Research published in the journal The Lancet Diabetes and Endocrinology demonstrates a link between higher vitamin D levels and lower mortality risk. However, the link was only observed in people who are vitamin D deficient. Results from this natural experiment, in which people were compared based on their genetic make-up, suggest that taking vitamin D supplements will reduce mortality risk for those with low levels of vitamin D.

There have been many claims of health risks of low vitamin D, such as higher rates of heart attack, stroke and cancer. However, several large randomized trials have failed to demonstrate any reductions in risk of these diseases amongst people given vitamin D supplements. This raises the question of whether taking vitamin D reduces the risk of these diseases, or whether healthier people tend to have higher vitamin D levels. This is a classic question of correlation versus causation.

A team led by researchers at the MRC Biostatistics Unit, University of Cambridge studied data on over 380,000 volunteers from 4 studies, and compared participants in a statistical analysis not by their measured level of vitamin D, but according to whether they have inherited genetic variants predisposing them to higher vitamin D levels. By making comparisons based on genetic variations rather than vitamin D levels directly, several of the pitfalls of judging causation from observational data are avoided, as the genetically-defined groups compared are similar with respect to factors other than vitamin D levels.

In analyses including all the volunteers, there was no association between genetic predisposition to higher vitamin D levels and risk of coronary heart disease, stroke, or death. However, in analyses restricted to people who are vitamin D deficient (defined as those with concentrations of 25‑hydroxyvitamin D, a form of vitamin D found in the bloodstream, below 20 nmol/L), there was a strong association between predisposition to higher vitamin D levels and lower mortality risk. For these people, a genetic predisposition to 10 nmol/L higher levels of 25‑hydroxyvitamin D levels was associated with 31% lower mortality risk. Similar associations were also observed for cardiovascular and cancer mortality.

This study provides a potential explanation for previous negative results from randomized trials of vitamin D supplementation. Most large trials have recruited volunteers without reference to their vitamin D status, and so these trials have not been able to reliably assess evidence for beneficial effects of vitamin D in deficient people. Although it would be possible to design a trial that specifically recruits vitamin D deficient participants, if a participant is diagnosed as vitamin D deficient, they may begin to take vitamin D supplementation outside of the trial. This would limit the validity of the trial. Additionally, it would be unethical to offer a placebo to a trial volunteer diagnosed as vitamin D deficient.

A notable limitation of the research is that genetic analyses were restricted to people of European genetic ancestry, whereas vitamin D levels are typically lower in people with dark skin. Associations with mortality were only seen up to a threshold level for 25‑hydroxyvitamin D of 40 nmol/L. Around 25% of European descent participants in the UK Biobank study, a large study of middle-aged UK residents, had vitamin D levels below this threshold.

Dr Stephen Burgess, Programme Leader at the MRC Biostatistics Unit, who led the study, said:

Our investigation provides intriguing new evidence that suggests raising vitamin D levels may reduce the risk of major disease and mortality, but only for people who have low vitamin D levels. Maintaining adequate levels of vitamin D is important, but there appears to be no benefit in supplementation beyond a threshold level.”

Dr Adam Butterworth, another senior author of the study from the University of Cambridge, commented:

While our findings support the theory that vitamin D may be related to a broader range of diseases than just bone disease, they also suggest that most people in the UK population are unlikely to benefit from taking vitamin D supplements as they already have sufficient levels of vitamin D.”

Read full paper published in The Lancet Diabetes & Endocrinology: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00263-1/fulltext