Does Sufficient Evidence Exist to Support a Causal Association between Vitamin D Status and Cardiovascular Disease Risk? An Assessment Using Hill’s Criteria for Causality

Abstract: Serum 25-hydroxyvitamin D (25(OH)D) levels have been found to be inversely associated with both prevalent and incident cardiovascular disease (CVD) risk factors; dyslipidemia, hypertension and diabetes mellitus. This review looks for evidence of a causal association between low 25(OH)D levels and increased CVD risk. We evaluated journal articles in light of Hill’s criteria for causality in a biological system. The results of our assessment are as follows. Strength of association: many randomized controlled trials (RCTs), prospective and cross-sectional studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Consistency of observed association: most studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors in various populations, locations and circumstances. Temporality of association: many RCTs and prospective studies found statistically significant inverse associations between 25(OH)D levels and CVD risk factors. Biological gradient (dose-response curve): most studies assessing 25(OH)D levels and CVD risk found an inverse association exhibiting a linear biological gradient. Plausibility of biology: several plausible cellular-level causative mechanisms and biological pathways may lead from a low 25(OH)D level to increased risk for CVD with mediators, such as dyslipidemia, hypertension and diabetes mellitus. Experimental evidence: some well-designed RCTs found increased CVD risk factors with decreasing 25(OH)D levels. Analogy: the association between serum 25(OH)D levels and CVD risk is analogous to that between 25(OH)D levels and the risk of overall cancer, periodontal disease, multiple sclerosis and breast cancer. Conclusion: all relevant Hill criteria for a causal association in a biological system are satisfied to indicate a low 25(OH)D level as a CVD risk factor.

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Alex’s Notes: I had never heard of Sir Austin Bradford Hill’s criteria for causality until reading this review. It is interesting criteria in that no single type of study (be it randomized controlled trials, prospective, cross-section, or epidemiological studies) can evaluate each of Hill’s criteria. They include the strength of the association, consistency of the observed association, specificity of the association, temporal relationship of the association, the dose-response curve, plausibility and coherence with biology, the experiment, and analogy. The study at hand is thus very unique and very insightful in that the inclusion criteria only require that the research be representative of current research.

The stronger the association between two variables, the more likely the association is causal. But this isn’t always the case, and we could only make such a conclusion if everything about both variables was known, which is unlikely to be the case. For instance, there could be a strong association, but one that is mediated by a third variable, or one that only occurs under very specific circumstances. Serum 25(OH)D levels have shown strong inverse correlations to myocardial infraction (MI), cardiovascular disease (CVD) related mortality, stroke risk, hypertension, diabetes, vascular disease, hyperlipidemia, hyperglycemia, and insulin resistance.

The above association is not very helpful if it is not replicated, and consistency must be demonstrated with different populations and study designs. The studies for vitamin D have shown mixed results with the main reason being melanin. Yes, the stuff that gives your skin color. This has significant implications for different ethnicities because vitamin D production is inversely proportional to skin pigmentation. However, controlling for skin color can be done just as easily as other variables and it is clear that consistency exists for the relationship between serum 25(OH)D levels and MI stroke, heart disease, vascular disease, diabetes, and metabolic syndrome.

Temporality refers to the direction of influence in a sequence of events. It makes sense when you think about it; how can one thing cause another if it doesn’t precede it? Unfortunately, determining whether low vitamin D status is a risk factor for CVD is difficult because CVD is a chronic and slowly-progressing disease. Thankfully, there are a handful of prospective studies and meta-analyses that have taken a baseline serum 25(OH)D level (which precedes the adverse event or death) and shown that there is an increased incidence of CVD and its risk factors with decreasing serum 25(OH)D levels.

Satisfying the dose-response curve, or biological gradient, criteria is one of the most difficult as it involves being able to predict with a good degree of confidence the dependent variable (CVD) when the independent variable (serum 25(OH)D levels) is known. Nonetheless, most the reviewed studies did show a graded association between vitamin D levels and CVD.

Plausibility is the common sense and critical thinking criterion. It is satisfied when the suspected causation is consistent with known biology. Several cellular mechanisms have been proposed, and some or all of them may be accurate because CVD is a broad category of diseases, each of which has multiple causes. Overall, dyslipidemia, hypertension, diabetes, and metabolic syndrome have been shown to be strong mediators between low serum 25(OH)D levels and increased risk of CVD. Specifically, the studies show increased serum LDL-C, VLDL-C and TG levels, decreased serum HDL-C levels, increased arterial stiffness, increased insulin resistance, hyperglycemia and increased incident metabolic syndrome as potentially plausible mediators.

Vitamin D randomized controlled trials have mixed results because they have been designed largely on the model used for pharmaceutical drugs that assumes that the agent used in the trial is the only source of the agent and that a linear dose-response relation exists. Neither of these assumptions are true for vitamin D. More complications arise when we give consideration to the fact that chronic disease is caused by more than one risk factor and may occur only after long-term versus short-term vitamin deficiency, and vitamin supplementation studies are usually designed to assess the decrease in risk due to increasing vitamin intake to meet the minimum sufficiency level. Additional information would be gained from studies that also test the effects of supplementation on levels beyond those previously established for disease risk. All that said, vitamin D RCTs support a causal relationship between serum 25(OH)D levels and CVD risk.

Approximately 32% of the U.S. population has serum 25(OH)D levels of below 20 ng/mL, with worldwide deficiency estimated at one billion. Vitamin D supplements are easily accessible and cheap, especially compared to the cost of ill-health. As the current study concludes,

“Current scientific evidence supports a causal association between serum 25(OH)D levels and increased risk for CVD on the basis of Hill’s criteria for causality in a biological system. Only RCTs starting with low serum 25(OH)D levels found significant beneficial effects of vitamin D supplementation in reducing risk factors associated with CVD. However, evidence to date suggests that raising serum 25(OH)D levels to at least 30 ng/mL will reduce the risk of CVD.”

I feel that the evidence is conclusive. There is literally no excuse for having serum 25(OH)D levels below 30 ng/mL. However, as mentioned previously, most studies look at the effects of avoiding deficiency. Hopefully analyses such as the current study put these trials to rest. We don’t need more research to confirm what is already known. Both time and money would be better utilized in finding not the deficiency amount, but the optimal amount. Many researchers agree that 30-100 ng/mL is the ideal range, but perhaps future studies could help narrow it down a little.


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