by Trygve Bergeland, PhDVice President Science & Product Development

Kappa Bioscience AS

The role of vitamin K2 (Mk-7) in

Overview

Health effects

Biomarkers Biochemistry

Physiology &metabolism

Vitamin K2

Dam discovered a fat-soluble substance that reduced

bleeding; Doisy determined the chemical structure of vitamin K & succeeded in synthesizing it

K2 forms were first identified. Price’s

‘Activator X’ (K2), the missing ingredient for

Teeth and bone health

Vermeer started scientific work on

enzymes an coagulation

Studies investigation K2 and bone health

as well as K2biomarkers

Møller et. al. demonstrated that synthetic K2

(K2VITAL®), and natural-fermented K2 are

biologically equivalent

Japanese warriors consumed K2-rich fermented soya beans – natto

Dam an Doisy shared the Nobel Prize in Medicine for discovery of vitamin K family

K2 as MK4 became an approved drug in Japan

Motohara et. al. studied the transfer of K2between mothers and newborns

Knapen et. al and Kurnatowska et. al. demonstra-ted K2 effect on reducing cardiovascular risk

1600s 1943 1960s 1990s 2015

1930s 1950s 1970s 2000s 2016

History Introduction

Timeline overview – Discovery and rediscovery of vitamin k2

Vitamin K2-PubMed Results by Year

Scientific attention

PubMed results showing a spike in K2 publications in the last decade

Introduction

CHEMISTRY

Vitamin K2 MK-4Menaquinone-4

Vitamin K2 MK-7Menaquinone-7

Vitamin K1Phylloquinone

Introduction

Dietary sources

Meat Fish Milk Cheese Butter Margarine Green Vegetables

NattoDish Fruit

Introduction

Function - biochemistry

n Carboxylation (protein activation)

n Vitamin K cycle

n Coagulation factors

n Osteocalcin

n Matrix gla-protein (MGP)

Inactive protein

Active protein

Vitamin KVitamin K

epoxide

carboxylation

n Coagulation factors

n Osteocalcin

n MGP

Booth et al. 2013, Nature Review

Vitamin K dependent modifications of glutamic acid residues in prothrombin(proton magnetic resonance spectroscopy/ mass spectrometry)

Proc. Nat. Acad. Sci. USA – Vol. 71, No. 7, pp. 2730–2733, July 1974Johan Stenflo*, Per Fernlund*, William Egan † and Peter Roepstorff ‡

12 weeks on Warfarin + low dose Vit. K16 weeks on Warfarin + low dose Vit. K16 weeks on high dose K2

A Calcium (by Von Kossa),

B Total MGP, C ucMGP, D cMGP

n Higher levels cMGP in thoracic aorta

n Lower levels of ucMGP in thoracic aorta

n Reversed arterial calcification

High intake of vitamin K:

Blood 109(7): 2823-2831

Reversion of calcification in animal model

Regression of warfarin-induced medial elastocalcinosisby high intake of vitamin K in rats Schurgers et al. 2007

Association between mgp and mortality

Ueland et al., J Intern Med 2010; 268(5);483-92

Population Severe aortic stenosis

Sample size 147dp

-ucM

GP

(pM

)All cause mortality

Association between mgp and mortality

Schlieper et al., J Am Soc Nephrol 2011; 22(2);387-95

All cause mortalityCardiovascular

mortalityMK-7 and ucMGP

Population Dialysis patients

Sample size 188

Dietary Intake of Menaquinone is ASSOCIATED WITH A Reduced Risk of Coronary Heart Disease: The Rotterdam Study

J Nutr. 2004; 134(11); 3100-5

Heart Health

Design Observational trial

Participants 4807 men and women(55yrs and above)

Follow-up period

7.2 yrs ± 1.9 (mean ± SD)

Endpoints n Dietary intake of vitamin K1 and K2

n incidences of CHDn all-cause mortality

Johanna M. Geleijnse†, Cees Vermeer, Diederick E. Grobbee‡, Leon J. Schurgers, Marjo H. J. Knapen, Irene M. van der Meer, Albert Hofman and Jacqueline C. M. Witteman

Men (n = 1836) Women (n = 2971)Age, y 66.9 ± 7.4 67.7 ± 8.0

BMI, kg/m2 25.7 ± 2.9 26.6 ± 4.0

Smoking status, %Current 29.8 19.1Former 61.5 28.8Never 8.7 52.0Alcohol use, % 88.1 74.4Educational level, %Low 23.3 41.1Intermediate 57.1 52.1High 19.7 6.8Blood pressure, mm HgSystolic 138.5 ± 21.9 138.7 ± 22.2Diastolic 74.8 ± 11.4 73.1 ± 11.0Serum cholesterol level, mmol/LTotal 6.3 ± 1.1 6.9 ± 1.2HDL 1.2 ± 0.3 1.5 ± 0.4Diabetes mellitus, % 3.1 3.6

The Rotterdam study

… Showing the benefits of vitamin K2 on cardiovascular health

Geleijnse et al. 2004

Intake of menaquinone could be important for CHD prevention

Cardiovascular health

Publications Participants Population Dose Duration Results

Knapenet al. 2015

244Healthy postmenopausal women

180µg/d 3 yearsSignificant reduction in arterial stiffness

Kurnatowska et al. 2015

42 Kidney patients 90µg/d 9 monthsSlower progression of calcification by MK-7

Mc Farlinet al. 2017

26Healthy aerobically trained athletes

160-320µg/d

8 weeksIncreased maximal cardiac output during exercise

mansouret al. 2017

60Renal transplant patients

360µg/d 8 weeksImproved arterial stiffness

Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: double-blind randomised clinical trial

Design Double-blinded, randomized, placebo controlled

Participants 244 healthy postmenopausal women

Intervention 180µg/d or placebo in 3 years

Main Endpoints n Arterial stiffness by pulse wave velocity and echotrackingn ucMGP

Heart Health

Marjo H. J. Knapen, Lavienja A. J. L. M. Braam, Nadja E. Drummen, Otto Bekers, Arnold P. G. Hoeks, Cees VermeerVitaK & Cardiovascular Research Institute (CARIM), Maastricht University, The Netherlands; Central Diagnostic Laboratory, University Hospital Maastricht, The Netherlands; Biomedical Engineering, Maastricht University, The Netherlands

Thromb Haemost. 2015; 113(5); 1135-44

MK-7 Placebo Knapen et al. 2015

Arterial stiffness

Conclusion

Long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women high arterial stiffness

MK-7 Placebo

Change in serum ucMGP(mean±SD)

Whole population Elevated stiffnessat baseline

McFarlin et al 2017

Oral Consumption of Vitamin K2 for 8 Weeks Associated With Increased Maximal Cardiac Output During Exercise

Brian K. McFarlin, PhD, FACSM, FTOS; Andrea L. Henning, MS; S. Venable , PhD

n=13

n=13

Measuresn Graded exercise test (ergometer cycling)n O2 consumption, CO2 production, respiration,

cardiac output, stroke volume, heart rate

MK-7 (320 µg/d) in 4 weeks

PlaceboRandomization

Week 8Week 1

MK-7 (160 µg/d) in 4 weeks

Design Randomized, double blinded, placebo controlled

Participants Aerobically trained males and females Alternative Therapies, Jul/AUG 2017 VOL. 23 NO. 4

McFarlin et al 2017

Conclusion

This is the first study to report a potential cardiovascular benefit in active individuals

Blood Lactate Max Cardiac Output

Alternative Therapies, Jul/AUG 2017 VOL. 23 NO. 4

summary

Health effects

Biomarkers Biochemistry

Physiology &metabolism

Vitamin K2

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