Vitamin D and cardiovascular disease and cancer: not too much and not too little? The need for clinical trials

Abstract

Low vitamin D levels are more common in women than in men. Low vitamin D levels have been implicated in numerous disease processes including fracture risk, falls, cardiovascular disease, hypertension, diabetes mellitus and cancers. In this article we review recent evidence regarding associations between low vitamin D levels and cancers and cardiovascular disease. We also review evidence regarding associations between high vitamin D levels and vascular calcifications and pancreatic cancer. It appears that there is probably an optimal level of vitamin D that is neither too high nor too low that is required to maximize health. On going clinical trials should aid in elucidating the optimal levels of 25-hydroxyvitamin D for numerous health outcomes

There has been much interest in the past few years among both medical professionals and the public regarding the possible health benefits of vitamin D. While vitamin D is referred to as a vitamin, it actually functions as a hormone in the body. There are few natural dietary sources of vitamin D. Other than fatty fish and egg yolk, most other dietary sources of vitamin D are fortified foods, such as milk and other dairy products. In addition to exogenous sources, vitamin D is synthesized endogenously in the body by the skin’s exposure to UVB radiation. UVB radiation changes 7-dehydrocholestrol, present in skin, into previtamin D which then becomes vitamin D and circulates in the bloodstream. It then undergoes 25-hydroxylation in the liver. The circulating 25-hydroxyvitamin D (25[OH]D), which has a half-life of approximately 2–3 weeks, is measured to evaluate a person’s vitamin D status. The kidney and other organs have the 1-α hydroxylase enzyme which converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D which then acts at a cellular level. In this article, we will weigh the evidence surrounding vitamin D and cardiovascular disease (CVD) and cancer.

Vitamin D & CVD

CVD: animal studies

Cardiovascular disease is the leading cause of death in both men and women. There are several lines of evidence to suggest that low vitamin D levels may contribute to CVD. First, the vitamin D receptor (VDR) knock-out mice develop hypertension and left ventricular hypertrophy [1,2]. Animals that constitutively express the 24-hydroxylase enzyme, thereby making the animal vitamin D deficient, develop aortic atherosclerosis [3]. However, there is also evidence that high levels of vitamin D contribute to CVD. These include the fact that one of the first models of atherosclerosis was a mouse that was fed a high cholesterol, high vitamin D diet [4].

CVD: cardiovascular risk factors

Low 25(OH)D levels have been associated with incident hypertension, insulin resistance and diabetes mellitus, all risk factors for CVDs. A recent meta-analysis evaluating vitamin D supplementation trials concluded that among 429 participants in aggregate, vitamin D supplementation lowered systolic blood pressure by 2.44 mmHg but did not lower diastolic blood pressure [5]. However, another meta-analysis including data from more trials did not demonstrate a statistically significant difference in systolic blood pressure [6]. This same meta-analysis revealed a lower incidence of diabetes mellitus in observational studies but no effect of vitamin D supplementation on the incidence of diabetes in randomized clinical trials [6]. Another meta-analysis which included 99,745 participants demonstrated a lower prevalence of cardiometabolic disorders (CVD, diabetes mellitus and the metabolic syndrome) in participants with the higher 25(OH)D levels [7]. A randomized clinical trial of 3332 IU of cholecalciferol versus placebo in 200 overweight subjects who were participating in a weight-reduction program revealed that those on vitamin D had lower parathyroid hormone levels, triglycerides and tumor necrosis factor-α levels but higher low density lipoprotein cholesterol levels [8].

CVD: clinical cardiovascular events

The association between low 25(OH)D levels and cardiovascular events and mortality has been found in prospective cohort studies in Italy [9], Germany [10], the Netherlands [11], Tanzania [12] and the USA [13–15]. Ecological data show that ischemic heart disease rates are higher in Northern Europe than in Southern Europe [16]. In addition to all-cause mortality, low 25(OH)D levels have been linked to individual CVD outcomes including stroke [17,18], sudden cardiac death [19], congestive heart failure [20] and peripheral arterial disease [21]. A recent analysis of 41,000 patients from an electronic medical records database in the north of the USA showed that low 25(OH)D levels (<30 ng/ml) were associated with prevalent CVD risk factors and with the later development of CVD and its risk factors [22]. Lower 25(OH)D levels were associated with incident CVD in five of seven observational studies recently reviewed [6]. Another recent review demonstrated reductions in cardiovascular mortality in observational studies among adults on vitamin D supplements but there were no differences found when pooling data from two randomized clinical trials [23]. The pooled relative risk (RR) for cardiovascular disease, which was not a primary prespecified outcome in any of the trials, was 0.90 (95% CI: 0.77–1.05) for vitamin D supplementation compared with placebo and 1.04 (95% CI: 0.92–1.18) for combination vitamin D plus calcium supplementation versus placebo [23].

There are several possible reasons for the differences observed between the observational studies, and the results of randomized clinical trials. These include the possibility of residual confounding in observational studies and the possibility of lack of power in randomized clinical trials which tend to be smaller than the observational trials. Clinical trials may also test inappropriate dosages (e.g., too low) and can also have some cross over where participants are taking over the counter vitamin D supplements thereby washing out the differences between the groups. Another limitation of vitamin D supplementation trials in noninstitutionalized individuals is the increase in 25(OH)D concentrations that occur in the placebo group during the summer months owing to UVB-induced skin synthesis of vitamin D. Some of the meta-analyses also combined nutritional and activated vitamin D supplementation, which may obscure the effects of one or the other. The gold standard for evidence remains the randomized clinical trial, and while there is an accumulating body of observational data showing associations between low 25(OH)D levels and CVD, well-designed, large randomized controlled clinical trials are required to provide conclusive evidence.

There is also some evidence from observational studies that too much vitamin D may be harmful. In a case–control study of 143 patients with coronary heart disease by Rajasree et al., 25(OH)D levels >222.5 nmol/l (>89 ng/ml) were associated with a multivariable-adjusted odds ratio for coronary heart disease of 3.18 (95% CI: 1.31–7.73) [24]. A recent cross -sectional analysis of 340 African–Americans with diabetes mellitus found that 25(OH)D levels were directly correlated to carotid and aortic calcified atherosclerotic plaques but not to coronary artery calcified plaque [25]. The mean 25(OH) D level in the study was 50 nmol/l (20 ng/ml). In an analysis of 13,331 participants of the third National Health & Nutrition Examination Survey (NHANES III) mortality linked data, levels of 25(OH)D ≥125 nmol/l (≥50 ng/ml) were associated with a higher risk of all-cause mortality in women but not in men [13]. These studies suggest that high 25(OH)D levels may cause vascular calcification; thus, levels either too high or too low are associated with adverse outcomes and there is probably an optimal level.

Vitamin D & cancers

Cancer: biological models of vitamin D & cancer pathogenesis

Cancers occur in the body when cells start growing without inhibition. Several cellular models show that vitamin D may aid in controlling the cellular proliferation that occurs with cancers. Vitamin D has been shown to repress growth factors such as IGF-1 and EGFR [26,27]. Vitamin D also has proapoptotic effects on cancer cells by repressing survival proteins or activating proapoptotic proteins [28–30]. Vitamin D may also inhibit growth in prostate cancer cells through regulation of prostaglandin metabolism [31]. Activated vitamin D has also been shown to suppress growth of numerous other cancers in cell cultures [27,32–35].

25(OH)D levels & cancer: observational studies

The results of observational studies evaluating associations between low 25(OH)D levels and cancer incidence and mortality have been mixed. An analysis of the Health Professionals Follow-up Study revealed that predicted high 25(OH)D levels, with modeling based on region, sun exposure, skin pigmentation, BMI, vitamin D intake, season and age, were associated with a lower risk of total cancer incidence (n = 4286 cancers) and a lower risk of total cancer mortality (n = 2025 deaths) [36]. This was found to be particularly strong in cancers of the digestive system (e.g., colorectal, esophageal, stomach and pancreatic cancers) [36]. An analysis of 16,818 participants of NHANES III revealed no association between baseline measured 25(OH)D levels and total cancer mortality [37]. In a follow-up study, which included an additional 6 years of data, the investigators again found no association between 25(OH)D levels and overall cancer mortality but did find that in men, there was a higher risk of cancer mortality at higher 25(OH)D levels ≥100 nmol/l compared with <37.5 nmol/l (RR: 1.85; 95% CI: 1.02–3.35) [38]. In another study of 3299 patients referred for coronary angiography, per 25 nmol/ml increase in serum 25(OH)D level the hazard ratio for fatal cancer over 7.75 years of follow-up was 0.66 (0.49–0.89) [39]. Recent studies from the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers revealed no associations between 25(OH)D levels and ovarian, esophageal, gastric, endometrial and kidney cancers or non-Hodgkin’s lymphoma [40]. The consortium, a pooling of eight different cohorts, did find a higher risk of pancreatic cancer in participants with 25(OH)D levels ≥100 nmol/l with an odds ratio of 2.12 (95% CI: 1.23–3.64) [41].

Diagnosis of cancer during the summer, when vitamin D levels are highest, is associated with improved cancer survival. Diagnosis of cancer during the summer or autumn has been associated with better cancer survival in breast and lung cancer [42]. Surgery during summer months for non-small-cell lung cancer was associated with better recurrence-free survival hazard ratio 0.75 (95% CI: 0.56–1.01) compared with patients who had surgery during the winter among 456 early stage non-small-cell lung cancer patients [43]. This has also been shown in other studies for breast and lung cancer in Norway [44–46].

Colorectal cancer

The strongest evidence of an association between 25(OH)D levels and cancer is probably with colorectal cancer. Recently, in a large case–control study of 1248 cases and 1248 controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) study cohort in ten western European countries, patients in the highest quintile of 25(OH)D levels had a 40% lower risk of colorectal cancer compared with those in the lowest quintile [47]. A meta-analysis of eight original articles evaluating associations of 25(OH)D levels and the risk of colon and rectal cancer showed a pooled odds ratio of 0.57 (95% CI: 0.43–0.76) for those with high 25(OH)D levels compared with those with low levels [48].

Breast cancer

Case–control studies have found a lower risk of breast cancer in women with higher 25(OH)D levels [49]. There have been a few meta-analyses of the associations between 25(OH)D levels and breast cancer, which show inconsistent results. One meta-analysis of case-controlled and prospective cohort studies has demonstrated no association between serum 25(OH) D levels and breast cancer [50]. Another meta-analysis showed an association between low 25(OH)D levels and the risk of breast cancer in case-controlled studies but not in prospective studies [51].

Pancreatic cancer

While most observational studies show a protective effect between higher 25(OH)D levels and colon cancer, the opposite has been found for pancreatic cancer. In a nested case–control study from the α-Tocopherol, β-Carotene Cancer Prevention cohort, higher 25(OH)D concentrations (>65.5 nmol/l) were associated with a higher odds (OR: 2.92; 95% CI: 1.56–5.48) of developing pancreatic cancer compared with those with lower 25(OH)D levels (<32 nmol/l) [52]. An analysis of the prostate, lung, colorectal and ovarian screening trial did not reveal the same associations between high 25(OH)D and the risk of pancreatic cancer [53]. As mentioned previously, a pooled analysis of eight prospective cohorts did reveal a higher odds of developing pancreatic cancer in participants with high 25(OH)D levels [41].

Vitamin D supplementation & cancer: clinical trial evidence

There are only a few clinical trials evaluating the effects of vitamin D on cancer incidence and mortality. A study of 2686 individuals aged 65–85 years randomized to receive cholecalciferol 100,000 IU supplementation or placebo every 4 months for 5 years revealed no difference in cancer mortality among participants (RR: 0.86; 95% CI: 0.61–1.20) [54]. In another study of 1179 women randomized to daily 1400–1500 mg of supplemental calcium, calcium plus 1100 IU vitamin D or placebo, there were fewer incident total cancers in the women assigned to calcium or calcium plus vitamin D compared with placebo [55]. Interestingly, there was no statistically significant difference between the women assigned to calcium and those assigned to calcium and vitamin D [55]. In the Women’s Health Initiative, the largest (n = 36,000) clinical trial of vitamin D (400 IU/day) and calcium (1000 mg/day), there was no difference between the active and placebo groups when comparing the incidence of colorectal cancer or breast cancer risk [56,57]. There was also no statistically significant difference in overall mortality in the two groups [58]. The Vitamin D and Omega-3 Trial (VITAL) will test the role of 2000 IU/day of vitamin D and omega-3 fatty acids (in a 2 × 2 factorial design) in the primary prevention of cancer and CVD among 20,000 men and women throughout the USA; results are expected in 5 years. While the VITAL trial is currently the largest on going clinical trial, a recent query revealed over 1000 records of on-going or completed clinical trials of vitamin D for various health outcomes [101].

Conclusion

Animal and tissue studies suggest that low vitamin D levels have a role in the pathogenesis of CVD and cancers; two leading causes of death among women. The evidence from observational studies and clinical trials evaluating the associations between vitamin D levels and outcomes and the effects of vitamin D supplementation on outcomes are inconsistent and the majority of clinical trials reported to date have been null. Most observational data suggest that having low 25(OH)D levels <37.5 nmol/l is associated with increased risk of cardiovascular events and some cancers. However, there is also evidence to suggest that very high levels of 25(OH)D (>100 nmol/l) are associated with cardiovascular calcifications, pancreatic cancers and possibly all-cause mortality in women. The recent Institute of Medicine (IOM) report on dietary reference intakes for calcium and vitamin D also concluded that the evidence for a role of vitamin D in preventing cancer and CVD was inconsistent, inconclusive as to causality, and not yet sufficient to inform nutritional recommendations [59]. On going clinical trials of vitamin D will provide further evidence on the balance of health benefits and risks associated with moderate-to-high dose vitamin D supplementation.

Future perspective

In 5–10 years there should be results from several on going clinical trials testing whether vitamin D supplementation has an effect on cardiovascular events, cancers, colonic adenomas and blood pressure. If randomized trials confirm benefits of vitamin D for health outcomes, future public health recommendations regarding vitamin D supplementation will change.

Executive summary.

Vitamin D & cardiovascular disease

• Low 25-hydroxyvitamin D (25[OH]D) levels, a measure of a person’s vitamin D status, have been associated with a higher risk for diabetes mellitus, hypertension, cardiovascular disease and all-cause mortality.

• High levels of 25(OH)D have also been associated with vascular calcification and all-cause mortality in women.

Vitamin D & cancers

• Low levels of 25(OH)D have been associated with colon cancer and high levels have been associated with pancreatic cancer.

• To date randomized clinical trials have shown inconsistent results in cancer prevention.

Conclusion

• There are current on going clinical trials that will hopefully answer the question of the ideal 25(OH)D level and the dose of supplementation.