Disappointing K2 study

[ironfist]

This was originally posted on longecity and I am posting it here to encourage k2 discussion.

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Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial

Axel C.P. Diederichsen,

Jes S. Lindholt,

Sören Möller,

Kristian A. Øvrehus,

Søren Auscher,

Jess Lambrechtsen,

Susanne E. Hosbond,

Dilek H. Alan,

… See all authors
Originally published25 Apr 2022https://doi.org/10.1...NAHA.121.057008Circulation. 2022;145:1387–1397

https://www.ahajourn...aortic stenosis.

In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 µg MK-7 plus 25 µg vitamin D or matching placebo for 24 months...The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo.

A noncontrast cardiac CT scan was obtained at baseline, and repeated after 1 and 2 years of intervention.

The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo.

This result will be disbelieved or questioned by some in the K2 community, but this trial seems seems very well-designed and executed AFAICT.

 

[tankasnowgod]

This result will be disbelieved or questioned by some in the K2 community, but this trial seems seems very well-designed and executed AFAICT.

I don't really know how "well done" the study was, at least 76% (and maybe 100%) of patients were on some other sort of medication-

Treatment with angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers was common (54%), 76% received statin therapy, and 2% (n=8) had a bicuspid aortic valve. Of the 365 included patients, 333 completed the study, 171 (94%) in the MK-7 plus vitamin D group and 162 (89%) in the placebo group. Reasons for abandoning the study are shown in Table S1.

Statins apparently raise the calcium score (and they were the most common medication in the study)-

Plaque Paradox: Statins Increase Calcium in Atheromas Even as They Shrink Them

A Cleveland Clinic analysis of IVUS images from eight large clinical trials suggests that coronary artery calcification might in fact be cardioprotective. We explore implications for research and practice.

consultqd.clevelandclinic.org

How Statins Can Increase Calcium Scores While Reducing Cardiac Risk

Learn why statin treatment reduces the risk of a heart attack, but at the same time can increase your calcium score.

www.verywellhealth.com

So, that is a massive confounder. If statins themselves can nullify any positive effects of K2 and/or D, then the result was a foregone conclusion before it began. Or, it may have needed a higher dose to show any sort of improvement.

Also, they used the MK-7 form. The initial studies that showed a lot of promise all used the MK-4 version (at higher doses) than this study.

 

[Limon9]

I don't really know how "well done" the study was, at least 76% (and maybe 100%) of patients were on some other sort of medication-



Statins apparently raise the calcium score (and they were the most common medication in the study)-

Plaque Paradox: Statins Increase Calcium in Atheromas Even as They Shrink Them

A Cleveland Clinic analysis of IVUS images from eight large clinical trials suggests that coronary artery calcification might in fact be cardioprotective. We explore implications for research and practice.

consultqd.clevelandclinic.org

How Statins Can Increase Calcium Scores While Reducing Cardiac Risk

Learn why statin treatment reduces the risk of a heart attack, but at the same time can increase your calcium score.

www.verywellhealth.com

So, that is a massive confounder. If statins themselves can nullify any positive effects of K2 and/or D, then the result was a foregone conclusion before it began. Or, it may have needed a higher dose to show any sort of improvement.

Also, they used the MK-7 form. The initial studies that showed a lot of promise all used the MK-4 version (at higher doses) than this study.

Agreed. It's quite confounded. Haidut also mentioned that a bunch of pioneering and promising MK-7 studies were essentially supplement PR pieces, so perhaps it has spawned well-meaning but futile imitators using it instead of MK-4.

 

[ironfist]

Here is the original thread with longecity

Very disappointing K2 trial - Supplements

Very disappointing K2 trial - posted in Supplements: Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial Axel C.P. Diederichsen, Jes S. Lindholt, Sören Möller, Kristian A. Øvrehus, Søren Auscher, Jess Lambrechtsen, Susanne E...

www.longecity.org

 

[Ras]

MK-7 is junk, and they gave them only 1,000 IU of Vitamin D3, which is essentially nothing. And most of these patients were on statins, which are pills of death.

This study can go into the trash.

 

[crazypatriot]

MK-4 is the body's preferred form.

This is like saying a study regarding beta-carotene implies the same results for retinol.

 

[ironfist]

MK-7 is junk, and they gave them only 1,000 IU of Vitamin D3, which is essentially nothing. And most of these patients were on statins, which are pills of death.

This study can go into the trash.

Link to report showing mk7 is junk?

 

[ironfist]

There is a supplement by Life Extension that has mk4, mk6, mk7 and mk9.

I see a lot of things describing mk4 as better, and mk7 as better. One has a shorter half life, one crosses the bbb, one is found in food, whatevs etc.

 

[crazypatriot]

Link to report showing mk7 is junk?

Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1

Vitamin K family molecules—phylloquinone (K1), menaquinone (K2), and menadione (K3)—act as γ-glutamyl carboxylase (GGCX)-exclusive cofactors in their hydroquinone state, activating proteins of main importance for blood coagulation in the liver and for arterial calcification prevention and energy...

www.mdpi.com

Structural Insights into Phylloquinone (Vitamin K1), Menaquinone (MK4, MK7), and Menadione (Vitamin K3) Binding to VKORC1

Vitamin K family molecules—phylloquinone (K1), menaquinone (K2), and menadione (K3)—act as γ-glutamyl carboxylase (GGCX)-exclusive cofactors in their hydroquinone state, activating proteins of main importance for blood coagulation in the liver and for arterial calcification prevention and energy metabolism in extrahepatic tissues. Once GGCX is activated, vitamin K is found in the epoxide state, which is then recycled to quinone and hydroquinone states by vitamin K epoxide reductase (VKORC1). Nevertheless, little information is available concerning vitamin K1, K2, or K3 tissue distribution and preferential interactions towards VKORC1. Here we present a molecular modeling study of vitamin K1, menaquinones 4, 7 (MK4, MK7), and K3 structural interactions with VKORC1. VKORC1 was shown to tightly bind vitamins K1 and MK4 in the epoxide and quinone states, but not in the hydroquinone state; five VKORC1 residues were identified as crucial for vitamin K stabilization, and two other ones were essential for hydrogen bond formation. However, vitamin MK7 revealed shaky binding towards VKORC1, induced by hydrophobic tail interactions with the membrane. Vitamin K3 exhibited the lowest affinity with VKORC1 because of the absence of a hydrophobic tail, preventing structural stabilization by the enzyme. Enzymatic activity towards vitamins K1, MK4, MK7, and K3 was also evaluated by in vitro assays, validating our in silico predictions: VKORC1 presented equivalent activities towards vitamins K1 and MK4, but much lower activity with respect to vitamin MK7, and no activity towards vitamin K3. Our results revealed VKORC1’s ability to recycle both phylloquinone and some menaquinones, and also highlighted the importance of vitamin K’s hydrophobic tail size and membrane interactions.

 

[tankasnowgod]

There is a supplement by Life Extension that has mk4, mk6, mk7 and mk9.

I see a lot of things describing mk4 as better, and mk7 as better. One has a shorter half life, one crosses the bbb, one is found in food, whatevs etc.

I am only aware of "Super K" by Life Extention, that has K1, and K2 as MK-4 and MK-7. Do they also have a "Super Duper K" or something?

Regardless of the effects of MK-7, the fact that 76% of patients in the study were on statins is a massive confounder, especially since it seems to be well known that statins increase calcification.

Maybe try emailing the study authors, to get a breakout of the non-statin users in both Placebo and K2 groups.

 

[crazypatriot]

I am only aware of "Super K" by Life Extention, that has K1, and K2 as MK-4 and MK-7. Do they also have a "Super Duper K" or something?

Well.. They do have a "Mega" with 45mg of MK4
Amazon product ASIN B08MR2D124View: https://www.amazon.com/Life-Extension-Mega-Vitamin-Count/dp/B08MR2D124

 

[tankasnowgod]

Well.. They do have a "Mega" with 45mg of MK4
Amazon product ASIN B08MR2D124View: https://www.amazon.com/Life-Extension-Mega-Vitamin-Count/dp/B08MR2D124

Whoa, didn't know that. Impressive! Usually, it's 15mg and 3 times the pills.

 

[EvanHinkle]

Yeah, this is super impressive, great find, thanks!

 

[ironfist]

The K2 product with MK9 and MK6 is called Super K Elite.

Life Extension Super K Elite 30 Sgels - Swanson®

Improve your day-to-day wellness with Life Extension Super K Elite 30 Sgels from Swanson Health Products.

www.swansonvitamins.com

 

[Ras]

I'm skeptical K2 MK-4 is really so powerful. Many people take milligrams of it every day, some along with Vitamin D3, and they still have cavities, heart disease, and other issues. Green Pastures butter oil has only about 80 mcg of MK-4 per 100 grams. Chicken thigh, about 60 mcg per 100 grams. If people take milligrams of MK-4 daily and still have cavities, how could Price have cured so many cavities with butter oil?

Masterjohn's K2 resource.

 

[crazypatriot]

I believe the recommendations from Price are not just to take K2 (and nutrient dense foods in general) for cavity prevention, but to actually limit refined sugars and grains. The strongest bone will still decay from acid producing bacteria which thrive on sugar. My opinion is that diets high in sugar will require a lot more attention to teeth brushing, flossing, and mouth washing -- you can't just take K2 and think you don't have to do these things. I also don't believe K2 can reverse cavities, from my own experience.

 

[ironfist]

Well.. They do have a "Mega" with 45mg of MK4
Amazon product ASIN B08MR2D124View: https://www.amazon.com/Life-Extension-Mega-Vitamin-Count/dp/B08MR2D124

This surprised me. I thought the prescription for osteoporosis was 15mg 3x a day.

 

[ironfist]

Some member on longecity posted about being uncertain whether they used trans mk7 or cis mk7. Cis is basically pointless and isn't bioavailable but some supplements are this form.

 

[crazypatriot]

The Relentless Improvement brand claims to be 99% Trans. My wife and I have been using that one for years.

 

[haidut]

This was originally posted on longecity and I am posting it here to encourage k2 discussion.

```````````````````````

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial

Axel C.P. Diederichsen,

Jes S. Lindholt,

Sören Möller,

Kristian A. Øvrehus,

Søren Auscher,

Jess Lambrechtsen,

Susanne E. Hosbond,

Dilek H. Alan,

… See all authors
Originally published25 Apr 2022https://doi.org/10.1...NAHA.121.057008Circulation. 2022;145:1387–1397

https://www.ahajourn...aortic stenosis.



A noncontrast cardiac CT scan was obtained at baseline, and repeated after 1 and 2 years of intervention.







This result will be disbelieved or questioned by some in the K2 community, but this trial seems seems very well-designed and executed AFAICT.

As other users already mentioned, most people in that trial were on statins. Statins are actually known to increase vascular calcification, so I am not even sure how they are still prescribed as "therapy" for CVD, but that is a separate topic. Assuming MK-7 and vitamin D worked, this trial actually showed that those vitamins managed to block the pro-calcification effects of statins - i.e. the overall effects on calcification was null, despite the usage of pro-calcification statins. Yay!
In addition, MK-7 is not the form usable by the human body, as other users also mentioned. Its long side chain will have to get cleaved a few times and eventually get shortened to become MK-4. So, since MK-7 is administered in microgram (mcg) amounts, at best you'd be getting mcg amounts of MK-4 as a metabolite. However, in order for MK-4 to have an effect on bone resorption, human studies have shown that at least ~1mg daily is needed, and at least 5mg daily are needed for optimal effect.

Low-dose menaquinone-4 improves γ-carboxylation of osteocalcin in young males: a non-placebo-controlled dose–response study - Nutrition Journal

Background Menaquinone-4 is a type of vitamin K that has a physiological function in maintaining bone quality via γ-carboxylation of osteocalcin. However, little is known about the beneficial effect of intake of dosages below1500 μg/day. Findings Fifteen healthy males aged 25.0 years (median)...

nutritionj.biomedcentral.com

"...Fifteen healthy males aged 25.0 years (median) participated in a non-placebo-controlled dose-examination study. They received menaquinone-4 daily for 5 weeks at 0, 300, 600, 900, and 1500 μg/day in weeks 1, 2, 3, 4, and 5, respectively. Compared with baseline, serum γ-carboxylated osteocalcin levels were significantly greater at an intake of 900 μg/day or more;..."

So, with the MK-7 administration of mcg amounts in this study getting mg amounts of MK-4 is impossible. I still view the study results as good though. We now know that vitamin K can prevent the calcification effects of statins The bad news is that Big Pharma will stop at nothing in its quest to bash effective, OTC therapies while the real villain is its own toxic drugs (statins in this case). Just a few months ago they were again bashing aspirin, while the real culprit were the blood-thinners aspirin often gets co-administered with.
@tankasnowgod @Ras @EvanHinkle @crazypatriot @competentmouser

Statins Accelerate Coronary Calcification and Reduce the... : Cardiology in Review

en accelerate progression of CAC; meanwhile, some researchers demonstrate opposite results. With the purpose of seeking out the effect of statin therapy on CAC, we summarized the existing evidence on statins and undertook meta-analyses of clinical trials assessing the effect of statin therapy on...

journals.lww.com

Plaque Paradox: Statins Increase Calcium in Atheromas Even as They Shrink Them

A Cleveland Clinic analysis of IVUS images from eight large clinical trials suggests that coronary artery calcification might in fact be cardioprotective. We explore implications for research and practice.

consultqd.clevelandclinic.org

Progression of Vascular Calcification Is Increased With Statin Use in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE. To determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM).RESEARCH DESIGN AND METHODS. Progressio

diabetesjournals.org

Statins May Contribute to Vascular Calcification by Inhibiting Vitamin K-Dependent Proteins

Researchers suggest the finding may open up inquiries on vitamin K2 supplementation for statin patients.

www.nutraceuticalsworld.com

INCREASING DURATION OF STATIN THERAPY IS ASSOCIATED WITH HIGH CORONARY ARTERY CALCIUM SCORE:

www.jacc.org