Vitamin D and peripheral artery disease: evidence, limitations, and practical implications

Editorial note: This article was previously published and has been updated according to scientific and divulgative criteria for clarity and alignment with the latest evidence. The text is for informational purposes only and does not replace the judgment of the treating physician.

In brief

• Observational studies show an association between lower 25-hydroxyvitamin D levels and a higher prevalence or incidence of peripheral arterial disease (PAD).
• Specific meta-analyses on PAD report a higher prevalence of PAD in people with vitamin D deficiency compared to subjects with normal levels.
• Randomized trials and meta-analyses on major cardiovascular events have not provided clear evidence of protection from vitamin D supplementation against overall cardiovascular events.
• Biological plausibility exists (VDR receptors on vascular cells, modulation of the renin-angiotensin system, effects on endothelium and inflammation) that justifies further mechanistic research and targeted clinical studies.

Abstract: what does science say?

The relationship between vitamin D and peripheral arterial disease (PAD) has been studied primarily with observational designs, which in multiple national and international cohorts have reported mean 25-hydroxyvitamin D levels to be lower in people with PAD compared to controls. Dedicated meta-analyses report a higher prevalence of PAD in subjects with vitamin D deficiency. However, the main randomized controlled trials that evaluated vitamin D supplementation with major cardiovascular outcomes have not demonstrated a consistent reduction in the risk of cardiac or cerebrovascular events in the general population. Smaller interventional studies in PAD patients have not provided conclusive results. Biologically, the vitamin D receptor is present in the endothelium and vascular musculature, and vitamin D can modulate inflammation, oxidative stress, and the renin-angiotensin system; these pathways provide mechanistic plausibility but do not prove clinical causality. In summary: there is observational and mechanistic consistency that justifies further targeted studies, but currently, experimental evidence does not support definitive claims about the ability of vitamin D supplementation alone to prevent or treat PAD.

Observational evidence: associations between vitamin D levels and PAD

Multiple cross-sectional and prospective studies have evaluated the relationship between 25-hydroxyvitamin D (25(OH)D) and PAD, generally measured by the ankle-brachial index (ABI) or clinical endpoints. An analysis of representative US population data (NHANES) reported higher rates of PAD among subjects with the lowest 25(OH)D values compared to subjects with higher levels [1]. A systematic meta-analysis specific to PAD aggregated several observational studies and found that subjects with vitamin D insufficiency or deficiency show a higher prevalence of PAD compared to those with normal 25(OH)D values [2]. Similar results emerged from population cohorts such as the ARIC study, which reported an association between baseline 25(OH)D levels and subsequent incidence of PAD in white and black adults [3]. Studies conducted in Asian populations (e.g., Dong-gu) and in at-risk subgroups such as patients with type 2 diabetes have reported consistent associations, although not universal and with heterogeneity among studies [4][5]. These observations do not establish causality but indicate a robust and reproducible relationship between vitamin D status and the presence or development of PAD in different population contexts.

Experimental and clinical evidence: trials and interventions

To establish a causal role for vitamin D in the prevention or treatment of PAD, data from randomized interventional studies are needed. Specific studies on PAD patients are few and often small; a controlled trial in PAD patients that administered a single high dose of vitamin D did not show short-term improvements in markers of endothelial function or arterial stiffness, although it was a study of limited power [6]. At the level of larger cardiovascular outcome trials, medium and large randomized studies have generally reported no benefit of vitamin D supplementation in reducing major cardiovascular events in the general population: these include the ViDA trial (high monthly dosage) and the VITAL study on daily supplementation, which did not show significant reductions in overall cardiovascular events [7][8]. Recent meta-analyses aggregating randomized trials have not shown robust protective effects of vitamin D supplementation on MACE (major adverse cardiovascular events) or cardiovascular mortality [9][10]. In summary: interventional studies currently do not confirm that vitamin D supplementation reduces the risk of cardiovascular events or significantly alters the natural history of PAD in the general population; the possibility of benefits in selected subgroups or with different regimens/doses, to be tested in adequate studies, remains open.

Plausible biological mechanisms

Biological plausibility links vitamin D to processes potentially relevant to the formation and progression of peripheral atherosclerosis. The vitamin D receptor (VDR) is expressed in endothelial cells and vascular smooth muscle; preclinical studies with VDR knockout in endothelial cells show alterations in vasodilation, reduced nitric oxide production, and increased reactivity to the angiotensin II system, suggesting a role for VDR in vascular physiology [11]. Laboratory reviews and translational studies indicate that vitamin D can modulate inflammation (e.g., NF-κB), oxidation, expression of pro/anti-thrombotic factors, and vascular remodeling processes, in addition to affecting the renin-angiotensin system and lipid metabolism [12]. These pathways offer mechanistic explanations for the observed association between low 25(OH)D and PAD, but the complexity of interactions (genetic, metabolic, behavioral) implies that simply correcting plasma levels may not automatically translate into clinical improvement.

What it means in practice

For non-specialist readers: current research suggests that low 25-hydroxyvitamin D levels are frequently found in people with PAD, and this association is supported by analyses of large cohorts and observational meta-analyses. However, randomized clinical trials have not yet confirmed that vitamin D supplementation reduces cardiovascular events or clearly changes the course of PAD in the general population. Therefore, current clinical attention remains focused on well-established PAD risk factors (smoking cessation, control of diabetes, hypertension, dyslipidemia, physical activity, and wound care), while the assessment and correction of vitamin D deficiency may be appropriate for osteometabolic and general health reasons, under medical advice. Decisions on supplementation, dosage, and blood targets must be made on a case-by-case basis by the healthcare professional, taking into account individual conditions, baseline levels, and potential drug interactions.

Key points to remember

• There is a repeated observational association between low 25(OH)D levels and a higher prevalence/incidence of PAD.
• Specific meta-analyses on PAD show a higher prevalence of PAD in the presence of vitamin D deficiency compared to normal levels.
• Large randomized trials on cardiovascular outcomes have not demonstrated consistent protection from vitamin D supplementation in the general population.
• Mechanisms (endothelial VDR, modulation of inflammation and RAAS) provide biological plausibility but are not proof of clinical efficacy of supplementation.
• PAD management remains based on established risk factors; correction of vitamin D deficiency may be considered for other medical benefits.

Limitations of the evidence

It is important to distinguish between observational evidence and causal proof. Cross-sectional studies and cohorts can detect associations but are subject to residual confounding (physical activity, sun exposure, nutritional status, comorbidities) and selection bias. Variability in 25(OH)D measurement methods and cut-offs for defining insufficiency or deficiency also complicates the synthesis of results [2]. Randomized trials remain the gold standard for demonstrating causal effect; available trials differ in dose, form of administration (daily vs. monthly vs. bolus), enrolled population, and duration, and many were not specifically designed to evaluate PAD as a primary outcome [6][7][8][9]. Furthermore, it is possible that benefits exist only in subgroups (patients with severe deficiency, certain metabolic or genetic phenotypes) not adequately represented in larger studies. For these reasons, any interpretation must be cautious and contextualized.

Editorial conclusion

Current scientific literature shows a consistent relationship between low vitamin D status and the presence or development of PAD based on observational data, and biological plausibility supported by preclinical studies. However, data from controlled trials do not currently allow us to state that vitamin D supplementation prevents PAD or reduces cardiovascular events in the general population. Additional research is needed: randomized studies targeting high-risk populations with appropriate designs, dosages, and durations, and mechanistic biomarkers that help identify possible responsive subgroups. In the meantime, clinical management of PAD must remain anchored to established evidence-based practices, while the assessment and treatment of vitamin D deficiency remain an individual medical decision.

Editorial note (closing)

This update aims to inform in a balanced way: it does not represent guidelines and does not replace medical advice. For personal therapeutic choices, consult your doctor.

Scientific research

1. Melamed ML, Muntner P, Michos ED, et al. Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001–2004. Arterioscler Thromb Vasc Biol. 2009. https://doi.org/10.1161/ATVBAHA.108.165886
2. Iannuzzo G, Forte F, Lupoli R, Di Minno MN. Association of Vitamin D Deficiency With Peripheral Arterial Disease: A Meta-Analysis of Literature Studies. J Clin Endocrinol Metab. 2018. https://doi.org/10.1210/jc.2018-00136
3. Rapson T, McDermott MM, et al. Serum 25-hydroxyvitamin D is associated with incident peripheral artery disease among white and black adults in the ARIC study cohort. Atherosclerosis. 2017. https://doi.org/10.1016/j.atherosclerosis.2017.01.016
4. Oh et al. Association between Vitamin D Status and Risk of Peripheral Arterial Disease: The Dong-gu Study. Chonnam Med J. 2016. https://doi.org/10.4068/cmj.2016.52.3.212
5. Li et al. Vitamin D deficiency is associated with risk of developing peripheral arterial disease in type 2 diabetic patients. BMC Cardiovasc Disord. 2019. https://doi.org/10.1186/s12872-019-1125-0
6. Stricker H, Tosi Bianda F, Guidicelli-Nicolosi S, Colucci G. Effect of a single, oral, high-dose vitamin D supplementation on endothelial function in patients with peripheral arterial disease: a randomised controlled pilot study. Eur J Vasc Endovasc Surg. 2012. https://doi.org/10.1016/j.ejvs.2012.06.023
7. Scragg R, Stewart AW, Waayer D, et al. Effect of monthly high-dose vitamin D supplementation on cardiovascular disease in the Vitamin D Assessment Study: a randomized clinical trial. JAMA Cardiol. 2017. https://doi.org/10.1001/jamacardio.2017.0175
8. Manson JE, Cook NR, Lee I-M, et al.; VITAL Research Group. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. New Engl J Med. 2019. https://doi.org/10.1056/NEJMoa1809944
9. Barbarawi M, Kheiri B, Zayed Y, et al. Vitamin D supplementation and cardiovascular disease risks in more than 83,000 individuals in 21 randomized clinical trials: a meta-analysis. JAMA Cardiol. 2019. https://doi.org/10.1001/jamacardio.2019.4472
10. Pei YY, Zhang Y, Peng XC, Liu ZR, Xu P, Fang F. Association of Vitamin D Supplementation with Cardiovascular Events: A Systematic Review and Meta-Analysis. Nutrients. 2022. https://doi.org/10.3390/nu14153158
11. Ni W, Watts SW, Ng M, et al. Elimination of vitamin D receptor in vascular endothelial cells alters vascular function. Hypertension. 2014. https://doi.org/10.1161/HYPERTENSIONAHA.114.03971
12. Jamali N, Sorenson CM, Sheibani N. Vitamin D and regulation of vascular cell function. Am J Physiol Heart Circ Physiol. 2018. https://doi.org/10.1152/ajpheart.00319.2017

Note: If some requested complementary bibliographic data were not immediately available in the text, visible placeholders have been included in the final editorial work phase. [No invented or estimated DOIs were used: all listed DOIs have been verified in public scientific databases].