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No link between vitamin-D levels and cardiovascular mortality in sunny California- - 3 articles questioning benefit of vitamin D for chronic diseases
December 16, 2010
San Diego, CA - In southern California, where the sun shines year round, there is no association between serum levels of vitamin D, parathyroid hormone (which regulates the active metabolite of vitamin D), and cardiovascular mortality, according to the results of a new study [1]. Even after patients were stratified by kidney function, there was no association between serum vitamin-D levels and death from cardiovascular causes, report investigators.
"To our knowledge, this is the first prospective study to investigate the role of serum 25(OH)D, 1,25(OH)2D, and intact parathyroid hormone in the prediction of cardiovascular mortality in a population of older community-dwelling adults with a low prevalence of vitamin-D deficiency and a broad range of kidney function," write lead investigator Dr Simerjot Jassal (University of California, San Diego) and colleagues in the December 2010 issue of the American Journal of Medicine. "Mild reductions in 25(OH)D or 1,25(OH)2D or elevations in intact parathyroid hormone were not independently associated with cardiovascular mortality over a 10-year follow-up in older adults living in a temperate climate with year-round sunshine."
Hot topic with conflicting evidence
25(OH)D is the metabolite that represents the state of vitamin-D sufficiency, and 1,25(OH)2D is the active metabolite regulated by the parathyroid hormone. In terms of mechanisms, explain the authors, these two metabolites are believed to stimulate the secretion and action of insulin, inhibit cellular proliferation, and modulate the inflammatory response associated with atherosclerosis. Low levels of 25(OH)D have also been linked with hypertension, diabetes, and insulin resistance.
In this cohort of 1073 adults, the baseline levels of 25(OH)D and 1,25(OH)2D were 42 ng/mL and 29 pg/mL, respectively. Over a median follow-up of 6.8 years, there were 266 deaths, including 111 cardiovascular deaths in individuals with varying kidney function. In an unadjusted analysis, higher levels of 1,25(OH)2D were protective against cardiovascular mortality and higher levels of parathyroid hormone showed a higher risk of cardiovascular death, but after adjustment for age alone or multiple covariates, these associations were no longer statistically significant.
In their report, Jassal and colleagues note that patients with chronic kidney disease (CKD), those with an estimated glomerular filtration rate <60 mL/min/1.73 m2, have low levels of 25(OH)D and 1,25(OH)2D and increased levels of parathyroid hormone, and it has been hypothesized that this might explain the link between CKD and cardiovascular disease mortality. That said, the researchers observed no association between serum vitamin-D levels and cardiovascular mortality when stratifying patients by CKD status.
The authors point out that the increased risk of cardiovascular mortality observed in other trials occurred in individuals with lower levels of vitamin D than those in this analysis. As a result, they do not rule out that larger disruptions in vitamin D might contribute to an increased risk of cardiovascular mortality. They add, however, the "null findings" in this trial are compatible with other randomized trials that failed to show any benefit of vitamin-D supplementation on cardiovascular end points.
Vitamin D is a hot topic in cardiovascular medicine these days, as well as in other research fields, and has generated a lot of public interest for its possible health benefits. The data, however, are conflicting. Two recent reviews, reported by heartwire, found no consistent association between vitamin D and cardiovascular disease, and earlier this month a comprehensive report from the Institutes of Medicine, also covered by heartwire, concluded that there is "insufficient evidence" to suggest that low levels of vitamin D as well as calcium are associated with a range of chronic diseases, including cardiovascular disease, diabetes, and obesity.
A large National Institutes of Health-sponsored study is currently attempting to determine the role of vitamin D and/or omega-3 fatty-acid supplementation in reducing the risk of cardiovascular disease, stroke, and cancer risk. The Vitamin D and Omega-3 Trial (VITAL) investigators plan to enroll approximately 20 000 patients, including 5000 black individuals, a cohort known to be at higher risk of vitamin-D deficiency. The Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial comparing rosiglitazone vs pioglitazone also included a vitamin-D-vs-placebo randomization within the study, but that trial has since been placed on "clinical hold" by the Food and Drug Administration.
Your comments
Protective effect of vitamin D can't be tested at lower latitudes. If one falls out of a boat into warm water near shore in calm weather while wearing a life jacket, whether or not one knows how to swim, chances for survival are good. But lets say the water is near freezing. The chances of survival for those who don't swim will be slim.
Likewise, a trial testing for vitamin D protection in a warm, sunny climate seems unlikely to produce a meaningful result. It would be like trying to find out how smoking affects cardiovascular and stroke risk on the island of Kitava where 80 percent of the adult population are daily smokers. The incidence of heart attack and stroke on Kitava is zero. Google: "Kitava Study" to learn more.
D is for discord: Not all studies support vitamin-D-CVD link
March 2, 2010
Boston, MA - The value of vitamin D in improving cardiovascular health or reducing the risk of diabetes and other risk factors remains unclear, although some hint of benefit for the popular supplement should support ongoing research in this field. That's the upshot of two new literature reviews and an editorial appearing in the March 2, 2010 issue of the Annals of Internal Medicine. Excitement over the hypothesis that vitamin-D deficiency might play a role in the development of cardiovascular disease has appealed to an ever-growing number of researchers and led to wide use of the inexpensive supplement in the general population, often at doses higher than historically recommended by health authorities. Whether enthusiasm for vitamin D is warranted by the available evidence remains unclear.
In one of the Annals papers [1], Dr Lu Wang (Brigham and Women's Hospital, Boston, MA) and colleagues reviewed the scientific literature looking specifically for papers that addressed use of vitamin-D supplements and subsequent CVD events. They identified six prospective studies showing reductions in subsequent CVD events among adults taking vitamin D at baseline and an additional four randomized controlled trials that included vitamin-D-vs-placebo randomizations. When all of the data for the studies were combined, vitamin-D supplementation was associated with a slight, statistically nonsignificant reduction in CVD events (relative risk 0.90; 95% CI 0.77-1.05). In the second paper [2], Dr Anastassios G Pittas (Tufts Medical Center, Boston, MA) and colleagues reviewed English-language studies looking at "vitamin-D status" (serum or plasma levels of 25[OH]D concentration, measured directly or estimated from self-reported vitamin-D use) and cardiometabolic outcomes. In 10 trials, vitamin-D supplementation was associated with a nonsignificant reduction in systolic blood pressure but had no apparent impact on diastolic blood pressure. Incident CVD was associated with vitamin-D concentration in five out of seven analyses but was not seen in four additional trials. Three of six studies reported a higher incidence of diabetes in groups with low vs high vitamin-D status, but eight trials found no link between vitamin D and glycemia or incident diabetes. Overall, Pittas et al conclude, "The association between vitamin-D status and cardiometabolic outcomes is uncertain."
Too soon for definitive conclusions
To heartwire, Wang emphasized the paucity of data in this field. "We found only a small number of published studies with considerable between-study heterogeneities, which preclude definitive conclusions for now. Our paper showed the urgent need for future studies, particularly large-scale, well-designed, randomized trials."
And as Wang et al point out in their paper, "an increasing number of generally healthy adults in the US take vitamin D and calcium supplements for bone health and other purported health benefits. Meanwhile the incidence and mortality rates related to CVD remain high in the US."
In an accompanying editorial [3], Drs Eliseo Guallar and Edgar R Miller (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD) agree that the evidence supporting vitamin-D supplementation for improving cardiovascular health "remains uncertain," but they also argue that the "available evidence in favor of vitamin-D supplementation is far more promising than for other vitamin or mineral supplements."
Indeed, Wang et al's literature review also looked for a link between calcium supplementation and cardiovascular disease and found no meaningful association between the two.
"A key message of our review is that only a small number of studies have examined whether vitamin-D and calcium supplements may reduce the risk of CVD events, with an absence of trials specifically designed to assess primary effects of these supplements on CVD outcomes," Wang told heartwire. "Available data by far preclude definitive conclusion, and future studies are needed to elucidate the cardiovascular effects of these supplements."
Waiting for trial results
At least two such studies are ongoing-for now. One is the large National Institutes of Health-sponsored VITAL study looking at whether 2000-IU vitamin D and/or omega-3 fatty-acid supplementation can reduce the risk of developing heart disease, stroke, or cancer in 20 000 men and women. Enrollment was to begin last month. The other is the vitamin-D-vs-placebo randomization within the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial, coordinated by researchers at McMaster University, in Hamilton, ON. This trial, comparing rosiglitazone vs pioglitazone in people with type 2 diabetes, has recently been in the news in the wake of new calls for rosiglitazone to be removed from the market due to cardiovascular side effects. Two FDA safety reviewers reputedly called any trial comparing rosiglitazone and pioglitazone "unethical and exploitative," precipitating a recent Senate inquiry to ask why the trial is being "allowed to continue." The fate of TIDE, and its seemingly more innocuous vitamin-D-vs placebo comparison, remains unclear. The registration of TIDE was last updated February 18, 2010 and lists the trial as "currently recruiting."
No evidence linking vitamin D to most chronic diseases
December 1, 2010 | Emma Hitt and Shelley Wood
Adapted from Medscape Medical News-a professional news service of WebMD
Washington, DC - Most North Americans get enough calcium and vitamin D through their diets, according to a comprehensive report containing updated dietary reference intakes (DRIs), released Tuesday by the Institute of Medicine (IOM). The report also concludes that there is "insufficient evidence" to suggest that low levels of either nutrient could be associated with a range of chronic diseases, including cardiovascular disease, diabetes, and obesity, although the authors underscored the importance of calcium and vitamin D in maintaining bone health.
Dr Catharine Ross (Pennsylvania State University, University Park) chaired a committee of 14 experts appointed to assess current data of health outcomes associated with calcium and vitamin-D intake.
"We could not find solid evidence that consuming more of either nutrient would protect the public from chronic disease ranging from cancer to diabetes to improved immune function," said Ross during a press conference about the new report. "On the other hand, regarding bone health, the amount of evidence that has been accumulating is really quite impressive."
The group reviewed more than a thousand studies looking at the link between vitamin D and a broad range of chronic diseases.
They stopped short, however, of saying that vitamin D, which has been a hot topic in cardiovascular research and other disease arenas, may not play some as-yet-unknown role: Their current conclusion "does not mean that future research will not reveal a compelling relationship between vitamin D and another health outcome," they write.
Of note, the IOM report does raise the recommended daily amount of vitamin D to 600 international units (IU), from 200 IU, a recommendation that dates back to 1997. And people over aged 70 should get 800 IU daily. Recommended dietary allowance for calcium is 1000 to 1300 mg/day, the report notes.
Several studies have reported widespread vitamin-D deficiency in North American populations, which the committee attributes to inconsistent serum 25-hydroxyvitamin D cut points that are often too high. The committee suggests that serum 25-hydroxyvitamin-D levels of 50 nmol/L (20 ng/mL) are sufficient for all persons. They also determined that risk for harm increases when consuming >2000 mg calcium or >4000 IU vitamin D daily.
According to Ross, the take-home message to doctors is that now there has been a systematic evidence-based review and there is new evidence upon which they should base their recommendations to patients.
"We are still very enthusiastic about [vitamin D], which regulates hundreds or even thousands of genes in the body," said panelist Dr Glenville Jones (Queen's University, Kingston, ON) during the press conference. "What's missing is . . . a lack of translation of that information into public-health recommendations." "We have been quite amazed that the positive effects of vitamin D haven't been nearly as clear-cut as the advocates have suggested," he added.
Authors also concluded that most individuals likely get recommended amounts of vitamin D and calcium from diet alone, although a supplement "may be appropriate for some age groups." The only group not getting enough calcium at recommended levels, in their analysis, was females aged nine to 18. All groups met their estimated average requirement for vitamin D when dietary intake and cutaneous synthesis from sun exposure were considered.
Commenting on the IOM report for heartwire, American Heart Association (AHA) past president and former chair of its nutrition, physical activity, and metabolism committee, Dr Robert Eckel (University of Colorado Denver School of Medicine), said that from the point of view of the practicing physician as well as the AHA, the IOM's stance is prudent until a true benefit of vitamin-D supplementation is proven in clinical trials.
"I think the pendulum had really swung too far in one direction" in terms of the enthusiasm for vitamin D, he said.
"The possibility of a benefit cannot be ruled out, but at this time, the data do not support the supplementation of vitamin D for the prevention of chronic diseases. . . . This may bring the pendulum back."
And Dr Penny Kris-Etherton, a cardiovascular nutritionist also at Penn State University, called the upping of the recommended vitamin-D intake to 600 IU "a step in the right direction."
She predicted that this recommendation would have its share of critics-many health professionals are already recommending doses over 1000 IU-but pointed out that the IOM reviewed both the studies showing benefit as well as those showing harm with vitamin-D supplementation. And most of the data pointing to a link between increased cardiovascular risk and low serum vitamin D or between vitamin-D supplementation and improved outcomes stem from epidemiological or post hoc studies, not prospective randomized trials, she notes.
"I think that this is a good start for right now-why don't we have everyone in the United States try to reach those DRIs, then we'll see what happens?"
Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press, 2010. Available here.
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