Vitamin D is an essential vitamin that plays many important roles in the body. Vitamin D3, also known as cholecalciferol, is one of the most common supplemental forms of vitamin D. Vitamin D3 can be synthesized in the skin through sun exposure or acquired through foods and supplements.
In recent years, vitamin D supplementation has become increasingly popular due to its potential health benefits. However, there have been some concerns that taking high doses of vitamin D3 may adversely affect cardiovascular health. Specifically, some studies have suggested that excessive vitamin D3 intake could potentially lead to high blood pressure (hypertension).
What is vitamin D3?
Vitamin D3, or cholecalciferol, is one of two major forms of vitamin D found in supplements, along with vitamin D2 or ergocalciferol. Vitamin D3 is produced in the skin when it is exposed to ultraviolet B (UVB) radiation from sunlight. It can also be obtained from animal-based foods such as fatty fish, egg yolks, liver and fortified foods like milk and cereals.
The structure of vitamin D3 is very similar to steroid hormones. In the liver, vitamin D3 undergoes hydroxylation to become 25-hydroxyvitamin D3 (calcidiol), the major circulating form of vitamin D. It is then further hydroxylated in the kidneys to become the biologically active form, 1,25-dihydroxyvitamin D3 (calcitriol).
Calcitriol acts as a hormone, binding to vitamin D receptors found in different tissues to regulate various biological processes like calcium absorption, bone mineralization and innate immunity. Vitamin D3 supplementation aims to increase blood levels of both calcidiol and calcitriol.
What is high blood pressure?
Blood pressure refers to the force exerted by blood against the walls of the arteries as it is pumped around the body by the heart. It is recorded as two numbers – systolic pressure (when the heart contracts) over diastolic pressure (when the heart relaxes between beats).
Normal blood pressure levels are less than 120/80 mmHg. High blood pressure (hypertension) is diagnosed when blood pressure is consistently elevated above 130/80 mmHg. There are generally no signs or symptoms associated with high blood pressure, which is why it is often called the “silent killer”.
Over time, persistent high blood pressure can damage blood vessels and lead to serious health issues like heart attack, stroke, kidney failure and blindness. That is why managing high blood pressure through lifestyle modifications and medication is so important.
Some factors that can increase the risk of developing high blood pressure include age, family history, being overweight or obese, physical inactivity, tobacco use, excessive alcohol intake and chronic conditions like diabetes, kidney disease and sleep apnea. Vitamin D status has also been proposed as a potential risk factor, but findings from studies have been mixed.
Vitamin D and blood pressure regulation
To understand if vitamin D3 supplementation could potentially influence blood pressure, it is important to first look at how vitamin D may impact blood pressure control mechanisms in the body. Some ways that vitamin D could hypothetically affect blood pressure regulation include:
– Renin-angiotensin-aldosterone system – 1,25-dihydroxyvitamin D suppresses renin expression. Renin leads to production of angiotensin II, which causes vasoconstriction and fluid retention, increasing blood pressure.
– Sympathetic nervous system – Activated vitamin D influences sympathetic activity. Increased sympathetic drive can elevate blood pressure.
– Endothelial function – Vitamin D may improve endothelial cell-dependent vasodilation. Endothelial dysfunction impairs vascular relaxation and increases blood pressure.
– Parathyroid hormone – Vitamin D negatively regulates parathyroid hormone secretion. High parathyroid hormone levels are associated with hypertension.
– Vascular calcification – Vitamin D helps prevent development of arterial stiffness and calcification. Vascular stiffening raises systolic blood pressure.
– Inflammation – Vitamin D has anti-inflammatory effects. Inflammation is implicated in hypertension pathogenesis.
So in theory, vitamin D supplementation could potentially help lower blood pressure through several mechanisms. But does the evidence from clinical studies actually support this hypothesis?
Observational studies on vitamin D levels and blood pressure
A number of observational studies have analyzed the association between blood levels of 25-hydroxyvitamin D (the main circulating form) and hypertension risk or blood pressure values. However, the findings have been mixed.
Some cross-sectional studies have found an inverse correlation, with lower vitamin D status associated with higher blood pressure or greater prevalence of hypertension. For example, a study of over 12,000 US adults found that subjects with 25(OH)D levels <15 ng/ml had a multivariable-adjusted odds ratio of 1.3 for hypertension compared to those with sufficient levels (>30 ng/ml).
However, other cross-sectional studies have found no significant association between vitamin D status and blood pressure when adjusting for potential confounders like age, BMI and socioeconomic status. The discrepancies may be due to differences in study populations and cut-offs used to define vitamin D deficiency.
Prospective cohort studies following subjects over time provide stronger evidence than cross-sectional studies. But again, findings from these longitudinal studies have been inconsistent.
Some studies like the Health Professionals Follow-up Study found an elevated hypertension risk with lower baseline plasma 25(OH)D levels. In contrast, other cohort studies like the Framingham Offspring Study found no relationship between baseline vitamin D status and future risk of high blood pressure.
Overall, the observational data mostly leans towards an inverse association between lower vitamin D levels and adverse blood pressure outcomes. However, the presence of conflicting results demonstrates the need for placebo-controlled trials to determine causality.
Clinical trials examining vitamin D supplementation and blood pressure
Given the uncertain findings from observational studies, randomized controlled trials (RCTs) can provide higher-quality evidence on whether vitamin D3 supplementation affects blood pressure. RCTs have the advantage of minimizing confounding factors through the randomization process.
Numerous clinical trials have been conducted to evaluate the efficacy of vitamin D supplementation for lowering blood pressure in both hypertensive and normotensive individuals. Doses of vitamin D3 (cholecalciferol) used in most trials ranged from 1000 IU/day to 5000 IU/day, with treatment durations spanning from a few weeks to a year.
The findings from these RCTs remain inconsistent, with some showing modest blood pressure reduction while others show null results:
– In a 2012 meta-analysis of 5 trials with total 284 participants, vitamin D supplementation resulted in a non-significant decrease of 2.44 mmHg in systolic blood pressure and 0.53 mmHg in diastolic blood pressure. The effect was small and clinically irrelevant.
– A 2016 randomized trial in 200 hypertensive patients found that 2000 IU/day of vitamin D3 for 12 weeks reduced systolic blood pressure by 9.3 mmHg compared to placebo. However, diastolic pressure was unchanged.
– Conversely, a 2019 meta-analysis of 46 RCTs concluded that vitamin D supplementation did not significantly alter systolic or diastolic blood pressure, regardless of baseline blood pressure or vitamin D status.
– Similarly, in a 2022 RCT of 317 adults, 12-week supplementation with 4000 or 6000 IU/day vitamin D3 did not lower 24-hour ambulatory blood pressure relative to placebo.
– But a 2022 meta-analysis reported that vitamin D supplementation modestly reduced systolic blood pressure by 3.19 mmHg while diastolic pressure was unaffected. Greater reductions were seen in trials with durations over 6 months.
In summary, findings from the numerous RCTs are inconsistent, with most showing little to no clinically meaningful effect of vitamin D supplementation on blood pressure reduction. Some studies suggest long-term supplementation may have a small beneficial impact on systolic pressure. But overall, strong evidence for a causal blood pressure lowering effect is lacking.
Potential reasons for inconsistent trial results
There are several potential reasons why clinical trials looking at vitamin D supplementation and blood pressure have yielded inconsistent results:
– Variable doses used – Trials have used daily vitamin D doses ranging from 400 IU to 5000 IU. The antihypertensive effect may require higher doses that more effectively raise 25(OH)D levels.
– Differences in treatment duration – Significant blood pressure reductions may only occur with long-term supplementation of at least 6-12 months. Shorter trials may be insufficient to detect changes.
– Baseline vitamin D status – Subjects with vitamin D deficiency may experience greater blood pressure improvements with supplementation compared to vitamin D replete subjects.
– Background medications – The influence of vitamin D could be masked in subjects already taking antihypertensive medications.
– Small sample sizes – Many trials included less than 100 subjects, limiting statistical power to detect blood pressure differences between groups.
– Variability in measurement – Single office blood pressure readings vs 24-hour ambulatory monitoring can yield different results.
– Interactions with calcium – Co-supplementing with calcium may enhance vitamin D’s blood pressure lowering effect.
– Genetic factors – Gene polymorphisms related to vitamin D metabolism may influence individual responses to supplementation.
Well-designed trials that address these limitations by using sufficiently high doses, long treatment duration, large sample size, calcium co-supplementation and ambulatory blood pressure monitoring may provide more definitive conclusions on vitamin D’s antihypertensive effects.
Potential adverse effects of excessive vitamin D supplementation
While the benefits of vitamin D on blood pressure at moderate doses are uncertain, taking vitamin D supplements at very high doses for long periods does carry potential risks of adverse health effects.
Some possible side effects of excessive vitamin D supplementation include:
– Hypercalcemia – High vitamin D intake can cause excessive calcium absorption. Severe hypercalcemia can cause nausea, vomiting, kidney stones, bone pain and cardiac arrhythmias.
– Hypercalciuria – Excessive calcium excretion in urine that may lead to kidney stones. Those with existing kidney disease are at greater risk.
– Vascular calcification – In some cases, very high vitamin D intake promotes arterial calcification and stiffness, negatively impacting cardiovascular health.
– Functional hypoparathyroidism – High vitamin D downregulates parathyroid hormone secretion, which regulates calcium homeostasis. This can exacerbate hypercalcemia.
According to the Institute of Medicine, the tolerable upper intake level for vitamin D is 4000 IU daily for adults. Consistently exceeding this dosage long-term could possibly lead to adverse effects in some individuals.
Of note, vitamin D toxicity is extremely rare at daily intakes below 10,000 IU. But people with certain conditions like primary hyperparathyroidism or granulomatous disorders like tuberculosis are more susceptible to toxicity at lower doses.
Who may need to limit vitamin D intake?
For most healthy adults, vitamin D supplementation within the Institute of Medicine’s upper limit of 4000 IU per day is well-tolerated and unlikely to cause adverse effects. Vitamin D doses up to 10,000 IU daily are also generally regarded as safe for short periods.
However, the following individuals should exercise greater caution with vitamin D intake:
– Those with hypercalcemia or history of kidney stones – Hypercalciuria increases kidney stone risk.
– Patients with chronic kidney disease – Impaired vitamin D metabolism and reduced calcium excretion increases toxicity risk.
– Granulomatous disorders like sarcoidosis – Unregulated conversion of vitamin D to active form exacerbates hypercalcemia.
– Primary hyperparathyroidism – Excess parathyroid hormone already causes hypercalcemia, worsened by supplemental vitamin D.
– Medications – Taking thiazide diuretics, anticonvulsants or calcineurin inhibitors (e.g, after organ transplant) affects calcium regulation.
– Older adults – Reduced kidney function with age makes it harder to excrete excess calcium.
For people taking high dose vitamin D supplements, monitoring calcium levels and kidney function is prudent to avoid potentially dangerous elevations in serum calcium. Watching out for symptoms like nausea, vomiting, confusion and heart palpitations is also advisable.
In summary, while vitamin D deficiency is associated with increased risk of hypertension and cardiovascular disease, the evidence that vitamin D supplementation significantly lowers blood pressure is currently weak and inconsistent. Most well-controlled trials using moderate doses up to 5000 IU daily have found minimal or no impact on blood pressure.
Supplementation with vitamin D within recommended upper limits appears safe for the majority of people. However, high dose long-term supplementation above 4000 IU daily may increase the risk of hypercalcemia and hypercalciuria in susceptible individuals.
More rigorously designed RCTs in large samples using prolonged treatment durations, calcium co-supplementation and ambulatory blood pressure monitoring could help clarify whether vitamin D supplementation has a meaningful role in blood pressure management. In the meantime, hypertensive patients are better served by proven lifestyle changes and antihypertensive medications rather than relying on vitamin D supplementation alone.