This transcript has been edited for clarity.
Pam R. Taub, MD, FACC, FASPC: Hi. I’m Pam Taub. I’m a cardiologist and professor of medicine at UC San Diego. I’m really delighted to have Dr Michael Holick and Dr JoAnn Manson join us today. They’re both world experts on vitamin D.
Dr Holick is a pioneer in the space and a professor of medicine at Boston University. He was the first to identify the major circulating form of vitamin D in human blood as 25-hydroxyvitamin D3. Over the past four decades, he’s led many of the studies demonstrating the benefits of vitamin D and is responsible for bringing vitamin D to the radar of healthcare professionals.
Dr JoAnn Manson is another luminary in the field and a professor of medicine at Harvard Medical School. She’s been involved in many landmark clinical trials that have changed our clinical practice, including the Nurses’ Health Study, the Women’s Health Initiative, and most recently, the VITamin D and OmegA-3 TriaL (VITAL study).
It’s a pleasure to have you both here, and I’m looking forward to a very lively discussion. I’m going to start by asking Dr Holick a question. You have shown throughout your career that vitamin D has a variety of health benefits, ranging from being anti-cancer to improving blood sugar, to enhancing immune response. Can you highlight some of these trials?
Michael F. Holick, MD, PhD: Sure. We’re now recognizing that vitamin D, of course, has to get activated, like you said, first in your liver to 25-hydroxyvitamin D and then in your kidneys to 1,25-dihydroxyvitamin D. Originally, we realized that vitamin D is really important for your bone health. Therefore, looking at receptors for 1,25-dihydroxyvitamin D, they were found in the intestine, bone, and kidney, which regulate calcium metabolism.
Then we began to realize that basically every tissue and cell in your body has a vitamin D receptor, and the obvious question is, why would they be there? There’s now a large amount of evidence to suggest that immune cells, colon, breast, skin, and other cells in your body can activate vitamin D locally.
We think that it does it for the purpose of regulating cellular growth and a variety of genes. As a result, there are a multitude of association studies that have related vitamin D deficiency with increased risk for autoimmune disorders like type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, and increased risk for cardiovascular disease, neurocognitive dysfunction, infectious diseases, and some malignancies.
Taub: One of the things that has come up in many of these clinical trials is the biomarker by which we measure vitamin D. I’d love to get both of your comments on what is the best biomarker to measure vitamin D levels.
Holick: I don’t think there’s any debate about this. The only one to measure is 25-hydroxyvitamin D. It’s the major circulating form of vitamin D and it’s used worldwide by doctors to measure the vitamin D status of patients. The active form of vitamin D gives you no insight into your vitamin D status. It’s often normal or even elevated in a vitamin D–deficient state because of secondary hyperparathyroidism. Only 1,25-hydroxyvitamin D is useful for inborn and acquired disorders in calcium and vitamin D metabolism.
JoAnn E. Manson, MD, DrPH, MACP: Yes, I agree that there really isn’t controversy about that point. There are some more recently discovered biomarkers and evidence that the bioavailable and free 25-hydroxyvitamin D may provide some additional information, but the research has been quite limited, and certainly from a clinical standpoint, it would be the serum 25-hydroxyvitamin D that’s the main biomarker of vitamin D status.
Taub: Dr Manson, you recently led a very important landmark clinical trial, the VITAL trial, and you showed that vitamin D supplementation did not reduce cardiovascular risk. But there were some other pearls from that trial on some benefits of vitamin D. Can you go over the trial with us?
Manson: The vitamin D and omega-3 trial, VITAL, is a large-scale, nationwide trial in the United States, including more than 25,000 men and women. The primary endpoints were cancer and cardiovascular disease. We found no significant reduction in total invasive cancer, nor in total cardiovascular disease.
However, we did see a strong signal for reduction in cancer death. We had a 17% reduction in cancer death that just missed being statistically significant. When we accounted for cancer latency and looked at those who had been in the trial for at least 2 years — long enough to actually have an effect on cancer death — we did see a statistically significant 25% reduction.
The reason this was of particular interest is that several other randomized trials had suggested that there may be an effect of vitamin D supplementation on reducing cancer death. We did a meta-analysis of five large-scale trials available looking at vitamin D supplementation and having information on cancer death. The result in the meta-analysis was of a statistically significant 13% reduction in cancer death.
All but one of the trials showed that the hazard ratio was on the side of benefit. Only one, bolus dosing — very high doses given monthly, given less frequently — did not show a clear reduction. There has been increasing evidence that vitamin D given daily may be of greater biological benefit than vitamin D given in very high doses and in a bolus form only once a week or once a month, or even less frequently. Some trials are testing bolus vitamin D every 3 or 6 months.
Taub: In the VITAL trial, the average vitamin D level was around 30 [ng/mL]. Do you think we would have seen more of a benefit if we took people that were really vitamin D deficient, maybe levels less than 10, and then repleted them?
Manson: I think the benefits of vitamin D supplementation are greatest in those who are truly deficient. The problem is that it’s not ethical to do a long-term trial in people who are known to be deficient because half of them — or close to half, usually, in most clinical trials — will be randomized to a placebo, and that means they will remain vitamin D deficient for 5 years or longer.
For example, the median duration of the VITAL trial was 5.3 years. Usually when we do test for vitamin D and find that someone is deficient, we want to treat them on a relatively urgent basis and not wait 5 years to let them know the results of the trial.
We did a trial that included a usual-risk population. Most of the trials in the United States do include people who, on average, have a 25-hydroxyvitamin D level close to 30 ng/mL, but many of the participants still do have levels below 20.
When these levels are measured at baseline and you’re not targeting those who are deficient, then it’s reasonable to just try to get a broad, generalizable group of participants and see if the results differ by baseline vitamin D status. We couldn’t find strong evidence for that in VITAL, but I think that’s because we did not have a very large number of people who were profoundly vitamin D deficient.
Taub: Any comments on that, Dr Holick, about what level you start with and the benefit you can achieve?
Holick: I agree with JoAnn completely. More than 50% of the VITAL participants were vitamin D sufficient. You really have to ask the question, if your vitamin D is sufficient and you’re now given vitamin D, is it going to have some additional health benefit and are you going to be able to see that distinction? As Dr Manson said, she did not. To me, that was not at all a surprise.
Manson: I do want to say that the goal of the VITAL trial was not to determine whether we should treat vitamin D deficiency. We know that vitamin D is essential to health and we know it’s important to avoid vitamin D deficiency. The key question was whether there is a benefit of increasing vitamin D intake and supplementation beyond what is obtained in the usual US population with that type of baseline vitamin D blood level and getting, on average, maybe only 600 or even 400 IUs a day of vitamin D from various sources.
The question was whether giving more would reduce risk, and I think that the randomized trials do help to answer those questions. Having a neutral result by no means negates the importance of vitamin D to human health. I think it’s really important that people understand that some of the disagreement may be about the amount of vitamin D we need in order to have optimal cardiovascular health or an optimal reduction in cancer risk. If anything, I do think the VITAL trial showed that more-than-usual intake of vitamin D is a benefit in reducing cancer death.
Taub: Great point. Let’s talk about some clinically important areas where there is debate about vitamin D supplementation; one is statin intolerance. Dr Holick, what are your thoughts about giving patients who are statin intolerant vitamin D?
Holick: Statins, of course, can cause muscle aches and pains. If you’re vitamin D deficient, you can have osteomalacia, which causes aches and pains in your bones and muscles. There is some evidence that by improving vitamin D status and helping patients become vitamin D sufficient, they would be less prone to developing that complication.
Manson: We’re actually looking at this in VITAL. We’re hoping to have the results published shortly. We’re looking at people in the study who were new initiators of statins, with reported muscle aches and pains as some of the symptoms associated with statins, and whether those who were randomized to vitamin D were less likely to develop these symptoms than those randomized to placebo. We’re in the process of analyzing the data and preparing a manuscript.
Taub: Those are really important results that will also guide our clinical practice. Let’s shift to something that is on everyone’s mind, which is COVID-19. There’s a large amount of data that shows low vitamin D levels are associated with patients who have more complications from COVID-19 and are in the ICU. What are your thoughts on supplementation with vitamin D for everyone? Because we all want to have fewer complications if we acquire COVID-19.
Manson: I think the research is promising but not conclusive to date. We’re doing a randomized trial and we’ll see if it’s addressing some of the issues that Mike brings up.
Holick: We initiated studies almost immediately. We worked with Quest Diagnostics and looked at more than 191,000 COVID-positive patients throughout all 50 states, all ages, ethnicities, and latitudes, and showed that if you have a blood level of 25-hydroxyvitamin D of 20 ng/mL compared with 34 ng/mL, you had a 54% higher risk of acquiring the infection. We know that vitamin D does have an important role to play in immunomodulation and that the COVID-19 infection causes the cytokine storm. The thinking is that the active form of vitamin D can help to downregulate cytokines that are damaging and improve cytokines that can help.
We’ve done a couple of studies. The first was in Iran with Dr Maghbooli and included more than 200 patients coming in to the hospital, including 74% with serious infection. When we looked at their baseline blood levels of 25-hydroxyvitamin D and their outcomes, there was a significant decrease in morbidity and mortality. In fact, among those over the age of 40, there was more than a 50% reduced risk of dying of the infection simply by being vitamin D sufficient at the time they went into the hospital.
We did a study at Boston Medical Center and looked at patients coming to the hospital. We got their baseline blood level and then followed them for their morbidity and mortality, and again, showed very significant differences. Those who were deficient had more significant morbidity and mortality.
We do believe that improving vitamin D status throughout your life can help reduce the risk for infections and COVID-19. More importantly, patients going into the hospital, if nothing else, should be treated with vitamin D almost immediately. [Editor’s note: Citation identified as Charoenngam N, Shirvani A, Holick MF. Vitamin D and its potential benefit for the COVID-19 pandemic. Endocr Pract. 2021;27:484-493. Epub 2021 Mar 17.]
Manson: I agree with what Mike has said in terms of the correlation between low vitamin D status and increased risk for COVID-19, severity of COVID-19, hospitalization, and adverse outcomes, including mortality. I think the evidence is really strong for that. I totally agree with what he said about vitamin D. There are many biological mechanisms that have been shown for vitamin D to be important in boosting immune response as well as tamping down inflammation and immune modulation, which are mechanisms that are very relevant to preventing severe COVID-19 infection.
However, correlation doesn’t prove causation, as we say in epidemiology, which is why I know Mike believes the randomized trials are very important, and there are many potential confounders. We know that people who have low vitamin D blood levels tend to be more likely to have these comorbidities that are linked to an increased risk for severe COVID-19 illness, including diabetes, hypertension, cardiovascular disease, and obesity. They’re more likely to be in socioeconomic groups and racial/ethnic groups that have had a higher risk for severe COVID-19 illness. There’s tremendous potential for confounding.
That said, during a pandemic, if anything, we would want to err on the side of encouraging more intake of vitamin D because we do think it’s very safe. One of the lessons from VITAL was that 2000 IUs today was virtually free of adverse events for 5.3 years. It had a very good safety profile. During a pandemic, why not recommend that everyone ensure they’re outdoors, getting sun exposure, being physically active, as well as maybe taking a supplement of 1000 or 2000 IUs a day? I think that’s quite reasonable.
To have conclusive evidence about causality, we need the randomized trials. So far, the randomized trials that have been done have been small. Some of them have been promising, some of them not. We are doing a trial right now called the Vitamin D for COVID-19 trial (VIVID). We’re in the process of recruiting, with several hundred people enrolled already, and we hope to have close to 2000 participants overall. We’re looking at vitamin D supplementation started right after the diagnosis: high-dose supplementation 10,000 IUs a day for 2 days as a loading dose, then 3200 IUs a day for 4 weeks. We are looking to see whether that will reduce severity of symptoms, risk for hospitalization, need for healthcare visits, and outcomes of that nature.
We hope to have the results at the end of this year or early 2022. I think these randomized trials are very important, but I do agree that recommendations should go out to the general public to avoid vitamin D deficiency at all times, but particularly during a pandemic when there is promising evidence for vitamin D being a benefit.
There was the meta-analysis of acute respiratory infections that was published in The BMJ in 2017 that suggested, if you look across the board at acute respiratory infections, that vitamin D supplementation was associated with a significant 12% reduction and was of greatest benefit in those who were vitamin D deficient.
Holick: Along those concepts, we did an intervention trial and took vitamin D–deficient and –insufficient adults and gave them 600, 4000, or 10,000 units a day. We assessed their white blood cells at the beginning of the trial and at the end of the trial, after 6 months. We asked if vitamin D intake is improved, what is its impact on gene expression in immune cells?
The data were quite remarkable. At just 600 units a day, we saw about 150 genes being up- and downregulated. At 4000 units a day, we saw about 300, and at 10,000 units a day, in which we saw no toxicity, up to 1200 genes were being up- and downregulated.
Another question I think should be asked — and we have a study that’s now been initiated and is underway — is whether improving vitamin D status will improve immune response to the vaccine. We know that it’s an immunomodulator. That’s number one. Number two is whether it is possible that if you’re vitamin D sufficient or if you start taking vitamin D, that the long-haul consequences of COVID-19 could be significantly reduced. We have a study underway looking at this as well. [Editor’s note: The study is not yet registered.]
Manson: We’re also going to be looking at these questions in VIVID and some of our other cohorts where we have the information on vitamin D status. I think those are really important points. Mike and I are collaborating on a project in VITAL looking at gene expression and seeing if there is a better gene-expression profile in those who were randomized to vitamin D vs placebo.
Taub: One thing I’m seeing frequently in my clinical practice is that after patients get COVID-19, there seems to be an acceleration in the progression of prediabetes to diabetes. For instance, I will see a patient who has an A1c of 5.7 or 5.9 and then they get COVID-19 and they see me a couple of months after, and their A1c is 7.5. I think that’s something that needs to be investigated.
In the context of vitamin D, there are some data that vitamin D can help with preventing progression of prediabetes to diabetes. Your thought on these data?
Holick: In the D2d study, they actually didn’t find — very much like what JoAnn found — much benefit in reducing risk of going from pre- to full-blown type 2 diabetes. They also had the same issue. Many of their subjects were vitamin D sufficient at the very beginning. I think that when patients are vitamin D sufficient and getting vitamin D, even if it may or may not have a little bit of a benefit, it dilutes the effect for those who were vitamin D deficient.
Manson: We did a meta-analysis of all of the randomized trials that have looked at progression from prediabetes to diabetes, and we are seeing a significant 12% reduction overall. It’s not large. However, there is a signal that vitamin D supplementation does prevent progression to type 2 diabetes, especially if it’s taken in a dose of 1000 IUs a day or more.
What was most interesting to us is that there appears to be a modifying effect of body mass index (BMI). This was found in the D2d trial as well. Vitamin D seemed to be most bioactive in those who were not in an obese BMI range. I think this needs to be better understood.
Those who had a BMI < 30 did have a significant 29% reduction in type 2 diabetes in the D2d trial with the 4000 IUs a day if they were not in an obese BMI range. However, those with BMI > 30 didn’t really have any reduction of risk. There may be something about adiposity and the inflammatory state or other factors associated with adiposity that are counteracting some of the bioactivity of vitamin D supplementation.
If we understood this better, we might be able to make vitamin D supplementation of benefit to everyone, regardless of BMI levels. Some of it may relate to dilution and sequestering of vitamin D, and that could be just a dose-related effect. I think it goes far beyond that because D2d tested 4000 IUs a day and did not demonstrate any benefit of the vitamin D in those with a BMI > 30, whereas they saw a very substantial benefit in those with a BMI < 30.
We’re seeing this in VITAL for a number of outcomes, including total invasive cancer. When we looked at those who started out with BMI < 25, there was a statistically significant 24% reduction in the development of invasive cancer, which was our primary endpoint. At the higher BMI, we did not even see a signal for a reduction in cancer. Mike and I and his colleagues are going to be exploring further whether obesity is affecting, in any way, the gene expression signaling or the bioactivity of vitamin D, and if so, what can be done to counter that.
Holick: We even saw this in our publication for the COVID-19 study out of our hospital. Those that had a BMI > 30 had much less benefit even though their 25-hydroxyvitamin D was the same as those who were normal weight. You’re absolutely right — there’s much going on in obesity that we don’t understand.
One possibility of being able to overcome all of this is related to a study we did recently where we gave 25-hydroxyvitamin D to obese patients, patients with gastric bypass surgery, and patients with fat malabsorption. We asked whether you can give the same dose of 25-hydroxyvitamin D — which is more water soluble, likely getting absorbed directly into the portal system rather than having to be formed into micelles, the chylomicrons, into the lymphatic system — to an obese person, a normal-weight person, and a malabsorption patient.
At least from our initial data, we showed that the pharmacokinetics are identical in obese and normal-weight patients and patients with inflammatory bowel disease. Something that we can think about down the line is that it would be really neat as physicians to be able to give one dose that is good for all. You don’t have to worry about all of these other issues and how to tailor the dose of vitamin D. It turns out that 25-hydroxyvitamin D was available as a pharmaceutical back in the 1970s and then lost favor because they said, “Why spend money for that drug when you can get vitamin D?”
Now it’s becoming available, even in Australia, as a supplement over the counter. Over time, hopefully that will become available and will be much easier to use. It’ll be interesting, then, to do studies on whether giving 25-dehydroxyvitamin D could even overcome the obesity issue associated with responsiveness.
Manson: I think this will be so important. I really do think that one of the reasons why so many of the vitamin D supplementation trials, using mostly D3 but also some with D2, have not shown a benefit in the overall study population is because of this interaction with BMI. In several of these trials, those who are at healthy weight or not in the obese BMI range are seeing some benefit, even a substantial benefit, from the vitamin D supplementation. That’s just not being seen in the higher BMI groups.
Further exploring and delving into this issue, I think, could provide such important information for making vitamin D supplementation benefits available to the entire population, and using 25-hydroxyvitamin D could be a great approach to the problem.
Taub: Thank you both for your incredible insights. I want to conclude by getting recommendations from both of you on what you tell your patients today and what vitamin D levels you aim for.
Holick: I certainly think that following the Endocrine Society practice guidelines is a reasonable approach. They recommend for all adults 1500-2000 units a day. They recognize that if you’re obese, you need two to three times more. For my patients, I typically have them on 3000-5000 units a day.
For children, the recommendation is 600-1000 units a day. I think that that’s very appropriate. Teenagers, I think, should be treated like adults and they should be getting 1500-2000 units a day. Finally, I personally take 6000 units a day; my blood level is 72 ng/mL. I like for my patients to be in the preferred range recommended by the Endocrine Society of 40-60 ng/mL, and up to 100 is perfectly safe.
Manson: I would say that the recommendations need to vary according to the health status of the person. During this pandemic, I would err on the side of recommending more vitamin D. Currently, I would recommend, even on a population-wide basis, 1000- 2000 IUs a day.
In general, prior to the pandemic and once we can get over the pandemic, I do think the Institute of Medicine (National Academy of Medicine) guidelines are not that far off for a generally healthy population, at 600-800 IUs a day; but certainly, taking 1000-2000 IUs a day should be perfectly safe. I don’t think anyone who wants to hedge their bets and get up to 2000 IUs a day or even a little more should be cautioned against that.
The Institute of Medicine did say to avoid more than 4000 IUs a day. I don’t think there’s much evidence that that’s a dangerous dose, but it just hasn’t been tested really long term to know whether the benefits would outweigh the risks taking 4000, 5000, or 10,000 IUs a day for 5 years, 10 years, or 15 years. We don’t know. Those trials haven’t been done. That’s why I recommend that people stay more with a moderate dose because there hasn’t been strong evidence to date that getting above 1000-2000 IUs a day would be any better.
Mike and I are both endocrinologists, so we’re going to be seeing patients who have bone health problems and endocrine problems, and there is always clinician latitude in adapting the dose of vitamin D to the patient’s needs. Many patients will need much more than what I’ve just been talking about for a generally healthy population. Giving someone who has bone health problems or who’s had a fracture 4000 IUs a day could be very reasonable. Other examples could include someone with fat malabsorption, someone who is post–gastric bypass surgery, or someone who is taking certain medications that interfere with vitamin D metabolism.
There will be many patients in a clinical setting who will need more vitamin D. I think clinicians should feel that their hands are not tied, and that there is much clinical discretion and clinical latitude in deciding what is the best dose for their patients.
Taub: Thank you both for sharing your expertise. We have many exciting clinical trial results to look forward to, and hopefully we can reconvene and discuss those trial results. Thank you both.
Manson: Thank you.
Holick: My pleasure. Have a delightful day.
Manson: Great seeing you.
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