To D or not to D: Will someone please answer the question?

"One billion human beings are vitamin-D deficient," Dr Erin Michos of Baltimore began. "What do we care?" I thought, "It has never been shown to reduce mortality." Although I would never intend any disrespect, I'm grateful she wasn't telepathic. She forged ahead with the statistic that "41% of men and 53% women have insufficient-D levels. The risk factors include darker skin coloring, dwelling in the northern hemisphere or lower altitude, avid use of sunscreen, and the presence metabolic syndrome, renal disease and obesity." "Hmm . . . I have lots of patients with those demographics whom I haven't tested," I thought. Quickly, I corrected my wrongful thinking by reminding myself that it really doesn't matter. Then she discussed vitamin-D toxicity that occurs if levels rise to greater than 150. I recalled the patient who took a whopping 50 000 IU/wk for months on end when she misunderstood her prevention clinic's instruction. It cost her four days in the hospital. That alone is proof enough that no matter whether any of us agree or disagree with the vitamin-D hypothesis, it behooves us to be informed. I straightened up a bit and focused more attentively.

Dr Michos, in a very objective fashion, then outlined the pros and cons of vitamin-D supplementation. She referred to the observational NHANES publication in the 2007 Archives of Internal Medicine in which levels of less than 15 were linked with hypertension. Wild-mice studies indeed demonstrate vitamin D to be a negative inhibitor of the RAS system. "Hmm  . . . wonder if I should take a little vitamin D? After all, I'm the last person standing in my family that's not on antihypertensives. Maybe a little bit wouldn't hurt."

There were slides of macrophages in a milieu of oxidized LDL that did not produce foam cells if exposed to vitamin D. "That was intriguing," I thought. Although I've never given a rat's butt about a rat's aorta, by golly, I was impressed by images of teensy-tiny aortas that were as clean as whistles compared with their little vitamin-D–deficient mice friends. Then there was the thought-provoking Framingham offspring study, in which there was a 16% decrease in risk of CV events with adequate D levels. Other studies were cited with up to 18% lower all-cause mortality with adequate levels. But, just as I was getting comfortable with the thought of recommending vitamin D supplementation, the troubling truth reemerged.

In the WHI, 36 282 postmenopausal women took 400 IU/day of vitamin D with no mortality benefit, but Dr Michos pointed out that the placebo-arm cohorts were allowed to take their own supplements and the dose was too low. The PRIMO randomized controlled trial was also troubling because there was no improvement in LV mass with supplementation, but the dose again was too low, genetic responses assumed to be highly variable, and there was no control for BMI. The VITAL trial, currently enrolling, seems doomed from the beginning, with 20 000 healthy cohorts who will be delivered 2000 IU of vitamin D per day. Dr Michos seems pessimistic that it will answer any of our questions, since being vitamin-D deficient was not part of the enrollment criteria. "Currently, the evidence is inconclusive for vitamin-D supplementation," she said. "It's a risk factor, but whether it is causal or confounding remains to be seen. We need large randomized clinical trials, since the saga of hormone therapy, antioxidants, folate, and vitamin B did not match our enthusiasm."

Although I'm definitely not, as of yet, enthusiastic about vitamin-D supplementation, I was mesmerized by thought of the lack of foam cells, clean mouse aortas, and an "association with" a lower mortality with adequate D levels. Like Hamlet, I lamented at the end of the presentation, "To D or not to D?" 'Tis indeed still the question, and though it remains unanswered, I'm at least much less hostile and certainly better informed. At least that's something. 

Your comments

	To D or not to D: Will someone please answer the question?
	# 1 of 10	March 26, 2012 08:21 (EDT)
	oldie	I read that D supplements are D3 which the body must transform into true D and that only sunlight gives the latter. Is this not a factor, unmentionned in the above, which must be addressed?
	# 2 of 10	March 26, 2012 09:47 (EDT)
	Ray	Dr. You might visit vitamindcouncil.org It is a non-profit site, started by John J. Cannell,MD. Latest world-wide research on vitamin D.  A very informative site. Ray
	# 3 of 10	March 26, 2012 09:58 (EDT)
	Dr. Disgruntled	Michael Hollick also has a lot of experience with Vitamin D On another note, is it only mortality that is important - lowest common denominator? Vitamin D deficiency is linked with a lot of other health issues such as osteoporosis; how much money could be saved if people are screened early and fractures prevented, not to mention human suffering; simple blood test; simple treatment; low costs; guess we can't hae that, can we;
	# 4 of 10	March 31, 2012 09:50 (EDT)
	Professor Kasim Salim	Personally I am a proponent of Vitamin D supplementation for the past 48 years from the knowledge I gained during my Medical training complemented by the experience of my father who was also a doctor and who believed in Cod Liver Oil and Vitamin D from Sunlight sources and treated many of his patients with Tuberculosis affecting the Liver and organs other than the classical pulmonary TB. Some of those patients are still alive into their 60s and 80s of age. On my assumption of immunomodulation by Vitamin D, I treated my young 6 year old Nephew with Asthma with regular Vitamin D in addition to the use of Beta agonist inhalers and he is an M Tech Engineering student now, quite healthy and free from Asthma. There are several such patients who benefited from Vitamin D supplementation even before 2006 when the land mark paper by Philip Liu et al appeared in Science(Science Vol 311,page 1770-4, 24 March 2006) stating the fact that the antimicrobial response of Vitamin D through generation of antimicrobial peptide , Cathelicidin is by upregulating the Vitamin D receptor(VDR) and Vitamin D1 Hydroxylase genes in human Macrophages and the fact that this peptide can kill even the intracellular Mycobacterium tuberculosis. In this context we should remember the Denmark Physician Niels Finsen who treated Skin TB(Lupus Vulgaris) with Light and received a Nobel Prize in 1903, 2 years prior to Robert Koch claiming the Prize in 1905 for identifying the causative agent of Tuberculosis. Philip Liu and team again published their observations in Nature Medicine(Nat Med Vol 18,No 2 Feb 2012) regarding the connection between upregulation of MicroRNA 21 by Mycobacterium Leprae, and inhibition of the genes encoding Vitamin D dependent antimicrobial peptides in progressive Lepromatous Leprosy in contrast to the self limited Tuberculoid type where the reverse happens viz downregulation of MiRNA21 and enhanced expression of the Vitamin D dependent Antimicrobial peptides. Vitamin D Receptor polymorphism and its relation to acquiring pulmonary TB in Gujarati families in England was published in Lancet almost 20 years back. Vitamin D mediated induction of Cathelicidin is also effective in preventing recurrent urinary tract infections especially in ladies and I usually advise such ladies to take supplementary Vitamin D in addition to washing after urination. Moreover Vitamin D helps to suppress the compensatory Renin increase while blocking Renin-angiotensin system by Losartan or other ARBs and combination of Vitamin D derivative Paricalcitol along with ARBs prevented renal injury of Diabetic Nephropathy by reversing the loss of Slit diaphragm proteins and suppressing Renin and Angiotensi II. Vitamin D on its own also showed similar beneficial effects in reversing the Podocyte dysfunction of Diabetic Nephropathy. Regarding the yet unexplained Cancer preventing properties of Vitamin D, present studies showing the influence of Vitamin D and its receptor in almost 200 and odd genes in Breast, Colon and Prostate, which are concerned with cell proliferation, differentiation, apoptosis definitely speaks of a positive role which will soon be established. Moreover the link between low levels of Vitamin D and Chronic Lymphocytic Leukaemia and Multiple Sclerosis mostly seen in the latitudes with stanting sushine tells us to start Vitamin D supplementation earlier if we don't want to end up with having such disorders in later life. By the time the proposed prospective trials recruiting 30,000 people for 30 years to study the effects of Vitamin D beyond the bone health, as suggested by IOM proposals(NEJM perspective 2011) we will all end up in mental depression for not starting the supplementation earlier. Now the Psychiatrists also have expressed their views of the connection of Schizophrenia and Depression to low levels of Vitamin D.
	# 5 of 10	April 1, 2012 08:28 (EDT)
	Melissa	Professor Salim, I appreciate your post. I am just as enthusiastic as the next person when it comes to finding a use for "Vitamin"  anything but there has to be some proof that it has an impact on hard outcomes.  No matter the theory, it has to actually effect a change. We were mesmerized for a decade by niacin, before that folate, preceding that, Vitamin C, Vitamin E, etc. etc. Now we actually have signals of harm with Beta carotene and multivitamins.    I agree wholeheartedly vitamin D in regular food stuffs does something "good" for us,, but we are still trying to prove that it actually "WILL" do something good for cardiovascular outcomes via po supplementation routes. It's not the "D" itself, it's just that we have not figured how to efficaciously supplement it.  I think the secret to all of this supplement theory is that we are unable to mimic a natural route of processing and then ingestion. Once packaged, it's really not natural.  Can it get through hydrochloric acid in its current marketed form? probably not.  For now, the beach and the grocery aisle (not the supplement shelves) seem to be the best avenues to gain exposure to any vitamin except for those who are deficient in B12 and iron. Actual harm can come to those who don't need iron and are taking it anyway. Unfortunately, the  toilet bowles are the ones who are benefiting the most from B12 unless those folks are truly deficient. The FDA has allowed supplementation of our foods to the point that iodine is no longer an issue. Folate is really only needed by those who are pregnant or who can't eat a normal diet. Tube fed patients are a whole different deal, who have no opportunities for natural nutrition at all and don't forget about those who are on rifampin or are supplementing with B12 for true deficiencies. Those folks are entirely a different situation.   Melissa
	# 6 of 10	April 1, 2012 08:33 (EDT)
	Dr Tolonen	A new large observational retrospective population study from Kansas University suggests that vitamin D may help us live healthier and longer. The critical blood concentration of vitamin D seems to be 30 ng/ml. According to this criteria, 70% of the Kansas population was deficient in vitamin D. http://www.agdnutrition.com/articles/Heart_Vitamin_D.pdf Recent studies from Málaga University (Southern Spain, Costa del Sol) also show that a considerable part of the population is deficient and the deficiency may increase the risk of diabetes type 2. http://www.sciencedirect.com/science/article/pii/S0261561411002329
	# 7 of 10	April 1, 2012 05:03 (EDT)
	S. Nelson	Melissa -    It is the MAGNITUDES of the correlations and relative risk reductions that I find so shocking with vitamin D3.   A few cites on correlations:   Arch Intern Med. 2008;168(11):1174-1180. "After adjustment for matched variables, men deficient in 25(OH)D (<15 ng/mL ) were at increased risk for MI compared with those considered to be sufficient in 25(OH)D (>30 ng/mL) (relative risk ... 2.09)."    Clin Endocrinol (Oxf). 2009 Nov;71(5):666-72. "After adjustment ... the hazard ratios [for the first 25(OH)D quartile when compared with the upper three] remained significant for all-cause [HR=1.97] and for cardiovascular mortality [HR=5.38]."   Note that these magnitudes are far higher than anything having to do with lipids.  See also:   Am J Cardiol. 2010;106:963–968;  Circulation. 2008;117:503-511; and J. Am. Coll. Cardiol. 2008;52;1949-1956. Note how new all this is in the scheme of things.  We really need to recognize that a paradigm shift should likely be going on.   (On the one hand, we have to be very careful about confounding variables associated with being outside in the sun, but on the other hand, these hazard ratios are many times higher than with, say, exercise.  So it may be the other way around: it may be that there is really no benefit from exercise if vitamin D levels are controlled for!)   OK, so what about the effects of supplementation? I highly recommend reading the Clinical Nutrition study cited by Dr. Tolonen above, "Vitamin D Deficiency and Supplementation and Relation to Cardiovascular Health," J.Vacek et al.   The difference in hard outcomes was dramatic:   "Vitamin D supplementation conferred substantial survival benefit (odds ratio for death 0.39)."    That is a 60% relative all-cause mortality reduction with an average supplementation of 2254 IU! (Too good to be true, of course, but still...)   And for a meta-analysis of 18 randomized controlled trials, including 57,311 participants, none for cardiovascular effects: Arch Intern Med. 2007;167(16):1730-1737 "The summary relative risk for mortality from any cause was 0.93."  And this for a tiny, tiny average supplement value of only 528 IU, which should hardly affect 25(OH)D levels.  That is in all-cause mortality!   Vitamin D (D3) may be the most important new thing cardiologists can do to decrease future morbidity & mortality, but no one is likely to get behind it because there is no money to be made, only intervention revenues to be lost.   I also agree that the VITAL trial, still years away, will not tell us much.  It is on a low-risk, primary prevention population and its 2000 IU dosage is too low (it should be around 5000 IU, which would make a big difference with respect to the ultimate D levels achieved and long-term).  And we need good short & long-term secondary prevention trials ASAP.
	# 8 of 10	April 1, 2012 08:55 (EDT)
	Melissa	S, No adequately powered prospective randomized trials are there? Also, I completely agree with the concerns regarding D deficiency but as you say, low D may just be a surrogate for sedentary lifestye. I hope what seems too be to good be true, is really true! Time should tell but won't.  Don't let them fool you. The supplement studies have plenty of cash to donate to the NIH for a well controlled randomized trial but they will never do it. They have plenty to lose and nothing to gain. Melissa
	# 9 of 10	April 2, 2012 11:45 (EDT)
	S. Nelson	Melissa -   I think that it is a real possibility that "sedentary lifestyle" is the surrogate for vitamin D3, not the other way around.  If vitamin D has higher mathematical correlations, and that is the way it is looking, then that is the way it is likely to be.  Sedentary lifestyle isn't as obviously biochemical... Have any exercise/morbidity studies controlled for D?  Hopefully some datasets have both variables in them so that they can be compared?   No supplement manufacturer has any way of excluding others on D3.  And D3 is soooo cheap. There is no financial incentive for anyone but NIH to fund proper trials.  Certainly foreign single-payer governments do, though.   VITAL may indicate something slight, but I doubt it.  The mechanism of action for D3 (and it could be any of lots of pathways), if any, is likely for long-term prevention, not immediate plaque rupture (but I could be wrong).  In the latter case, you'd need a very long-term trial; in the former, you'd need a secondary prevention population.  VITAL is neither (and the dosage is too low).
	# 10 of 10	April 2, 2012 02:00 (EDT)
	Melissa	Thanks S. for your insight!! Have a great "D"....er day!!! Melissa

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