Functional food ingredients as adjunctive therapies to pharmacotherapy for treating disorders of...

review ArTiCLe

Functional food ingredients as adjunctive therapies to pharmacotherapy for treating disorders of metabolic syndrome

Christopher p. F. Marinangeli & peter J. h. Jones

The Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, 196 Innovation Drive, Winnipeg, Manitoba, R3T 2N2, Canada

Annals of Medicine, 2010; 42: 317–333

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Abstractinformation regarding the use of functional foods and nutraceuticals (FFn) in combating disease is rarely communicated to health care practitioners as medicinal strategies for patients. Metabolic syndrome (Mets) is an ideal paradigm for dem-onstrating the therapeutic properties of FFn. encompassing multiple etiologies, including atherogenic dyslipidemia, insu-lin resistance, and hypertension, Mets affects over a third of american adults. however, as disease-related risk factors accumulate over time, guidelines for treating disorders of Mets progressively de-emphasize the use of FFn. Using marine omega-3 fatty acids, plant sterols, fiber, and tomato extract as examples, the purpose of this review is to endorse FFn as long-term adjunctive therapies to pharmaceutical treatment for disorders and risk factors for Mets. an additional goal is to compare physiological and molecular targets of FFn against corresponding prescription medications. results reveal that FFn are viable treatment strategies for disorders of Mets, complementing pharmacological interventions by targeting and improving the biological processes that foster the development of disease. thus, efficacious FFn therapies should be emphasized throughout all stages of treatment as adjuncts to pharmacotherapy for disorders of Mets. accordingly, new developments in FFn research must be implemented into clinical guidelines with the prospect of improving disease prog-noses as accessories to prescription medications.

Key words: Functional foods, hypercholesterolemia, hypertension, hypertriglyceridemia, insulin resistance, metabolic syndrome, nutraceutical

introduction

nutraceuticals are bioactive compounds that confer protection from chronic disease via mechanisms beyond simply providing nutrition. a food becomes ‘functional’ when levels of one or more nutraceuticals are present at concentrations such that regular con-sumption elicits a positive biological effect. nonethe-less, nutraceuticals can also be isolated from functional foods and added to other food matrices or concen-trated for distribution in capsules or tablets. similar to pharmaceutical agents, research clearly demonstrates that functional foods and nutraceuticals (FFn) pos-sess physiological and molecular targets that modulate clinical end-points associated with chronic disease. Despite current research demonstrating that FFn

Correspondence: Dr peter J. h. Jones phD, richardson Centre for FunctionWinnipeg, MB r3t 2n2, Canada. Fax: 1 204 474 7552. e-mail: peter_jone

(Received 28 November 2009; accepted 30 March 2010)

issn 0785-3890 print/issn 1365-2060 online © 2010 informa UK ltd.Doi: 10.3109/07853890.2010.484026

combined with pharmaceuticals can benefit patients better than pharmaco-monotherapy (1–3), informa-tion regarding the efficacy of FFn-based therapies is rarely communicated to health care practitioners and implemented into disease treatment regimens. Meta-bolic syndrome (Mets) is an ideal and timely example for asserting FFn efficacy in treating chronic disease given that Mets is a multifaceted ailment affecting a third of american adults (4).

Mets is characterized as a combination of medi-cal disorders including central obesity, insulin resis-tance (ir), hypertension, as well as atherogenic dyslipidemia, itself characterized as hypertriglyceri-demia (htg), low hDl-C and high levels of circu-lating small dense lDl-C (sdlDl) (5,6) (Figure 1).

al Foods and nutraceuticals, University of Manitoba, 196 innovation Drive, [email protected]

318 C. P. F. Marinangeli & P. J. H. Jones

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Abbreviations

aBCg atp-binding cassette g transportersaMp adenosine monophosphateaMpK aMp-activated protein kinaseatp adenosine triphosphateBp blood pressureCVD cardiovascular diseaseDBp diastolic blood pressureDha docohexaenoic acidepa eicosapentaenoic acidFDa U.s. Food and Drug administrationFFn functional foods and nutraceuticalsFXr farnesol X receptorglUt-1 glucose transporter 1gpr g-coupled proteinshCh hypercholesterolemiahDl high-density lipoproteinhMg-Coa 3-hydroxy-3-methylgutaryl-

coenzyme ahnF-4a hepatocyte nuclear factor 4ahtg hypertriglyceridemiair insulin resistanceJnCBp the Joint national Committee on prevention,

Detection, evaluation, and treatment of high Blood pressure

lDl low-density lipoproteinlDl-C low-density lipoprotein cholesterollXr liver X receptorMets metabolic syndromeMoM-3 marine-derived omega-3 fatty acidsnaDph nicotinamide adenine dinucleotide phosphatenCep the national Cholesterol education programneFa non-esterified fatty acidsnFκB nuclear factor kappa-light-chain-enhancer of

activated B cellsno nitric oxideppar peroxisome proliferator-activated receptorrs resistant starchsBp systolic blood pressuresCFa short-chain fatty acidssdlDl small dense low-density lipoproteinsreBp 1c sterol regulatory element-binding protein 1ctg triglycerideVlDl very-low-density lipoproteinVlDl-C very-low-density lipoprotein cholesterol

Key messages

similar to pharmaceutical agents, func- •tional foods and nutraceuticals (FFn) possess phy siological and molecular targets that modulate clinical end-points associated with chronic disease. Despite current research demonstrating that FFn combined with pharmaceuticals can benefit patients better than pharmaco-monotherapy, FFn-based therapies are de-emphasized as risk factors for chronic disease accumulate over time.in the context of metabolic syndrome, a •multifaceted disease state, FFn including marine-derived omega-3 fatty acids, plant sterols, fiber, and tomato extract have been shown to target metabolic processes associ-ated with atherogenic dyslipidemia, hyper-cholesterolemia, insulin resistance, vascular dysfunction, and hypertension.FFn should be emphasized throughout all •stages of treatment as adjuncts to pharma-cotherapy. For this to happen, however, new developments in FFn research must be communicated to health care practitio-ners and implemented into clinical guide-lines so that they may be utilized by modern medicine as tools for combating disease.

hypercholesterolemia (hCh), more specifically high levels of circulating low-density lipoprotein choles-terol (lDl-C), has been described as a therapeutic target for atherogenic dyslipidemia (6,7). Moreover, patients with Mets demonstrate an progressive trend towards lower antioxidant activity with onset of Mets co-morbidities (8). Finally, antioxidant status has been associated with the pathogenesis of ir and hypertension (9). Clinical guidelines such as the national Cholesterol education program (nCep) and the Joint national Committee on prevention, Detection, evaluation, and treatment of high Blood pressure (JnCBp) recommend a spectrum of life-style and pharmaceutical therapies for treating spe-cific disorders of Mets (7,10). While life-style interventions are emphasized during the initial stages of treatment for Mets-related disorders, dietary inter-ventions, specifically FFn, become overshadowed by pharmacological agents as risk factors for chronic dis-ease accumulate over time. For example, current nCep guidelines recommend plant sterols and stanols (ps) as therapeutic options to clinicians for reducing circulating levels of lDl-C. however, ps are not emphasized as a constituent of the therapeutic life-style Change Diet or during the later stages of hCh treatment (7). similarly, the JnCBp’s algorithm

for the treatment of hypertension accentuates a com-bination of pharmacological agents when blood pres-sure levels (Bp) are 140/90 mmhg with no mention of FFn (10). in addition, the JnCBp advocates the use of additional drugs until an ideal Bp is achieved. that being said, specific FFn have been identified as efficacious and safe adjunctive therapies for disorders of Mets. noteworthy are supplemental marine-derived omega-3 fatty acids (MoM-3) and ps. the former has been shown to be a potent treatment for htg as well as possess secondary cardio-protective benefits including improvements in antioxidant sta-tus, vascular function, and inflammatory biomarkers. the latter is an efficacious treatment for hCh, a fact that is supported by over 50 years of research. other

Functional foods as adjuncts to pharmacotherapy 319

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FFn showing promise include sup plemental fiber for treating ir and tomato extracts for hypertension.

accordingly, the first objective of this review is to describe the efficacy of MoM-3, ps, fiber, and tomato extract in reducing htg, hCh, ir, oxidative stress, hypertension, and improving vascular function (Figure 1). the second objective is to provide a com-parison of physiological, metabolic, and molecular targets between the described FFn and corre-sponding prescription medications currently used for treating disorders of Mets. Finally, this review will discuss studies that have examined the use of pharma-cological agents in conjunction with FFn therapies for treating htg, hCh, ir, and hypertension.

Marine-derived omega-3 fatty acids, triglycerides, and vascular health

Marine-derived omega-3 fatty acids for the treatment of hypertriglyceridemia

supplemental MoM-3, eicosapentaenoic acid (C20: 5n-3) (epa), and docohexaenoic acid (22:6n-3) (Dha) have been shown to be efficacious in treating htg (11). effects of MoM-3 on circulating triglyc-eride (tg) concentrations are dose-dependent, with tg-lowering efficacy being demonstrated with dos-ages ranging from 1.3 to 12.0 g/d (12–15). in a com-prehensive review of 65 human clinical studies, harris et al. (16) demonstrated that MoM-3 consis-tently reduce tg levels by 25% and 34% in normal

and htg patients, respectively, concluding that additional trials are no longer needed to demonstrate MoM-3’s tg-lowering efficacy. Concerns regarding the safety of supplemental MoM-3 stem from greenland inuit peoples having significantly longer bleeding times (17). however, in a dose-dependent study whereby MoM-3 was administered at 4.5, 7.5, and 12 g/d, blood coagulation times only increased when volunteers received the highest dose of MoM-3 (14). hence, 3–4 g/d of supplemental MoM-3 can be regarded as a safe and efficacious treatment for htg.

Medications versus marine-derived omega-3s for the treatment of hypertriglyceridemia: mechanisms of action

primary medications used to treat htg include statins and fibrates. as 3-hydroxy-3-methylgutaryl-coenzyme a (hMg-Coa) reductase inhibitors, sta-tins inhibit hepatic cholesterol synthesis. Unlike statins, fibrates are ligands for nuclear receptors, activating hepatic peroxisome prolifer ator-acti-vated receptor-a (ppar-a) and inhibiting hepato-cyte nuclear factor 4a (hnF-4a), resulting in higher lipoprotein lipase levels, high-density lipoprotein cholesterol (hDl-C) levels, fatty acid b-oxidation, as well as reduced very-low-density lipoprotein (VlDl) secretion and lower expression of genes involved in carbohydrate and lipid metabolism (18–20) (table i).

Figure 1. Mets as a multifaceted disease encompassing central obesity, atherogenic dyslipidemia, hypertension, and insulin resistance. low antioxidant status can contribute to the development of hypertension and insulin resistance, while hypercholesterolemia, specifically high lDl-C, is a primary target for atherogenic dyslipidemia.


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MoM-3 reduce tg levels by modulating the expression of nuclear receptors. alongside an increase in ppar-a and inhibition of hnF-4a gene expression, MoM-3 up-regulate and down-regulate farnesol X receptor (FXr) and liver X receptor (lXr) expression, respectively, resulting in an inhi-bition of sterol regulatory element-binding protein 1c (sreBp 1c) activity and expression (21). sreBp 1c up-regulates the expression of genes involved i n tg synthesis (21–23). together, the effects of MoM-3 on FXr and ppar-a also enhance hepatic tg uptake and tg oxidation, respectively (21). altogether, MoM-3 act on similar molecular targets to pharmaceutical therapy to modulate intra-cellular tg metabolism and decrease circulating tg levels (table i).

Medications versus marine-derived omega-3 fatty acids on oxidant status, vascular function, and inflammation

statins have been shown to reduce C-reactive pro-tein by 67% (24), Dna damage by 20% to 40% (25,26), superoxide anion by 36% (27), auto- antibodies against lDl oxidation by 19% (28), and conjugated diene production by 41% (29). increases in glutathione peroxidase activity by 38% (29), paraoxonase levels by 32% (30), a-tocopherol levels by 29% and retinol levels by 40% (31) have also been observed with statin therapy. statins enhance vascular function by inhibiting thromboxane a2 production and inducing vasodilation via increasing nitric oxide synthase levels (32). additional cardio-protective effects of statins include increased circulating hDl-C levels 3% to 10% (33,34) as well as reductions in sdlDl 24% to 57% (35–38). Compared to large lDl subfractions, sdlDl are better able to infiltrate arteriole walls, possess higher susceptibility to oxidation, and thus initiate develop-ment of atherosclerotic plaques. given that oxidative stress promotes inflammation and has been linked to atherosclerosis (39) and cancer (40,41), statins have been given considerable attention for promoting

improvements in oxidative biomarkers in conjunc-tion with their lipid-lowering properties.

similar to statins, MoM-3 supplementation has been shown to improve antioxidant status via increasing glutathione peroxidase by 30% (42). supplemental MoM-3 have also been shown to reduce lipid peroxidation by 19% (42), ultraviolet light-induced Dna damage by 70%, and p53 gene expression by 50% (43). MoM-3 consumption also fosters the production of anti-inflammatory signal-ing molecules including trienoic prostaglandins and 5-series leukotrienes while reducing levels of urinary F2-isoprostanes (44). products of omega-6 fatty acid oxidation, F2-isoprostanes are biomarkers for the production of pro-inflammatory dienoic prostaglan-dins (45). MoM-3 promote vasodilation by inhibit-ing thromboxane a2 production and promoting thromboxane a3 and B3 synthesis (45,46). in addi-tion, nomura et al. (47) showed that supplementa-tion with 1.8 g/d epa significantly reduced markers of coagulation including CD62p, CD63, annexin V, as well as platelet and monocyte-derived micropar-ticles, which are prothrombotic. in the same study, epa decreased e-selectin levels, a biomarker of vas-cular damage (47). Finally, MoM-3 have been shown to reduce levels of sdlDl by 21% to 37% (48,49) and remnant-like lipoprotein particles by 21% (50), which, as outlined above, are both athero-sclerotic. therefore, MoM-3 can be considered a valuable means for improving vascular function.

Combining marine-derived omega-3 fatty acids and medications as adjunctive treatments for hypertriglyceridemia and other risk factors for cardiovascular disease

recent studies have emerged advocating adjunctive statin/MoM-3 therapy for treating htg. the extent to which MoM-3 amplify the tg-lowering effects of statin monotherapy is demonstrated in table ii, showing that combination MoM-3/statin treatments reduce tg an additional 10% to 30% compared with statin therapy alone (1,51–57). Combination

table i. summary comparison of triglyceride-lowering mechanisms of action between marine-derived omega-3 fatty acids and prescription medications.

hypertriglyceridemia

Functional food and nutraceuticals prescription medication

Marine-derived omega 3 fatty acids: Statins:

↑ ppar-a expression↑ FXr expression↓ lXr expression↓ hnF-4a expression

↓ sreBp 1c↓ tg synthesis↑ tg oxidation

hMg-Coa reductase inhibition

Fibrates:

↑ ppar-a activity↓ hnF-4a activity

↑ tg oxidation↓ tg synthesis

FXr farnesol X receptor; hMg-Coa 3-hydroxy-3-methylgutaryl-coenzyme a; hnF hepatocyte nuclear factor; lXr liver X receptor; ppar peroxisome proliferator-activated receptor; sreBp 1c steroid regulatory element binding protein 1c; tg triglyceride.

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tab

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.


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therapy has also been shown to further reduce levels of total circulating cholesterol (24% to 230%) (1,52,54,55), VlDl-C (220% to 240%) (1,52,53), VlDl-tg (253%) (56), apoB100 (232%), and apoB48 (236%) (56), as well as increase hDl-C levels (4% to 18%) (1,52,56) compared to statins alone. these findings indicate that MoM-3 therapy may help improve patients’ overall lipid profiles. in addition, combining MoM-3 with pitavastatin was shown to synergistically improve vascular function by reducing prothrombotic platelet-derived micropar-ticles as well as increasing levels of adiponectin (58). adiponectin increases no levels, promoting vasodi-lation (59,60), as well as decreases monocytes from adhesion to endothelial cells (61). Furthermore, 3.6 g/d MoM-3 further reduced tg and homocysteine levels 28% and 29%, respectively, in patients already receiving statin and fibrate therapy (57). recently lovaza® became the first prescription MoM-3 sup-plement approved by the U.s. Food and Drug administration (FDa), substantiating the notion that FFn are potent therapies for treating disorders of Mets. the above studies highlight MoM-3 as a potent complementary therapy to pharmacological medications for htg and other cardiovascular risk factors.

Plant sterols/stanols and hypercholesterolemia

Plant sterols and stanols as treatments for hypercholesterolemia

in 1954, Best et al. (62) first demonstrated that supplemental ps reduce total cholesterol levels in humans. since then, over 100 clinical trials have shown that ps consumption significantly decreases lDl-C by 5% to 15% (63). a recent meta-analysis

confirmed that ps-derived reductions in lDl-C are dose-dependent with maximum efficacy peaking at 2.0–2.5 g/d (64). typically, food-based vehicles are used to administer ps. however, ps capsules are available and have also been shown to be efficacious for reducing lDl-C (65,66).

Medications versus plant sterols for the treatment of hypercholesterolemia: mechanisms of action

statins, bile acid resins, niacin, and cholesterol absorption inhibitors (ezetimibe) are among the most popular treatments for hCh (table iii). as outlined above, statins inhibit hepatic cholesterol synthesis, while bile acid resins bind bile and inhibit cholesterol reabsorption in the large intestine (67). niacin reduces hepatic lipid synthesis and adipo-cyte lipolysis (68). ezetimibe reduces biliary cho-lesterol absorption by interacting with enterocyte niemann-pick C1-like protein 1 transporters, resulting in an increase in hepatic lDl uptake (67). similar to ezetimibe ps are believed to displace dietary cholesterol from being incorporated into mixed micelles in the small intestine (69) (table iii). absorption of ps into the circulation is poor at 0.1%–1.9% (70) thus the majority of ps action occurs in the lumen through competition. evidence suggests that ps act as lXr agonists and induce the expression of enterocyte atp-binding cassette g transporters (71) which subsequently pump ps from the enterocytes back into the gastrointestinal lumen (72).

Medications and plant sterols: mechanisms for reducing vascular plaque formation

the lDl-C-lowering effects of ps and statins may also confer protection against the formation of

table iii. summary comparison of lDl-lowering mechanisms of action between plant sterols and stanols and prescription medications.

hypercholesterolemia


Plant sterols and stanols: Statins:

↑ Displacement of dietary cholesterol

↓ Cholesterol absorption ↓ hMg-Coa reductase activity

Niacin:↓ hepatic cholesterol synthesis↓ adipose tissue lipolysis

↑ lXr ↑ aBCg transporters Cholesterol absorption inhibitors (ezetimibe):

↓ Cholesterol absorption via niemann-pick C1-like protein 1 transporters

↑ hepatic lDl uptake

Bile acid resins:Bind negatively charged bile acid in the gastrointestinal tract

aBCg atp-binding cassette g transporter; hMg-Coa 3-hydroxy-3-methylgutaryl-coenzyme a; lDl low-density lipoprotein; lXr liver X receptor.

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atherosclerotic plaques via nuclear factor kappa-light-chain-enhancer of activated B cells (nFκB) and monocyte chemoattractant protein-1 (MCp-1) path-ways. lDl-cholesterol levels have been shown to increase MCp-1 expression directly as well as indi-rectly via nFκB. endothelial expression of MCp-1 has been implicated for increasing vascular lipid accu-mulation, macrophage recruitment, and atheroscle-rotic plaque growth (73). studies demonstrate that statin treatment decreases atherosclerotic plaque for-mation alongside reduced nFκB and MCp-1 expres-sion (74–76). although not demonstrated in vivo, in vitro experiments show that ps inhibited MCp-1 pro-duction in umbilical venous endothelial cells treated with oxidized lDl (77). the authors hypothesize that ps could modulate nFκB activity or expression and would suggest that, similar to statins, ps reduce MCp-1 through lDl-C-lowering and nFκB-related pathways. Further studies are needed to determine if combination ps/statin therapy can produce an addi-tive effect on MCp-1 expression.

Combining plant sterols/stanols and prescription medications as adjunctive treatments for hypercholesterolemia

the magnitude of ps/statin therapy on lDl-C is demonstrated in table iV. studies reveal that when ps are combined with statins, lDl-C levels are reduced an additional 5% to 17%, compared to sta-tins alone (3,65,78–82). ps efficacy is not affected by the type or dose of statin administered, with lDl-C reductions being observed in patients taking simvas-tatin, lovastatin, atorvastatin, pravastatin, fluvastatin, rosuvastatin, and cerivastatin (3,65,78–82). simons et al. (81) demonstrated that combination ps/statin therapy is additive, reducing lDl-C levels by 39%, which is equivalent to the effect of doubling the dose of statins. Furthermore, the proportion of patients with lDl-C levels 4 mmol/l increased from 33% in subjects receiving statins alone to 67% and 72% for patients receiving combination statin/plant sterol or statin/plant stanol therapy, respectively (80). plant sterols should be touted as a safe and efficacious adjunctive therapy to statin treatment for hCh, a major contributor to the development of Mets.

the area of concomitant ps therapy with other hCh medications has been understudied. ezetimibe/ps therapy has been found to reduce lDl-C levels 25%, but was insignificant compared to ezetimibe therapy alone (222%) (83). given that ps and ezetimibe both inhibit cholesterol absorption it is possible that the effects of ps on lDl-C were over-shadowed by the action of ezetimibe. Conversely, ps/fibrate therapy has been shown to reduce lDl-C levels 11.1% compared to 7.7% after ps therapy

alone (84). studies combining ps with bile acid sequestrants or niacin have yet to be published. Undoubtedly, further research exploring the benefits of using ps together with lipid-lowering medications other than statins is warranted. Until then, patients prescribed statin medications can be advised, with confidence, to ingest ps to produce greater reduc-tions in lDl-C compared to statins alone.

Fiber and insulin resistance

Soluble and insoluble fiber and resistant starch as treatments for insulin resistance

recently soluble fiber, insoluble fiber, and resistant starches have been explored for their effects on ir. insulin resistance, a Mets co-morbidity, has been long associated with the development of other metabolic disorders and disease risk factors, includ-ing polycystic ovary syndrome, type ii diabetes, cardiovascular disease (CVD), hypertension, obesity, and inflammation (85,86). as such, in 1992, rupp et al. (87) emphasized the need for dietary interven-tions that target and subsequently reduce ir. recent insights into the biological effects of non-digestible carbohydrates suggest fibers can signifi-cantly improve ir.

epidemiological studies have found associations between fiber intake and ir. a case-control study showed that higher consumption of soluble fiber amongst vegetarians from whole grains, pulses, oats, and barley preserved insulin sensitivity independent of age (88). on the other hand, non-vegetarians began to show evidence of ir between 31 and 40 years of age (88). Cross-sectional data from the Framingham offspring Cohort noted an inverse association between cereal fiber intake and ir (89), while a cross-sectional analysis of men and women from the inter99 study showed a relationship between low-fiber consumption and the probability of devel-oping ir (90).

an association between supplemental fiber intake and ir has also been shown in randomized clinical trials. studies utilizing euglycemic-hyperinsulinemic clamps demonstrate a 14% and 8% decrease in ir with resistant starch and cereal fiber, respectively (91,92). Moreover, homeostasis-modeling assess-ment, a non-invasive method for measuring ir using fasted blood samples, showed a 33% and 24% reduc-tion in ir after 3 weeks of consuming 3 g/d b-glucan and 4 wks of a fiber-rich (20 g/d) meal replacement beverage, respectively (93,94). similarly, despite no effect on postprandial glycemia, high-fiber bread increased postprandial insulin economy (95). Fur-thermore, using the minimal model index as a mea-sure of ir, 60 g/d resistant starch ingested 24 hrs prior to a fiber-free meal was shown to decrease


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tab

le i

V. s

umm

ary

of s

tudi

es s

how

ing

plan

t st

erol

s an

d st

anol

s as

a b

enefi

cial

adj

unct

ive

ther

apy

to s

tati

n th

erap

y fo

r th

e tr

eatm

ent

of h

yper

chol

este

role

mia

.

ref

eren

cen

tim

et

reat

men

tsp

roto

col

eff

ect

on l

Dl

- C

lev

els

sim

ons

et a

l. (8

1)15

2h

Ch

4 w

ksp

lace

bo

cont

rol

mar

gari

nep

lace

bo

ps

(st

erol

)s

tati

n

cont

rol

mar

gari

nes

tati

n

ps

(st

erol

) m

arga

rine

sub

ject

s w

ere

rand

omly

ass

igne

d to

one

int

erve

ntio

n.

the

tes

t st

atin

was

Ce

riV

pla

cebo

co

ntro

l:

2%p

lace

bo

ps

: 2

8%s

tati

n

cont

rol:

232

%s

tati

n

ps

: 2

39%

gol

dber

g et

al.

(65)

26 hl

9 w

kss

tati

n

pla

cebo

sta

tin

p

s t

able

t (s

tano

l) (

1.8

g/d)

sub

ject

s on

sta

ble

stat

in t

reat

men

t fo

r 9

0 d.

sub

ject

s w

ere

rand

omly

ass

igne

d to

one

int

erve

ntio

ns

tati

n

pla

cebo

:

3%s

tati

n

ps

: 2

6%B

lair

et

al.

(3)

146

hl

8 w

kss

tati

n

cont

rol

mar

gari

nes

tati

n

ps

(st

anol

) m

arga

rine

(5.

1 g/

d)s

ubje

cts

on s

tabl

e st

atin

tre

atm

ent

for

90

d (s

iMV

, p

ra

V, a

to

rV

, l

oV

) w

ere

rand

omly

ass

igne

d to

one

in

terv

enti

on

sta

tin

co

ntro

l: 2

7%s

tati

n

ps

: 2

17%

Cas

tro

Cab

ezas

et

al.

(78)

20 hl

6 w

kss

tati

n (8

0 m

g/d)

co

ntro

l m

arga

rine

sta

tin

(80

mg/

d)

ps

(st

anol

)m

arga

rine

(3

g/d)

sub

ject

s re

ceiv

ing

max

imal

dos

e of

at

or

V o

r s

iMV

th

erap

y (8

0 m

g/d)

for

6

mo

wer

e ra

ndom

ly a

ssig

ned

to o

ne i

nter

vent

ion

sta

tin

co

ntro

l: 2

8%s

tati

n

ps

: 2

16%

de J

ong

et a

l. (7

9)54 h

Ch

85 w

kss

tati

n

cont

rol

mar

gari

nes

tati

n

ps

(st

erol

) m

arga

rine

(2.

5 g/

d)s

tati

n

ps

(st

anol

) m

arga

rine

(2.

5 g/

d)

sub

ject

s on

sta

tin

ther

apy

(pr

aV

, s

iMV

, at

or

V,

ro

sU

V,

Fl

UV

) 8

5 w

ks w

ere

rand

omly

ass

igne

d on

e in

terv

enti

on

Con

trol

: n/

cp

s (

ster

ol):

29%

ps

(st

anol

): 2

13%

Ket

omak

i et

al.

(80)

18 Fh

4 w

kss

tati

n

ps

(st

anol

) m

arga

rine

(2

g/d)

sta

tin

p

s (

ster

ol)

mar

gari

ne (

2 g/

d)s

ubje

cts

rece

ivin

g st

atin

tre

atm

ent

(siM

V,

pr

aV

, a

to

rV

, l

oV

) fo

r se

vera

l ye

ars

rece

ived

bot

h in

terv

enti

ons

sta

tin

ps

(st

anol

): 2

15%

sta

tin

p

s (

ster

ol):

214

%

tak

eshi

ta e

t al

. (8

2)61 h

Ch

12 w

kst

g o

ilD

ag

oil

Da

g o

il

ps

(4%

)

sub

ject

s re

ceiv

ing

pr

aV

(10

mg/

d)

4 w

ks w

ere

rand

omly

ass

igne

d to

one

int

erve

ntio

n. s

ubje

cts

repl

aced

the

ir r

egul

ar c

ooki

ng o

il w

ith

a tr

eatm

ent

oil

tg

: n/

cD

ag

: n/

cD

ag

p

s:

25%

at

or

V

ator

vast

atin

; C

er

iV

ceri

vast

atin

; D

ag

d

iacy

lgly

cero

l; h

Ch

h

yper

chol

este

role

mia

; h

l

hyp

erlip

idem

ia;

Fh

fa

mili

al h

yper

chol

este

role

mia

; F

lU

V

fluv

asta

tin;

lD

l-C

lo

w-

dens

ity

lipop

rote

in c

hole

ster

ol;

lo

V

lova

stat

in;

n/c

no

chan

ge;

pr

aV

p

rava

stat

in;

ps

p

lant

ste

rol/s

tano

l; r

os

UV

ro

suva

stat

in;

siM

V

sim

vast

atin

; tg

= t

rigl

ycer

ides

.


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postprandial ir 69%, compared to controls (96). resis-tant starch has also been shown to increase muscle and adipose glucose clearance by 44% and 87%, respectively (91). in another study, lack of effect of 1.5 g/d b-glucan on ir could have been secondary to the low dose administered to subjects (97). an acute dose-dependent study demonstrated that only the maximum dose of 10 g/d b-glucan was able to blunt postprandial insulin responses, despite no effect on postprandial glucose response (98). overall, data suggest that the dose and duration of intake of fiber impact when and if changes in ir will be observed.

Fibers versus prescription medications for treating insulin resistance: mechanisms of action

in addition to treating hyperglycemia, metformin and thiazolidinediones are prescription medications that have also been shown to decrease ir. the exact mechanisms by which metformin reduces ir remain to be completely understood. studies suggest that met-formin stimulates adenosine monophosphate (aMp)- activated protein kinase (aMpK) (99–101), tyrosine kinase phosphorylation at the b-subunit on the insulin receptor (102–104), as well as muscle atypical protein kinase C activation (105). similar to metformin, thiazolidinediones activate aMpK (106) (table V). Moreover, thiazolidinediones target adipose tissue and act as a ppar-g ligand (107), reducing free fatty acid release (108) as well as the expression of ir-related substances such as leptin (109), tumor necro-sis factor (tnF)-a (110,111), and resistin (112). it has also been suggested that thiazolidinediones decrease inhibitory insulin receptor substrate protein

1 serine phosphorylation (113) and increase glucose disposal via higher expression of glucose transporter (glUt)-1 in adipose (114) and skeletal muscle (115).

short-chain fatty acids (sCFa), primarily acetate, butyrate, and propionate, are metabolites of microbial fermentation of dietary fiber in the large intestine and are thought to be important signaling molecules responsible for fiber-mediated decreases in ir (116). since high levels of circulating non-esterified free fatty acids (neFa) have been linked to ir (117), it has been suggested that sCFa reduce circulating neFa (table V). Conclusive evidence of this phenomenon has yet to be presented in vivo. however, compared to controls, robertson et al. (91) observed a signifi-cant increase in sCFa production in subjects con-suming 30 g/d rs alongside an increase in propionate and acetate uptake by adipose and muscle tissue, respectively. at the same time, subjects noted a decrease in adipose-derived neFa and an increase in skeletal muscle and adipose glucose clearance. inter-estingly, robertson et al. also observed an increase in circulating ghrelin after resistant starch (rs) supple-mentation (91) and noted that higher ghrelin levels associate with reduced ir (118–120). rat adipocytes showed an increase in ppar-g expression and lipo-genesis after cells were treated with ghrelin (121). Moreover, recent studies point towards sCFa acting as ligands for adipose g-coupled proteins (gpr). robertson (116) has also suggested that interactions between sCFa and adipose gpr43 could be of importance in decreasing neFa levels while stimulat-ing adipogenesis (122) and adipocyte differentiation (123). adipocyte differentiation has been implicated

table V. summary comparison of insulin resistance-lowering mechanisms of action between fiber and prescription medications.

insulin resistance


Fiber: Metformin:↑ sCFa production ↓ neFa

↑ skeletal muscle glucose uptake↑ adipose glucose uptake↑ Mitochondrial biogenesis↑ adaptive thermogenesis↑ Fat oxidation?↓ adiposity?↑ adipocyte differentiation

aMpK activationMuscle atypical protein kinase C activationphosphorylation of tyrosine kinase at the b-subunit on the

insulin receptor

Thiazolidinediones:aMpK activation↓ inhibitory insulin receptor substrate protein 1 serine

phosphorylation↑ glUt-1 in muscle and adipose tissue

↑ ghrelin ↑ ppar-g↑ lipogenesis

ppar-g ligand ↓ neFa↓ leptin↓ tnF-a↓ resistin

↓ hepatic glucose output

aMpK aMp-activated protein kinase; neFa non-esterified fatty acids; ppar-g peroxisome proliferator receptor gamma; sCFa short-chain fatty acids; tnF-a tumor necrosis factor alpha.

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in decreasing ir, since adipocyte size inversely cor-relates with ir (124,125). sCFa secondary to micro-bial fermentation of supplementary fiber may thus modulate ir by targeting adipose tissue metabolism.

Muscle and hepatic carbohydrate metabolism have also been implicated as possible sites of action for fiber-derived sCFa for decreasing ir. in fact, thorburn et al. (126) attributed colonic carbohy-drate fermentation of barley after an evening meal to a reduction in hepatic glucose output during an oral glucose tolerance test the following morning. rats fed psyllium showed a significant reduction in ir combined with an increase in skeletal muscle glUt-4 transporters (127). enhanced skeletal muscle 5’ aMp-activated protein kinase in mice sup-plemented with butyrate was reflected with an increase in adaptive thermogenesis, fat oxidation, mitochon-drial activity, and biogenesis in muscle and brown adipose as well as reduced adiposity (128). overall, available evidence suggests that sCFa produced during colonic fermentation of fibers reduces ir by mechanisms acting in adipose, liver, and muscle.

Combining fibers and prescription medications as adjunctive treatments for insulin resistance

to date, combining fiber and prescription medica-tion for treating ir has yet to be explored. it is there-fore worth noting that testing such a combination for potential additive or synergistic effects on adi-pose, muscle, and hepatic tissues would be highly important for developing treatment strategies for Mets. studies outlined above support the notion that dietary fibers possess similar as well as diverse molecular targets compared to medications, suggest-ing that combination fiber/pharmaceutical therapies would positively modulate various facets of insulin metabolism and reduce ir.

Tomato extract and hypertension

Tomato extract as a treatment for hypertension

having an elevated blood pressure 135/85 mmhg is considered a co-morbidity for Mets (5). recently, tomato extract has shown promise as a treatment for grade 1 hypertensive and pre-hypertensive patients. Following a 4 wk placebo, grade 1 hypertensive patients were given a tomato extract for 8 wks. the major constituent of the 250 mg supplement was lycopene at 15 mg/capsule suspended in tomato oil. in addition, the lycopene content in one capsule is reported to be equivalent to six large tomatoes. other substances included vitamin e (6 mg), b-carotene (0.4 mg), and ps (1.5 mg). the tomato-based sup-plement reduced systolic (sBp) and diastolic blood pressure (DBp) 7% and 6%, respectively (129).

When given the placebo for a second time, blood pressure reverted back to levels observed prior to receiving the tomato-based treatment, strongly sug-gesting that the tomato extract was the efficacious agent (129). in a follow-up study by paran et al. (2), the same tomato-derived supplement reduced sBp from 139.4 mmhg to 130.0 mmhg (26%) and DBp from 79.8 to 76.0 (-5%). subjects who received the tomato supplement during the first treatment phase had reduced sBp and DBp, only to have Bp increase during phase two while on the placebo. the reverse was observed in patients receiving the placebo fol-lowed by the treatment. researchers also noted a negative correlation between blood lycopene levels and sBp (2). in addition to hypertension being an risk factor for myocardial infarction (Mi), results from the eUraMiC study concluded that lycopene was the only carotenoid that significantly and inde-pendently lowered the risk of Mi, producing an odds ratio of 0.5 (130). a recent investigation into the relationship between lipid-soluble antioxidants and atherosclerosis risk showed a negative correlation between lycopene and carotid intima-media thick-ness in hypertensive patients (131). these data dem-onstrate the potential for using tomato extracts for the treatment of hypertension.

Medications versus tomato extract for the treatment of hypertension: mechanism of action

Current prescription medications used for treating hypertension include angiotensin-converting enzyme (aCe) inhibitors, angiotensin ii receptor antago-nists, calcium blockers, b-blockers, and thiazides (table Vi). aCe inhibitors prevent the production of angiotensin ii, a potent vasoconstrictor (132). angiotensin ii receptor antagonists block angio-tensin ii from binding to its receptor in vascular smooth muscle, while calcium blockers decrease car-diac and arteriole muscle contraction. b-Blockers reduce cardiac output, inhibit kidney-mediated renin release, and inhibit vasoconstriction (132). Finally, thiazides are diuretics that inhibit sodium reabsorp-tion in the kidney, promoting diuresis and a decrease in blood volume (132).

researchers hypothesize that high levels of anti-oxidants found in tomato extracts account for their hypotensive properties (2,129) (table Vi). pro-oxi-dation is a known risk factor for hypertension, with nicotinamide adenine dinucleotide phosphate (naDph) oxidase, xanthin oxidase, mitochondrial-derived oxidants, and uncoupled endothelial nitric oxide synthase being amongst a few of the contribu-tors to the production of reactive oxygen species (133). lycopene is considered the most potent anti-oxidant amongst carotenoids (134). Bose et al. (135)


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showed that 200 g/d cooked tomatoes improved anti-oxidant defense systems in hypertensive patients by increasing activities of superoxide dismutase, gluta-thione, glutathione reductase, and glutathione per-oxidase. a recent editorial proposed that inhibition of peroxynitrate formation secondary to nitric oxide oxidation as a plausible mechanism for tomato’s hypotensive effects since nitric oxide is a known vaso-dilator (136). Furthermore, mice fed an atheroscle-rotic diet with tomato had reduced lipid peroxide levels and maintained acetylcholine-mediated vasodi-lation compared to mice not receiving tomato (137).

lycopene may work in concert with other tomato-derived bioactives including flavonoids, vitamins, other carotenoids, and minerals, such as potassium, and may produce better results than supplements with lycopene alone (2,136). a study examining the phytochemical content of the Dash diet attributed its hypotensive effects to higher levels of flavonoids and carotenoids, including lycopene (138), indicat-ing high intakes of tomatoes. in general, the anti-oxidant action of tomato extract ascribes to its hypotensive effects. additional research is, however, needed to define specific mechanisms of action.

Medications versus tomato extract as adjunctive therapies for hypertension

to date, only one study has examined the combina-tion of hypotensive medications and tomato extracts for treatment of hypertension. the paran et al. (2) study described above recruited subjects on low-dose calcium blockers and angiotensin-converting enzyme inhibitors alone, or in combination with diuretics. in the same study, it should be noted that the 6% and 5% reductions in sBp and DBp observed with tomato extract are comparable to average reductions

in sBp and DBp with prescription medications at 8.8% and 4.4% for thiazides, 9.2% and 6.7% for b-blockers, 8.5% and 4.7% for aCe inhibitors, 10.3% and 5.7% for angiotensin ii-converting enzyme antagonists, and 8.8 and 5.9% for calcium blockers, respectively (139)—thus suggesting that concentrated tomato extract can complement hypotensive medica-tions. although current research regarding tomato extract as a treatment for hypertension is still in its infant stages, present evidence suggests that the hypotensive mechanisms of tomato extracts are dis-tinct from those induced by pharmaceutical agents and their combination could be additive.

Safety and regulatory aspects of implementing functional foods and nutraceuticals as adjunctive therapies to pharmacotherapy

in the present review, FFn have been described as efficacious adjuncts to pharmaceuticals in treating disease. hence, concerns over safety are well founded, especially since FFn modulate biological pathways. the position that a biological compound is safe because it is ‘natural’ or ‘food-derived’ is misleading. hence, it is our position that therapeutic FFn must be evaluated by the appropriate regulatory agencies to establish dosages for efficacy and toxicity, indica-tions for treatment, FFn–drug and FFn–food inter-actions, and distribution. the last-mentioned is a complicated issue. part of the FFn appeal is their potential for circumventing high costs associated with pharmaco-monotherapy (140) and, in some instances, the need for a physician’s prescription. however, the question remains: ‘should FFn only be available through a physician, or incorporated into food products for purchase in supermarkets?’ obviously, safety is a corner-stone to this debate

table Vi. summary comparison of blood pressure-lowering mechanisms between lycopene and tomato extracts and prescription medications.

hypertension


Tomato extract and lycopene: ACE inhibitor:↑ antioxidant defenses ↓ angiotensin ii production↑ nitric oxide levels?↓ peroxynitrate formation

↓ Vasoconstriction angiotensin ii receptor antagonistinhibits angiotensin ii from binding to its receptor in vascular

smooth muscle

Calcium blockers:↓ Cardiac and arteriole muscle contraction

b-Blockers:↑ Cardiac output↑ renin release

Thiazides:Diuretics↑ sodium reabsorption

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and, as for medications that are available over the counter or with a prescription, FFn must be evaluated on an individual basis regarding efficacy, effective-ness, and ultimately safety. indeed, regulatory agen-cies are beginning to recognize FFn as therapeutic agents. Canada, europe, China, Japan, and the United states have all implemented stringent regula-tory guidelines for health claims surrounding FFn (141–146). however, for FFn to be recognized as treatments for disease, regulatory agencies respon-sible for approving drugs should also bear the respon-sibility for evaluating therapeutic FFn. as described, the recent approval of lovaza®, a fish-oil supplement that is available in the United states only with a prescription with an indication for treating htg, is evidence that FFn are gaining recognition by the medical community.

regarding the FFn described in the present review, both fish-oil and ps have undergone rigorous assessment by regulatory agencies. in addition to their availability with a prescription in the United states, fish-oil supplements are also sold over the counter. Moreover, Dha and epa are added to foods as ingredients. Whether fish-oil supplements are consumed with or without a prescription is depen-dent on how the fish-oil will be utilized. as prescrip-tion fish-oil supplements are indicated as a treatment for htg, over-the-counter supplements and func-tional foods containing fish-oil are likely utilized by the public for the purpose of preventing disease.

Many countries, including the United states, the european Union, australia, Japan, switzerland, south africa, turkey, israel, norway, and Brazil, have approved ps as a safe lDl-C-lowering agent and allow ps to be incorporated into food-based matrices for sale in supermarkets. thus, the next steps are to heighten the medical community’s awareness to ps lDl-C-lowering efficacy so that they are implemented as a key therapy in treatment regimens for hCh. as for fiber and tomato extracts, their use as insulin sensitizers and hypotensive agents represent newer developments in FFn research and have yet to undergo reviews for health claims. the current literature suggests that doses of lycopene and fiber discussed in the present review possess minimal safety concerns (147,148).

similar to prescription medications, FFn–food interactions must be thoroughly evaluated by regu-latory agencies. rats fed high doses of lycopene along-side alcohol demonstrated greater levels of hepatic CYp2e1 protein, tnF-a mrna, and histological evidence of hepatic inflammation compared to rats fed lycopene alone (149). given that FFn will likely be utilized as adjuncts to prescription medications, FFn–drug indications must also be examined. grapefruit is well known for its ability to produce

drug toxicity when combined with certain medi-cines (150). a recent review has identified over 80 herbal remedies that demonstrate ill effects when taken together with certain prescription medica-tions (151). Further work is required in this area.

the debate surrounding the regulatory aspects and logistics for implementation of FFn into treat-ment guidelines is beyond the scope of the present review. Using Mets as an example, the goal of this review was to demonstrate that FFn are viable, effi-cacious adjuncts to pharmacotherapy that deserve attention by the medical community. nonetheless, new efficacious FFn entities must be evaluated by regulatory agencies, establishing dosages, proper uti-lization by physicians and patients, as well as safety to ensure FFn are implemented to treatment guide-lines with confidence.

Summary and conclusions

the present review demonstrates that FFn should be viewed as more than life-style interventions, but as adjunctive therapies to pharmacological agents for treating disease. in addition, this review substanti-ates FFn ability to target molecular processes that foster the development of disease. in the context of Mets, MoM-3 modulate the expression of tran-scription factors that affect tg metabolism. Conse-quently, studies repeatedly show that combination MoM-3/statin therapy is more effective than statins alone for treating htg. MoM-3 also improve over-all vascular health, a risk factor for hypertension. over 50 years of research supports the use of ps for treating hCh. similar to MoM-3, therapeutic strat-egies that utilize both ps and statins are more effec-tive than statins alone for reducing circulating lDl-C levels, a primary target for decreasing athero-genic dyslipidemia. Moreover, Volpe et al. (152) sug-gest that the use of ps may delay the onset or reduce the dosage of prescriptions required for treating hCh. the observation that fiber-fermentation prod-ucts modulate ir at multiple sites of glucose disposal supports the notion that the benefits of fiber con-sumption extend beyond that of gastrointestinal health. although studies that examine fiber/met-formin and fiber/thiazolidinedione therapies are required, it is hypothesized that fiber intake would complement pharmacological strategies for treating ir since fiber and corresponding medications target different facets of ir and glucose disposal. Finally, the observation that tomato extracts lower blood pressure to the same extent as hypertensive medica-tion is encouraging. even more encouraging is the observation that tomato extracts were able to reduce hypertension in subjects already taking one or more hypertensive medications.


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in conclusion, efficacious FFn can modulate clinical end-points associated with disease. thus, FFn should be emphasized throughout all stages of treatment as adjuncts to pharmacotherapy. For this to happen, however, efficacious FFn must be acknowledged by medical and regulatory agencies and undergo proper review to ensure their safety. in the end, new developments in FFn research must be communicated to health care practitioners so that they may be utilized by modern medicine as tools for combating disease.

Declaration of interest: the authors report no conflicts of interest. the authors alone are respon-sible for the content and writing of the paper.

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