HTN: Vitamins (2015)


Larsen T, Mose FH, Bech JN, Hansen AB, Pedersen EB. Effect of cholecalciferol supplementation during winter months in patients with hypertension: A randomized, placebo-controlled trial. Am J Hypertens. 2012; 25: 1,215-1,222.

PubMed ID: 22854639
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Neutral NEUTRAL: See Quality Criteria Checklist below.
Research Purpose:
To determine the effect of vitamin D supplementation during the winter months on blood pressure in adults with hypertension who live at a northern latitude.
Inclusion Criteria:
  • Caucasian
  • Arterial hypertension
  • Living in Denmark
  • Informed consent.
Exclusion Criteria:
  • 24-hour ambulatory blood pressure (24-hour BP) systolic BP higher than 150mm Hg and diastolic BP higher than 95mm Hg
  • Cancer
  • Atrial flutter or fibrillation
  • Hypercalcemia
  • Pregnant or nursing
  • Alcohol abuse (higher than 36g for men, higher than 24g for women)
  • Routine use of non-steroidal anti-inflammatory drugs or glucocorticoids
  • Daily vitamin D intake greater than 10mcg of cholecalciferol or ergocalciferol
  • Use of tanning beds
  • Change in anti-hypertensive medications during the study.
Description of Study Protocol:


  • Newspaper advertisements
  • Pamphlets in physician office
  • Recruitment and follow-up occurred between October 2010 and March 2011.


  • Assigned to placebo or vitamin D by hospital pharmacy via permutated block randomization generated by computer. Assignment was received after baseline exam but before ambulatory BP monitoring
  • Study duration: A total of 20 weeks
  • Data collected included:
    • Blood pressure 
    • Arterial stiffness
    • Blood sampling for calcium metabolism and vasoactive hormones.

Blinding Used

  • Placebo identical in size, color, shape, consistency, taste and ingredients except for cholecalciferol
  • Participants, investigators and study personnel were blinded to treatment assignment.


A total of 75mcg cholecalciferol (25mcg x three tablets) vs. placebo for 20 weeks.

Statistical Analysis

  • Sample size calculation suggested that 54 participants were needed in each group
  • Independent T-test or Mann Whitney U-test assessed differences between groups
  • General linear model: Differences in plasma 25OH-D were assessed during the study
  • Significance: P<0.05.
Data Collection Summary:

Timing of Measurements

  Baseline Week Five Week 10 Week 15 Week 20
Clinical exam x x x x x
Urine sample x x x x x
Applanation tonometry x x x x x
Safety assessment labs (plasma calcium, phosphate, 25OH-D) x x x x x
Ambulatory BP x x x x x
Plasma 25OH D2+D3 x x x x x
Brain natriuretic peptide x x x x x
Plasma renin x x x x x
Angiotensin II  x x x x x
Aldosterone x x x x x
Intact plasma fibroblast growth factor 23 x x x x x

Dependent Variables

  • Primary: 24-hour systolic blood pressure
  • Secondary:
    • 24-hour diastolic blood pressure
    • Heart rate
    • Central BP
    • Central augmentation index
    • Carotid-femoral pulse wave velocity (PWV): Surrogate for arterial stiffness and measured with applanation tonometry
    • Urinary calcium to creatinine ratio
    • Plasma renin, angiotensin II, aldosterone
    • Brain natriuretic peptide
    • Plasma 25OH-D (chemilumescence immunoassay)
    • Plasma intact parathyroid hormone, ionized calcium, phosphate
    • Plasma fibroblast growth factor 23 (FGF23).

Independent Variables

75mcg cholecalciferol vs placebo.
Description of Actual Data Sample:

Initial N


  • Placebo: N=65
  • Cholecalciferol: N=65.

Attrition (Final N)

N=112 (35 males and 77 females):

  • Placebo: N=57 (18 males and 39 females):
    • Did not complete the initial 24-hour BP measurement: N=2
    • Mean systolic 24-hour BP higher than 150mm Hg: N=3
    • Withdrew consent: N=2
    • Medication change: N=1.
  • Cholecalciferol: N=55 (17 males and 38 females):
    • Mean systolic 24-hour BP higher than 150mm Hg: N=2
    • Withdrew consent: N=4
    • Medication change: N=1
    • Initial NSAID therapy: N=1
    • Breast cancer diagnosis: N=1
    • Major surgery: N=1.


Years (Mean age±SD):

  • Placebo: 61.9±9 years
  • Cholecalciferol: 60±1.2 years.



Other relevant demographics:

  • Initial 24-hour BP (mm Hg):
    • Placebo: 131/77±9/6
    • Cholecalciferol: 132/77±10/6.
  • Plasma 25OH-D (ng per ml):
    • Placebo: 23±12
    • Cholecalciferol: 23±9
    • Levels less than 32ng per ml: N=92
    • Levels less than 20ng per ml: N=47.
  • No difference between groups at baseline for the following:
    • Smoking status
    • Type 2 diabetes
    • Medications:
      • Multivitamins
      • Bisphosphonates
      • Statins
      • Diuretics
      • Calcium channel or beta blockers
      • Angiotensin-converting enzyme inhibitors.
    • Chemistries except for higher ionized calcium (P=0.003) and plasma alkaline phosphatase (P=0.01) in the placebo group.


BMI, kg/m(mean±SD):
  • Placebo: 28.3±3.7
  • Cholecalciferol: 27.7±4.2.


Holstebro, Denmark.


Summary of Results:

Key Findings

  • Blood pressure:
    • 24-hour systolic BP (primary): No significant differences were observed between the cholecalciferol or placebo groups at the end of the study
    • In post-hoc analysis comparing response to vitamin D supplementation in participants with low plasma 25OH-D (less than 32ng per ml) at baseline, both 24-hour systolic and diastolic BP were significantly reduced in the cholecalciferol group (N=46) compared to the placebo group (N=46) by 4/3mm Hg (P=0.05/0.01)
    • Central BP decreased by 7/2mm Hg in the cholecalciferol group (N=52) compared to the placebo group (N=55), P=0.007.
  • Arterial stiffness: At study end, no significant differences were noted between the cholecalciferol and placebo groups for central augmentation index or carotid-femoral pulse wave velocity. An increase in PWV was observed within both groups throughout the study (placebo, P=0.06; cholecalciferol, P=0.004)
  • Calcium metabolism:
    • A mean reduction in plasma 25OH-D was observed within the placebo group (3±6ng per ml, P<0.001) at the end of 20 weeks. The cholecalciferol group showed a mean increase of 21±10ng per ml, P<0.001
    • Compared to placebo at study end, the cholecalciferol group experienced an increase in ionized calcium (0.06±0.11mg per dL, P<0.05) and a reduction in PTH (–9.2±8.8pg per ml, P<0.01)
    • Pearson correlation showed a negative relationship between changes in plasma 25OH-D and changes in plasma PTH (N=112, R=–0.48, P<0.001)
    • A positive correlation was suggested between changes in plasma PTH and changes in systolic 24-hour BP (N=112, r = 0.28, P=0.04)
    • Compared to placebo, no significant differences were observed relative to plasma phosphate, plasma FGF23 or the urinary calcium to creatinin ratio at study end.
  • Vasoactive hormones: At study end, no significant changes were observed between the placebo and cholecalciferol groups for brain natriuretic peptide, plasma renin, angiotensin II and aldosterone.

Other Findings

  • Using pill count, mean adherence was 99% in both groups
  • Adverse event: Raised, pruritic rash on trunk (N=6, three in each group)
  • Nine traveled to latitudes or altitudes that could result in cutaneous vitamin D synthesis:
    • Placebo: Smaller decrease in plasma 25OH-D compared to others in placebo group (N=5)
    • Cholecalciferol: Experienced similar increase in plasma 25OH-D as others in the treatment group (N=4).
Author Conclusion:
Cholecalciferol supplementation in adults with hypertension living in a northern latitude during the winter months did not produce significant reductions in 24-hour systolic BP. A borderline reduction in both 24-hour systolic and diastolic BP was observed in participants with low levels of plasma 25OH-D (less than 32ng per ml) at baseline. Cholecalciferol supplementation produced a significant reduction on central BP.
Funding Source:
Government: Research Foundation of Central Denmark Region
Ferrosan A/S
Pharmaceutical/Dietary Supplement Company:
Reviewer Comments:
  • Including participants with adequate vitamin D levels reduced the effect of cholecalciferol supplementation. Post-hoc analysis was underpowered when they were removed.
  • May have missed an effect of cholecalciferol supplementation on BP, by including those with well-controlled hypertension
  • Dietary intake was not addressed
  • Due to the two-month half-life of cholecalciferol, future studies should aim to maintain a high plasma 25OH-D level for an extended period of time to evaluate effects on the cardiovascular system.
  • No intention to treat.
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? Yes
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? ???
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? ???
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? N/A
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? ???
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? No
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? ???
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? No
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? No
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? Yes
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes