoassays is limited by inaccuracies and new approaches to measure
Lp(a) levels are being developed (Clarke et al., 2009).
LP(A) LEVELS AND CARDIOVASCULAR
There is evidence, including genome‐wide association and Mendelian
randomization studies, that elevated plasma Lp(a) concentrations are
linked to CVD (Banach, Stulc, Dent, & Toth, 2016; Dubé, Boffa, Hegele,
& Koschinsky, 2012; Katsiki, Al‐Rasadi, & Mikhailidis, 2017; Kronen-
berg & Utermann, 2013). In particular, increased plasma Lp(a) levels
represent a moderate, independent CVD risk factor (Emerging Risk
Factors Collaboration, 2009). Elevated plasma Lp(a) levels are
associated with coronary artery disease (Bennet et al., 2008;
Gurdasani et al., 2012; Mellwig et al., 2015), peripheral artery disease
(Gurdasani et al., 2012), cerebrovascular disease (Emerging Risk
Factors Collaboration, 2009; Gurdasani et al., 2012), abdominal aortic
aneurysm (Kotani et al., 2017), aortic valve calcification and stenosis
(Vongpromek et al., 2015), as well as venous thromboembolism (Lippi,
Franchini, & Targher, 2011). In this context, each 1 standard deviation
increase in log‐transformed Lp(a) levels can raise the hazard ratio for
CVD by 1.1–1.2 (Emerging Risk Factors Collaboration, 2009) and is
parallel to as much as a 3.6‐fold increased risk for CVD events at high
Lp(a) concentrations (≥120 mg/dl; Kamstrup, Benn, Tybjærg‐Hansen, &
Lp(a) increases CVD risk through multifaceted atherothrombotic
pathways, including binding of proinflammatory oxidized phospholi-
pids via apoB100 (Tsimikas et al., 2005), stimulation of the
expression of adhesion molecules such as vascular cell adhesion
protein 1 (VCAM‐1) and E‐selectin (Allen et al., 1998), infiltration into
the arterial wall and impaired generation of plasmin due to a unique
structural mimicry between Lp(a) and plasminogen (Kang et al., 2002;
Tsimikas, Tsironis, & Tselepis, 2007). When Lp(a) immigrates into the
arterial intima, it attaches to the extracellular matrix via both apo(a)
and apoB components, leading to the enlargement of the athero-
sclerotic lesion (Nielsen, 1999).
In 2010/2011, the European Atherosclerosis Society (EAS;
Nordestgaard et al., 2010) and the National Lipid Association
(Davidson et al., 2011) guidelines recommended screening for
elevated Lp(a) levels in individual with intermediate‐to‐high risk of
CVD. These subjects include patients who present with premature
CVD, familial hypercholesterolemia (FH), family history of ele-
vated Lp(a), recurrent CVD despite statin therapy, and patients
with high CVD risk scores (Nordestgaard et al., 2010). An Lp(a)
level of 30 mg/dl has been stated as the risk threshold, and relative
risk of CVD increases continuously in patients with Lp(a) levels
above this threshold (Jacobson, 2013). Hence, lipid‐lowering
agents reducing Lp(a) levels to below 30 mg/dl can be considered
as promising therapies to decrease the risk of CVD. Recently, it has
been suggested that large absolute (rather than relative) reduc-
tions in Lp(a) are needed to lower CVD risk (Burgess et al., 2018).
Therefore, only individuals with very high Lp(a) baseline concen-
trations could indeed benefit in terms of CVD risk from Lp(a)‐
lowering therapeutic strategies.
As recommended by the Canadian Cardiovascular Society, plasma
Lp(a) concentration should be <30 mg/dl (Anderson et al., 2013).
Niacin (nicotinic acid) monotherapy and niacin‐combination therapy
MOMTAZI‐BOROJENI ET AL.
are the only lipid‐lowering treatments that consistently, substan-
tially, durably, and dose‐dependently (from 1 to >3 g/day) reduce
elevated plasma Lp(a) levels by 20–40% (Capuzzi et al., 1998;
Marcovina et al., 2003; Williams, 2002), accompanied by beneficial
effects on plasma low‐density lipoprotein‐cholesterol (LDL‐C), high
density lipoprotein‐cholesterol (HDL‐C), and very low‐density
lipoprotein‐cholesterol (VLDL) levels (Stein et al., 1996). The clinical
use of niacin was limited due to its side effects through the
stimulation of prostaglandin D2 and E2 synthesis (Lippi & Targher,
2012). The main adverse event that reduced patients compliance
was flushing, an issue that was partly overcome by the combination
of niacin‐extended release with laropiprant (Yadav et al., 2012).
Although the EAS and the American Heart Association/American
Stroke Association guidelines recognized niacin as a drug of choice
for the treatment of elevated plasma Lp(a) concentrations (Gold-
stein et al., 2011; Nordestgaard et al., 2010), the two large
randomized controlled clinical trials with niacin (that is, the Heart
Protection Study 2–Treatment of HDL to Reduce the Incidence of
Vascular Events [HPS2‐THRIVE] and the Atherothrombosis Inter-
vention in Metabolic Syndrome with Low HDL/High Triglycerides:
Impact on Global Health Outcomes (AIM‐HIGH) trials; Investiga-
tors, 2011) did not find any significant effect of niacin on CVD risk
in statin‐treated patients with established CVD. Furthermore,
niacin was reported to increase the risk of side effects compared
withplacebointheHPS2‐THRIVE trial (HPS2‐THRIVE Collabora-
tive Group, 2014). Based on such negative results, niacin was
withdrawn from the EU market (http://www.ema.europa.eu/ema/
b01ac05805c516f) and its use was suspended worldwide.
Currently, statin therapy represents the first‐line treatment to
decrease individual’s CVD risk (Banach, Serban, et al., 2015; Lippi &
Targher, 2012) not only because of its LDL‐lowering activity but also
due to its several pleiotropic actions (Banach, Dinca, et al., 2016;
Bianconi, Sahebkar, Banach, & Pirro, 2017; Chrusciel et al., 2016;
Ferretti, Bacchetti, & Sahebkar, 2015; Ferretti, Bacchetti, Banach,
Simental‐Mendia, & Sahebkar, 2016; Momtazi, Derosa, Maffioli,
Banach, & Sahebkar, 2016; Panahi, Badeli, Karami, & Sahebkar,
2015; Parizadeh et al., 2011; Rysz‐Gorzynska et al., 2016; Sahebkar,
Kotani, et al., 2015; Sahebkar, Serban, Mikhailidis, et al., 2015;
Sahebkar, Pećin, et al., 2016b; Sahebka, Serban, et al., 2016d;
Sahebkar, Ponziani, Goitre, & Bo, 2015a; Sahebkar, Rathouska,
Derosa, Maffioli, & Nachtigal, 2016c; Serban et al., 2015). Inten-
sive‐statin therapy leading to maximal LDL‐C‐lowering in patients
with Lp(a) elevation is supported as a potential therapeutic choice by
a growing body of observational studies that have shown CVD risk
reduction parallel to LDL‐C‐lowering in such patients (Banach,
Aronow, et al., 2015a; Nicholls et al., 2010). However, the effects
of statin therapy on plasma Lp(a) levels are scarce and controversial,
and in some cases even raised Lp(a) level is found after the initiation
of statin treatment (Sahebkar et al., 2017; Yeang et al., 2016). In
addition, statin intolerance and resistance may be present in some
dyslipidemic patients and therefore, alternative Lp(a)‐lowering
therapies are considered as an unmet clinical necessity (Kotani
et al., 2015).
Apart from niacin, there are other developed and under
development drugs that were found to reduce elevated Lp(a) levels,
although their correlation with CVD risk is yet unknown. These drugs
include evolocumab and alirocumab (Sahebkar & Watts, 2013), the
two monoclonal antibodies targeting proprotein convertase subtili-
sin/kexin type‐9 (PCSK9) which can reduce Lp(a) up to 26% (Banach
et al., 2013; Dragan, Serban, & Banach, 2015; Kotani & Banach,
2017), cholesteryl ester transfer protein inhibitors (Banach et al.,
2013), mipomersen that is, an antisense oligonucleotide (ASO)
against apoB mRNA can reduce Lp (a) up to 26% (Raal et al.,
2010), ASO therapy (ISIS APO(a) Rx) directly against apo(a) mRNA
(Merki et al., 2011; Tsimikas et al., 2015), eprotirome that is, an
analogue of the thyroid hormone (Ladenson et al., 2010), tibolone
that is, a synthetic steroid drug with estrogenic and progestogenic
activities (Kotani et al., 2015), and lomitapide that is, a microsomal
triglyceride transfer protein inhibitor can reduce Lp(a) by 17%
(Samaha, McKenney, Bloedon, Sasiela, & Rader, 2008). In addition,
lipoprotein apheresis can be used to treat homozygous FH, severe
heterozygous FH and in some countries, it is approved for the
treatment of patients with high levels of Lp(a) >60 mg/dl (Leebmann
et al., 2013; Thompson &, Group H‐ULAW, 2008). However, the
clinical use of these drugs is still limited. An alternative therapeutic
strategy to lower Lp(a) may involve natural products (Asgary,
Rafieian‐Kopaei, Shamsi, Najafi, & Sahebkar, 2014; Banach, Aronow,
et al., 2015a; Cicero et al., 2017; Panahi, Khalili, Hosseini,
Abbasinazari, & Sahebkar, 2014b; Sahebkar, Catena, et al., 2016a;
Serban et al., 2016).
The present review summarizes the Lp(a) reducing effects of
known LDL‐C‐lowering natural products by discussing the evidence
from both preclinical and clinical studies.
L‐Carnitine is derived from the amino acid lysine and plays a role in
mitochondrial fatty acid oxidation and adenosine triphosphate production
(Broderick, 2008). L‐Carnitineisknowntoberichinredmeatandcertain
fish, and at smaller amounts in dairy products and some fruits, such as
avocado (Rajasekar & Anuradha, 2007). Several experimental and clinical
studies investigated the effect of L‐carnitine on lipid metabolism and
found that L‐carnitine may be associated with reductions in Lp(a) levels
(Broderick, 2008; Rajasekar & Anuradha, 2007).
Recently we conducted a comprehensive systematic review and
meta‐analysis of several randomized controlled trials and reported
that L‐carnitine supplementation (1–4 g/day) can significantly de-
crease Lp(a) levels (weighted mean difference [WMD], −8.82 mg/dl;
95% confidence interval [CI], −10.09 to −7.55; p<0.001) after 1–24
weeks in patients with Lp(a) hyperlipoproteinemia (i.e., serum Lp
(a) ≥30 mg/dl). Analysis of data based on the route of administration
MOMTAZI‐BOROJENI ET AL.
also suggested that oral administration significantly lowered Lp(a)
levels (WMD, −9.00 mg/dl; 95% CI, −10.29 to −7.72; p< 0.001), while
intravenous administration showed no significant effect (Serban
et al., 2016). Although the exact mechanism underlying the observed
Lp(a)‐lowering effect of L‐carnitine is yet unknown, it is suggested
that L‐carnitine may decrease the hepatic production of Lp(a) via
inducing the break‐down of fatty acids in the mitochondria
(Rajasekar & Anuradha, 2007). Overall, oral L‐carnitine might be an
effective natural strategy to reduce Lp(a) levels, although further
research is needed to establish this association.
We recently carried out a systematic review and meta‐analysis on the
results of six randomized controlled trials studying the effects of
supplementation (120–300 mg/day) on serum Lp(a)
levels in 409 dyslipidemic patients (Serban et al., 2016b). Coenzyme Q
intake moderately but significantly reduced serum Lp(a) levels (WMD,
−3.54 mg/dl; 95% CI, −5.50 to −1.58; p< 0.001), although it did not
affect other lipid parameters, including total cholesterol, LDL‐C, HDL‐C,
and TG (Serban et al., 2016). Lp(a)‐lowering effect of coenzyme Q
inversely associated with the supplemented doses; doses of coenzyme
< 150 mg/day decreased Lp(a) levels at a greater degree than
doses ≥150 mg/day (WMD, −9.24 mg/dl; 95% CI, −15.19 to −3.29;
p= 0.002 and WMD, −2.75 mg/dl; 95% CI, −4.28 to −1.23; p< 0.001,
respectively; Serban et al., 2016). Furthermore, baseline Lp(a) levels
were found to affect the Lp(a)‐lowering impact of coenzyme Q
supplementation; baseline Lp(a) ≥30 mg/dl led to higher Lp(a) reduction
compared with baseline levels < 30 mg/dl (WMD, −11.72 mg/dl; 95% CI,
−21.01 to −0.42; p=0.013 and WMD, −3.14 mg/dl; 95% CI, −4.92 to
−1.35; p= 0.001, respectively; Serban et al., 2016b). Lp(a) levels were
decreased by 31.3–32.1% when baseline levels were ≥30 mg/dl and by
12.8% at baseline levels <30 mg/dl (Serban et al., 2016b).
In the same meta‐analysis, it was hypothesized that different
formulations administered in the studies might
influence the relative bioavailability of coenzyme Q
quently reducing coenzyme Q
absorption as the supplemented
doses are increased. Furthermore, it was observed that the highest
doses were used in the studies with the lowest
baseline Lp(a) levels, thus possibly “masking”the effect of the higher
doses (Serban et al., 2016). Treatment duration did not change the
effect of coenzyme Q
supplementation on Lp(a) concentrations;
administration for <8 weeks produced similar decreases in Lp(a)
levels compared with those lasting ≥8 weeks (WMD, −4.00 mg/dl;
95% CI, −5.45 to −2.54; p< 0.001 and WMD, −3.99 mg/dl; 95% CI,
−11.15 to 3.18; p= 0.275), thus suggesting a lack of time‐dependent
Lp(a)‐lowering efficacy of coenzyme Q
(Serban et al., 2016).
Overall, coenzyme Q
supplementation can significantly reduce
(by 12.9–32.1%) plasma Lp(a) levels; the dose of coenzyme Q
the baseline Lp(a) concentrations may affect the degree of Lp(a)‐
lowering. It could be suggested that combination therapy of
with other lipid‐lowering drugs may be a promising
therapeutic option to further reduce plasma Lp(a) levels.
Red yeast rice, known as cholestin, is a yeast product that is grown on
rice and exerts documented cholesterol‐lowering effects (Liu et al.,
2006; Pirro, Mannarino, Bianconi, et al., 2016; Pirro, Mannarino,
Ministrini, et al., 2016; Pirro, Vetrani, et al., 2017; Trimarco et al.,
2011) via suppressing cholesterol synthesis through the inhibition of
3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase
(Menéndez et al., 2001; Singh, Li, & Porter, 2006). Xuezhikang (XZK)
is a cholestin extract that contains a mixture of lovastatin (dominant
compound), plant sterols, and isoflavones (Heber et al., 1999; Jiang,
Hao, Deng, Zhou, & Lin, 1999). XZK exerts lipid‐lowering properties
and is also well tolerated in patients with statin intolerance (Becker
et al., 2009; Lu et al., 2008). A randomized study in patients with
coronary heart disease showed that consumption of XZK (1.2 g/day)
significantly reduced plasma Lp(a) levels by 23% after 6 weeks of
treatment (Liu, Zhao, Cheng, & Li, 2003).
Dietary fibers comprise a group of dietary components such as fruit,
vegetables, cereals, and whole grains. Dietary fibers can be totally
classified by their water solubility, including viscous or water‐soluble
fibers such as pectin, fenugreek, and guar gum, and nonviscous or
water‐insoluble fibers, such as wheat bran (Dhingra, Michael, Rajput, &
Experimental and clinical studies have shown that the intake of
viscous fibers or a mix of viscous and nonviscous fibers may protect
against atherosclerosis through decreases in LDL‐C (Anderson, 1995;
Glore, Van Treeck, Knehans, & Guild, 1994; Haskell, Spiller, Jensen,
Ellis, & Gates, 1992; Jenkins et al., 1993; Vergara‐Jimenez, Furr, &
Fernandez, 1999; Vigne et al., 1987; Viuda‐Martos et al., 2010; Wu
et al., 2003). The exact mechanism of the cholesterol‐lowering effect
of dietary fibers is yet unknown. Evidence suggests that fibers
mediate regulation of plasma cholesterol via their viscosity (gel‐
forming capacity; Glore et al., 1994) and by enhancing biodegrada-
tion of cholesterol into bile acids (Horton, Cuthbert, & Spady, 1994;
Viuda‐Martos et al., 2010) or via enhancing the hepatic clearance of
LDL‐C by LDLR (Vergara‐Jimenez, Conde, Erickson, & Fernandez,
1998; Viuda‐Martos et al., 2010).
Pectin, fenugreek, and guar gum are water‐soluble gel‐forming
fibers reducing plasma cholesterol via the formation of a viscous
matrix that prevents absorption of micelles containing cholesterol
and bile acids into the enterocyte (Jones, 2008). Reduction of bile
acid uptake leads to enhanced bile acid synthesis from hepatic
cholesterol via downregulation of liver cholesterol 7 α‐hydroxylase
(Buhman, Furumoto, Donkin, & Story, 2000; Moriceau et al., 2000;
Rodriguez, Jimenez, Fernández‐Bolaños, Guillén, & Heredia, 2006),
which drops the intracellular cholesterol content and/or reduces the
uptake of intestinal cholesterol (Górecka, Korczak, Balcerowski, &
Decyk, 2002; Viuda‐Martos et al., 2010).
Apart from the aforementioned findings, pectin and fibernat were
found to decrease Lp(a) levels. In this context, Veldman et al. (1999)
MOMTAZI‐BOROJENI ET AL.
found that the supplementation of 15 g/day of pectin can reduce
plasma Lp(a) concentrations in hyperlipidemic patients by up to 27%
after a 4‐week intervention. Fibernat is a fiber cocktail containing
70% fenugreek, 15% guar gum, and 15% wheat bran (Venkatesan,
Devaraj, & Devaraj, 2003; Venkatesan, Devaraj, & Devaraj, 2007).
Venkatesan et al. (2007) showed that fibernat supplementation
) for 6 weeks led to Lp(a) decreases by 24.7% in rats
fed an atherogenic diet. Such findings suggest that fibers may
influence plasma Lp(a) levels, although further research is needed to
evaluate the effects of dietary fibers on Lp(a) metabolism.
G. biloba (ginkgo) is one of the most famous herbal remedies and it
has been traditionally used by Chinese clinicians for the treatment of
a variety of pathological conditions, such as asthma, digestive, and
cognitive disorders including memory loss and dementia (Kiefer,
2004). Ginkgo leaves exert antioxidant and anti‐inflammatory
properties (Han, 2005; Yoshikawa, Naito, & Kondo, 1999).
Ginkgo extract was reported to affect Lp(a) levels thus exerting
antiatherosclerotic effects. In detail, 2 months of ginkgo intake (EGb
761; 240 mg/day) led to plasma Lp(a) concentration reduction by
23.4% (Schäfer et al., 2006). Furthermore, ginkgo decreased the
atherosclerotic plaque formation in patients undergoing coronary
artery bypass graft (Rodríguez et al., 2007).
Lp(a)‐lowering effects were suggested to be due to the anti‐
inflammatory properties of ginkgo (Lippi, Targher, & Guidi, 2007).
The extract of ginkgo with a higher amount of active terpenes and
bioﬂavonoids was found to profoundly reduce proinflammatory
cytokines, such as interleukin 6 (IL‐6; He, Zhang, & Yuan, 2005;
Park et al., 2006; Pirro, Bianconi, et al., 2017). The expression of apo
(a) gene is known to be upregulated through acute phase response
via the enhancing effect of IL‐6 on Lp(a) transcription. Mechan-
istically, IL‐6 has a responsive element within the apo(a) gene and can
increase the expression of apo(a) in a dose‐dependent manner,
leading to a 2–4‐folds increase in the hepatic production of Lp(a)
(Ramharack, Barkalow, & Spahr, 1998). Overall, ginkgo extract
containing IL‐6 suppressing compounds can efficiently reduce
atherogenic Lp(a). Therefore, ginkgo may be considered as a potential
Lp(a)‐lowering agent but further investigations are needed to provide
a comprehensive understanding of this effect.
Flaxseed (Linum usitatissimum) is a cholesterol‐lowering plant‐based
nutraceutical that was found to diminish the atherosclerotic lesion
progression (Babu, Mitchell, Wiesenfeld, Jenkins, & Gowda, 2000;
Dupasquier et al., 2006; Dupasquier et al., 2007; Lucas et al., 2002)
and also reduce CVD risk (Rodriguez‐Leyva, Bassett, McCullough, &
Pierce, 2010). Experimental and human interventional studies also
showed Lp(a)‐lowering effects of flaxseed. In an animal study with
female hamsters, Campbell et al. (2013) reported that diet containing
15% and 22.5% flaxseed may reduce plasma Lp(a) levels by 51.1%
and 93.2%, respectively. A double‐blind, randomized, controlled trial
conducted by Bloedon et al., 2008 showed that 10 weeks
supplementation of ground flaxseed (40 g/day) can decrease plasma
Lp(a) concentrations by 14% in hypercholesterolemic patients. In
another double‐blind crossover study on postmenopausal women
with elevated Lp(a) levels, Arjmandi et al. (1998) demonstrated that 6
weeks consumption of whole flaxseed (38 g/day) can lower plasma Lp
(a) levels by 7.4%.
Flaxseed is known to be a rich source of dietary lignans,
potential lipid‐lowering and antioxidant phytoestrogens (Vanhar-
anta et al., 2002), which were associated with a reduced CVD risk
(Vanharanta et al., 1999). Flaxseed is also rich in α‐linolenic acid
(ALA), the plant omega‐3(n‐3) fatty acid which has shown to reduce
plasma cholesterol levels (Chan, Bruce, & McDonald, 1991; Garg,
Wierzbicki, Thomson, & Clandinin, 1989; Harris, 1997) and CVD
risk (Hu et al., 1999; Mozaffarian et al., 2005; Rodriguez‐Leyva
et al., 2010). Soluble fiber is the other main compound of flaxseed,
which is linked to lower cholesterol (Brown, Rosner, Willett, &
Sacks, 1999) and reduced CVD risk (Pereira et al., 2004). Such
findings can support the Lp(a)‐lowering effect of flaxseed, thus
emerging this functional food as a valuable lipid‐managing and
atheroprotective nutritional option.
Red wine and resveratrol
Moderate alcohol consumption, independently of the type of
alcoholic beverage, has been frequently associated with reduced
CVD risk (Ronksley, Brien, Turner, Mukamal, & Ghali, 2011). Alcohol
consumption may also increase HDL‐C and Apo A‐I concentrations
(Brien, Ronksley, Turner, Mukamal, & Ghali, 2011). Among the
alcoholic beverages, red wine contains abundant polyphenolic
compounds, which have been reported to inhibit the progression of
the atherosclerotic lesions (Auger et al., 2005), thus possessing
further benefits on decreasing CVD risk (Costanzo, Di Castelnuovo,
Donati, Iacoviello, & de Gaetano, 2011).
A randomized crossover clinical trial on men with high CVD risk
found that red wine consumption (30 g/day) for 4 weeks could
reduce plasma Lp(a) levels by 12% when compared with the
consumption of dealcoholized red wine and/or gin (Chiva‐Blanch
et al., 2013). Furthermore, resveratrol (trans‐3,40,5‐trihydroxystil-
bene) is one of the predominant natural polyphenols present in red
wine (Sevov, Elfineh, & Cavelier, 2006). Cho et al. (2008) evaluated
the effect of a high‐fat diet containing 0.025% resveratrol on lipid
profile administered for 8 weeks in male Syrian golden hamsters.
Plasma Lp(a) levels were reduced by 60% in the resveratrol‐fed
group compared with the control group (Cho et al., 2008). None-
theless, the potential Lp(a)‐lowering efficacy of alcohol and/or
polyphenols deserves further investigation.
Curcuminoids are therapeutic ingredients of the famous dietary spice
turmeric, which are mainly derived from Curcuma longa. These
MOMTAZI‐BOROJENI ET AL.
polyphenolic natural products are known for various pharmaceutical
properties such as lipid‐lowering, antitumor, immunomodulatory,
anti‐inflammatory, antioxidant, antidepressant, and hepatoprotective
effects (Abdollahi, Momtazi, Johnston, & Sahebkar, 2018; Iranshahi
et al., 2015; Lelli et al., 2017; Mirzaei et al., 2017; Momtazi and
Sahebkar, 2016; Momtazi & Sahebkar, 2016; Momtazi, Derosa, et al.,
2016; Momtazi, Shahabipou, et al., 2016; Panahi, Badeli, et al., 2015;
Panahi, Hosseini, et al., 2015; Rezaee, Momtazi, Monemi, & Sahebkar,
2016; Sahebkar, Cicero, et al., 2016; Sahebkar & Henrotin, 2016;
Sahebkar, 2014; Sahebkar, Serban, Ursoniu, & Banach, 2015;
Strimpakos & Sharma, 2008). With regard to lipids, curcuminoids
may decrease plasma triglycerides and cholesterol (DiSilvestro,
Joseph, Zhao, & Bomser, 2012; Mohammadi et al., 2013a; Panahi
et al., 2016; Panahi, Khalili, Hosseini, Abbasinazari, & Sahebkar,
2014a) and increase HDL‐C concentrations (Ganjali et al., 2017; Soni
& Kuttan, 1992) through modulation of the expression of genes and
the activity of enzymes involved in lipoprotein metabolism. In a
previous randomized controlled trial, we evaluated the effects of
curcuminoids on lipid profile in patients with metabolic syndrome
(Panahi et al., 2014b). The consumption of 1 g/day of curcuminoids
decreased serum Lp(a) levels by 9.7% at the end of the 8 weeks
compared with baseline levels (Panahi et al., 2014b).
Chenodeoxycholic acid (CDCA)
Bile acid CDCA is a natural farnesoid X receptor (FXR) agonist
(Bramlett, Yao, & Burris, 2000; Chiang, Kimmel, Weinberger, & Stroup,
2000), which reduces the biliary secretion of cholesterol and decreases
the cholesterol saturation of bile (Adler, Bennion, Duane, & Grundy,
1975; LaRusso, Hoffman, Hofmann, Northfield, & Thistle, 1975), leading
to the reduction of cholesterol and bile acid synthesis (Kallner, 1975;
LaRusso et al., 1975). Furthermore, CDCA has been found to decrease
hepatic production of VLDL (Angelin, Einarsson, Hellström, & Leijd,
1978; Miller & Nestel, 1974), HMG‐CoA reductase, LDLR, and PCSK9
(Langhi et al., 2008; Nilsson et al., 2007) in human, while plasma levels of
circulating LDL‐C have been often increased (Albers et al., 1982; Perez‐
Aguilar, Breto, Alegre, & Berenguer, 1985).
The most recent published human interventional study show that
CDCA treatment can strongly reduce plasma levels of circulating Lp
(a) that was along with reduction of plasma PCSK9 (Ghosh Laskar,
Eriksson, Rudling, & Angelin, 2017). This finding is supported by
other studies showing a decreased liver production of Lp(a) in
patients with biliary obstruction, in whom FXR signaling is activated
(Chennamsetty et al., 2011). Although exact Lp(a)‐lowering effect of
CDCA is unclear, the reduction in plasma PCSK9 during CDCA
treatment have probably an important role in Lp(a)‐lowering effect of
CDCA (Ghosh Laskar et al., 2017), as far as PCSK9 inhibitors are able
to reduce plasma Lp(a) levels.
Coffee is an aqueous extract of the Coffea plant’s beans, which is
the most widely consumed caffeine‐containing beverage in
western societies (Doepker et al., 2016). Associations between
coffee consumption and plasma lipids levels have been previously
described, suggesting that coffee consumption may increase
plasma LDL‐C and total cholesterol concentrations in a dose‐
dependent manner (Cai, Ma, Zhang, Liu, & Wang, 2012; Jee
et al., 2001).
The lipid‐modulating effects of coffee may be attributed to
kahweol and cafestol, the two diterpenes present in coffee (Heckers,
Gobel, & Kleppel, 1994; Weustenvanderwouw et al., 1994). The
amount of the diterpenes in the coffee is influenced by methods of
coffee preparation. In this context, coffee prepared by paper filters
that trap these diterpenes was shown to have no significant effects
on plasma cholesterol concentrations, while unfiltered coffee was
associated with elevated plasma LDL‐C levels (Cai et al., 2012;
Dusseldorp, Katan, Vliet, Demacker, & Stalenhoef, 1991; Heckers
et al., 1994; Jee et al., 2001; Urgert & Katan, 1997; Urgert et al.,
1995; Weustenvanderwouw et al., 1994).
Taking into consideration the negative effects of coffee on lipid
profile, the evaluation of Lp(a)‐modulating impact of coffee can be
valuable. Several trials investigated the effect of coffee consump-
tion on plasma Lp(a) concentrations. A recent comprehensive
systematic review showed that coffee affects plasma Lp(a)
depending on coffee source, dose, and duration of consumption,
method of preparation, and baseline Lp(a) levels. Interestingly,
short‐term coffee consumption was shown to reduce plasma
Lp(a) concentrations, whereas chronic intake was associated
with elevated plasma Lp(a) levels (Penson, Serban, Ursoniu, &
Table 1 summarizes the changes in Lp(a) levels induced by
natural product supplementation in both clinical and preclinical
LDL‐C‐lowering natural products with no
effect on plasma Lp(a)
Despite affecting LDL‐C, some natural products do not change
plasma Lp(a) levels. There are randomized controlled trials showing
that certain natural products, including berberine (Cicero, Rovati, &
Setnikar, 2007), brazil nut flour (Carvalho et al., 2015), ginger
(Tabibi et al., 2016), garlic (Rysz‐Gorzynska et al., 2016), tea
catechin (Inami et al., 2007), olive oil (Chan, Demonty, Pelled, &
Jones, 2007; Lichtenstein et al., 1993; Perona, Fitó, Covas, Garcia, &
Ruiz‐Gutierrez, 2011), onion (Ebrahimi‐Mamaghani, Saghafi‐Asl,
Pirouzpanah, & Asghari‐Jafarabadi, 2014), palm oil (Fattore, Bosetti,
Brighenti, Agostoni, & Fattore, 2014), rice bran oil (Jolfaie, Rouhani,
Surkan, Siassi, & Azadbakht, 2016), soy proteins and isoflavones
(Hall et al., 2006; Merz‐Demlow et al., 2000; Sacks et al., 2006;
Turhan, Duvan, Bolkan, & Onaran, 2009), phytosterols (Garoufi
et al., 2014; Nigon et al., 2001; Quílez et al., 2003), policosanol
(Dulin, Hatcher, Sasser, & Barringer, 2006; Reiner, Tedeschi‐Reiner,
&Romić, 2005), vitamin C (Loots, Oosthuizen, Pieters, Spies, &
Vorster, 2004), and B group of vitamins (Loots et al., 2004) do not
change Lp(a) concentrations.
MOMTAZI‐BOROJENI ET AL.
TABLE 1 Changes in Lp(a) levels in clinical and preclinical studies with natural product supplementation
Human interventional studies
Interventions Study design Trial protocol % of Lp(a) reduction Weighted mean difference References
L‐Carnitine Meta‐analysis 1–4 g/day for 1 –24 weeks 13–29.3% −8.82 md/dl Serban et al. (2016)
Meta‐analysis 120–300 mg/day for 4–12 weeks 12.5–28.6% −3.54 mg/dl Sahebkar, Simental‐Mendia, Stefanutti,
and Pirro (2016)
Pectin Randomized, placebo‐controlled, and
15 g/day for 4 weeks 27% −96 U/L Veldman et al. (1999)
Ginkgo biloba Long‐term explorative clinical trial 2 × 120 mg/day for 2 months 23.4% −10.4 mg/dl Rodríguez et al. (2007); Schäfer
et al. (2006)
Xuezhikang Randomized and placebo‐controlled trial 1.2 g/day for 6 weeks 23% −67.8 mg/L Liu et al. (2003)
Flaxseed Double‐blind, randomized, and controlled
40 g/day for 10 weeks 12% −4 mg/dl Bloedon et al. (2008)
Red wine Randomized crossover trial 30 g/day for 4 weeks 12% −4.2 mg/dl Chiva‐Blanch et al. (2013)
Curcuminoids Randomized controlled trial 1 g/day for 8 weeks 9.7% −8 mg/dl Panahi et al. (2014a)
Flaxseed Double‐blind crossover trial on
38 g/day for 6 weeks 7.4% −1.96 mg/dl Arjmandi et al. (1998)
Natural products Experimental model Dose of natural product Duration of treatment % of Lp(a) reduction Weighted mean difference References
Flaxseed Hamsters Diet containing 22.5% flaxseed 4 months 93.2% −0.3 mg/dl Campbell et al. (2013)
Diet containing 15% flaxseed 4 months 51.1% −2.15 mg/dl
Resveratrol Hamsters Diet containing 0.025% resveratrol 8 weeks 60% −8.83 mg/dl Cho et al. (2008)
Fibernat Rat 100 g·kg
6 weeks 24.7% −6.8 mg/dl Venkatesan et al. (2007)
Note. Lp(a): lipoprotein(a).
MOMTAZI‐BOROJENI ET AL.
Data from preclinical and clinical studies as well as meta‐analyses
showed that natural products, including L‐carnitine, coenzyme Q
xuezhikang, pectin, fibernat, G. biloba, flaxseed, red wine, resveratrol,
curcuminoids, and CDCA exert significant Lp(a)‐lowering effects.
Efficient Lp(a)‐lowering therapy is achieved with an agent that can
reduce Lp(a) levels to <30 mg/dl in patients with Lp(a) hyperlipoprotei-
nemia(a) (Lp(a) ≥30 mg/dl). Niacin (from 1 to >3 g/day), which is
generally considered as a strong Lp(a)‐lowering agent, can reduce Lp
(a) by 20–40%. Among the aforementioned natural products, L‐carnitine
(1–4g/day), coenzyme Q
(120–300 mg/day), and xuezhikang (1.2 g/
day) were found to decrease elevated plasma Lp(a) levels to <30 mg/dl,
and by 13–29%, 12–29%, and 13–29%, respectively, in patients with
hyperlipoproteinemia(a). Such natural products can be appropriate
alternatives for niacin which has limited clinical use due to adverse
effectssuchasflushing.L‐Carnitine, coenzyme Q
, and xuezhikang are
potential adjuncts to statins, known to lack any meaningful Lp(a)‐
lowering effects. Such natural products are known to be safe and can be
potentially useful in patients on residual cholesterol risk after statin
therapy, as well as in statin‐intolerant patients. Besides, many of the
natural products discussed in this review possess beneficial effects on
other lipids and lipoprotein indices (Cicero et al., 2017). However, the
effects of these natural products on CVD risk should be further
evaluated in robust randomized controlled trials. Other natural
products, including pectin, ginkgo, flaxseed, red wine, resveratrol,
curcuminoids, and CDCA have been shown to significantly lower
plasma Lp(a) levels in patients with Lp(a) <30 mg/dl but their efficacy in
hyperlipoproteinemia(a) is unknown.
CONFLICTS OF INTEREST
M. B. has served on the speaker’s bureau and as an advisory board
member for Amgen, Sanofi, Aventis, and Lilly. N. K. has given talks,
attended conferences, and participated in trials sponsored by Amgen,
Angelini, Astra Zeneca, Boehringer Ingelheim, Galenica, MSD,
Novartis, Novo Nordisk, Sanofi, and WinMedica. K. R. received
research grant from Sanofi, served on the speaker’s bureau and as an
advisory board member for Sanofi, Astra Zeneca, and Pfizer. The
authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial
conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
Niki Katsiki http://orcid.org/0000-0003-0894-2644
Matteo Pirro http://orcid.org/0000-0002-5527-4821
Amirhossein Sahebkar http://orcid.org/0000-0002-8656-1444
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How to cite this article: Momtazi‐Borojeni AA, Katsiki N,
Pirro M, Banach M, Rasadi KA, Sahebkar A. Dietary natural
products as emerging lipoprotein(a)‐lowering agents. J Cell
Physiol. 2019;1–14. https://doi.org/10.1002/jcp.28134
MOMTAZI‐BOROJENI ET AL.