NIH CLINICAL CENTER GRAND ROUNDS
Episode 2010-09
Time: 1:06:08
Recorded March 10, 2010

Contemporary Clinical Medicine: Great Teachers
Vitamin D, Cardiovascular Disease, and Cancer: Emerging Evidence
JoAnn E. Manson, MD, DrPH
Chief, Division of Preventive Medicine, and Co-Director of the Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital
Professor of Medicine and Elizabeth Fay Brigham Professor of Women's Health, Harvard Medical School

ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future - this is NIH Clinical Center Grand Rounds.

(Music establishes, goes under VO)

ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds, recorded March 10, 2010. Today, we have a special Contemporary Clinical Medicine: Great Teachers Grand Rounds. Our speaker today is Dr. JoAnn Manson, chief of the Division of Preventive Medicine and co-director of the Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital, and Professor of Medicine and Elizabeth Fay Brigham Professor of Women's Health at Harvard Medical School. She will speak on the topic, "Vitamin D, Cardiovascular Disease, and Cancer: Emerging Evidence."

We take you to the Lipsett Ampitheater at the NIH Clinical Center in Bethesda, Maryland for today's presentation.

MANSON: Well, thank you so much, JoAnne. It's a pleasure to be here and extra privilege to be introduced by Dr. Joan McGowan a long term colleague in the Women's Health Initiative. I'm really honored to give to great teachers lecture.

I think this is a wonderful time to talk about the sunshine vitamin, vitamin D, which looks so promising for prevention of cancer and cardio vascular disease especially after the long hard winter in Washington DC; we had one in Boston as well.

With spring right around the corner, it's a good time to talk about the sunshine vitamin. I do have a disclosure, I don't think that I have any conflicts of interest, but I do want to mention that I've received funding from the national institutes of health to conduct a large scale randomized study of vitamin D and the omega fatty acids. That'll be part of the focus of the presentation today.

So the goals of this talk are to first discuss the rationale for large scale randomized trials of vitamin D in the prevention of cancer and cardiovascular disease, to actually look at the evidence. And what is the need for a large scale or more than one large scale randomized trials to discuss the biological mechanisms, the science and the currently available evidence space that link vitamin D to a reduced risk of cancer and cardiovascular disease. And, I do want to present to you the design and some of the complexities of doing a large scale randomized trial of vitamin D, some of the dosage considerations, the logistics of our vitamin D and omega three trial. And this will include both the parent trial that is testing the role of vitamin D and omega threes in prevention of cancer and cardiovascular disease as well as ancillary studies addressing some of the other outcomes.

Further, I want to thank and acknowledge members of our working group on the vitamin D omega three trial. It's really a team effort, a lot of people have been working very hard on this study and the launch of the study, the really wonderful staff we work with. We have consultants from throughout the country that are leading experts in vitamin D. I also want to thank colleagues and scientists at NIH who have been absolutely wonderful to work with and done so much to make this trial possible. So I really can't thank all these individuals enough for all of their help and support in moving this trial forward.

So, I actually would like to present to you the overall design of the vitamin D omega three trial so that when we go through the evidence phase through the design rationale issues it is clear what we're referring to. So, the vital trials goal is to test in primary prevention, in 20,000 initially healthy men and women selected primarily on the basis of age, men being at least sixty years old, women at least sixty five years old, the role of vitamin D, given as D 3 in a dose of two thousand IUs a day, I'll discuss the rationale for that dose which we feel is the best balance of efficacy and safety vs placebo, then further randomized to the marine omega threes EPA plus DHA one gram a day in what's called a factorial design where you have these two by two four treatment groups able to disentangle the individual effects of each intervention as well as possible joint or synergistic effects of the intervention.

So, the study will be done with the 20,000 with a mean treatment period of five years together with about 1.5, one and half years of recruitment, start up, and six months of closeout, the overall study will be seven years. We hope to have a blood collection in about 80 percent of study participants, which will be sixteen thousand and then follow up was in at least two thousand, we'll talk further about that the primary outcomes as I’ll discuss in more detail are cancer and cardiovascular disease a composite of mi stroke and cardiovascular deaths.

Okay, so the primary aims and secondary aims of the trial, we want to test rigorously test, whether vitamin D 3 reduces the risk of total cancer and major cardiovascular events. We'll be able to look at the major sites of cancer, and test for lower risk of rectal cancer, breast cancer, prostate cancer and total cancer mortality. We also want to test whether these agents lower the risk of an expanded composite CVD outcome, which includes coronary revasculartion, mi stroke, CBD deaths, cabbage BCI as well as the individual components of this outcome. In addition, we have some tertiary aims, because it's important for us to be able to explore whether these two agents, these two interventions have synergistic or additive effects, and there's some reasons to think they might.

On risk of cancer and major CVD events as well as secondary end points and then to be able to explore certain key effect modifiers, such as whether the effects of these agents vary by baseline blood levels of these nutrients, for example, is it only in those individuals who have a low 25 hydroxy D level, only those that are low fatty acid levels, who benefit or is there benefit across the spectrum r. Are there risks that might be identified, especially in those that start out in high level. Are there differences by race or skin pigmentation for vitamin D, are there differences by body mass index, also of particular interest to vitamin D as a soluble vitamin. So the underlying rationale for this trial is the growing and emerging evidence that vitamin D and omega threes reduce the risk of cancer and cardiovascular disease.

There's really a limited window of opportunity to do a randomized trial of this nature. First the evidence has to be strong enough to justify the launching of very large scale randomized trial. Secondly, there has to be some uncertainty about the results, because if there's already a conclusive answer there’s no need to do the trial. So the growing use of these supplements underscores the need for getting conclusive evidence on the benefits and risks before it really becomes impossible to even test the hypothesis.

Believe it or not, despite the very widespread use of vitamin D and all of the attention vitamin D is getting as a magic bullet throughout the poplar press, there are no previous large scale randomized clinical trials of these agents in the primary prevention of cancer for cardiovascular disease or cancer and cardiovascular disease are the primary prespecified outcomes.

Now, for background I just want to review, everyone in this auditorium is familiar with sources of vitamin D. But, as you know, vitamin D can be both endogenously produced through UVB exposure, sunlight, leading to the conversion of 7 D hydrochlosterol, or taken through the diet or supplements. In the liver it is 25 hydroxylated to 25 hydroxine many the tissues throughout the body actually have the one alpha hydroxylyate, at least the classical teaching, is that in the kidney, the 25 hydroxy D is converted in to 125 dyehydroxy vitamin D receptor, the primary active form of vitamin D.

There are bone and calcium effects as well as extraskeletal effects that have been more recently identified.

I think it's of great interest to give you an idea of how widespread the effects of vitamin D are likely to be, at least two hundred genes have been identified that have a vitamin D response element. It's been postulated that as much as two thousand and even ten percent of the human genome they have some regulation by vitamin D. So, it is very likely to have important biological effects in a diverse organ system. One alpha hydroxlyde and vitamin D receptor are nearly ubiquitous throughout the body.

Now, this slide shows a main reason that we should not rely on sun exposure to get adequate vitamin D. Not only is UV exposure now classified as a carcinogen, and we know a lot of skin cancers are related to UV, but even if we wanted to, there is just not enough over exposure throughout the entire year or parts of the country not to mention Canada and other areas of the world that are above the 37th parallel do not get adequate UV exposure to produce enough vitamin D during at least six months of the year, the fall and winter months and also we know that with darker skin pigmentation there is less synthesis of vitamin D in the skin as the form of a sun block in terms of the production of vitamin D, but it is just not something that we can rely on. We have to think about what other sources, dietary sources can be used for by adequate vitamin D.

I want to mention what the current guidelines are for vitamin D. I won’t ask if anyone in the auditorium takes more than this amount, but I've asked that at a few talks and just about everyone raises their hand.

The institute of medicine last provided guidelines in 1997 and these were the amounts of vitamin D that were recommended for ages 19 50, 200 IUs a day. 51 to 70, 400 IUs a day. 71 and over 600 IUs a day and at the level of two thousand IUs a day. The institute of medicine is currently re evaluating the dietary reference intakes for vitamin D and calcium and serving on that committee, and we're hoping that these guidelines will be available by summer, so, these may change.
Stay tuned.

I also want to mention that there are certain levels, as we look at the literature, as we go through the different studies that have been done and associations between 25 hydroxy D levels and cancer cardiovascular outcomes, it's important to keep it in perspective and to look at what levels of 25 hydroxy D can be linked to various levels of risk.

I just want to show you a current categorization, a current scheme. There's a lot of controversy about what is deficient, insufficient, sufficient, and even potentially harmful, risk of high per calcemia, this is a common kind of categorization that's used with nanograms per mil, think about the interconversion one nanogram per mil to two point five per liter, this column is 2.5 times that column. Very commonly deficiency is defined as less than ten nanograms. In sufficient 25 or up to 74 so a lot of groups are saying sufficient begins at 75, nanograms, and then potentially harmful you have to get quite high. However, this may also be revised and may be received by the Institute of Medicine Committee in terms of changing these categories a little based on a really close look at the literature. But this would give you a general framework for thinking about levels.

Now, what are some of the risk factors for low vitamin D levels, this is obviously important from a clinical, public health standpoint, but also important when you look at the literature, you may want to, actually ask yourself very carefully at whether studies adjust for some of these variables because if they don't, there's potential for confounding. So, for example, most studies will adjust for older age. But other and older ages associated with decreased efficiency of absorption of vitamin D, decrease skin conversion of vitamin D, synthesis of vitamin D, also, decreased vitamin D receptor concentration so age is a factor.

Living in the north as we discussed, avoidance of sun, where this may come in to play is that if a study is looking at the relationship between 25 hydroxy D and colo rectal cancer and they're not adjusting for physical activity, which may be correlated with more time spent outside being physically active, then there's some potential for confounding of the cancer relationship by physical activity. It's an important variable to adjust for.

Skin pigmentation, race ethnicity, important to look at.

Obesity, vitamin D is fat soluble, it's lower in the presence of obesity, this may be related to sequestering of vitamin D in fat tissue, it's a complex relationship. Low intake, of course, would be a risk factor, and various medical consider such as malabsorption would be a risk factor.

Let's talk about what does the evidence show, what is in the evidence base?

Beginning with cancer, so these are some mechanisms by which vitamin D may lower cancer risk, based primarily on laboratory studies and vivo invitro studies, animal studies. There's quite strong evidence that vitamin D has a role in several pathways that are related to cancer and cancer prevention. And these include effects on inhibiting cell proliferation, affecting the levels of some of the cycle independent kinase inhibitors, I see increasinging levels of p 21, p 27, decreasing some of the growth factors, insulin growth factor one, epidetermal growth factor levels, increasing transforming growth factor b, which actually has a protective effect in terms of inhibiting cell proliferation, also inducing a cell differentiation by the cells related to self survival. Increasing back and over all having the effect of inducting cell differentiation.

Then in terms of later stages of cancer, cancer invasion and metastisis, there is some evidence vitamin D may inhibit angiogensis affecting Il 8 and definite effects on inflammatory pathways, prostalgandins, cuts two pathways, decreasing Il 6, actually increasing Il 10 which has the opposite affect on inflammation and decreasing the TNF alpha, so multiple biological effects that may relate to cancer pathways in both early and later stages of particular interest in terms of the trial that's going to last, maybe only five years, we really, hope that there'll be some effect of vitamin D in later stages so that it would be possible to look at this question in less than fifteen, twenty years. We'll keep an eye on that.

Some other things that may affect cancer, animal studies, there's several studies of this nature, one study was done in mice, and these were mice that were injected with the mc 26 cells, actually a graft of these colorectal cells and then the volume of tumor growth monitored over almost three weeks, looking at the growth in the vitamin D deficient mice vs the growth in the vitamin D replete mice, and even though these numbers are very small, the tumor size in the vitamin D deficient mice only nine mice here and the dash line, only ten talk about nineteen mice, but a significant difference, .002, in terms of the growth of the colo rectal tumor cells.

So, I think this is an exciting finding and of interest, but we don't yet know that this is going to be relevant to humans. I'll come back to some additional evidence, but if I were to summarize what the evidence is, the main sources of evidence are ecologic, looking for example at differences in cancer rates in different parts of the globe that get more sun exposure vs less sun exposure, looking at survival in winter months, that sort of thing.

There actually is a fair amount of ecologic evidence for colorectal reduction with more sun exposure. Maybe a little with breast cancer, looking at how it varies by latitude. And total cancer mostly being influenced by colorectal, but less evidence for prostate. Vitamin D intake studies are strongest from colo rectal cancer reduction.

Little evidence there for prostate, less evidence for breast for total cancer and then the studies that have looked at circulating 25 hydroxy D, very strong for colorectal, and less strong, though still present for prostate, breast and total cancer.

Okay, so this is an example of a meta analysis of studies, observational studies, looking at 25 hydroxy D levels, followed participants followed perspectively.

Over all these studies do tend to show, this is comparing the highest vs the lowest. We will get into what actual levels of 25 D were in a minute. But the studies are fairly consistent in show that those who were in highest quintile tended to have lowest risk of rectal cancer, lower odds than those that were in the lowest category and with these studies pulled met that analysis, the ratio was 0.49. Very significant P value that looks very exciting. But keep in mind, this is observational research, this is not some randomized trial.

Now, looking at specific values of 25 hydroxy D, this paper is hot off the press, it was just published in British medical journal a few weeks ago. The European epic cohort study and multiple studies that involve 520 thousand for participants from ten western European countries, they looked at lowest to highest category of vitamin D, these are the levels, the mean 25 hydroxy D, this is in animals per liter. Here you can see that the highest gets up quite high, that's level 125 nanimals you would have to take three high dose supplements more than three thousand, four thousand IUs a day to get to that level or have a fair amount of sun exposure, that's the kind of level you get among life guards or even get a little higher, but, this is quite high intake, increasing categories, these are the multivariety relative risk, you can see that here the referent is the middle category is a mean of 61.2 intervals.

Here you see an increased risk, even though it's not quite significant for the lowest group. There's an increased group among the lowest category and it seems to be a fairly linear inverse increasing risk as you get to higher levels and a very significant p value for trend. The analyses were adjusted for body mass index, physical activity and important variables.

So this is, you know, quite interesting finding, but before you get, you know, get on the band wagon here, I want to show you that there may be a dark side to the sunshine vitmain, and there have been some concerning findings, for example, with pancreatic cancer, is it really clear that they're now at least three studies, pancreatic cancer, as you get increasing quintiles of 25 hydroxy D, it's the highest category here, not that high, just 65.5 and higher.

You see this strong positive association of increased risk of pancreatic cancer, this was in the alpha beta karatine study among smokers, we don't know yet how meaningful this is, something to keep in mind, the results have not been all favorable. There are a few little concerns lurking there. Especially in terms of pancreatic cancer, so we have to keep in mind that these are observational studies, we really need randomized trials, and we can't assume that everything will be favorable. We have to look at the risk side of the equation as well.

I've shown you observational studies, I want to show you randomized trials, we're working with a very, very limited database in terms of randomized trials, as I mentioned, not a single large scale randomized trial that had cancer or cardiovascular disease as a primary prespecified outcome, the Women's Health Initiative, very important trial, this was looking at calcium, 1000 milligrams of elemental calcium with 400 IUs of vitamin D 3, a low dose, but the background intake of vitamin D is about 365 IUs of vitamin D, so you're really talking about a total intake of about 765, close to 800 IUs vs 400, 365 in the placebo group in the background intake.

With this comparison and seven years of treatment and follow up, there was no association at all with colorectal cancer, the ratio 1.08. There was, maybe a hint, but certainly a very wide confidence interval of some reduction in colorectal cancer deaths. This is of interest because if in fact there are effects with late stage cancer promotion terms of invasiveness of the tumor and likelihood of metastisis, maybe you're seeing something even with a relatively low dose, but definitely too small a sample size in terms of number of colorectal cancer deaths confidence intervals are wide and this was not found for breast cancer. Hazard ratio was very low for both incidence and mortality from breast cancer in the study. But, of course, the criticism has been that the dose is very low, it's not really testing the hypothesis of moderate to high doses of 25 hydroxy D that would get you to 75 nanimals.

Now one other standardized trial I want to mention, again cancer was not a prespecified primary outcome. In a trial done in Nebraska, 929 women, now, this trial looked at calcium combined with vitamin D at a dose of about 1100 IUs a day of the vitamin D. Vs calcium alone, vs placebo. Now, there was a suggestion of a reduced risk of breast cancer over the four years of treatment with calcium plus D and also with calcium alone. This reduction with calcium and D was close to fifty percent and with, I'm sorry, this was close to sixty percent, it was calcium alone. It was close to 47 percent. But there was not a significant difference between the calcium plus D group and the calcium only group. And that's the real test of the vitamin D.

So this trial is actually suggesting that calcium lowers the risk of total cancer. Which, I'm going to go back to this slide. This Women's Health Initiative trial was testing a similar dose of calcium, plus the 400 IUs of vitamin D, in a trial with 36 thousand participants and showed no reduction over an even longer follow upper period, no reduction in colorectal cancer, or total cancer with calcium. Calcium together with D. So, it's very difficult to reconcile a reduction with calcium even in the calcium alone arm, but these are the findings and this is something that we need to try to understand better and continue to explore these associations.

Now, let's move on to cardiovascular disease, then we'll come back to several issues relevant to both cancer and cardiovascular disease. Some of the mechanisms by which vitamin D may reduce risk of cardiovascular disease are similar to those for cancer.

Mostly the very powerful effect of vitamin D in high doses in inhibiting inflammation, and we all know inflammation plays a major role in atherosclerosis and cardiovascular events, all of these as we discussed with cancer, working to inhibit inflammation.

There's also evidence in terms of other pathways relevant to cardiovascular disease that vitamin D in animal studies and laboratory, invitro studies, may inhibit vascular smooth muscle proliferation, they have in animal studies some effects on vascular calcification by regulating the influx of calcium into the cell, decreasing the influx and increasing matrix protein which actually is an inhibitor of vascular calcification, these effects may lead to less vascular disease. Also perhaps the evidence is stronger for, and I'll show you a little more, for effects of vitamin D on genoexpression and bio synthesis of renin, which would regulate blood pressure, effects of reducing blood pressure, and also regulating volume, which may play an important role in terms of heart failure reduction. And then several studies particular in rodents looking at effects of high dose vitamin D on insulin sensitivity and insulin secretion and the regulation of glucose metabolism also looks promising, but most of the evidence is from laboratory animal studies at this point.

Okay, so, coming back to possible affects on cardiac hyperthy and blood pressure. There are some interesting studies in animal knock out models.

So first we know that the vitamin D receptor is present in cardiac myocytes, and the vascular system as well as throughout most of the body. Vitamin D deficient animals have higher pressures during contraction. Vitamin D has been shown in animal studies to suppress genoexpression. Vitamin D knock out animal models, these are mostly rodent models, when the vitamin D receptor is knocked out, these animals develop myocyte hypertrophy, left ventricular hypertrophy and increased blood pressure. At one alpha hydroxlyde model, they can't produce the bio active 125 hydroxy vitamin D, these animals also develop hyperthy and can be rescued and this process can be prevented with administration of 125 hydroxy D.

Also we all know well that in the clinical scenario of end stage renal disease where there is inadequate production of the bio active 125 hydroxy vitamin D and in the absence of administering vitamin D, there is less ventricular hypertrophy, heart failure and also accelerated sclerosis. There are several pathways that have been suggested that would implicate vitamin D in possibly preventing cardiovascular disease and heart failure and hypertension.

What do the actual human studies show? What we're limited here, again, to mostly observational studies. We've recently done an meta analysis, systematic review, just published this hot off the press, last week in annals of internal medicine, I’ll show you some additional data in this. If you look at the studies, and I have another slide to provide more details about these studies, 25 hydroxy vitamin D levels, the risk of coronary heart disease, and the lowest vs the highest category, you do see you have the Thomas Wane study heart study, Benucci study, several studies that suggest those that have lower levels of 25 hydroxy D have lower risk of coronary events. In a pulled analysis, there was a significant 59 percent increase among the lowest vs the highest category. And similarly for cardiovascular mortality among subjects with or without the existing coronary disease, you see suggestions increase risk among those with the lowest and a pool of estimate that is borderline significance there.

Now, this was in our paper last week. If you look at the randomized clinical trials, again, I'll show them in more detail, there's not too much to write home about. These studies, again, do not have prevention of cardiovascular diseases as a primary prespecified outcome, and they tend to show fairly null results. One is the Tratiti trial in the United Kingdom done with about 2500 participants, tested the dose that was the equivalent of 800 IUs a day or a hundred thousand IUs every four months. What they found was a hazard ratio of 0.90, not at all significant. And then in the Women's Health Initiative, this looked at the association between calcium and vitamin D supplementation and risk of cardiovascular events and with a completely neutral result as if you combine the two you get 0.98.there are a few more details about these cardiovascular studies.

The Tommy Wane study, this included a little over 1700 men and women aged 59, 5.4 years of follow up. This study was looking at a group of levels less than 37.5 vs those with higher levels and found a relative risk of 1.6  so 62 percent increase risk in those that were low, fall into a category of vitamin D deficiency or close deficiency by most categorizations. Health professionals follow up look at slightly different levels in terms of they looked at the same group, but they were comparing to a much higher level of getting to 75 or higher, which some researchers now consider to be an optional getting bonn 75 nammals. So coronary incidents was about double in those who were in a vitamin D deficient category vs those that got up above 75 namalls. Then the representative study population did not see a significant increase in CBD mortality with the bottom vs the top quartile, but they did see significant though fairly modest increase in total mortality for the lowest vs the highest quartile.

What about the randomized trials of vitamin D. This is the British trial, Women's Health Initiative that I mentioned, there's also a meta analysis, this is published by Otar and archived about three years ago. It was very interesting, these were mostly randomized trials looking at bone outcomes, fractures, physical performance, etc.

Again, not to be specifying to look at cardiovascular disease, cancer or mortality, but taking them all together the hazard ratio was 0.93 for mortality. That just made statistical significance. Suggesting there may be something about vitamin D, lowering all causes of mortality, certainly not a huge magnitude of reduction, but I'm going to show you the results of the WHI which makes an interesting point about dose. The relationship of dose through this risk reduction.

Again, the British trial, as I mentioned about 2600 or so, men and women in the united kingdom, vitamin D one hundred thousand used every four months vs placebo so that comes out to close to 800 IUs a day. CBD incidence 0.90, mortality 0.84, not significant. You might look at those numbers and say, this is a small trial, they're testing a higher dose, finally, above 400, I use a supplementation, looks like something is going on, if this was a larger trial maybe this would be significant reduction, at least is on the left side, which is the right side.

And the Women's Health Initiative as I mentioned 36 thousand participants over seven years testing calcium plus vitamin D at 400 IUs, not at all significant, stroke incident, so really not very much going on in terms of CBD in that trial.

Now, here more details about the Women's Health Initiative result, if you want to see, is there a lot of end points, MI or CHD death, you know, getting up to a thousand in total, 1.04, about as low as you can get. Your PCI very null, stroke, null, and stroke TIA, null. So, you know, no matter how many you look at, there's nothing going on.

Now, another point I want to make another 25 hydroxy D, even in the studies that suggest an association between increasing level of vitamin D, this is nanogram per mil, such as the Framingham offspring study, tom swains study looking at coronary cardiovascular events, even where this is the overall relative risk and these are the 95 percent confidence, even when you do see increased risk in the vitamin D deficient group and some reduction, it appears that it nadirs in the middle range and then there's some hint of an increase at higher levels of 25 D. So it isn't necessarily the case that more is better and that it's a clear linear response, the higher you get, you know, it's just going to keep improving lower and lower risk. So for coronary disease it appears you reach a nadir close to about 25 or so nanograms so that's going to be a little above sixty, nanimals, 65 nanimals or so, then you're not really getting a clear additional benefit.

I think that's important to look at. You know, the shape of this dose response curve. Is it clearly a linear association or is there more, you know, quadratic. Here is another study. Again, this is an nanagram, multiplied by 2.5.here, you start to see a nadir, this is all cause mortality, nadar in risk as you get to about 35 or so nanagrams  90 or some nanimals, then it starts to increase. So, again, you are not, you know, as you get to 50 nanagrams, 60 nanagrams, you're starting to see a suggestion of an increase. Whether this is some artifact, we don't know. But, even the observational research is not showing just a clear linear, direct, inverse association between 25 D and CBD cause mortality. And showed you some concerns about pancreatic cancer.

Now getting back to the trial, I wanted to talk about the dose we're testing, 2000 IUs a day, which is also the equivalent of 50 micrograms a day. A rule of thumb for how much vitamin D supple menation will increase the 25 hydroxy D level is for every microgram increase is about one nanimal. If we start out at moderate levels of 25 D, especially low levels in the trial of 25 D we may expect about a 50 nanimal increase. So for example, if we start out around 40 nanimals, you may get up to 90, however, if we have a lot of participants who start out higher, there's some attenuation, the shape of the curve becomes, it's not totally linear, there's less of an increase in the 25 hydroxy D level as you get to higher levels and takes, you know, even greater doses to further increase the level of 25 D, so the increment in 25 hydroxy D becomes less as you get to a higher level. So, we believe that this dose I'm not going to talk about the A. A right now, represents the best balance of ethicacy and safety because it will get us to levels of intake and 25 D levels that have been associated with the lowest risk in the observation studies, and should not have any clear risk.

So the vitamin D dose will provide an average serum 25 D level of about 90 nanimals. If you consider an optimal range between 75 and 100 this will place us right in the middle of that, and would be a delta anywhere between 25 and 50 depending on what your starting level is.

If you start high it may be only 35 nanimal increase or possibly lower, but 15 compared to the placebo. Compared to DHA, though it seems like a low dose, it's what's recommended for patients with cardiovascular disease, it's actually five to ten times higher than the average intake in the population.

I'm going to go quickly through these slides, I don't know how much interest you have in the last part of the trial, in case anyone in the audience is interested in collaborations we're certainly open to that and want you to have some of the background information on the trial.

It's going to be logistically very challenging, we're throughout the United States, mass mailings, we're going to be mailing anywhere between 1.2 and 2.5 million and pending on our response rate, it'll be less.

If we have higher response rate it could be lower response rate, higher end throughout United States, several mailing lists, other forms of recruitment.

We're definitely interested in having at least 25 percent African American to look at some of these key questions about whether vitamin D may be able to reduce some of the health disparities.

We did a pilot study in about five thousand, which suggested that we would be able to reach our recruitment goal with a mailing of close to 1.2 million. We'll see if that airs out.

We plan to do a placebo run in to assess pill taking behavior, so that we're randomizing only those that are good with pill taking otherwise you have by noncompliance. So we have to enroll 40 thousand who are willing and eligible for three month run with placebo which we're going to do a lot of baseline measurements and assessments. The total randomized would be 20,000, those who are willing, eligible and compliant with the run in, and the projected racial ethnic distribution, only 63 percent white. That may seem like a lot, for the randomized trials it's low. 25 percent African American, 7 percent Hispanic, 2 percent Asian, American Indian, Alaskan native.

We're hoping to have racial ethnic diversity. In absolute numbers, out of the 20,000 randomized, we're hoping to have five thousand black or African American, at least fourteen hundred Hispanic Latino, a little over twelve thousand white non Hispanic, four hundred Asian and 80 native Hawaii or Pacific Islander.

And the eligibility criteria mostly on the basis of age, at least 60 in men, 65 in women, at least a high school education to give true informed consent and understand the form that has to be completed and provide reliable information.

It is a primary prevention trial, so no history of cancer, except basal cell or non melanoma skin cancer, no history of CBD for safety reasons, no history kidney stone, dialysis, not so much renal failure, no history of hyper calcemia or parathyroid problems, and chronic TB, some of these conditions actually can be of concern because of hyper calcemia the activated macrophages in these conditions can synthesize fairly high quantity of the vitamin D. So we're definitely excluding anyone that reports it.

But our bigger concern is there may be some undiagnosed disease in the population.but with two thousand IUs, we're hope that will not be a problem.allergy to fish for the omega three part. We are allowing background intake of vitamin D up to 800 IUs a day in supplements, we don't want to induce any more vitamin D deficiency, so people can still take up to recommended levels. And up to 1200 milligrams of calcium, they can't take the fish oil supplements, that's exactly what we're testing.

I mention the blood collection, getting blood from at least 16000, this will not only help us to assess pill taking compliance, but we can look at a lot of changes in biomarkers, we can also look at the effect of background fortification of the food supply in the placebo group changing trends in fortification, both the vitamin D and omega threes and certainly a lot of increase in fortification of both over time.

We also want to look at some groups are of great interest, African American, and ratifying by body mass index.

We also hope to look at whether there are any signs of hypercalcemia, thyroid levels will be monitored and sampled. The cohort size, as I mentioned the 40 thousand in to the run in and then twenty thousand compliant randomized. We'll have excellent power with five years of follow up, the power will be more than ninety percent to detect a relative risk of 0.85 for the primary cancer outcome. We can detect with greater than 90 percent power, relative risk of 0.80 for the primary mortality outcome, ND risk of 0.85, even 0.9 if we include coronary re vascularization.

Want to mention we're planning several ancillary studies we're excited about since it's such a large scale trial of vitamin D, we want to be able to look at the overall balance of benefits and risks and look at other outcomes that have been linked to vitamin D, we plan to look at heart failure and cardiac 2d echo, hopefully that will be funded.

Atrial defiblation, cognitive decline, mood disorders and depression, bone health, fractures, hypertension, some of the asthma and respiratory disease including a composite of a number of auto immune outcomes, and in this particular study we also plan to look at effects on joint pain, which is such a common condition and there's some promising data that vitamin D may actually by reducing inflammation they have, in fact, or perhaps other mechanism in reducing joint pain.

We hope to have several bio marker and genetic studies, we hope to assess mineral density to look at affects on breast tissue and non invasive vascular imaging. One part of the study involves the clinical translation where a thousand participants would come in for more detailed typing which would include blood pressure, blood glucose tolerance test, imaging studies. This would be a collaboration of four sites throughout the country where have a lot of geographic diversity, a thousand participants would be seen, about 250 at each of these four sites for the more detailed assessments.

This is just a preliminary protocol blood pressure, weight, glucose tolerance testing, blood, respiratory outcome, physical performance, strength-frailty assessments, cognition, the noninvasive imaging.

So, in conclusion, we believe that vitamin D and omega threes, we discussed that, vitamin D is complex enough, are promising interventions for prevention of cancer, cardiovascular disease, many other chronic diseases, include evidence for their efficacy is inadequate and lacking in both primary and secondary prevention, we do not have large scale randomized trials that have addressed these issues with adequate dosing getting to moderate to high doses of vitamin D. Vital would be the first large scale randomized clinical trial of these agents in the primary prevention of cancer and CVD with prespecified outcomes.

And lastly, this is the logo of the vital trial and our study website. This isn't too shameless. Vital study.org if you want to get more information.

Thank you very much.

[APPLAUSE]

QUESTION: This is more of a practical question, you're bringing in lot of older folks that may have problems swallowing, have you thought about putting these supplements in a glass of milk?

MANSON: We are going to work closely with the study participants to find ways to enhance compliance if they have any difficulty with the study pills, so we will make suggestions such as taking with liquids or mixing with apple sauce or whatever that might make it easier. The vitamin D is simple to swallow. Omega 3s are a little larger tablet.

QUESTION: What's the fat storage difference between supplement and the sun. I heard you can't really OD on the sun besides skin cancer, I don't know how well that's stored in the body.

MANSON: It seems that you cannot get to toxic levels of 25 D from sun exposure, but there seems there's some local skin inactivation of the vitamin D once you get to a certain amount of UV exposure. So it isn't so much that, you know, there are differences in the storage. It is interesting that for about six months of the year you really do not have adequate vitamin D stored, but the amount that's in your fat tissue will be of some value for at least six weeks or so. The half life of vitamin D in the plasma is two to three weeks, but in the fat tissue you can make use of those stores for a couple months into the late fall and early winter.

ANNOUNCER: You've been listening to NIH Clinical Center Grand Rounds recorded March 10, 2010. Today you heard a special Contemporary Clinical Medicine: Great Teachers Grand Rounds. Our speaker today was Dr. JoAnn Manson, chief of the Division of Preventive Medicine and co-director of the Connors Center for Women's Health and Gender Biology at Brigham and Women's Hospital, and Professor of Medicine and Elizabeth Fay Brigham Professor of Women's Health at Harvard Medical School. She spoke on the topic, "Vitamin D, Cardiovascular Disease, and Cancer: Emerging Evidence." You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link -- or by clicking the "View Videocast" link on the podcast homepage at www.cc.nih.gov/podcast. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison. For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America's Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I'm Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services