Vitamin D and CV Disease - Part III

For the final part of the series on Vitamin D and cardiovascular disease, we'll focus on the relevant clinical trials. Again, for full attribution, the primary source for this is the excellent review at Nature Reviews Nephrology. Parts 1 and 2 of this series can be found by clicking here and here.

Again, we'll break up the trials into categories:

1. Inflammation: As mentioned before, vitamin D has been shown to have anti-inflammatory effects in animal studies. A number of studies have examined the effect of vitamin D supplementation on inflammatory mediators. One study took ~120 patients with CHF and treated them with cholecalciferol or placebo for 9 months. Levels of anti-inflammatory IL-10 were higher and TNF was lower in treated patients. However, there was no difference in LVEF or mortality between the two groups and about 20% of patients did not complete even 9 months with more dropouts occurring in the vitamin D group. Similar reductions in pro-inflammatory cytokines have been noted in HD patients and patients with diabetes although these studies were too small and short-term to show any clinical effects.

2. Hypertension: Results from meta-analyses have been inconsistent with one study showing a non-significant decrease in BP with vitamin D therapy and another showing a reduction in systolic BP only. Currently, there is insufficient evidence to suggest that vitamin D is effective to treat hypertension.

3. Chronic Kidney Disease: Given the well-described relationship between vitamin D and the kidney, it is unsurprising that there has been a focus on CVD prevention in patients with CKD. Again, the results are inconsistent with some studies showing a benefit in terms of CV risk and others being negative. The PRIMO study examined LV mass index in patients with CKD and looked at the effect of 48 weeks treatment with activated vitamin D. There was no difference in the primary outcome among the two groups. One important point is that, in the past, there was no focus on 25OH vitamin D in patients with CKD due to the perception that it is biologically inactive. This perception is changing and there may be a role for increased 25OH vitamin D supplementation in CKD patients although this role has not yet been fully defined.

4. Cardiovascular Death and stroke: Large meta-analyses have suggested a benefit of vitamin D therapy on all-cause mortality. The results for CV mortality and morbidity are less consistent although a benefit has been shown in some trials. One issue is that most studies do not limit treatment to patients with vitamin D deficiency while subgroup analysis of some trials shows that there is more benefit of therapy in these patients. There are a number of large trials of vitamin D currently ongoing (see table below from this recent review). Hopefully we will be able to get a clearer picture of the benefits of vitamin D therapy in the near future.

Overall, the results of the intervention trials have been disappointing and inconsistent - particularly given the strength of the observational and experimental data. At this point, we still don't know the exact role for vitamin D in the prevention and management of CV disease. There is always the suspicion that unmeasured confounders have an important part to play. The best way to get an answer is by doing well-designed RCTs and perhaps when these ongoing trials are complete, we will have a fuller idea of this role.

Vitamin D and CV Disease - Part II

In the second post on vitamin D and CV disease (again largely summarizing this excellent review in Nature Reviews Nephrology), we look at the epidemiological evidence for the association of low vitamin D levels and CVD.

1. Hypertension: Data from NHANES showed that there is an inverse relationship between vitamin D levels and hypertension after full covariate adjustment. Subsequently, data from the Nurses Health Study revealed that low baseline vitamin D levels were associated with an increased risk of incident hypertension. In patients with established hypertension, low levels of vitamin D were associated with an increased risk of CV and all-cause mortality.
2. CV Morbidity and Mortality: Multiple large cohort studies have demonstrated a relationship between low vitamin D levels and CV mortality after controlling for traditional risk factors in a wide variety of populations including Europeans and African-Americans. Data from the Framingham Heart Study suggest that a low level of vitamin D was associated with a HR of 1.62 for incident cardiovascular events after about 6 years follow-up.
3. Chronic Kidney Disease: In patients with chronic kidney disease, there is a U-shaped association between vitamin D levels and CV events. However, this relationship is attenuated after adjustment for baseline GFR suggesting that the primary portion of this risk is related to the severity of renal disease (which may be the cause of the vitamin D deficiency). Low levels of vitamin D have been associated with an increased risk of mortality in dialysis patients while also being a predictor of progression to ESRD.
3. Stroke: Low levels of vitamin D have been associated with an increased risk of ischemic stroke in participants from the Nurses Health Study.

Again, it is important to point out that all of these associations do not prove causality and that there is likely a strong lifestyle or other biologic component in these associations that is not being accounted for. Next we'll look at the clinical trials of vitamin D and CVD prevention.

(Image is from Jack Maypole at The Faster Times)

Vitamin D and CV disease

Another excellent review from the people at Nature Reviews Nephrology on the relationship between vitamin D and cardiovascular disease. Some key points:

Low vitamin D levels are associated with an increased risk of cardiovascular disease but, given the inconsistent results seen in trials of vitamin D repletion in high-risk populations, it remains uncertain whether or not vitamin D status is a mediator of disease or a consequence of poor health (decreased exercise and sunlight exposure etc.). There are a number of known pathways associated with vitamin D that could potentially influence cardiovascular risk (these headings are summarized from the NRN paper):

1. RAAS system: As mentioned in a previous post, vitamin D is a negative regulator of RAAS. Renin and angiotensin II levels are elevated in mice lacking the vitamin D receptor (VDR). In humans with low vitamin D levels, increased angiotensin II has been noted although it should be pointed out that patients with hereditary vitamin D resistant rickets (due to a lack of the VDR) do not have elevations in RAAS hormones.
2. Inflammation: Vitamin D has anti-inflammatory effects mediated via the downregulation of IL-6 and TNF expression. Cardiac endothelial cells contain VDRs and vitamin D treatment inhibits TNF activation in these cells. Given the association between inflammation and atherosclerosis, this is a potential mechanism for the putative link between vitamin D deficiency and atherosclerotic disease.
3. Endothelial Function: In vitro treatment with vitamin D downregulates the production of pro-thrombotic proteins in endothelial cells. Vitamin D deficiency has been associated with endothelial dysfunction in human studies but again, the contribution of residual confounding in these observational studies is uncertain and may be substantial.
4. Cardiac Remodeling: Studies in rodents have suggested a role for vitamin D in the prevention of LVH and adverse cardiac remodeling in models of hypertension and cardiovascular disease.

There is growing interest in the association between FGF-23 and CV disease. Treatment with vitamin D stimulates the release of FGF-23 and may be an adverse consequence of the use of supplements in patients with advanced CKD.

Given the amount of vitamin D prescribed in the dialysis world, it is important that we understand the potential consequences and mechanisms of the risks and benefits of this treatment. For appropriate references please see the NRN review. A previous summary of the use of vitamin D in CKD can be found here.