Daily supplementation with menaquinone plus cholecalciferol slows the progression of calcification among patients with severe coronary artery calcification (CAC) compared with menaquinone alone, according to the randomized DANCODE trial.
Over 24 months, the mean increase in CAC score was 196 AU among participants who received vitamin K2 plus D3 (intervention group) vs 248 AU among those who received vitamin K2 plus placebo (placebo group), yielding a treatment effect of −52 AU (95 percent confidence interval [CI], −79 to −24; p<0.001) and corresponding to a 21-percent relative reduction in calcium progression, reported lead investigator Dr Selma Hasific from Odense University Hospital in Odense, Denmark, and colleagues. [Circulation 2026;doi:10.1161/CIRCULATIONAHA.126.082363]
“The treatment effect was consistent across sex and baseline CAC subgroups,” Hasific and colleagues added.
In a subset of participants who underwent coronary CT angiography, the intervention and placebo groups showed a similar increase in total plaque volume and no change in noncalcified plaque volume. However, the progression of calcified plaque volume was attenuated in the intervention group (between-group difference, −8 mm3, 95 percent CI, −13 to −2).
Major adverse cardiovascular events were infrequent, occurring in two participants in the intervention group and three in the placebo group (1 percent vs 1.5 percent). The rate of any adverse events was 4.5 percent in the intervention group vs 8.1 percent in the placebo group. One participant in the placebo group had venous thromboembolism, and another participant in the placebo group died. There were no reports of severe bleeding events.
DANCODE included 398 patients (median age 71 years, 30 percent female) with a CAC score ≥400 Agatston units (AU). The median baseline CAC score was 903 AU, and 44 percent had CAC score ≥1,000 AU.
The patients were randomly assigned to undergo oral supplementation with vitamin K2 720 μg/d plus either vitamin D3 25 μg/d or placebo. The supplements were taken daily for 24 months.
Unclear clinical implications
Dr Rajiva Gupta, Senior Consultant Physician at CK Birla Hospital, Gurgaon, Haryana, India
Dr Rajiva Gupta from the CK Birla Hospital, Gurgaon, Haryana, India, who was not involved in the trial, commented that while the slowing of calcium progression with vitamin K2 and vitamin D3 is “encouraging,” it remains “a surrogate outcome.”
“The findings [from DANCODE] should not be interpreted as a reason to routinely add vitamin K2 and D3 to the treatment of every patient with diabetes, hypertension, or high CAC score,” Gupta noted. “This is particularly relevant in India, where vitamin D supplements are widely used and are often prescribed without a clearly documented deficiency.”
Gupta emphasized that in daily practice, controlling established cardiovascular risk factors—including apoB-containing lipoproteins, blood pressure, diabetes, smoking, obesity, and physical inactivity—remains utterly important. “These have a much stronger clinical foundation.”
Further work needed
In an accompanying editorial, Dr John Davis from Washington University in St. Louis, Missouri, and Dr JoAnn Manson from Harvard Medical School in Boston, Massachusetts, emphasized that clinicians interpret the findings from DANCODE “as hypothesis generating rather than conclusive.” [Circulation 2026;doi:10.1161/CIRCULATIONAHA.126.082639]
“Demonstrating that CAC progression can be slowed is not the same as demonstrating clinical cardiovascular benefit, and a trial powered for clinical events, or at minimum one with a prespecified plaque composition endpoint, will be required before CAC progression is treated as a therapeutic target,” Davis and Manson said.
“Supplementation with cholecalciferol and menaquinone-7 at this time should be reserved for patients with documented deficiency and a clear indication for treatment,” they added.