Potential pathophysiological role for the vitamin D deficiency in essential hypertension

Table 3 Randomized clinical trial investigating the protective effect of vitamin D supplementation on blood pressure

Ref.	Year	Study design	Country (ethnicity)Age	Intervention	Findings
Lint et al[137]	1988	(sample size) Prospective randomized double-blind placebo-controlled trial (65 men with glucose intolerance of which 26 hypertensive)	Sweden (Caucasian) 61-65 yr	(follow-up) α-calcidol 0.75 μg (12 wk)	In hypertensive patients supplementation has addictive effect to concomitant antihypertensive therapy in reducing BP (P < 0.01). In the whole population there was only non-significant trend in BP lowering
Pan et al[138]	1993	Prospective randomized double-blind 2 × 2 interventional trial (58 institutionalized elderly persons)	Taiwan (Asian) not provided	calcium 800 mg/d or 1,25(OH)2 vitamin D 5 μg/d or calcium 800 mg/d + 1,25(OH)2 vitamin D 5 μg/d, or placebo (11 wk)	Any type of supplementation failed to reduce BP
Scragg et al[139]	1995	Prospective randomized double-blind placebo-controlled trial (189 elderly subjects)	United Kingdom (not provided) 63-76 yr	25(OH) vitamin D 2.5 μg/d or placebo (5 wk)	Although treatment was effective in increasing serum 1,25(OH)2 vitamin D (P < 0.01) and decreasing PTH (P < 0.01), there was not difference in BP change
Krause et al[140]	1998	Prospective randomized double-blind controlled trial (18 patients with untreated mild essential hypertension)	Germany (Caucasian) 26-66 yr	Full body UVB or UVA thrice weekly (6 wk)	In accordance with a 162% rise in plasmatic 25(OH) vitamin D (P < 0.01) and 15% fall in serum PTH (P < 0.01), the UVB group showed also a reduction in 24-h ambulatory systolic and diastolic BP (P < 0.01)
Pfeifer et al[141]	2001	Prospective randomized double-blind controlled trial (148 elderly subject with 25(OH)D < 50 nmol/L)	Germany (Caucasian) 70-86 yr	Calcium 600 mg × 2/d or calcium 600 mg + 25(OH) vitamin D 10 μg twice daily (8 wk)	In accordance with a 72% rise in plasmatic 25(OH) vitamin D (P < 0.01) and 17% fall in serum PTH (P < 0.05), combined supplementation significantly reduced systolic BP (P < 0.05)
Sudgen et al[142]	2008	Prospective randomized double-blind placebo-controlled trial (34 elderly type 2 diabetic patients with 25(OH)D < 50 nmol/L)	United Kingdom (not provided)	Loading dose ergocalciferol 2500 μg or placebo (8 wk)	Supplementation significantly rise plasmatic 25(OH) vitamin D (P < 0.01) and reduced systolic BP, whereas there was only a trend in diastolic BP decrease
Alborzi et al[143]	2008	Prospective randomized double-blind placebo-controlled trial (24 elderly type 2 diabetic patients with 25(OH)D < 50 nmol/L)	mean 64 years United States (Caucasian and African Americans) 56-80 yr	Paricalcitol 1 or 2 μg/d or placebo (4 wk)	Any dose of paricalcitol failed to reduce BP
Margolis et al[144]	2008	Prospective randomized double-blind controlled trial (36282 n post-menopausal women from WHI study)	United States (Caucasian, Asian, Hispanic, African American) 50-79 yr	Calcium 500 mg × 2/d or calcium 500 mg + 25(OH) vitamin D 5 μg twice daily (7 yr)	There was no significant difference in over time change of BP in the whole population. In addition, supplementation failed to reduce the risk of developing hypertension in non-hypertensive patients at baseline
Nagpal et al[145]	2008	Prospective randomized double-blind placebo-controlled trial (71 older overweight men )	India (Indian population) 36-54 yr	25(OH) vitamin D 3000 μg every 2 wk for 3 times or placebo (7 wk)	Supplementation failed to reduce BP
Daly et al[146]	2009	Prospective randomized double-blind controlled trial (124 community-dwelling men)	Australia (Caucasian) 55-69 yr	Milk fortified with calcium (500 mg) and 25(OH) vitamin D (10 μg) twice a day or standard milk (2 yr)	Supplementation failed to reduce BP
Hilpert et al[147]	2009	Prospective randomized double-blind controlled trial (23 hypertensive adults)	United States (not provided)	Dairy-rich, high fruits and vegetables diet or a high fruits and vegetables diet or an average Western diet (5 wk)	High fruits and vegetables diet dairy-rich or not significantly reduced BP (P < 0.05). Moreover, in dairy-rich, high fruits and vegetables diet there was a greater lowering of intracellular calcium (P < 0.01), strongly associated with fall in diastolic BP (P < 0.05)
Witham et al[148]	2010	Prospective randomized double-blind placebo-controlled trial (56 patients with history of stroke and baseline 25(OH)D < 75 nmol/L)	United Kingdom (not provided) 53-79 yr	Loading dose ergocalciferol 2500 μg or placebo (8 and 16 wk)	Supplementation significantly increased serum 25(OH) vitamin D to both controls (P < 0.01). However, treatment failed to reduced BP
Witham et al[149]	2010	Prospective randomized double-blind placebo-controlled trial (61 patients with type 2 diabetes and baseline 25(OH)D < 100 nmol/L)	United Kingdom (not provided) 55-76 yr	Loading dose ergocalciferol 2500 μg or 5000 μg or placebo (8 and 16 wk)	Supplementation significantly increased serum 25(OH) vitamin D to both controls (P < 0.01 for both). However, supplementation failed to reduced BP
Judd et al[150]	2010	Prospective randomized double-blind controlled trial (9 patients with baseline 25(OH)D within 25 and 75 nmol/L in addition to systolic BP between 130 and 150 mmHg)	United States (African American) mean 45 yr	loading dose ergocalciferol 2500 μg or placebo weekly for 3 wk or 25 (OH) vitamin D 0.5 μg twice a day for 1 wk (3 wk)	Only supplementation with 25(OH) vitamin D decrease by 9% mean systolic BP (P < 0.01) in accordance with rise of serum 25(OH) vitamin D (P < 0.05)
Scragg et al[151]	2011	Prospective randomized double-blind controlled trial (119 patients with baseline 25(OH)D < 50 nmol)	New Zealand (Pacific islander, Caucasian and Maori) 23-87 yr	24 whole body exposures of either UVB or ultraviolet A (6 and 12 wk)	In the UVB arm there was a significant increase in serum 25 (OH) vitamin D after both 6 and 12 wk (P < 0.01 for both). However, treatment failed to reduced BP
Salehpour et al[152]	2012	Prospective randomized double-blind placebo-controlled trial (77 pre-menopausal overweight and obese women)	Iran (Arabian) 30-46 yr	25 (OH) vitamin D 25 μg daily or placebo (12 wk)	Supplementation significantly rise plasmatic 25 (OH) vitamin D (P < 0.01) and fall PTH (P < 0.01). Moreover, although treatment improved lipid profile, there was no effect on BP
Gepner et al[153]	2012	Prospective randomized double-blind placebo-controlled trial (110 post-menopausal women with baseline 25(OH)D within 10 and 60 nmol/L)	United States (not provided) 60-67 yr	25 (OH) vitamin D 62.5 μg daily or placebo (16 wk)	Supplementation, although significantly raised serum 25(OH) vitamin D (P < 0.01), failed in improving BP control assessed by changes in FMD, PWV and Aix
Wood et al[154]	2012	Prospective randomized double-blind placebo-controlled trial (305 healthy post-menopausal women)	United Kingdom (not provided) 48-72 yr	25 (OH) vitamin D 10 μg or 25 μg/d or placebo (1 yr)	Supplementation failed in improving CV risk profile, including BP control
Larsen et al[155]	2012	Prospective randomized double-blind placebo-controlled trial (112 hypertensive patients)	Denmark (Caucasian) 48-72 yr	25 (OH) vitamin D 75 μg/d or placebo (20 wk)	Supplementation significantly rise plasmatic 25 (OH) vitamin D (P < 0.01) and fall PTH (P < 0.01) but failed in improving BP control. However, in a post-hoc subgroup analysis of patient with 25 (OH) vitamin D deficiency at baseline supplementation significantly decrease 24-h systolic and diastolic BP (P < 0.05)
Zhu et al[156]	2013	Prospective randomized double-blind placebo-controlled trial (43 healthy subjects)	China (Asian) 20-22 yr	Calcium 600 mg + 25 (OH) vitamin D 3.12 μg daily or placebo, in addition to 500 kcal/d of caloric deficit (7 yr)	Except a reduction in visceral fat mass, supplementation failed in improving CV risk profile, including BP control
Forman et al[157]	2013	Prospective randomized double-blind placebo-controlled trial (283 healthy black subjects)	United States (African American) mean 51 yr	25 (OH) vitamin D 25 μg or 50 or 100 μg/d or placebo (12 and 24 wk)	Supplementation significantly decrease BP consistent with increasing dose (P < 0.05). Moreover, there was linear correlation between systolic BP decrease and rise of serum 25 (OH) vitamin D (P < 0.05)
Witham et al[158]	2013	Prospective randomized double-blind placebo-controlled trial (159 with isolate systolic hypertension)	United States (not provided) mean 77 yr	Loading dose 25 (OH) vitamin D 2500 μg or placebo (12, 24 and 36 wk)	Supplementation significantly rise plasmatic 25 (OH) vitamin D (P < 0.01) but failed in improving BP control. Moreover, treatment failed to achieve secondary outcomes including 24-h blood pressure, arterial stiffness and endothelial function

α-calcidol: Synthetic analog of 1,25(OH)2D; BP: Blood pressure; 1,25(OH)2D: Calcitriol; UVB: 94.5% UVA and 3.5% UVB; UVA: 99.5% UVA and 0.05% UVB; 25(OH)D: Cholecalciferol; PTH: Parathyroid hormone; WHI: Women’s Health Initiative Calcium/vitamin D trial; HyD: 25(OH)D metabolite with hydrophilic properties and much shorter half-life; FMD: Brachial artery flow-mediated vasodilation; PWV: Carotid-femoral pulse wave velocity; Aix: Aortic augmentation index; CV: Cardiovascular.