A relatively short course of aspirin plus clopidogrel immediately after sustaining a transient ischemic attack (TIA) or minor stroke outperforms aspirin alone in cutting the risk for a subsequent stroke, and it does this without a significant increased risk of major bleeding complications, results of a large trial show.
Results of the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial were presented here at the International Stroke Conference (ISC) 2013.
The CHANCE trial, carried out exclusively in China, is a few steps ahead of a similar trial, the Platelet Oriented Inhibition in New TIA and stroke (POINT) trial, now enrolling mostly in the United States.
Although CHANCE was a "well done" trial and its results showed "a larger treatment effect," it's important to note that healthcare in China is different from that in the United States, said CHANCE co–principal investigator, S. Claiborne Johnston, MD, PhD, professor, neurology, and director, Stroke Service, University of California, San Francisco.
"Secondary prevention practices are not as robust there as they are in Europe and in North America, and that could have impacted the trial," he told Medscape Medical News. "Also, usually genetic differences don't matter, but in this case, they might because there are differences in polymorphisms that affect clopidogrel metabolism in Asian populations."
For these reasons, although American neurologists might see the CHANCE trial as a signal to go ahead and use combined therapy, "I think it's wise for us to wait for a confirmatory trial outside of China, said Dr. Johnston, who is also co–principal investigator of the POINT trial.
High Risk for Hemorrhage
The study enrolled 5170 patients at least 40 years of age who had sustained a TIA or minor stroke. Within 24 hours of their symptom onset, they were randomly assigned to 1 of 2 groups: aspirin (1 day loading dose of 75 to 300 mg, followed by 75 mg/day) plus placebo, or the same aspirin regimen plus clopidogrel (loading dose of 300 mg followed by 75 mg/day).
Patients in the combination group were taken off aspirin at 21 days because of the concern that Chinese patients, as with other Asian populations, are at relatively high risk for hemorrhage. "Frankly, that belief comes from epidemiological studies, but the epidemiology may just reflect underlying risk factors and not a true propensity for it," said Dr. Johnston. He pointed out that the studies testing this have not been in the acute period.
The study showed that stroke occurred less frequently in those receiving both aspirin and clopidogrel. At 90 days, the hazard ratio (HR) for survival free of stroke — either ischemic or hemorrhagic — in the combination group was 0.68 (95% confidence interval [CI], 0.57 - 0.81; P < .001).
For the secondary outcome of combined events (stroke, myocardial infarction, vascular death), the HR was 0.69 (95% CI, 0.58 - 0.82; P < .001). The risk for hemorrhagic stroke was the same in the 2 groups (0.3%).
Notably, severe bleeding events occurred at a similar rate in the 2 groups (0.2% in each). Although mild bleeding occurred more often in the combination group (1.2% versus 0.7%), Dr. Johnston noted that these events included nose bleeds. "We did not see a signal that the combination was unsafe."
Both aspirin and clopidogrel affect platelets, but through different pathways. "Together, the 2 are much more powerful than either one alone," said Dr. Johnston.
CHANCE was the first trial to focus on the acute period in TIA and minor stroke, which Dr. Johnston emphasized is not being seen nearly enough in the emergency department. "People with TIA and minor stroke are not coming in acutely or they're calling the office and being seen in clinic," he said. "We need to remind people that this really is an emergency and it should be treated right away."
Asked whether the combination therapy would be an acceptable approach for more severe strokes, Dr. Johnston said it's impossible to know "where to draw the line." The researchers will do more subgroup analyses looking at stroke severity, but Dr. Johnston pointed out that "there was no difference between the TIA and stroke in terms of rates of hemorrhagic stroke or in the efficacy of the combination."
Compared with elsewhere in the world, the risk for stroke is very high in China. "There are a whole lot more strokes in China than there are in the US and even if you add Europe, you still have more strokes in China," said Dr. Johnston.
Healthcare Differences
Because the trial was so large and because standards for clinical research have improved dramatically in China, the CHANCE results are "incredibly important" and should have a major effect on public health around the world, said Dr. Johnston. However, there are important differences between healthcare in China and that in the United States.
For example, Dr. Johnston noted that about two thirds of the Chinese patients in the study had hypertension and less than half were receiving any drug for hypertension during follow-up. Undertreatment, he said, could "certainly" affect the absolute effect size that's seen in the trial.
It's probably wise to await what happens with the POINT trial before changing treatment approaches here in North America, said Dr. Johnston, who is that study's principal investigator. Interim POINT results will be available in May, he said. "That will provide an opportunity to say it's very important to continue POINT or it's not important to continue POINT."
The POINT trial, which is about a third of the way through recruitment, differs slightly from CHANCE, said Dr. Johnston. For example, it includes a higher loading dose of clopidogrel and requires enrollment within 12 hours instead of 24 hours. As well, patients in the combination group continue with aspirin for 90 days instead of stopping at 21 days as in the CHANCE study.
Dr. Johnston pointed out a graph showing times for survival free of stroke for the treatment groups. "Most of the separation in the 2 curves occurs just in the first couple of days, so certainly by 21 days, the curves are almost parallel."
POINT includes mainly centers in the United States, although some sites have been added internationally.
The idea of comparing aspirin plus clopidogrel in a North American trial dates back more than a decade, but the researchers ran into funding difficulties when the drug manufacturer pulled its backing. This, said Dr. Johnston, substantially delayed the start of the trial.
When asked about next steps for CHANCE, Dr. Johnston said the Chinese researchers will look at ancillary studies of biomarkers and subtyping based on vascular imaging. As well, they plan to provide outcomes at 1 year that will include results related to cognition.
Helpful Information
Invited to comment on the CHANCE trial results, Larry B. Goldstein, MD, professor, medicine, Division of Neurology, and director, Duke Stroke Center, Duke University, Durham, North Carolina, and a POINT investigator, said the information is "quite helpful" and could eventually alter the current treatment practice, which is to being aspirin alone. "This would suggest that aspirin with clopidogrel over a relatively short course may have some benefit."
He added that the "key" is the short course of the combination aspirin plus clopidogrel treatment. He pointed out that other trials, including SPS3 and MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients), found that long-term combinations are associated with an increased risk for major bleeding complications.
"Over the longer term, the addition of a more potent antiplatelet drug, or combinations in general, seem to carry a much higher risk of bleeding that attenuates any benefit they have in reducing ischemic stroke risk," said Dr. Goldstein. "In our current guidelines, there is actually a contraindication for the combination for long-term secondary stroke prevention."
The lack of increased risk of bleeding, at least in the short term, "is quite encouraging," said Dr. Goldstein. He added that bleeding complications are more of a concern in Asia than in the United States, which has a much more ethnically diverse population and where the proportion of Asians is relatively low.
Source: http://www.medscape.com/viewarticle/779089?nlid=28263_1301&src=wnl_edit_dail&uac=129655SZ
Welcome to my collection of health articles. Most of them contain little nuggets of health wisdom that we can easily apply to our daily lives. As you can gather, I've been consuming all sorts of supplements over the years, most of them from iherb. They deliver on time (DHL), and prices are good. If you're a first-time buyer, use my code 'pot089' to enjoy up to $10 off.
Tuesday, 19 February 2013
Thin Asians may be at risk for diabetes
Type 2 diabetes, usually associated with obesity, can occur in many seemingly thin people from ethnic minorities, physicians told attendees here at the Excellence in Diabetes 2013 meeting last week.
Researchers showed that Japanese American women are twice as likely to be diagnosed with diabetes as whites, despite having lower body-mass indexes (BMIs). Epidemiologist Gertraud Maskarinec, MD, from the University of Hawaii Cancer Center, Honolulu, presented the findings, which cover a number of studies from her group, in a poster.
She told Medscape Medical News: "Diabetes risk is higher in all ethnic groups than in whites, and of course some of this is just due to body weight, but evidence is now building that people of many races may be at increased risk of diabetes and cancer before they are even considered conventionally overweight."
In communities where there are a lot of Asians, "I think it's on everybody's radar already," said Dr. Maskarinec. "If an Asian walks in, you don’t have to wait until they weigh hundreds of pounds to do a diabetes test." The World Health Organization (WHO) has worked on the idea to lower the "at-risk" BMI to 23 kg/m2 for certain ethnic groups, she adds, but "not everybody has adopted it."
Meanwhile, Chittaranjan Yajnick, MD, from King Edward Memorial Diabetes Unit, Pune, India, also gave a talk on what makes Indians so susceptible to diabetes. "We have seen that Indians are often diagnosed with diabetes 10 years earlier and 5- to 10-units BMI thinner than whites," he noted.
Both believe the explanation lies in "hidden" visceral fat found inside the body, between organs, in Asians and probably other ethnic groups too, but not in whites. This in turn affects the levels of adipokines secreted, such as leptin and adiponectin, which can have adverse metabolic effects.
Japanese Americans: Much More Visceral Fat Than Whites
The knowledge that Asians and other ethnic groups are at much greater risk for diseases associated with obesity, such as diabetes and many cancers, than whites, is not new, Dr. Maskarinec explained. But more recently, researchers have begun to show that nonwhites who are not even particularly overweight or who are of "normal" weight are at much higher risk than whites.
If an Asian walks in, you don't have to wait until they weigh hundreds of pounds to do a diabetes test.
"People have talked about some kind of adaptation for white people, who have had a greater number of years to adjust to the type of food we are eating now," she postulated.
As part of their research, Dr. Maskarinec and her colleagues used the Hawaii component of the Multiethnic Cohort (MEC) to examine the influence of BMI on diabetes incidence.
They measured leptin and adiponectin by ELISA assay in 312 ethnically Japanese and 208 white women. Magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) were performed in 30 white and 30 Japanese cohort members.
Overall, Japanese women had significantly lower BMIs (23.7 vs 25.3 kg/m2), leptin (15.0 vs 25.9 ng/mL), and adiponectin (11.7 vs 16.0 µg/mL) than whites (P < .0001 for all).
But in adjusted models, Japanese were twice as likely to be diagnosed with diabetes as whites across all BMI categories: less than 22 kg/m2, 22.0 to 24.9, 25.0 to 29.9, and 30 kg/m2 or higher.
The DXA and MRI scans of the 30 white and 30 Japanese women, published in 2011, showed much more trunk fat and percentage of abdominal visceral fat in the Japanese than in the white women. Japanese women had higher trunk-to-peripheral-fat ratios and a greater percentage of liver fat and were twice as likely to have fatty livers as whites, the data showed.
"Greater central adiposity reflecting the adverse effects of visceral fat and/or patterns of adipokines may be responsible for the higher diabetes risk in Asians as compared with whites at the same BMI level," Dr. Maskarinec and colleagues concluded.
Dr. Maskarinec also showed data on DXA whole-body scans obtained for 101 adult women (>30 years) and their 112 daughters (age, 10 –16 years) in Hawaii, divided into all white, mixed of non-Asian descent, mixed of partly Asian, and all Asian, taken from another study by her colleagues published last year. These results confirmed previous reports of greater central adiposity in women of Asian ancestry and indicated that ethnic differences in adiposity were already present in adolescence.
Dr. Maskarinec said ethnic differences in body-fat amount or distribution that develops early in life may be key, with some scientists believing the intrauterine environment plays an important role, although this latter concept is still just a hypothesis, she stressed.
So Could It Be Epigenetics?
Dr. Yajnick is such a proponent of this theory: "All the risk factors for diabetes and adiposity, including blood chemistry, are present at birth," he told the meeting. His research includes evidence that Indian babies "are small but adipose; it's all about nutritional programming rather than the birth weight."
Susceptibility to noncommunicable diseases such as diabetes "is thus not only genetic, but epigenetic," with the latter representing heritable changes caused by mechanisms other than alterations in underlying DNA and being "modifiable," he explains. "Only about 10% of diabetes can so far be explained by genetics, for example," he notes.
And one factor he believes may be playing an important role in India is vegetarianism. People there consume high amounts of folate but are deficient in vitamin B12, creating a low-B12/high-folate intrauterine environment that "produces babies who are mostly insulin resistant." He is testing his hypothesis in the Pune Intervention trial, which began a year ago and involves giving adolescent boys and girls in the Indian region B12 supplementation. The participants and their offspring will be followed long term.
Dr. Maskarinec is skeptical of this theory, noting that most ethnic groups around the world are not B12 deficient. The Japanese Americans she is studying, for example, have very high per-capita meat consumption, she says.
The main message, she stressed, is that physicians need to understand that individuals of Asian descent and other ethnicities can have particularly high disease risks — not just for diabetes, but for breast and other cancers — at relatively low BMI levels.
"Just because they don't look fat doesn't mean they are healthy," she warns.
Source: http://www.medscape.com/viewarticle/779072?nlid=28263_1301&src=wnl_edit_dail&uac=129655SZ
Researchers showed that Japanese American women are twice as likely to be diagnosed with diabetes as whites, despite having lower body-mass indexes (BMIs). Epidemiologist Gertraud Maskarinec, MD, from the University of Hawaii Cancer Center, Honolulu, presented the findings, which cover a number of studies from her group, in a poster.
She told Medscape Medical News: "Diabetes risk is higher in all ethnic groups than in whites, and of course some of this is just due to body weight, but evidence is now building that people of many races may be at increased risk of diabetes and cancer before they are even considered conventionally overweight."
In communities where there are a lot of Asians, "I think it's on everybody's radar already," said Dr. Maskarinec. "If an Asian walks in, you don’t have to wait until they weigh hundreds of pounds to do a diabetes test." The World Health Organization (WHO) has worked on the idea to lower the "at-risk" BMI to 23 kg/m2 for certain ethnic groups, she adds, but "not everybody has adopted it."
Meanwhile, Chittaranjan Yajnick, MD, from King Edward Memorial Diabetes Unit, Pune, India, also gave a talk on what makes Indians so susceptible to diabetes. "We have seen that Indians are often diagnosed with diabetes 10 years earlier and 5- to 10-units BMI thinner than whites," he noted.
Both believe the explanation lies in "hidden" visceral fat found inside the body, between organs, in Asians and probably other ethnic groups too, but not in whites. This in turn affects the levels of adipokines secreted, such as leptin and adiponectin, which can have adverse metabolic effects.
Japanese Americans: Much More Visceral Fat Than Whites
The knowledge that Asians and other ethnic groups are at much greater risk for diseases associated with obesity, such as diabetes and many cancers, than whites, is not new, Dr. Maskarinec explained. But more recently, researchers have begun to show that nonwhites who are not even particularly overweight or who are of "normal" weight are at much higher risk than whites.
If an Asian walks in, you don't have to wait until they weigh hundreds of pounds to do a diabetes test.
"People have talked about some kind of adaptation for white people, who have had a greater number of years to adjust to the type of food we are eating now," she postulated.
As part of their research, Dr. Maskarinec and her colleagues used the Hawaii component of the Multiethnic Cohort (MEC) to examine the influence of BMI on diabetes incidence.
They measured leptin and adiponectin by ELISA assay in 312 ethnically Japanese and 208 white women. Magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) were performed in 30 white and 30 Japanese cohort members.
Overall, Japanese women had significantly lower BMIs (23.7 vs 25.3 kg/m2), leptin (15.0 vs 25.9 ng/mL), and adiponectin (11.7 vs 16.0 µg/mL) than whites (P < .0001 for all).
But in adjusted models, Japanese were twice as likely to be diagnosed with diabetes as whites across all BMI categories: less than 22 kg/m2, 22.0 to 24.9, 25.0 to 29.9, and 30 kg/m2 or higher.
The DXA and MRI scans of the 30 white and 30 Japanese women, published in 2011, showed much more trunk fat and percentage of abdominal visceral fat in the Japanese than in the white women. Japanese women had higher trunk-to-peripheral-fat ratios and a greater percentage of liver fat and were twice as likely to have fatty livers as whites, the data showed.
"Greater central adiposity reflecting the adverse effects of visceral fat and/or patterns of adipokines may be responsible for the higher diabetes risk in Asians as compared with whites at the same BMI level," Dr. Maskarinec and colleagues concluded.
Dr. Maskarinec also showed data on DXA whole-body scans obtained for 101 adult women (>30 years) and their 112 daughters (age, 10 –16 years) in Hawaii, divided into all white, mixed of non-Asian descent, mixed of partly Asian, and all Asian, taken from another study by her colleagues published last year. These results confirmed previous reports of greater central adiposity in women of Asian ancestry and indicated that ethnic differences in adiposity were already present in adolescence.
Dr. Maskarinec said ethnic differences in body-fat amount or distribution that develops early in life may be key, with some scientists believing the intrauterine environment plays an important role, although this latter concept is still just a hypothesis, she stressed.
So Could It Be Epigenetics?
Dr. Yajnick is such a proponent of this theory: "All the risk factors for diabetes and adiposity, including blood chemistry, are present at birth," he told the meeting. His research includes evidence that Indian babies "are small but adipose; it's all about nutritional programming rather than the birth weight."
Susceptibility to noncommunicable diseases such as diabetes "is thus not only genetic, but epigenetic," with the latter representing heritable changes caused by mechanisms other than alterations in underlying DNA and being "modifiable," he explains. "Only about 10% of diabetes can so far be explained by genetics, for example," he notes.
And one factor he believes may be playing an important role in India is vegetarianism. People there consume high amounts of folate but are deficient in vitamin B12, creating a low-B12/high-folate intrauterine environment that "produces babies who are mostly insulin resistant." He is testing his hypothesis in the Pune Intervention trial, which began a year ago and involves giving adolescent boys and girls in the Indian region B12 supplementation. The participants and their offspring will be followed long term.
Dr. Maskarinec is skeptical of this theory, noting that most ethnic groups around the world are not B12 deficient. The Japanese Americans she is studying, for example, have very high per-capita meat consumption, she says.
The main message, she stressed, is that physicians need to understand that individuals of Asian descent and other ethnicities can have particularly high disease risks — not just for diabetes, but for breast and other cancers — at relatively low BMI levels.
"Just because they don't look fat doesn't mean they are healthy," she warns.
Source: http://www.medscape.com/viewarticle/779072?nlid=28263_1301&src=wnl_edit_dail&uac=129655SZ
Calcium supplements may be unhealthy for men
The debate over the safety of calcium supplements has been muddied with the publication of a new analysis showing that a high intake of supplemental calcium increases the risk of cardiovascular disease (CVD) death in men but not in women [1]. Compared with individuals who took no calcium, men who consumed 1000 mg or more of supplemental calcium per day had a significant 20% increased risk of CVD death, a risk that was driven by a significant 19% increased risk of heart-disease death.
For women, however, there was no association between calcium intake and the risk of death.
"We found a significant interaction by sex," write Dr Qian Xiao (National Cancer Institute, Bethesda, MD) and colleagues in their paper, published online February 4, 2013 in JAMA: Internal Medicine. "Elevated CVD mortality with increasing supplemental calcium intake was observed only in men; however, we cannot rule out the possibility that supplemental calcium intake may be associated with cardiovascular mortality in women." The group calls the difference in risk between men and women "intriguing," adding that further studies are needed to determine whether such differential risks are real.
In an editorial [2], Dr Susanna Larsson (Karolinska Institute, Stockholm, Sweden) said the lack of association between calcium supplementation in women is "perplexing," especially given the results of a reanalysis of the WHI study conducted by Dr Mark Bolland (University of Auckland, New Zealand) and colleagues. In the original WHI analysis on the risks associated with calcium use, investigators found no adverse cardiovascular effects in women taking calcium and vitamin D when compared with those not taking the supplements. However, Bolland et al reexamined the WHI data because 54% of women were already taking calcium and vitamin D by personal choice at the start of the WHI study and were not told to stop if they were randomized to placebo. When the data were reanalyzed, the researchers observed a significant association between calcium intake, as well as vitamin D, with the risk of MI.
New Report From NIH Data
The latest report is taken from an analysis of the National Institutes of Health--AARP Diet and Health Study, a study that included 388 229 men and women 50 to 71 years of age from six US states. Individuals self-reported frequency of food intake and portion size during a one-year period and answered questions about the frequency in which they consumed multivitamins, calcium-containing antacids, or calcium supplements alone.
During a mean follow-up of 12 years, there were 7904 and 3874 CVD deaths in men and women, respectively. Dietary intake of calcium was initially associated with total CVD and heart-disease death in men and women, but the association was no longer significant after adjustment for CVD risk factors. Supplemental calcium intake (1000 mg/day vs no calcium supplementation), on the other hand, increased the risk of CVD death and heart-disease death by 20% and 19%, respectively, in men, but there was no association in women. In an analysis that looked only at those taking calcium supplements and not multivitamins, the risk of CVD death and heart-disease death was 24% and 37% higher in men who took 1000 mg/day of calcium compared with those who took no supplements. Again, no association was observed in women who took calcium supplements alone.
There is currently a debate surrounding the benefits and risks of supplemental calcium in men and women. In 2010, researchers published a meta-analysis inBMJ showing that the use of calcium supplements without coadministered vitamin D is associated with an increased risk of MI. This increased risk was later confirmed in an analysis of the patients participating in the European Prospective Investigation into Cancer and Nutrition Study (EPIC).
In the editorial, Larsson concludes that the available evidence is suggestive of an adverse cardiovascular effect with excessive use of calcium supplements. Published as part of JAMA: Internal Medicine's series on "less is more" in medicine, the editorial states that more calcium, which is promoted because of its proposed benefits on bone health, does translate into health benefits. The best source of calcium, says Larsson, remains diet and the consumption of calcium-rich foods such as low-fat dairy, beans, and green leafy vegetables.
Source: http://www.medscape.com/viewarticle/778718
For women, however, there was no association between calcium intake and the risk of death.
"We found a significant interaction by sex," write Dr Qian Xiao (National Cancer Institute, Bethesda, MD) and colleagues in their paper, published online February 4, 2013 in JAMA: Internal Medicine. "Elevated CVD mortality with increasing supplemental calcium intake was observed only in men; however, we cannot rule out the possibility that supplemental calcium intake may be associated with cardiovascular mortality in women." The group calls the difference in risk between men and women "intriguing," adding that further studies are needed to determine whether such differential risks are real.
In an editorial [2], Dr Susanna Larsson (Karolinska Institute, Stockholm, Sweden) said the lack of association between calcium supplementation in women is "perplexing," especially given the results of a reanalysis of the WHI study conducted by Dr Mark Bolland (University of Auckland, New Zealand) and colleagues. In the original WHI analysis on the risks associated with calcium use, investigators found no adverse cardiovascular effects in women taking calcium and vitamin D when compared with those not taking the supplements. However, Bolland et al reexamined the WHI data because 54% of women were already taking calcium and vitamin D by personal choice at the start of the WHI study and were not told to stop if they were randomized to placebo. When the data were reanalyzed, the researchers observed a significant association between calcium intake, as well as vitamin D, with the risk of MI.
New Report From NIH Data
The latest report is taken from an analysis of the National Institutes of Health--AARP Diet and Health Study, a study that included 388 229 men and women 50 to 71 years of age from six US states. Individuals self-reported frequency of food intake and portion size during a one-year period and answered questions about the frequency in which they consumed multivitamins, calcium-containing antacids, or calcium supplements alone.
During a mean follow-up of 12 years, there were 7904 and 3874 CVD deaths in men and women, respectively. Dietary intake of calcium was initially associated with total CVD and heart-disease death in men and women, but the association was no longer significant after adjustment for CVD risk factors. Supplemental calcium intake (1000 mg/day vs no calcium supplementation), on the other hand, increased the risk of CVD death and heart-disease death by 20% and 19%, respectively, in men, but there was no association in women. In an analysis that looked only at those taking calcium supplements and not multivitamins, the risk of CVD death and heart-disease death was 24% and 37% higher in men who took 1000 mg/day of calcium compared with those who took no supplements. Again, no association was observed in women who took calcium supplements alone.
There is currently a debate surrounding the benefits and risks of supplemental calcium in men and women. In 2010, researchers published a meta-analysis inBMJ showing that the use of calcium supplements without coadministered vitamin D is associated with an increased risk of MI. This increased risk was later confirmed in an analysis of the patients participating in the European Prospective Investigation into Cancer and Nutrition Study (EPIC).
In the editorial, Larsson concludes that the available evidence is suggestive of an adverse cardiovascular effect with excessive use of calcium supplements. Published as part of JAMA: Internal Medicine's series on "less is more" in medicine, the editorial states that more calcium, which is promoted because of its proposed benefits on bone health, does translate into health benefits. The best source of calcium, says Larsson, remains diet and the consumption of calcium-rich foods such as low-fat dairy, beans, and green leafy vegetables.
Source: http://www.medscape.com/viewarticle/778718
Vitamin D supplements vary in potency
Potency of vitamin D supplements often varies widely from what is listed on the label, according to results from a study of pills from 12 different manufacturers.
The study was authored by Erin S. LeBlanc, MD, MPH, from the Kaiser Permanente Center for Health Research, Portland, Oregon, and colleagues and published online February 11 inJAMA Internal Medicine.
In previous research that focused on vitamin D in menopausal women, Dr. LeBlanc and colleagues found that compounded vitamin D3(cholecalciferol) supplements varied significantly in potency and that only a third of the examined compounded study pills met US Pharmacopeial (USP) Convention standards.
"This variability in compounded cholecalciferol pills led us to additionally investigate over-the-counter (OTC) cholecalciferol pills, in which we also found variability," the authors write.
In this study, the investigators randomly tested the potency of 5 pills from 15 sealed bottles of OTC cholecalciferol dietary supplements (1000 IU, 5000 IU, and 10,000 IU) they purchased at 5 stores in Portland, Oregon.
They found the pills contained from 52% to 135% of the dose listed on the bottles. "When averaged over 5 pills, two-thirds of bottles met USP Convention standards for OTC cholecalciferol solution, which state that contents should be within 90% to 120% of the stated dose," the authors write. In about a quarter of the bottles, all 5 pills met the standards.
The investigators next checked a single pill from 5 bottles with the same lot number and found that potency ranged from 57% to 138% of what was on the label.
They then evaluated a single pill from 5 bottles with different lot numbers. Those pills ranged from 9% to 140% of the stated dose, with mean potencies over the 5 lots ranging from 89% to 105%.
Finally, the researchers analyzed compounded study cholecalciferol pills (1000 IU and 50,000 IU) that had been produced on 3 occasions over the course of several months. Those analyses were done over varied times (0 - 6 months) after compounding. They found that the 50,000-IU tablets contained 52% to 105% of the anticipated dose, whereas the 1000-IU tablets contained 23% to 146% of the expected dose.
"In our test, just over one-half of the OTC pills and only one-third of compounded pills met USP Convention standards," they write.
They say that although lack of accuracy in vitamin D dosing may not cause harm in most people, such deviations could render the supplements less effective. They also point out that variability from pill to pill may undermine the validity of vitamin D trials that use compounded pills to blind participants.
"As more people take vitamin D supplements, it is critical that health care providers and patients understand that cholecalciferol potency may vary widely," they conclude, adding that they agree with calls for increased regulation of dietary supplements.
The study was authored by Erin S. LeBlanc, MD, MPH, from the Kaiser Permanente Center for Health Research, Portland, Oregon, and colleagues and published online February 11 inJAMA Internal Medicine.
In previous research that focused on vitamin D in menopausal women, Dr. LeBlanc and colleagues found that compounded vitamin D3(cholecalciferol) supplements varied significantly in potency and that only a third of the examined compounded study pills met US Pharmacopeial (USP) Convention standards.
"This variability in compounded cholecalciferol pills led us to additionally investigate over-the-counter (OTC) cholecalciferol pills, in which we also found variability," the authors write.
In this study, the investigators randomly tested the potency of 5 pills from 15 sealed bottles of OTC cholecalciferol dietary supplements (1000 IU, 5000 IU, and 10,000 IU) they purchased at 5 stores in Portland, Oregon.
They found the pills contained from 52% to 135% of the dose listed on the bottles. "When averaged over 5 pills, two-thirds of bottles met USP Convention standards for OTC cholecalciferol solution, which state that contents should be within 90% to 120% of the stated dose," the authors write. In about a quarter of the bottles, all 5 pills met the standards.
The investigators next checked a single pill from 5 bottles with the same lot number and found that potency ranged from 57% to 138% of what was on the label.
They then evaluated a single pill from 5 bottles with different lot numbers. Those pills ranged from 9% to 140% of the stated dose, with mean potencies over the 5 lots ranging from 89% to 105%.
Finally, the researchers analyzed compounded study cholecalciferol pills (1000 IU and 50,000 IU) that had been produced on 3 occasions over the course of several months. Those analyses were done over varied times (0 - 6 months) after compounding. They found that the 50,000-IU tablets contained 52% to 105% of the anticipated dose, whereas the 1000-IU tablets contained 23% to 146% of the expected dose.
"In our test, just over one-half of the OTC pills and only one-third of compounded pills met USP Convention standards," they write.
They say that although lack of accuracy in vitamin D dosing may not cause harm in most people, such deviations could render the supplements less effective. They also point out that variability from pill to pill may undermine the validity of vitamin D trials that use compounded pills to blind participants.
"As more people take vitamin D supplements, it is critical that health care providers and patients understand that cholecalciferol potency may vary widely," they conclude, adding that they agree with calls for increased regulation of dietary supplements.
Source: http://www.medscape.com/viewarticle/779088?nlid=28263_1301&src=wnl_edit_dail&uac=129655SZ
Prenatal folic acid reduces autism risk
More evidence suggests that prenatal folic acid supplementation may lower the risk of developing autism.
A population-based cohort study of almost 85,000 children in Norway showed that those children whose mothers used supplemental folic acid early in pregnancy had 39% lower odds of having autistic disorder than those whose mothers did not use the supplements.
"We were a bit surprised about how large the reduction in risk was and how it was specifically related to folic acid and not to other supplements," Pål Surén, MD, from the Norwegian Institute of Public Health in Oslo, told Medscape Medical News.
"This was also reassuring, because if we had found [the reduction] was associated with other types of supplements as well, it would have been more likely to be explained by healthy behaviors in general, not the supplements per se," he added.
Dr. Surén noted that although more research is needed, "the results support the current recommendations of taking folic acid supplements during pregnancy and emphasize the importance of starting early — preferably before conception."
The study is published in the February issue of JAMA.
Public Health Benefit
Previous research has shown that folic acid supplementation "around the time of conception" can reduce the risk of offspring developing neural tube defects, report the investigators.
"This protective effect has led to mandatory fortification of flour with folic acid in several countries, and it is generally recommended that women planning to become pregnant take a daily supplement...starting 1 month before conception," they write.
"It is not implausible to think that it might also have other beneficial effects, and possibly be protective against other neurodevelopmental disorders, too," said Dr. Surén. "If folic acid truly has a preventive effect against autism in children, it would have great benefits from a public health perspective, because it would be a preventive measure that is cheap and already in use for other purposes."
In a study of more than 700 preschoolers published last year in the American Journal of Clinical Nutrition, investigators from California found that those children whose mothers received at least 600 μg per day of folic acid during their first month of pregnancy had a 38% lower chance of having autism or Asperger syndrome.
For the current analysis, the investigators sought to assess the association between maternal use of folic acid, from 4 weeks before the start of pregnancy to 8 weeks afterwards, and subsequent risk for autism spectrum disorders (ASDs), which include autistic disorder, Asperger syndrome, and pervasive developmental disorder–not otherwise specified (PDD-NOS), in offspring.
The investigators evaluated data on 85,176 children born between 2002 and 2008 who participated in the Norwegian Mother and Child Cohort Study. The mean age of the children at the end of follow-up in March 2012 was 6.4 years.
The Autism Birth Cohort substudy was used to identify cases of ASD in these children.
Inverse Association
Results showed that 270 of the children had been diagnosed with an ASD. Of these, 114 had autistic disorder, 100 had PDD-NOS, and 56 had Asperger syndrome.
Of the children whose mothers took folic acid during early pregnancy, 0.10% had autistic disorder vs 0.21% of those whose mothers did not take the supplements (adjusted odds ratio, 0.61; 95% confidence interval, 0.41 - 0.90).
The inverse association found for folic acid use in early pregnancy and subsequent risk for autistic disorder was not found for folic use during midpregnancy.
Although no association was found between prenatal folic acid supplementation and Asperger syndrome or PDD-NOS, "power was limited," note the investigators.
In addition, further analysis showed no association between risk for an ASD and use of fish oil supplements.
Overall, the main finding does not establish causation between use of folic acid and a lower risk for autistic disorder, write the researchers.
However, it does provide "a rationale for replicating the analyses in other study samples and further investigating genetic factors and other biological mechanisms that may explain the inverse association."
"Reassuring Study"
"It is reassuring that the study...found no association between folic acid supplementation and an increased risk for autistic disorder or ASDs," write Robert J. Berry, MD, and colleagues from the Centers for Disease Control and Prevention in Atlanta, Georgia, in an accompanying editorial.
They note that this has been a hotly debated issue previously. And it is "biologically plausible that folic acid intake might affect numerous conditions positively or negatively depending on timing and dose."
However, past studies have shown strong benefits from folic acid, including a previous report from the Norwegian Mother and Child Cohort Study that showed that supplementation during early pregnancy was associated with a reduced risk for severe language delay in offspring.
The editorialists point out that more research is now needed, including studies that evaluate timing, dose, and intake of supplements, as well as studies that assess children with autism and comorbid conditions.
Nevertheless, "this should ensure that folic acid intake can continue to serve as a tool for the prevention of neural tube birth defects," they write.
"The potential for a nutritional supplement to reduce the risk of autistic disorder is provocative and should be confirmed in other populations."
A population-based cohort study of almost 85,000 children in Norway showed that those children whose mothers used supplemental folic acid early in pregnancy had 39% lower odds of having autistic disorder than those whose mothers did not use the supplements.
"We were a bit surprised about how large the reduction in risk was and how it was specifically related to folic acid and not to other supplements," Pål Surén, MD, from the Norwegian Institute of Public Health in Oslo, told Medscape Medical News.
"This was also reassuring, because if we had found [the reduction] was associated with other types of supplements as well, it would have been more likely to be explained by healthy behaviors in general, not the supplements per se," he added.
Dr. Surén noted that although more research is needed, "the results support the current recommendations of taking folic acid supplements during pregnancy and emphasize the importance of starting early — preferably before conception."
The study is published in the February issue of JAMA.
Public Health Benefit
Previous research has shown that folic acid supplementation "around the time of conception" can reduce the risk of offspring developing neural tube defects, report the investigators.
"This protective effect has led to mandatory fortification of flour with folic acid in several countries, and it is generally recommended that women planning to become pregnant take a daily supplement...starting 1 month before conception," they write.
"It is not implausible to think that it might also have other beneficial effects, and possibly be protective against other neurodevelopmental disorders, too," said Dr. Surén. "If folic acid truly has a preventive effect against autism in children, it would have great benefits from a public health perspective, because it would be a preventive measure that is cheap and already in use for other purposes."
In a study of more than 700 preschoolers published last year in the American Journal of Clinical Nutrition, investigators from California found that those children whose mothers received at least 600 μg per day of folic acid during their first month of pregnancy had a 38% lower chance of having autism or Asperger syndrome.
For the current analysis, the investigators sought to assess the association between maternal use of folic acid, from 4 weeks before the start of pregnancy to 8 weeks afterwards, and subsequent risk for autism spectrum disorders (ASDs), which include autistic disorder, Asperger syndrome, and pervasive developmental disorder–not otherwise specified (PDD-NOS), in offspring.
The investigators evaluated data on 85,176 children born between 2002 and 2008 who participated in the Norwegian Mother and Child Cohort Study. The mean age of the children at the end of follow-up in March 2012 was 6.4 years.
The Autism Birth Cohort substudy was used to identify cases of ASD in these children.
Inverse Association
Results showed that 270 of the children had been diagnosed with an ASD. Of these, 114 had autistic disorder, 100 had PDD-NOS, and 56 had Asperger syndrome.
Of the children whose mothers took folic acid during early pregnancy, 0.10% had autistic disorder vs 0.21% of those whose mothers did not take the supplements (adjusted odds ratio, 0.61; 95% confidence interval, 0.41 - 0.90).
The inverse association found for folic acid use in early pregnancy and subsequent risk for autistic disorder was not found for folic use during midpregnancy.
Although no association was found between prenatal folic acid supplementation and Asperger syndrome or PDD-NOS, "power was limited," note the investigators.
In addition, further analysis showed no association between risk for an ASD and use of fish oil supplements.
Overall, the main finding does not establish causation between use of folic acid and a lower risk for autistic disorder, write the researchers.
However, it does provide "a rationale for replicating the analyses in other study samples and further investigating genetic factors and other biological mechanisms that may explain the inverse association."
"Reassuring Study"
"It is reassuring that the study...found no association between folic acid supplementation and an increased risk for autistic disorder or ASDs," write Robert J. Berry, MD, and colleagues from the Centers for Disease Control and Prevention in Atlanta, Georgia, in an accompanying editorial.
They note that this has been a hotly debated issue previously. And it is "biologically plausible that folic acid intake might affect numerous conditions positively or negatively depending on timing and dose."
However, past studies have shown strong benefits from folic acid, including a previous report from the Norwegian Mother and Child Cohort Study that showed that supplementation during early pregnancy was associated with a reduced risk for severe language delay in offspring.
The editorialists point out that more research is now needed, including studies that evaluate timing, dose, and intake of supplements, as well as studies that assess children with autism and comorbid conditions.
Nevertheless, "this should ensure that folic acid intake can continue to serve as a tool for the prevention of neural tube birth defects," they write.
"The potential for a nutritional supplement to reduce the risk of autistic disorder is provocative and should be confirmed in other populations."
Source: http://www.medscape.com/viewarticle/779205?nlid=28283_1301&src=wnl_edit_dail
Diet sodas linked to diabetes risk
A new study from France suggests that women who drink large amounts of diet soda are at increased risk for type 2 diabetes. The findings also support the previously documented association between high intake of regular sugar-sweetened beverages and the condition, report Guy Fagherazzi, from the Center for Research in Epidemiology and Population Health, Villejuif, France, and colleagues in a study published online January 30 in the American Journal of Clinical Nutrition.
Prior research into the relationship between diet soda (artificially sweetened beverages) and type 2 diabetes has produced conflicting results, and while the current study does not necessarily imply causation, there are some biologically plausible mechanisms, the researchers suggest.
And given that diet sodas are "considered — and marketed — as healthier than sugar-sweetened beverages," the findings require further investigation, they say. In the meantime, the authors advise that "a precautionary principle could be applied to the promotion of [artificially sweetened beverages]."
Highest Intake of Diet Soda More Than Doubles Diabetes Risk
The data come from a large prospective cohort study of 66,118 women in France investigating links between diet and cancer. There were 1369 new cases of type 2 diabetes diagnosed during the follow-up period from 1993 to 2007.
Based on self-reported dietary consumption, the average intake of regular sodas was 328 mL/week, while for diet sodas it was higher, at 568 mL/week.
The risk for type 2 diabetes was elevated among the women in the highest quartiles for both sugar-sweetened beverages (>359 mL/week) and artificially sweetened beverages (>603 mL/week) compared with women who did not consume those beverages, with hazard ratios of 1.34 and 2.21, respectively, after multivariate adjustment for a variety of covariates (other than body mass index [BMI]).
Strong positive trends in type 2 diabetes risk were observed across quartiles of consumption for both types of beverage (P = .0088 and P < .0001, respectively). Adjustment for BMI did modify the results somewhat, although the associations remained significant for both sugar-sweetened beverages and artificially sweetened beverages.
The authors also conducted sensitivity analyses to test the hypothesis that people who are at risk for type 2 diabetes by virtue of obesity may preferentially drink artificially sweetened beverages, but the results suggest that such a "reverse causation" mechanism is "unlikely," they note.
"Our results — in accordance with a recent joint scientific statement of the AHA and ADA — strongly suggest the need to conduct randomized trials that evaluate metabolic consequences of [artificially sweetened beverage] components, such as artificial sweeteners, to prove a causal link between [artificially sweetened beverage] consumption and type 2 diabetes," the study authors conclude.
Prior research into the relationship between diet soda (artificially sweetened beverages) and type 2 diabetes has produced conflicting results, and while the current study does not necessarily imply causation, there are some biologically plausible mechanisms, the researchers suggest.
And given that diet sodas are "considered — and marketed — as healthier than sugar-sweetened beverages," the findings require further investigation, they say. In the meantime, the authors advise that "a precautionary principle could be applied to the promotion of [artificially sweetened beverages]."
Highest Intake of Diet Soda More Than Doubles Diabetes Risk
The data come from a large prospective cohort study of 66,118 women in France investigating links between diet and cancer. There were 1369 new cases of type 2 diabetes diagnosed during the follow-up period from 1993 to 2007.
Based on self-reported dietary consumption, the average intake of regular sodas was 328 mL/week, while for diet sodas it was higher, at 568 mL/week.
The risk for type 2 diabetes was elevated among the women in the highest quartiles for both sugar-sweetened beverages (>359 mL/week) and artificially sweetened beverages (>603 mL/week) compared with women who did not consume those beverages, with hazard ratios of 1.34 and 2.21, respectively, after multivariate adjustment for a variety of covariates (other than body mass index [BMI]).
Strong positive trends in type 2 diabetes risk were observed across quartiles of consumption for both types of beverage (P = .0088 and P < .0001, respectively). Adjustment for BMI did modify the results somewhat, although the associations remained significant for both sugar-sweetened beverages and artificially sweetened beverages.
The authors also conducted sensitivity analyses to test the hypothesis that people who are at risk for type 2 diabetes by virtue of obesity may preferentially drink artificially sweetened beverages, but the results suggest that such a "reverse causation" mechanism is "unlikely," they note.
"Our results — in accordance with a recent joint scientific statement of the AHA and ADA — strongly suggest the need to conduct randomized trials that evaluate metabolic consequences of [artificially sweetened beverage] components, such as artificial sweeteners, to prove a causal link between [artificially sweetened beverage] consumption and type 2 diabetes," the study authors conclude.
Source: http://www.medscape.com/viewarticle/779290?nlid=28284_1301&src=wnl_edit_dail
Diclofenac and cardiovascular risks
The nonsteroidal anti-inflammatory drug (NSAID) diclofenac, a drug that is frequently used for the treatment of pain and inflammation caused by arthritis, is associated with a significantly increased risk of cardiovascular complications and should be removed from essential-medicines lists (EML), according to a new review.
Diclofenac, which is listed on the EML of 74 countries, increased the risk of cardiovascular events between 38% and 63% in different studies. The increased risk with diclofenac was similar to the COX-2 inhibitor rofecoxib (Vioxx, Merck), a drug withdrawn from worldwide markets because of cardiovascular toxicity.
Speaking with heartwire , Dr David Henry(Institute for Clinical Evaluative Sciences, Toronto, ON), who conducted the review along with Dr Patricia McGettigan (London School of Medicine and Dentistry, UK), said that while use of diclofenac in North America is low--the drug has about 5% or 6% of the NSAID market in the US and 17% of the market in Canada--its use is much more common in other non-Western countries.
"The exposure in the North American community is quite low," said Henry, "but the real issue is that it has 30% to 40% of the market share in countries like Vietnam, Pakistan, parts of China, and other countries. These countries are experiencing a real epidemic of cardiovascular disease at the same time these rates are coming down in the West. They are really heavy users of these drugs, in particular diclofenac."
In the review, published online February 12, 2013 inPLoS Medicine, Henry and McGettigan showed that in 15 countries, a list comprising high-, medium-, and low-income countries, diclofenac was the most widely used NSAID. It has a market share roughly equal to the combined market share ofibuprofen, naproxen, andmefenamic acid. The high-risk NSAIDs, diclofenac andetoricoxib, had one-third of the market share across the 15 countries.
Diclofenac, Even in Small Doses, Can Cause Problems
The meta-analysis by McGettigan and Henry also reviewed the relative cardiovascular risks of NSAIDs in observational and randomized studies. Rofecoxib, etoricoxib, and diclofenac were the three agents that were consistently associated with a significantly increased risk when compared with nonuse. Rofecoxib increased the risk of serious cardiovascular events between 27% and 45%, and etoricoxib increased the risk more than twofold compared with nonuse. In two observational studies, diclofenac increased risk of acute MI approximately 38% and 39%, respectively, and increased the risk of cardiovascular events 40%. In one randomized trial, diclofenac was associated with a 63% increased risk of cardiovascular events compared with nonuse.
To heartwire , Henry said the NSAIDs are familiar drugs for physicians and because of such familiarity might be casually prescribed. While the drugs are available over the counter, the cardiovascular risks are associated with the prescription strengths of NSAIDs. For diclofenac, the prescription dose ranges from 100 to 150 mg per day, and this dose is high enough to cause a risk of cardiovascular events, with higher doses associated with even greater risks. With diclofenac, as well as with rofecoxib, there does not appear to be a dose associated with no risk.
"We could find no-risk doses with some of the other drugs, like ibuprofen, naproxen, and celecoxib [Celebrex, Pfizer]," he said. "We could find a dose low enough that didn't increase the risk of heart attacks. The thing with diclofenac is that even in small doses it increases the risk of cardiovascular events. The average dose that is used and marketed is quite high."
Indometacin and meloxicam had a moderately increased risk of cardiovascular events, slightly higher than naproxen, while celecoxib and ibuprofen were associated with an increased risk of cardiovascular toxicity when used at high doses in clinical trials but not in lower doses available over the counter.
An Underappreciated Problem
Dr Gabriel Steg (Centre Hospitalier Bichaut-Claude Bernard, Paris, France), who was not affiliated with the analysis, told heartwire that the cardiovascular risks associated with NSAIDs are an underappreciated problem. He said that most NSAIDs, with the possible exception of naproxen, have some degree of cardiovascular risk associated with them. "I think the converging data from multiple sources indicates that, particularly in patients who are known to have cardiac disease, we should refrain from the chronic use of NSAIDs, if possible," said Steg. "It is conceivable that diclofenac might have a slightly higher risk than the others, but really the issue is the whole class rather than singling out a [particular] agent."
Steg noted that a study published last year inCirculation, reported by heartwire , showed that the use of NSAIDs was associated with a persistently increased risk of coronary events in patients with a previous MI. In more than 43 000 MI patients treated with NSAIDs, their use was associated with a 59% increased risk of death after one year and a 63% increased risk of death after five years of use. In addition, the use of the NSAIDs was associated with an increased risk of coronary death and recurrent MI.
"I think this is a completely underappreciated problem," said Steg. "Most physicians would not be alert to the long-term use of these agents. Many of these agents are over the counter, so physicians are not necessarily aware of their use. Also, they may be used fairly frequently by patients and for very long periods of time. In the elderly, because of bone and joint issues, their use is very common."
To heartwire , Henry said he has written to the World Health Organization(WHO) and has recommended that they advise the EML committees worldwide to preferentially recommend naproxen as the NSAID of choice. He said he does not expect drug regulatory committees, such as the Food and Drug Administration,Health Canada, or the European Medicines Agency (EMA), to withdraw the drugs. In October 2012, the EMA finalized a review that concluded there was a small increase in the risk of cardiovascular side effects with diclofenac compared with other NSAIDs.
"I don't think there is any real new information that would lead them to act, rather than information showing that diclofenac is the most popular drug and it has the same risks as Vioxx," said Henry. "I'm not expecting that change in attitude to suddenly occur. What we'd like to get across to prescribers is to not use diclofenac and to use naproxen. Also, these are not disease-modifying drugs, they're symptom-relieving drugs. We typically tell patients not to stop a medication and to talk to their doctor, but if you have heart disease and are taking diclofenac, do stop the medication and then go talk to your doctor about an alternative."
Source: http://www.medscape.com/viewarticle/779232?nlid=28284_1301&src=wnl_edit_dail
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