What randomized trials compare combined vitamin D3+K2 versus D3 alone for cardiovascular outcomes?
Executive summary
No randomized trials were identified in the provided reporting that directly compare combined vitamin D3+K2 against vitamin D3 alone for cardiovascular outcomes; instead, the contemporary randomized evidence base consists largely of trials testing vitamin K2 plus vitamin D3 versus placebo or trials of K2 alone, with mixed or null cardiovascular signals so far [1] [2] [3].
1. What the trials actually test: D3+K2 versus placebo, not D3 alone
Multiple high-quality randomized trial protocols and completed randomized trials described in the sources randomize participants to a combined vitamin K2 (typically MK‑7, 720 μg/day) plus vitamin D3 (25 μg/day) arm versus placebo, not an arm receiving vitamin D3 alone; examples include the DANCODE trial protocol (400 participants with CAC≥400 randomized to K2+D3 vs placebo for two years) and the registered AVADEC program designs (both described as K2+D3 vs placebo) (DANCODE protocol: [1]; BMJ Open summary: [4]; AVADEC description: [2]; p1_s9).
2. What completed randomized trials say about cardiovascular surrogates when K2+D3 is compared to placebo
Large randomized trials that tested combined K2+D3 against placebo in older, at‑risk cohorts have largely reported limited or null effects on key inflammation and imaging end points: the AVADEC randomized double‑blind trial (388 men, 24 months) showed biochemical evidence of vitamin K2 activity (lower dp‑ucMGP) but did not significantly change cardiac or systemic inflammation across CAC strata, statin use, or dp‑ucMGP levels in its primary inflammation analyses (AVADEC reporting: [2]; substudy on epicardial adipose tissue: [5]; atherosclerosis substudy: p1_s9). Protocols focused on calcification progression, such as DANCODE, aim to test change in coronary artery calcification vs placebo but are designed against inactive control, not against a D3‑only comparator [1] [4].
3. Other randomized designs and feasibility trials — signal hunting rather than head‑to‑head D3 comparisons
Feasibility and mechanistic trials such as INTRICATE have been designed to test imaging biomarkers and micro‑calcification with combined K and D interventions versus placebo, explicitly to inform larger trials rather than to answer the policy question of K2+D3 versus D3 alone (INTRICATE rationale: [3]; nutrients/feasibility descriptions: [6]1). Narrative and systematic reviews note several randomized K2 trials measuring vascular endpoints, but these are mostly K2 (with or without D) versus placebo; the reviews do not report any randomized head‑to‑head D3+K2 versus D3‑only trials in the assembled literature (narrative review and meta‑analytic context: [7]; [6]4).
4. Why the absence matters for clinical inference
Because the randomized evidence compares combined K2+D3 to placebo, it cannot isolate whether any observed benefit—or absence of benefit—stems from vitamin D3, vitamin K2, their interaction, or placebo effects; the field therefore relies on surrogate markers, subgroup analyses, and observational associations (for example, combined low K and D status associated with higher mortality in cohort data) to hypothesize synergy, but that is different from randomized head‑to‑head proof (observational synergy signal: [6]; BMJ Open discussion of rationale: p1_s5).
5. Bottom line and next steps for researchers and clinicians
The provided sources make clear that randomized, double‑blind, placebo‑controlled trials of combined K2+D3 exist (notably AVADEC and the planned/completed DANCODE work) and that investigators are pursuing calcification and inflammation end points, but no randomized trials comparing combined vitamin D3+K2 directly against vitamin D3 alone for cardiovascular outcomes were identified in this reporting; answering that head‑to‑head question will require trials designed with a D3‑only arm or network meta‑analytic approaches if enough diverse trial arms accumulate (trial protocols and completed RCTs: [2]; [1]; [5]; feasibility rationale: p1_s6). Where trials exist, results so far have been mixed—biochemical markers move, but consistent clinical cardiovascular benefit has not been demonstrated versus placebo in the cohorts reported to date (AVADEC inflammation null results: [2]; DANCODE primary outcome planned: p1_s3).