Statins and vascular calcification: The case for vitamin k2

Enhancing wellness in statin therapy users

Gnosis highlights evidence connecting statin use to increased cardiovascular risk, illustrating the impact of Vitamin K2 supplementation for statin users.

A new cross-sectional clinical study published in Kaohsiung Journal of Medical Sciences[1] adds to the evidence that statins, a heavily prescribed cholesterol medication used to lower blood cholesterol, including LDL cholesterol, may exacerbate calcium accumulation in artery walls by inhibiting vitamin K-dependent proteins involved in vascular protection.

Statins are first‐line prescriptions for the prevention and treatment of established atherosclerotic cardiovascular disease (CVD). Paradoxically, intensive statin therapy has been shown to increase vascular calcification and accelerate its progression. The aim of the recently published study, “Statins, vascular calcification, and vitamin K-dependent proteins: Is there a relation?”, was to find a putative relationship between statin use, coronary calcification, and the vitamin K-dependent proteins as a possible mechanism mediating the pro-calcification effect of statins.

“According to the study, statins negatively influence vitamin K status. To that end, supplementation with Vitamin K2, which has been shown to effectively improve vitamin K status and activate extrahepatic K-dependent proteins, might prove beneficial for statin users,” says Dr. Hogne Vik, chief medical officer with ex-NattoPharma, world leader in Vitamin K2 research and development.

What the evidence shows

The study enrolled 98 patients—adults with cardiovascular risk factors and established heart disease—plus a control group of healthy patients at moderate risk for CVD. The groups were then split into statin users and non‐users.

The results revealed that both CVD and statin use are independently and significantly associated with vascular calcification. Among all the study participants, coronary artery calcium measured by coronary artery calcification score (CACS) was more pronounced in statin users than non‐users; researchers found the same among the CVD patients and the controls.

The calcium score is used to assess cardiovascular risk and improve risk prediction. Calcium in the coronary arteries reflects coronary atherosclerosis and can signal higher risk of heart attack and stroke. Moreover, the researchers found that statins influenced vitamin K status, as represented by the activation of osteocalcin (OC), a vitamin K-dependent protein. Inactive OC and the ratio of inactive and active form of OC (UCR) were significantly elevated in statin users, indicating vitamin K deficiency.

According to researchers, statins also interacted with vitamin K antagonists; these findings may help clinicians and doctors decide who may benefit most, when to initiate therapy, and which patients should be treated more aggressively.

Inhibitor of vascular calcification and coronary artery calcium score

These results are in agreement with findings from existing research on statins, vascular calcification, and cardiovascular events. A 2015 paper published in Expert Review Clinical Pharmacology[2] stated that statins may act as “mitochondrial toxins” with adverse effects on the heart and blood vessels not only via the depletion of coenzyme Q10 (CoQ10), but also by inhibiting “the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification,” a process tied to atherosclerotic plaques that contribute to narrowing and possible blockage in coronary artery disease and coronary heart disease.

“Research confirms that Vitamin K2 as MK-7 (as MenaQ7) is the only known inhibitor of vascular calcification through the activation of matrix gla protein (MGP).[3,4] Yet this new study provides further evidence that statins interrupt the mechanism of action by which vitamin K2 is a cardioprotective nutrient,” Dr. Vik adds. Coronary artery calcium testing can help assess subclinical coronary atherosclerosis, through the coronary artery calcium score. An Agatston score supports risk prediction and primary prevention by identifying patients who may benefit from lipid-lowering therapy. “And while CoQ10 and vitamin K2 are both affected by statins, no recommendation exists for prescribing supplemental vitamin K2 to statin patients, and broader prevention decisions involving medications such as aspirin are typically informed by clinical practice guidelines.

Gnosis continues the work started by ex-Nattopharma, collaborating with the medical community on trials exploring Vitamin K2 as a potential therapy for patients that express heavy calcification,” Dr. Vik concludes. “We hope to encourage K2 supplementation as a recommendation in the future for statin users, especially considering this new evidence.” Cardiology groups such as the American College of Cardiology also inform how clinicians use CAC testing and related findings in treatment decisions for patients with elevated scores.

References:

1. Zhelyazkova-Savova MD, Yotov YT, Nikolova MN, Nazifova-Tasinova NF, Vankova DG, Atanasov AA, Galunska BT. “Statins, vascular calcification, and vitamin K-dependent proteins: Is there a relation?” Kaohsiung J Med Sci. 2021 Feb 26. Online ahead of print.
2. Okuyama H, Langsjoen PH, Hamazaki T, Ogushi Y, Hama R, Kobayashi T, Uchino H. “Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms.” Expert Rev Clin Pharmacol. 2015 Mar;8(2):189-99.
3. Knapen MHJ, Braam LAJLM, Drummen NE, Bekers O, Hoeks APG, Vermeer C. “Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomized clinical trial.” Thromb Haemost. 2015 May; 113(5):1135-44.
4. Vermeer C and Vik H. Effect of Menaquinone-7 (vitamin K2) on vascular elasticity in healthy subjects: results from a one-year study. 2020 Vascul Dis Ther, 5.