Hypocholesterolaemic Herbs - Rafe Bundy

Herbal Hypolipidaemics: an overview of Herbal Hypolipidaemics: an overview of

worldwide research on hypolipidaemic herbsworldwide research on hypolipidaemic herbs

Dr Rafe Bundy PhD RNutr

School of Food Biosciences

University of Reading

Presentation PlanPresentation Plan

Coronary Heart Disease and Cholesterol Hypolipidemic herbs : review of the human

literature Garlic, Guggul, Fenugreek, Red Yeast Rice, Artichoke

A new study of Artichoke: The ALE and Cholesterol Study

Coronary Heart Disease Coronary Heart Disease and Cholesteroland Cholesterol

Coronary Heart Disease is a BIG killer More than 1.4 million people in the UK suffer from angina 300,000 people have a heart attack each year Kills more than 110,000 people a year in England Cost impact to UK economy in 1999 about £7 billion

Primary cause of CHD is Atherosclerosis, linked to high blood cholesterol.

18 %and 22.4 %in UK have total cholesterol >6.5mmol/l (DoH 1998)

www.heartstats.org

Total Cholesterol is made up of Low Density Lipoprotein (LDL) Cholesterol High Density Lipoprotein (HDL) Cholesterol Other (Chylomicrons and VLDL)

The concentration of LDL and the ratio LDL/HDL is probably more important than the Total

Suggested healthy levels LDL-Cholesterol < 3.0-4.0mmol/l? HDL-Cholesterol >0.9 mmol/l LDL/HDL <3.0

Cholesterol Triacylglycerol (TAG)

Cell membranesFree cholesterol

Steroid hormones Androgens/Oestrogens

GlucorticoidsMineralocorticoids

Vitamin D

BileBile salts

Free cholesterol

Cell membranesPhospholipidsGlycoplipids

Hormones/messengersProstaglandins

Energy

General lipoprotein structure

ChylomicronsVLDL

LDL, HDL

Transport

Plasma

8g

Total Body Pool (excl. plasma)

132g

De novosynthesis

Dietary Cholesterol

1g

0.6g

0.4g 5gTurnover Bile

19g

(HMG CoA Reductase)

CMVLDLLDLHDL

FaecalLosses

1g

Daily Cholesterol Flux through the bodyDaily Cholesterol Flux through the body

GI TractGI Tract

Hypolipidemic herbs :Hypolipidemic herbs : review review of the human literatureof the human literature

Hypolipidemic Herbs: Literature ReviewHypolipidemic Herbs: Literature Review(based on Thompson and Ernst (2003) J Fam Prac. 52: p468-78 )

Randomized controlled trials in Humans Garlic (Allium satvium) Guggul (Commiphora mukul) Fenugreek (Trigonall foenum-graecum) Red yeast Rice (Monascus purpureus) Artichoke (Cynara scolymus)

In brief Yarrow (Achillea wilhelmsii), Holy Basil (Ocimum

sanctum), Eggpalnt (Solanum melongena), Arjun (Terminalia arjun), stannols

GarlicAllium satvium

Important to the ancient Egyptians and listed in their medical text Codex Ebers

Contains many important compounds including: allicin, S-allyl cysteine, diallyl-di-sulphide

46 Human studies since 1975 Most used garlic powder for 4 to 16 weeks Most show significant↓in TC and TAG LDL↓ 11 to 26 % (measured one-third of studies)

18 Human studies since 1993-2002 9 show NO effect on cholesterol Differences in composition may explain some

differences?

4 meta-analyses are available

GarlicGarlic: RCT trials for serum cholesterol reductionreduction (based on Banerjee and Maulik (2003) Nutrition Journal. 1: p1-14 )

Garlic: Meta-analyses for serum cholesterol reduction

Analysis Studies Setting Outcome

Warshafsky et al (1993)

5 RCT trials N=324TC > 5.17 mmol/l

TC↓9% approx. (significant) with garlic 0.5 to 1 clove/d

Slagy and Neil (1994)

16 trials (not all RCT)

N=952TC 6.4 mmol/l approx

TC↓12% approx. (significant)

Neil et al (1996)

17 trials (same as 1994 but including

1 new trial)

N=1067TC > 6.4 mmol/l approx


Stevinson et al (2000) +

13 RCT trials (included 5 new trials from 1996)

N=796TC 7.1 mmol/l approx


+ Conclusion: Garlic is superior to placebo – but the size of the effect is modest, and the robustness of the effect debateable. May in part be due to differences in Allicin yield?

Garlic: Summary of 13 RCT trials

From: Stevinson et al. (2000) Ann Intern Med. 19;133(6):420-9.

GuggulCommiphora mukul

Sticky gum resin from the mukul myrrh tree contains sterols guggulsterones E and Z

Guggul: RCT trials for serum cholesterol reduction (1)

Study Subjects Treatment Changes from baseline (%)

Singh et al (1994)

*****

N=61

TC 6.3 mmol/l

(Hypercholesterolemia)

Guggul sterones (100mg/d) or placebo

24 weeks

TC↓ 25.2

LDL↓ 16.9

Kuppurajan et al (1978)

*****

N=40

TC Not specified

(Obesity)

Gum guggul (6g/d)

Guggulu Fraction A (1g/d)

Clofibrate (1.5g/d)

Placebo 3 weeks

TC ↓ 17.5

TC ↓ 4.4

TC ↓ 2.4

TC ↓ 11.8

N=40

TC >7.8 mmol/l

(Hypercholesterolemia)

Gum guggul (6g/d)


Clofibrate (1.5g/d)

Placebo 3 weeks

TC ↓ 23

TC ↓ 51

TC ↓ 55

TC ↓ 35

N=40

TC Not specified

(Hyperlipidemia)

Gum guggul (6g/d)


Clofibrate (1.5g/d)

Placebo 3 weeks

TC ↓ 20

TC ↑ 14

TC ↓ 19

TC ↓ 21

Szapary et al (2003) ***

N=103

TC Not specified

(Hyperlipidemia)

Guggul sterones

(75 or 150mg/d) or placebo

8 weeks

No significant changes

Guggul: RCT trials for serum cholesterol reduction (2)

Study Subjects Treatment Changes from baseline (%)

Verma and Bordia (1998)

*

N=40

TC 7.1 mmol/l

(Hyperlipidemia)

Purified Gum Guggul (4.5g/d) or placebo

16 weeks

TC↓ 21.9

HDL↑ 35.8

LDL↓ 36.3

Bordia and Chuttani (1979)

*

N=20

TC 5.8 mmol/l

(Healthy)

Gum Guggulu Fraction A (1g/d) or placebo

4 weeks

TC ↓ 8.7

N=20

TC 7.2 mmol/l

(Coronary Artery Disease)

Gum Guggulu Fraction A (1g/d) or placebo

20 weeks

TC ↓ 7.3

Malhotra and Ahuja (1971)

*

N=44

TC Not specified

(Hyperliproteinemia)

Gum Guggulu Fraction A (1g/d)

EPC (1.5g/d)

Ciba (300mg/d)

6-34 weeks

TC ↓ 27

TC ↓ 24

TC ↓ 46

SUMMARY – Six trials involving 388 patients suggest TC↓ 7% to 27% over baseline

Fenugreek SeedsTrigonella foenum-graecum

Used as a yang tonic in the Chinese tradition

Contains soluble fibre, galactomannose and alkaloids, most abundantly trigonelline

Fenugreek: RCT trials for serum cholesterol reductionStudy Subjects Treatment Changes from

Baseline (%)

Singh et al (1998)

****

N=92TC Not specified(Hypercholesterolemia)

Fenugreek (60g/d) Triphala (6g/d)

Placebo

12 weeks

TC↓15.4 HDL ↓3.6 LDL↓18.8

TC↓4.7 HDL ↑ 5.3 LDL↓7.2

Prasanna (2000)

**

N=18

TC Not specified

(Obesity)

Fenugreek (50g/d)

Fenugreek (100g/d)

Placebo

3 weeks

TC↓26.1 HDL ↓6.7 LDL↓30.6

TC↓33.1 HDL ↑3.0 LDL↓38.2

Sharma and Raghuram (1990) **

N=15

TC 4.5 mmol/l

(NIDDM)

Fenugreek (100g/d) or no supplementation

1.5 weeks

TC↓16.7

Sharma and Raghuram (1990) **

N=5

TC Not specified

(NIDDM)


3 weeks

TC↓21.0

Sharma et al (1990) *

N=10

TC Not specified

(NIDDM)


1.5 weeks

“TC and LDL significantly reduced…compared to the control diet”

SUMMARY – Five trials involving 140 patients suggest TC↓ 15% to 33% over baseline

Red Yeast RiceMonascus purpureus

Some ‘statins’ are based on the active component mevinolin

Red Yeast Rice: RCT trials for serum cholesterol reduction

Study Subjects Treatment Changes from Baseline (%)

Keithly et al (2002)

***

N=14TC 5.4 mmol/l(HIV-related dyslipidemia)

Red Yeast Rice (2.4g/d) Placebo

8 weeks

TC↓30.8 LDL↓32.3

TC↓7.7 LDL↓26.3

Heber et al (1999)

***

N=83

TC 6.5 mmol/l

(Healthy)

Red Yeast Rice (2.4g/d) Placebo

12 weeks

TC↓16.1 LDL↓21.9

TC↓1.8 LDL↓2.6

Shen et al (1996) **

N=152

TC >6.5 mmol/l(Hypercholesterolemia)

Red Yeast Rice (5.0g/d) or control 8 weeks

TC↓19.2 HDL↑ 16.7 LDL↓ 27

TC↓1.5 LDL↑ 2.4

Wang et al (1997) *

N=446

TC >5.9 mmol/l(Hyperlipidemia)

Red Yeast Rice (2.4g/d) Jiagulan (1.2g/d)

TC↓22.9 HDL↑19.9LDL↓31.7TC↓6.7 HDL↑ 8.4 LDL↓ 8.3

SUMMARY – Four trials involving 695 patients suggest TC↓ 16% to 31% over baseline

Other herbs

Other herbs: RCT trials for serum cholesterol reduction (1)


Guimaraes et al (2000)

***

N=36


Egg Plant (2% w/v infusion)

Placebo

5 weeks

TC↓6.8 HDL↑ 13.6 LDL↓1.5

TC↓4.4 HDL↓ 2.3 LDL↓13.5

N=16

TC >6.4 mmol/l(Hypercholesterolemia)Diet recommendations

Egg Plant

Placebo

5 weeks

TC↑ 23 HDL↑10 LDL↑15

TC↓7.4 HDL↑4 LDL↓8

Gupta et al (2001) ***

N=105

(Coronary Artery Disease)

Arjun (500 mg/d)Vitamin EPlacebo4 weeks

TC↓9.7 HDL↓4.1 LDL↓15.8

TC↓2.6 HDL↑9.1 LDL↓7.9

TC↑8.5 HDL↑8.3 LDL↑12.5

Sotaniemi et al (1995) **

N=36

(NIDDM)

Asian Ginseng (100mg)Asian Ginseng (100mg)Placebo8 weeks

No change TC, HDL, LDL

Other herbs: RCT trials for serum cholesterol reduction (2)


Agarwal et al (1996)

**

N=40


(NIDDM)

Holy Basil

Placebo

8 weeks

TC↓ 7.6

TC↑ 1.3

Asgary et al (2000) ***

N=20(Hypercholesterolemia)

Yarrow (Achillea wilhelmsii)Placebo24 weeks

TC↓39 HDL↑20.4 LDL↓35.6

TC↑ 4.6 HDL↓4.3 LDL↑ 3.4

Petronelli et al (1981) *

N=20

(Dyslipidemia)

SilymarinPlacebo8 weeks

TC↑ 2.6

TC↓ 0.3

Stannols/Sterols: plant components that have been shown to reduce TC and LDL by 10 –15%

www.consumerlab.com

ArtichokeCynara scolymus

Artichoke Leaf Extract (ALE) contains cynarin

and luteolin

Globe Artichoke - HistoryGlobe Artichoke - History

First described in 4th century BC Used in Europe since Roman times for

improving digestive and urinary tract health Used mostly for indigestion (dyspepsia) in

Germany/Switzerland Modern research has concentrated on

Artichoke Leaf Extract (ALE)

ALE – Key ConstituentsALE – Key Constituents

Caffeoylquinic acids e.g. Cynarin, chlorogenic acid

Flavonoids e.g. Luteolin and derivatives

Bitters e.g. Cynaropicrin

ALE – Metabolic ActionsALE – Metabolic Actions

Hepatoprotective(similar to Milk Thistle)

Cholereticbile secretion

Carminative, Spasmolytic, Anti-emetic

Anti-atherogeniccholesterol

elimination (bile)cholesterol synthesis

LDL oxidation

ALE – previous human studiesALE – previous human studies

Study Subjects Treatment Change from Baseline (%)

Fintelmann & Menssen (1996) Post-Marketing Trial

N=302 Total Chol. 6.86 mmol/ Dyspepsia

Av. 1520 mg/d Artichoke extract 6 weeks

Total Chol. 11.5%

Fintelmann & Petrowicz (1998) Post-Marketing Trial

N=171 Total Chol. 6.31 mmol/l Dyspepsia

Av. 1600 mg/d Artichoke extract 6 months

Total Chol. 10.9% LDL Chol. 15.8% LDL/HDL 21%

N=59 (subset) Total Chol. >6.76 mmol/l

Total Chol. 15.1% LDL Chol. 20.8%

Petrowicz et al (1997) RCT Abstract only

N=44 Total Chol. <5.4mol/l? Healthy

1920 mg/d Artichoke extract vs. placebo 12weeks

No significant differences

Englisch et al (2000) RCT

N=143 Total Chol. >7.28 mmol/l Hypercholesetrolemia

1800 mg/d standardised dry extractvs. placebo 6 weeks

Total Chol. 18.5% vs.8.6% LDL Chol. 22.9% vs. 6.3% LDL/HDL 20.2% vs. 7.2%

The ALE and Cholesterol StudyThe ALE and Cholesterol Study

The ALE and Cholesterol Study:The ALE and Cholesterol Study:Aims and DesignAims and Design

Does ALE significantly alter plasma lipid profile in adults with moderately raised cholesterol?

Randomised double-blind placebo controlled parallel trial 12 weeks intervention 1280 mg Cynara Artichoke vs. placebo

The ALE and Cholesterol Study:The ALE and Cholesterol Study: Study Group Study Group

70 otherwise healthy individuals Total cholesterol 6.0 to 8.0 mmol/l, aged 18-75

Recruitment RBH Pathology Laboratory database search Information sent to patient via GP Further blood test if patient interested Exclusions

Pregnancy, major organ pathology or major mental illness, drug or alcohol abuse, biliary obstruction, cholesterol lowering drugs, anti-coagulants.

Additional recruitment through press release

The ALE and Cholesterol Study:The ALE and Cholesterol Study: Outcome Measures Outcome Measures

Primary Total cholesterol LDL- and HDL- cholesterol LDL oxidation Triglycerides

Secondary Plasma C-reactive protein, Bowel Health and

Quality of Life

SummarySummary CHD is a big killer, a huge drain on the NHS, the

economy, and society

There is clinical data showing some herbs have strong hypercholesteremic actions

Plasma

8g

Total Body Pool (excl. plasma)

132g

De novosynthesis

Dietary Cholesterol

1g

0.6g

0.4g

5gTurnover Bile

19g FaecalLosses

1g

Possible actions of herbs on cholesterol fluxPossible actions of herbs on cholesterol flux

GI TractGI Tract

Promote Secretion

ALEGarlic

Guggul

Inhibit Reabsorption

FenugreekInhibit Synthesis

ALEGarlic

Red Yeast RiceGuggul

Inhibit Absorption

StannolsFenugreek

SummarySummary CHD is a big killer, a huge drain on the NHS,

the economy, and society

There is clinical data showing some herbs have strong hypercholesteremic actions

We are further investigating ALE on plasma cholesterol, plus LDL-oxidation, triglycerides, bowel health and QoL

Food for thought - the Insulin link

Some herbs may be beneficial in hyperlipidemia and insulin resistance– is there a common pathway?

INSULIN

Glucose uptake into liver/muscle

(HMG CoA Reductase to produce cholesterol)

TAG uptake into adipose tissue

Release of Fatty Acids into plasma

- ++ +

AcknowledgementsAcknowledgements

Dr Ann Walker, Dr Steve Hicks University of Reading

Dr Hugh Simpson, Dr David Williams Royal Berkshire Hospital

Dr Dick Middleton Lichtwer Pharma Ltd.

Hypocholesterolaemic Herbs - Rafe Bundy

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