The DANCODE trial found vitamin K2 plus D3 reduced 24-month coronary artery calcification progression by 21% in patients with severe CAC.
Written By: Anshu Gupta, PharmD
Reviewed By: Pharmacally Editorial Team
Vitamin K2 plus vitamin D3 reduced 24-month progression of coronary artery calcification by 21% in adults with severe coronary calcification, but the findings do not yet establish a cardiovascular outcome benefit or support routine supplementation.
DANCODE Tests a Vitamin K–Dependent Calcification Pathway
The investigator-initiated, multicenter DANCODE trial randomized 398 adults with coronary artery calcium (CAC) scores of at least 400 Agatston units (AU) to vitamin K2 plus vitamin D3 or placebo for 24 months. The study used 720 μg/day of menaquinone-7 (MK-7) and 25 μg/day of vitamin D3, with serial noncontract cardiac CT at baseline, 12 months, and 24 months.
The MK-7 dose was a study-specific therapeutic dose and is higher than doses commonly found in consumer vitamin K2 supplements. The results therefore should not be interpreted as evidence that lower-dose over-the-counter supplementation produces the same effect.
The biological rationale centers on matrix Gla protein (MGP), an endogenous inhibitor of vascular mineralization. Vitamin K is required for MGP activation, while vitamin D increases its expression.
CAC Progression Fell by 21%
Participants had extensive coronary calcification at baseline, with a median CAC score of 903 AU and 44% having scores of at least 1,000 AU. Most were already receiving cardiovascular preventive therapy, including statins in 86.7% of participants.
At 24 months, mean CAC increased by 196 AU with vitamin K2 plus D3 versus 248 AU with placebo. The between-group difference was −52 AU (95% CI, −79 to −24; P<0.001), corresponding to a 21% relative reduction in CAC progression. The effect remained consistent across sex and baseline CAC categories.
Among participants with CAC of 400–999 AU, the between-group difference was −39 AU. It was −70 AU among those with CAC of at least 1,000 AU.
Plaque Analysis Shows Less Calcified Plaque Progression
A prespecified secondary coronary CT angiography sub-analysis provided exploratory mechanistic information in 143 participants with baseline CAC below 1,000 AU and evaluable imaging at 24 months. Calcified plaque volume increased less with vitamin K2 plus D3, with a between-group difference of −7.8 mm³ (95% CI, −13.5 to −2.2; P=0.007). Total plaque volume and non-calcified plaque volume did not differ significantly between groups.
The authors caution that this smaller imaging subgroup was selected by imaging quality and baseline CAC criteria, so these findings should not be generalized to the entire randomized population.
Biomarker Changes Support Target Engagement
The intervention substantially reduced circulating dephosphorylated-undercarboxylated MGP (dp-ucMGP), consistent with enhanced vitamin K-dependent MGP activation. At two years, dp-ucMGP was 383 pmol/L with supplementation versus 591 pmol/L with placebo.
However, DANCODE cannot determine the independent contribution of vitamin K2 and vitamin D3 because the trial tested them as a combination. The investigators note that further studies are needed to distinguish their individual and combined effects.
Safety and Clinical Significance Remain Uncertain
Major cardiovascular events were infrequent, occurring in 2 participants in the intervention group and 3 in the placebo group. No severe bleeding events occurred, and laboratory safety measures showed no clinically relevant differences.
The primary endpoint, however, was an imaging biomarker that has not been validated as a surrogate for cardiovascular outcomes. The 24-month study was also not powered to detect differences in myocardial infarction, stroke, or cardiovascular mortality. Larger, longer trials with clinical endpoints are therefore required to determine whether slowing CAC progression translates into meaningful cardiovascular benefit.
Reference
Hasific S. et al., Vitamin K2 and D3 Supplementation in Patients with Severe Coronary Artery Calcification: The DANCODE Trial. Circulation. 2026 Aug 28. https://doi.org/10.1161/CIRCULATIONAHA.126.082363
The DANish COronary DEcalcification (DANCODE) Trial (DANCODE), ClinicalTrials.gov ID NCT05500443
About the Writer
Anshu Gupta (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, regulatory affairs, and medical writing. She has presented research at academic conferences and completed certifications in Good Clinical Practice (GCP), ICH-GCP, and drug safety. Passionate about clinical trials and evidence-based medicine, she is committed to translating scientific evidence into accurate, reliable, and accessible healthcare content.