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What Strikes Terror in the Citadels of the Pharmaceutical Industry

January 2016

By Ward Dean, MD

PREAMBLE

What Strikes Terror in the Citadels of the Pharmaceutical Industry  

In response to medical reports that are misinterpreted by the media, Life Extension® has historically issued point-by-point rebuttals when the study’s methodologies/analyses are scientifically flawed and/or the findings blatantly false.

In response to sensationalized headlines appearing earlier this year about a flawed vitamin D study, Life Extension reached out to a medical doctor who has been fighting the establishment almost as long as we have.

Before you read Dr. Dean’s detailed rebuttal to this study published by the American Medical Association, it’s important for you to know why these kinds of reports garner so much media attention.

In pharmaceutical corporate boardrooms, charts are routinely presented showing how many people are projected to contract a terrible disease. Data about the potential benefits of a patented drug follows the chart projection. Then a financial calculation is done to show how much money will be made if the pharmaceutical company pushes this drug through the FDA’s arduous approval process.

An uncertainty has arisen regarding the lucrative financial projections coveted by drug companies. What if the chart showing growing numbers of aging Americans contracting a degenerative disease goes the other way…in other words declines? This destroys the profit expectation and incentive to spend hundreds of millions if not billions on new drug candidates.

The greatest threat to the profitability of Big Pharma may be vitamin D. This vitamin costs virtually nothing and has an incredible amount of data showing its ability to decimate the financial projections of drug companies who look forward to lots of aging Americans being diagnosed with some form of cancer every year. (Refer to chart on this page.)

Drug company ads dominate media advertising the way tobacco ads did in the 1950s through 1960s. It is in the economic interests of Big Pharma for the media to air headlines warning Americans to avoid vitamin D (and other supplements). The more people who believe these flawed reports, the more money the pharmaceutical industry makes.

As you will read, not only is this analysis attacking vitamin D without scientific merit, but newly published data reveals vitamin D to be even more effective in preventing death and disability than previously known. Drug companies would prefer that you not read these reports on vitamin D.

Ward Dean, MD
Ward Dean, MD

Rebuttal to JAMA Internal Medicine Report:

“Vitamin D Ineffective for Hypertension”

On March 15, 2015, the journal JAMA Internal Medicine published a systematic review and meta-analysis titled “Effect of Vitamin D Supplementation on Blood Pressure.”1

The authors of the article stated that their purpose was to conduct a systematic review of clinical trials to evaluate whether vitamin D supplementation reduces blood pressure compared to placebo. In their meta-analysis, they included studies that reported any baseline 25-hydroxyvitamin D blood levels, any blood pressure levels, studies that lasted as little as four weeks, and which involved supplementation with a variety of forms of vitamin D, including vitamin D2, vitamin D3, calcitriol (1,25-hydroxyvitamin D3), and 1-alpha-hydroxylated versions of vitamin D (paricalcitol and doxerocalciferol). The primary results the authors were looking for were changes in office-measured systolic or diastolic blood pressure readings.

The meta-analysis included 46 trials involving a total of 4,541 participants. After analyzing participant data, the authors proclaimed, “Vitamin D supplementation is ineffective as an agent for lowering blood pressure, and thus should not be used as an antihypertensive agent .

Two days later, on March 17th, CBS News jumped on the bandwagon and trumpeted, “Vitamin D useless for lowering blood pressure.” 2 CBS News medical contributor Dr. David Angus stated that although vitamin D was “the second most prescribed or taken vitamin in the country, there is no benefit that anybody derives…it doesn’t work in anybody,” and cautioned that “it may cause significant harm.” Dr. Angus went on to allege that “too much vitamin D in the blood can be harmful, causing nausea, constipation, and even damage to the kidneys.”

I was surprised at the conclusions reached by the JAMA Internal Medicine article, and even more dismayed by the off-the-wall “analysis” by CBS News. I knew of the multiple benefits of higher doses and increased blood levels of vitamin D, as well as the dangers to health of low levels,3,4 and that lower blood levels of vitamin D are associated with higher blood pressure levels in cross-sectional studies,5,6 and with increased rates of hypertension.7,8

Nevertheless, the above-cited meta-analysis on the surface sounded pretty definitive—followed by the drubbing from the CBS News medical commentator. A rational person would assume that the studies involved in the meta-analysis were studies of hypertensive patients who had deficient or low levels of vitamin D, and who were treated with therapeutic doses of vitamin D or placebo for an adequate period of time.

However, when I examined the individual studies that comprised the meta-analysis, a different picture emerged. Very few of the studies met these presumptive criteria. What I found was a mishmash of studies that used varying doses of vitamin D, ranging from 30 IU to 7,000 IU per day (including several studies which used doses as high as 300,000 IU, given as a single injectable dose administered to subjects who were, for the most part, neither hypertensive nor deficient invitamin D).

Like many long-time readers of Life Extension®, I believe that an optimal blood level of vitamin D should be higher than 50 ng/mL, and for most people to attain this level, it is necessary to consume between 5,000 to 10,000 IU per day.

Vitamin D blood levels were considered by the “meta-analyzers” to be “deficient” if less than 10 ng/mL, “insufficient” (10-20 ng/mL), and “adequate” (greater than 20 ng/mL). In contrast, Life Extension®’s recommended optimal blood level for vitamin D is 2.5 times higher than the blood level considered adequate by the meta-analysis authors.

Study Design and Details

The analysis included 46 studies. Of these, only 16 of the studies included participants who had mean systolic blood pressure greater than 140 mmHg (1,361 subjects), while 30 of the studies’ participants had mean systolic blood pressure less than 140 mmHg (3,180 subjects). Thus, nearly 75% of the participants in the study were not hypertensive. It is not surprising that vitamin D in any amount had little or no effect on those with normal blood pressure—in fact, it is reassuring that vitamin D does not further lower blood pressure in normotensives. A potential problem with most antihypertensive drugs is that too high a dose can cause dangerously low blood pressure—whether one is hypertensive or not. Correcting a nutritional deficiency should not be expected to lower normal blood pressure.

What You Need to Know
Rebuttal to Study That Declared Vitamin D Ineffective for Hypertension

Rebuttal to Study That Declared Vitamin D Ineffective for Hypertension

  • JAMA published a meta-analysis titled “Effect of Vitamin D Supplementation on Blood Pressure,” and concluded supplementation is ineffective as an agent for lowering blood pressure, and thus should not be used as an antihypertensive agent.
  • CBS News issued a report agreeing, and their medical contributor went on to say, “there is no benefit that anybody derives [from vitamin D]…it doesn’t work in anybody,” and “it may cause significant harm.”
  • The problem with this meta-analysis was the selection of the studies on which the analysis was based.
  • The meta-analysis was a collection of studies that used varying doses of vitamin D, ranging from 30 IU to 7,000 IU per day (including several studies that used monthly doses as high as 300,000 IU) and was administered to subjects who were, for the most part, neither hypertensive nor deficient in vitamin D. The studies in the analysis also used varying types of vitamin D.
  • Studies that were not included in the meta-analysis published by JAMA found that vitamin D is a useful adjunct to helpnormalize blood pressure in vitamin D-deficient hypertensives.

Inappropriate Study Selection

Inappropriate Study Selection  

It became increasingly clear that the problem with this meta-analysis was the selection of the studies on which the analysis was based. Few of the studies directly addressed the key question the meta-analysis was designed to answer: i.e., does supplemental vitamin D have a positive effect on hypertensive subjects with low levels of vitamin D? Few of the studies specifically included hypertensive subjects or subjects who suffered from vitamin D deficiency (or insufficiency). In fact, many of the studies included only “healthy” subjects, and several specifically excluded those who were hypertensive. In addition, there was no standard form of vitamin D or range of vitamin D used.

As mentioned previously, forms of vitamin D included vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), calcitriol (1,25-hydroxyvitamin D3), paricalcitol, and doxerocalciferol. Length of the studies varied from as short as four weeks to as long as 18 months. Most significant was the fact that only a few of the studies actually used blood pressure as a major end-point of the study. Most were primarily concerned with other parameters, and considered blood pressure as a secondary or incidental event.

Consequently, the 46 papers that were included in the meta-analysis were a poorly selected mélange of studies investigating a hodge-podge of unrelated physiological phenomena. The only unifying characteristics seemed to be that some dose of some form of vitamin D was used to evaluate some physiological functions that happened to include a measurement of blood pressure.

For example, one of the studies evaluated the effects of small doses of vitamin D3 (0, 200, 400, or 600 IU) in healthy (i.e., not hypertensive nor D-deficient) young (20-40) and older (over 64) men and women.9 Not surprisingly, the researchers found no significant effects of vitamin D on cardiovascular risk factors. What did they expect from these normal volunteers? The researchers conceded: “Putative effects of vitamin D on cardio-metabolic health will only be evident at higher intakes than the current RDA.

Another study involved healthy (not hypertensive) subjects, with vitamin D levels that were either normal or not checked. Subjects in this study were given 200,000 IU of vitamin D3 per month for two months, followed by 100,000 IU per month for the next sixteen months. Not surprisingly, the authors found that vitamin D supplementation “had no effect on systolic or diastolic blood pressure in predominantly white, healthy adults without severe vitamin D deficiency.10

Of all the studies in the meta-analysis, the study that administered the highest dose of vitamin D3 (300,000 IU via intramuscular injection) specifically excluded subjects with known clinical deficiency of vitamin D.11

Another study reported no benefit from vitamin D supplementation in depressed people with low levels of serum vitamin D, to whom 40,000 IU of vitamin D3 were administered each week for six months. This study specifically excluded subjects with hypertension from the trial.12

Another shortcoming in many of the trials was the limited length of the trial itself. For example, one study tested the effect of a single oral dose of100,000 IU vitamin D3 on patients with peripheral arterial disease (PAD), and hoped for positive changes after only one month!13 PAD does not come on overnight—and is not likely to be reversed in one month with a single dose of anything.

Another trial studied the effect of high-dose vitamin D3 (50,000 IU per week) for six months in patients suffering from heart failure.14 Over 60% of the subjects were classified as NYHA Class II, which means that the patients had cardiac disease resulting in slight limitation of physical activity, were comfortable at rest, but ordinary physical activity resulted in fatigue, palpitation, shortness of breath (dyspnea), or anginal pain. The remaining patients (36%) were in Class III, which means that they had severe cardiac disease with marked limitation of physical activity. Less-than-ordinary activity caused fatigue, palpitation, dyspnea, or angina. These were all very sick people, suffering from a serious chronic disease. Again, it is not surprising that increasing their vitamin D levels—even for six months—did not reverse their condition.

It is obvious that the articles selected for this meta-analysis were all over the map. It was a collection of miscellaneous studies grouped together and “analyzed” to produce what appeared to be a previously determined outcome—i.e., that vitamin D was not an effective treatment for hypertension for anyone—even though that premise was not the focus of the majority of studies included in the meta-analysis. This reminded me of the old computer dogma, GIGO—garbage in, garbage out.

Positive Results Nonetheless

Positive Results Nonetheless  

Despite the pattern of inappropriate study selection for this analysis, a number of the studies reported positive results.

In one study, 34 type II diabetics with low serum vitamin D levels (less than 20 ng/mL), were given 100,000 IU of vitamin D2 (ergocalciferol) or placebo, and monitored for eight weeks. Vitamin D2 significantly decreased systolic blood pressure by 14 mmHg.”15

One of the earliest studies in the meta-analysis used daily doses of 1 mcg of alfacalcidol (a synthetic vitamin D analog, roughly equivalent to 40 IU of vitamin D3) in 29 hypocalcemic patients. After six months, the authors reported a significant reduction of both systolic and diastolic blood pressures, compared with placebo. They concluded that a physiologic amount of active vitamin D has hypotensive effects and can be beneficial for patients with high blood pressure.16

In another study by the same team, 33 patients with primary hyperparathyroidism, mild hypercalcemia, and elevated diastolic blood pressure were given 1 mcg of alfacalcidol or placebo for six months. The scientists found a significant reduction of diastolic blood pressure, and concluded: “Vitamin D can lower blood pressure in hypercalcemic patients.”17

In yet another study, 148 women with vitamin D insufficiency (25OHD less than 20 ng/mL) received daily doses of either 800 IU vitamin D3 plus 1,200 mg of calcium or 1,200 mg of calcium for eight weeks. The results showed that 81% of the subjects in the vitamin D3 plus calcium group compared with only 47% in the calcium group showed a decrease in systolic blood pressure (SBP) of 5 mmHg or more. The scientists concluded that “short-term supplementation with vitamin D3 and calcium is more effective in reducing SBP than calcium alone.18

Paradoxically, the senior author of the meta-analysis (which claimed that vitamin D was ineffective as an antihypertensive agent) authored an earlier paper, in which he demonstrated that single doses of 100,000 or 200,000 IU of vitamin D3 administered to 39 diabetics with 25OHD levels less than 40 ng/mL resulted in significant lowering of systolic blood pressure after eight weeks, causing him to conclude that “high-dose vitamin D3 improved systolic blood pressure in patients with type II diabetes.”19

African-Americans are known to have significantly higher rates of hypertension than whites. Scientists from Brigham and Women’s Hospital, Boston, conducted a double blind study of 283 African Americans, using doses of vitamin D3 as high as 4,000 IU a day, which resulted in significantly lowered systolic pressure.20

Scientists from the University of Verona, Verona, Italy, administered 4,000 IU of vitamin D3 per day to 13 of 23 patients who suffered from chronic heart failure. The patients’ mean age was 74, and all had vitamin D levels less than 30 ng/mL. After six months, systolic blood pressure was lower in those treated with D3, and ejection fraction was improved.21

Other Studies (Not Included in Meta-Analysis)

In 2009, German scientists investigated the effect of vitamin D (calcitriol—the active form of vitamin D) levels on mortality in a cohort of 510 patients with serious, life-threatening illnesses: 67.7% with heart failure (two-thirds in end stage), 64.3% with hypertension, 33.7% with coronary heart disease, 20.2% with diabetes, and 17.3% with renal failure.

Many of these patients had multiple co-morbidities. The scientists assessed vitamin D (calcitriol) status at the beginning of the study, and assigned the patients to the following quintiles: <16.7 ng/L, 16.7-25.2 ng/L, 25.3- 33.2 ng/L, 33.3-43.4 ng/L, and >43.4 ng/L.

Other Studies  

No supplementation was provided, although the patients were administered standard medications, and were followed for one year.

Broken down by quintiles, the probability of survival was: 66.7% in the lowest quintile, 82.2% in the second quintile, 86.7% in the third quintile, 88.8% in the fourth quintile, and 96.1% in the highest quintile. (See Figure 1.) These survival improvement percentages in those with higher vitamin D blood levels are nothing short of astounding.

Significantly, none of the patients with calcitriol concentrations >58.5 ng/L died during follow-up.22

Figure 1. Freedom from one-year mortality according to quintile of circulating calcitriol.22

Relationship in the risk of all-cause  

More recently, in 2013, scientists from Johns Hopkins University, Baltimore, MD, examined 10,170 participants using National Health and Nutrition Examination Survey data to estimate hazard ratios (HRs) for all-cause and cardiovascular disease mortality for each 10-unit increase in serum 25OHD. The authors concluded that there is “an inverse association between 25OHD and all-cause and cardiovascular disease mortality in healthy adults with serum 25OHD levels of < 21 ng/mL.” Said differently, 25-hydroxyvitamin D blood levels below 21 ng/mL in this study increased the risk of dropping dead!

(See Figure 2)23

Figure 2. Relationship in the risk of all-cause (solid line) and cardiovascular disease (dotted line) mortality with increasing serum 25OHD levels. Note the steep increased risk in those with 25OHD levels less than 21 ng/mL.23

Why Interventionist Vitamin D Meta-Analyses Appear to Fail

This pattern of arriving at erroneous conclusions about vitamin D from an analysis of inappropriately selected studies has happened before. For example, a recent paper reported the positive effects of high-dose (300,000 IU over eight weeks) vitamin D2 (ergocalciferol) on vascular endothelial function and flow mediated dilation.24

The authors conceded that only three other studies had arrived at a similar (positive) conclusion15,25,26 while the rest failed to find any benefit. The authors explained, “The studies where vitamin D therapy was unable to show improvement often used low-dose vitamin D supplementation …,” and “… vitamin D was supplemented even when the baseline levels [of vitamin D] were within normal limits .”24 A third major reason may have been that flow mediated dilation or endothelial function (like blood pressure) was not abnormal.

While reviewing papers in the meta-analysis, I encountered another recently published article that was also not included in the meta-analysis. Appearing in the journal Blood Pressure Monitoring, it was titled “The Effect of Vitamin D Supplementation on Blood Pressure in Patients with Elevated Blood Pressure and Vitamin D Deficiency.”27 This was exactly the type of study that should have been the prototype for the meta-analysis. This was a straightforward double-blind placebo-controlled study of 42 patients with elevated blood pressure who suffered from vitamin D deficiency (defined by authors as serum 25-hydroxyvitamin D levels less than 30 ng/mL). Half of the subjects were treated with 50,000 IU vitamin D3 each week for eight weeks, while the other half were given an identical-appearing placebo. Both groups continued their use of conventional antihypertensive medications.

The findings of the study showed a significant reduction in systolic, diastolic, and mean arterial pressure in those in the vitamin D group. Despite improved blood pressure, 42% of the vitamin D group still had systolic blood pressure in excess of 140 mmHg, and 68% had diastolic blood pressure over 90 mmHg. However, 95% (i.e., twice as many) of those in the placebo group (whose blood pressure did not change) remained over 140/90.

This study shows that while vitamin D supplementation reduces blood pressure readings, hypertensives often need additional support to achieve optimal readings, which are considered to be in the range of 115/75 for most individuals.

 
vitamin D supplements

Editor’s Note: People take vitamin D supplements for a variety of reasons including reduced risks of certain cancers and suppression of chronic inflammation. Published reports over the past 10 years indicate that higher vitamin D levels may help protect against virtually all degenerative diseases.

Hypertension, however, has not been a primary reason people supplement with vitamin D as it does not reduce blood pressure enough in most individuals to achieve optimal ranges.

Optimal blood pressure readings for most people are about 115/75 mmHg.

Life Extension’s recommended anti-hypertensive drug is a generic called telmisartan taken in the dose of 40 to120 mg once daily.* In addition to lowering blood pressure, telmisartan improves markers of endothelial function and has demonstrated some impressive longevity benefits.

The next article reports on remarkable new studies showing huge improvements in ischemic stroke outcomes in those with higher vitamin D blood levels.

* Drugs. 2001;61(10):1501-29.

Summary

Rather than being a meta-analysis of relevant studies of the effect of therapeutic doses of vitamin D or placebo on vitamin D-deficient hypertensive patients, the JAMA Internal Medicine article was a selection of unrelated, often irrelevant studies, which appeared to indicate that vitamin D had no effect on blood pressure.

However, the authors were often not just comparing apples to oranges—they were comparing apples and oranges to the whole fruit basket!

What the meta-analysis did show was that high-dose vitamin D will not lower normal blood pressure, nor affect blood pressure of hypertensives with normal serum vitamin D. Furthermore, if one “reads between the lines,” and analyzes the studies that were relevant, it becomes clear that vitamin D appears to be a useful adjunct to help normalize blood pressure in vitamin D-deficient hypertensives.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

References

  1. Beveridge LA, Struthers AD, Khan F, et al. Effect of Vitamin D Supplementation on Blood Pressure: A Systematic Review and Meta-analysis Incorporating Individual Patient Data. JAMA Intern Med. 2015 May;175(5):745-54.
  2. Available at: http://www.cbsnews.com/videos/vitamin-d-useless-for-lowering-blood-pressure-study-finds/. Accessed September30, 2015.
  3. Edlich R, Mason SS, Chase ME, et al. Scientific documentation of the relationship of vitamin D deficiency and the development of cancer. J Environ Pathol Toxicol Oncol. 2009;28(2):133-41.
  4. Holick MF. Vitamin D: important for prevention of osteoporosis, cardiovascular heart disease, type 1 diabetes, autoimmune diseases, and some cancers. South Med J. 2005 Oct;98(10):1024-7.
  5. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. Am J Hypertens. 2007 Jul;20(7):713-9.
  6. Dorjgochoo T, Ou Shu X, Xiang YB, et al. Circulating 25-hydroxyvitamin D levels in relation to blood pressure parameters and hypertension in the Shanghai Women’s and Men’s Health Studies. Br J Nutr. 2012 Aug;108(3):449-58.
  7. Kunutsor SK, Apekey TA, Steur M. Vitamin D and risk of future hypertension: meta-analysis of 283,537 participants. Eur J Epidemiol. 2013 Mar;28(3):205-21.
  8. Burgaz A, Orsini N, Larsson SC, et al. Blood 25-hydroxyvitamin D concentration and hypertension: a meta-analysis. J Hypertens. 2011 Apr;29(4):636-45.
  9. Muldowney S, Lucey AJ, Hill TR, et al. Incremental cholecalciferol supplementation up to 15 mug/d throughout winter at 51-55 degrees N has no effect on biomarkers of cardiovascular risk in healthy young and older adults. J Nutr. 2012 Aug;142(8):1519-25.
  10. Scragg R, Slow S, Stewart AW, et al. Long-term high-dose vitamin D3 supplementation and blood pressure in healthy adults: a randomized controlled trial. Hypertension. 2014 Oct;64(4):725-30.
  11. Heshmat R, Tabatabaei-Malazy O, Abbaszadeh-Ahranjani S, et al. Effect of vitamin D on insulin resistance and anthropometric parameters in Type 2 diabetes; a randomized double-blind clinical trial. Daru. 2012 Aug 28;20(1):10.
  12. Kjaergaard M, Waterloo K, Wang CE, et al. Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial. Br J Psychiatry. 2012 Nov;201(5):360-8.
  13. Stricker H, Tosi Bianda F, Guidicelli-Nicolosi S, et al. Effect of a single, oral, high-dose vitamin D supplementation on endothelial function in patients with peripheral arterial disease: a randomised controlled pilot study. Eur J Vasc Endovasc Surg. 2012;44(3):307-12.
  14. Boxer RS, Kenny AM, Schmotzer BJ, et al. A randomized controlled trial of high dose vitamin D3 in patients with heart failure. JACC Heart Fail. 2013;1(1):84-90.
  15. Sugden JA, Davies JI, Witham MD, et al. Vitamin D improves endothelial function in patients with Type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008 Mar;25(3):320-5.
  16. Lind L, Wengle B, Ljunghall S. Blood pressure is lowered by vitamin D (alphacalcidol) during long-term treatment of patients with intermittent hypercalcaemia. A double-blind, placebo-controlled study. Acta Med Scand. 1987;222(5):423-7.
  17. Lind L, Wengle B, Wide L, et al. Hypertension in primary hyperparathyroidism--reduction of blood pressure by long-term treatment with vitamin D (alphacalcidol). A double-blind, placebo-controlled study. Am J Hypertens. 1988;1(4 Pt 1):397-402.
  18. Pfeifer M, Begerow B, Minne HW, et al. Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab. 2001 Apr;86(4):1633-7.
  19. Witham MD, Dove FJ, Dryburgh M, et al. The effect of different doses of vitamin D(3) on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial. Diabetologia. 2010 Oct;53(10):2112-9.
  20. Forman JP, Scott JB, Ng K, et al. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension. 2013 Apr;61(4):779-85.
  21. Dalbeni A, Scaturro G, Degan M, et al. Effects of six months of vitamin D supplementation in patients with heart failure: a randomized double-blind controlled trial. Nutr Metab Cardiovasc Dis. 2014 Aug;24(8):861-8.
  22. Zittermann A, Schleithoff SS, Frisch S, et al. Circulating calcitriol concentrations and total mortality. Clin Chem. 2009 Jun;55(6):1163-70.
  23. Amer M, Qayyum R. Relationship between 25-hydroxyvitamin D and all-cause and cardiovascular disease mortality. Am J Med. 2013;126(6):509-14.
  24. Chitalia N, Ismail T, Tooth L, et al. Impact of vitamin D supplementation on arterial vasomotion, stiffness and endothelial biomarkers in chronic kidney disease patients. PLoS One. 2014;9(3):e91363.
  25. Harris RA, Pedersen-White J, Guo DH, et al. Vitamin D3 supplementation for 16 weeks improves flow-mediated dilation in overweight African-American adults. Am J Hypertens. 2011;24(5):557-62.
  26. Witham MD, Dove FJ, Sugden JA, et al. The effect of vitamin D replacement on markers of vascular health in stroke patients - a randomised controlled trial. Nutr Metab Cardiovasc Dis. 2012;22(10):864-70.
  27. Mozaffari-Khosravi H, Loloei S, Mirjalili MR, et al. The effect of vitamin D supplementation on blood pressure in patients with elevated blood pressure and vitamin D deficiency: a randomized, double-blind, placebo-controlled trial. Blood Press Monit. 2015;20(2):83-91.