Adverse Events From Supplements Merit Scrutiny

Data are lacking on the adverse events that potentially can arise from the millions of people taking nutritional supplements along with pharmaceuticals, but researchers are making some headway in sorting the real causes for concern from the unfounded worries.

Many of the red flags physicians hear about are little more than isolated and unverified case reports that someone has called in to a regulatory agency, according to Philip Gregory, Pharm.D., assistant professor of pharmacy practice at Creighton University's Center for Drug Information and Evidence-Based Practice in Omaha, Neb.

With its limited resources, the Food and Drug Administration investigates a potential adverse event or interaction only if there are multiple reports, clustered in time, that practically scream for attention, he said.

It was only recently that the FDA mandated supplement companies to put adverse event reporting phone numbers on product labels. In reality, most companies have not yet complied, so adverse event and interaction surveillance is spotty, he noted at a meeting sponsored by the Scripps Center for Integrative Medicine.

Nonetheless, Dr. Gregory, editor of the Natural Medicines Comprehensive Database, and his team of researchers there have identified a number of significant concerns, and also exonerated herbs or nutrients that have been unduly vilified. They have screened tens of thousands of published and unpublished research reports, surveys, and regulatory alerts worldwide in an effort to help physicians figure out which potential interactions and adverse events warrant serious attention. Dr. Gregory highlighted a few of their findings:

▸ Bitter orange and cardiovascular effects. Also known as Citrus aurantium and Fructus aurantii, bitter orange has been used in traditional Chinese medicine for hundreds of years in herbal decoctions used to treat digestive problems. More recently, it has become a common ingredient in weight loss and energy supplements, owing to its stimulant and thermogenic properties. The popularity of bitter orange has soared over the past few years, following the FDA's ban on the herb ephedra.

This fruit contains high levels of synephrine, sometimes as much as 30%, and if used in an indiscriminate way can induce the same adverse effects as ephedra, including arrhythmias, ischemic stroke, syncope, QT interval prolongation, myocardial infarction, rhabdomyolysis, and ischemic colitis.

Reports of these problems are exceedingly rare, and in some cases they occurred in people taking bitter orange with other stimulants such as caffeine and the popular South American herb, guarana, Dr. Gregory said.

But given the seriousness of these potential side effects, physicians should discourage patients from using this herb for weight loss. “The risks outweigh the potential benefits, in my mind,” he said.

Be aware that some products containing bitter orange are promoted as “ephedra free,” leading consumers to believe that they're getting a safer alternative. Although these products may technically be free of ephedra, they're not necessarily free of ephedralike risks.

▸ Glucosamine and chondroitin plus warfarin. Several years ago, there was a widely publicized case report of bleeding and bruising in a patient on warfarin who also was taking this popular combination as an arthritis remedy. Since then, there have been 40 reports to the FDA and the World Health Organization of interactions between warfarin and glucosamine alone or between warfarin and the glucosamine/chondroitin combination.

On closer examination of the reports, most involved individuals taking very high doses of the supplement, in some cases up to six times the recommended dose.

“It is probably not a real problem in people who take the recommended doses of glucosamine/chondroitin, but patients taking warfarin should be careful,” he said, adding that this message holds true for almost any drug or supplement added on top of warfarin.

Glucosamine has a “heparinoid” structure, which could explain a plausible mechanism for a mild anticoagulant effect, but data to support this notion are pretty weak, Dr. Gregory noted. Another possible explanation is that the supplement somehow modifies gastrointestinal tract flora, thus altering warfarin pharmacokinetics, but again, this is theoretical.

▸ Calcium and cardiovascular risk. Findings from a large study suggested that older women taking more than 1 g/day of calcium citrate had a twofold increase in myocardial infarctions and significant increases in coronary artery calcification over a 5-year period (BMJ 2008;336:262–6).

These are worrisome findings, given how many postmenopausal women are taking calcium to prevent or attenuate osteoporosis, but this study was riddled with confounding variables and unanswered questions that make it difficult to draw a firm conclusion that calcium is problematic, Dr. Gregory said.

The study gives no data on the patients' magnesium levels, and since calcium and magnesium are antagonistic, the problems observed in the study may reflect the fact that patients were given unopposed calcium without mitigation from magnesium. In those with already low baseline magnesium, that could be dangerous.

The observed increase in heart problems also may be related to low levels of vitamin D and vitamin K, which play a role in calcium metabolism and bone formation, he suggested.

“This study is an alert, not absolute proof, and the finding has not shown up in other calcium studies. So it is not appropriate to conclude that calcium is causing the problem. Do not dissuade patients from taking calcium, but don't overdo it: 1,200 mg/day is fine.” He added that it's a very good idea to make sure patients are also getting enough magnesium.

▸ Selenium and type 2 diabetes. Selenium has been recommended as a possible preventive for several different conditions, including Alzheimer's disease, prostate cancer (though its merits in this context were challenged by the Selenium and Vitamin E Cancer Prevention Trial [SELECT]), and type 2 diabetes. The latter recommendation is based on epidemiologic data showing a strong inverse correlation between incidence of diabetes and selenium intake.

But a secondary analysis of data from the Nutritional Prevention of Cancer Trial indicated that individuals taking 200 mcg of supplemental selenium daily had a significant increase of type 2 diabetes over an 8-year period (Ann. Intern. Med. 2007;147:217–23).

This unexpected finding was corroborated by SELECT, which also showed an increased rate of diabetes in those taking selenium alone, though the difference was not statistically significant.

Complicating matters, there was no diabetes increase in SELECT among patients taking selenium plus vitamin E, compared with those taking placebo. In fact, the incidence actually went down slightly, though, again, the difference was not significant.

“When selenium is taken by itself, it may be oxidative rather than antioxidative. So taking high doses of selenium or any other independent antioxidant may not be so healthy,” Dr. Gregory hypothesized. He added that selenium may also stimulate glucagon release.

Though the picture is hardly clear, he advised against recommending selenium alone, especially for individuals prone to insulin resistance and diabetes. “The diabetes finding is a signal. We can't draw definitive conclusions from it, but we do need to be aware of it,” he concluded.

Dr. Gregory reported having no financial conflicts of interest related to his presentation.

Glucosamine should be used with care by patients also taking warfarin.

Source ©Lamiel/Istockphoto.com

Data are lacking on the adverse events that potentially can arise from the millions of people taking nutritional supplements along with pharmaceuticals, but researchers are making some headway in sorting the real causes for concern from the unfounded worries.

Many of the red flags physicians hear about are little more than isolated and unverified case reports that someone has called in to a regulatory agency, according to Philip Gregory, Pharm.D., assistant professor of pharmacy practice at Creighton University's Center for Drug Information and Evidence-Based Practice in Omaha, Neb.

With its limited resources, the Food and Drug Administration investigates a potential adverse event or interaction only if there are multiple reports, clustered in time, that practically scream for attention, he said.

It was only recently that the FDA mandated supplement companies to put adverse event reporting phone numbers on product labels. In reality, most companies have not yet complied, so adverse event and interaction surveillance is spotty, he noted at a meeting sponsored by the Scripps Center for Integrative Medicine.

Nonetheless, Dr. Gregory, editor of the Natural Medicines Comprehensive Database, and his team of researchers there have identified a number of significant concerns, and also exonerated herbs or nutrients that have been unduly vilified. They have screened tens of thousands of published and unpublished research reports, surveys, and regulatory alerts worldwide in an effort to help physicians figure out which potential interactions and adverse events warrant serious attention. Dr. Gregory highlighted a few of their findings:

▸ Bitter orange and cardiovascular effects. Also known as Citrus aurantium and Fructus aurantii, bitter orange has been used in traditional Chinese medicine for hundreds of years in herbal decoctions used to treat digestive problems. More recently, it has become a common ingredient in weight loss and energy supplements, owing to its stimulant and thermogenic properties. The popularity of bitter orange has soared over the past few years, following the FDA's ban on the herb ephedra.

This fruit contains high levels of synephrine, sometimes as much as 30%, and if used in an indiscriminate way can induce the same adverse effects as ephedra, including arrhythmias, ischemic stroke, syncope, QT interval prolongation, myocardial infarction, rhabdomyolysis, and ischemic colitis.

Reports of these problems are exceedingly rare, and in some cases they occurred in people taking bitter orange with other stimulants such as caffeine and the popular South American herb, guarana, Dr. Gregory said.

But given the seriousness of these potential side effects, physicians should discourage patients from using this herb for weight loss. “The risks outweigh the potential benefits, in my mind,” he said.

Be aware that some products containing bitter orange are promoted as “ephedra free,” leading consumers to believe that they're getting a safer alternative. Although these products may technically be free of ephedra, they're not necessarily free of ephedralike risks.

▸ Glucosamine and chondroitin plus warfarin. Several years ago, there was a widely publicized case report of bleeding and bruising in a patient on warfarin who also was taking this popular combination as an arthritis remedy. Since then, there have been 40 reports to the FDA and the World Health Organization of interactions between warfarin and glucosamine alone or between warfarin and the glucosamine/chondroitin combination.

On closer examination of the reports, most involved individuals taking very high doses of the supplement, in some cases up to six times the recommended dose.

“It is probably not a real problem in people who take the recommended doses of glucosamine/chondroitin, but patients taking warfarin should be careful,” he said, adding that this message holds true for almost any drug or supplement added on top of warfarin.

Glucosamine has a “heparinoid” structure, which could explain a plausible mechanism for a mild anticoagulant effect, but data to support this notion are pretty weak, Dr. Gregory noted. Another possible explanation is that the supplement somehow modifies gastrointestinal tract flora, thus altering warfarin pharmacokinetics, but again, this is theoretical.

▸ Calcium and cardiovascular risk. Findings from a large study suggested that older women taking more than 1 g/day of calcium citrate had a twofold increase in myocardial infarctions and significant increases in coronary artery calcification over a 5-year period (BMJ 2008;336:262–6).

These are worrisome findings, given how many postmenopausal women are taking calcium to prevent or attenuate osteoporosis, but this study was riddled with confounding variables and unanswered questions that make it difficult to draw a firm conclusion that calcium is problematic, Dr. Gregory said.

The study gives no data on the patients' magnesium levels, and since calcium and magnesium are antagonistic, the problems observed in the study may reflect the fact that patients were given unopposed calcium without mitigation from magnesium. In those with already low baseline magnesium, that could be dangerous.

The observed increase in heart problems also may be related to low levels of vitamin D and vitamin K, which play a role in calcium metabolism and bone formation, he suggested.

“This study is an alert, not absolute proof, and the finding has not shown up in other calcium studies. So it is not appropriate to conclude that calcium is causing the problem. Do not dissuade patients from taking calcium, but don't overdo it: 1,200 mg/day is fine.” He added that it's a very good idea to make sure patients are also getting enough magnesium.

▸ Selenium and type 2 diabetes. Selenium has been recommended as a possible preventive for several different conditions, including Alzheimer's disease, prostate cancer (though its merits in this context were challenged by the Selenium and Vitamin E Cancer Prevention Trial [SELECT]), and type 2 diabetes. The latter recommendation is based on epidemiologic data showing a strong inverse correlation between incidence of diabetes and selenium intake.

But a secondary analysis of data from the Nutritional Prevention of Cancer Trial indicated that individuals taking 200 mcg of supplemental selenium daily had a significant increase of type 2 diabetes over an 8-year period (Ann. Intern. Med. 2007;147:217–23).

This unexpected finding was corroborated by SELECT, which also showed an increased rate of diabetes in those taking selenium alone, though the difference was not statistically significant.

Complicating matters, there was no diabetes increase in SELECT among patients taking selenium plus vitamin E, compared with those taking placebo. In fact, the incidence actually went down slightly, though, again, the difference was not significant.

“When selenium is taken by itself, it may be oxidative rather than antioxidative. So taking high doses of selenium or any other independent antioxidant may not be so healthy,” Dr. Gregory hypothesized. He added that selenium may also stimulate glucagon release.

Though the picture is hardly clear, he advised against recommending selenium alone, especially for individuals prone to insulin resistance and diabetes. “The diabetes finding is a signal. We can't draw definitive conclusions from it, but we do need to be aware of it,” he concluded.

Dr. Gregory reported having no financial conflicts of interest related to his presentation.

Glucosamine should be used with care by patients also taking warfarin.

Source ©Lamiel/Istockphoto.com

Data are lacking on the adverse events that potentially can arise from the millions of people taking nutritional supplements along with pharmaceuticals, but researchers are making some headway in sorting the real causes for concern from the unfounded worries.

Many of the red flags physicians hear about are little more than isolated and unverified case reports that someone has called in to a regulatory agency, according to Philip Gregory, Pharm.D., assistant professor of pharmacy practice at Creighton University's Center for Drug Information and Evidence-Based Practice in Omaha, Neb.

With its limited resources, the Food and Drug Administration investigates a potential adverse event or interaction only if there are multiple reports, clustered in time, that practically scream for attention, he said.

It was only recently that the FDA mandated supplement companies to put adverse event reporting phone numbers on product labels. In reality, most companies have not yet complied, so adverse event and interaction surveillance is spotty, he noted at a meeting sponsored by the Scripps Center for Integrative Medicine.

Nonetheless, Dr. Gregory, editor of the Natural Medicines Comprehensive Database, and his team of researchers there have identified a number of significant concerns, and also exonerated herbs or nutrients that have been unduly vilified. They have screened tens of thousands of published and unpublished research reports, surveys, and regulatory alerts worldwide in an effort to help physicians figure out which potential interactions and adverse events warrant serious attention. Dr. Gregory highlighted a few of their findings:

▸ Bitter orange and cardiovascular effects. Also known as Citrus aurantium and Fructus aurantii, bitter orange has been used in traditional Chinese medicine for hundreds of years in herbal decoctions used to treat digestive problems. More recently, it has become a common ingredient in weight loss and energy supplements, owing to its stimulant and thermogenic properties. The popularity of bitter orange has soared over the past few years, following the FDA's ban on the herb ephedra.

This fruit contains high levels of synephrine, sometimes as much as 30%, and if used in an indiscriminate way can induce the same adverse effects as ephedra, including arrhythmias, ischemic stroke, syncope, QT interval prolongation, myocardial infarction, rhabdomyolysis, and ischemic colitis.

Reports of these problems are exceedingly rare, and in some cases they occurred in people taking bitter orange with other stimulants such as caffeine and the popular South American herb, guarana, Dr. Gregory said.

But given the seriousness of these potential side effects, physicians should discourage patients from using this herb for weight loss. “The risks outweigh the potential benefits, in my mind,” he said.

Be aware that some products containing bitter orange are promoted as “ephedra free,” leading consumers to believe that they're getting a safer alternative. Although these products may technically be free of ephedra, they're not necessarily free of ephedralike risks.

▸ Glucosamine and chondroitin plus warfarin. Several years ago, there was a widely publicized case report of bleeding and bruising in a patient on warfarin who also was taking this popular combination as an arthritis remedy. Since then, there have been 40 reports to the FDA and the World Health Organization of interactions between warfarin and glucosamine alone or between warfarin and the glucosamine/chondroitin combination.

On closer examination of the reports, most involved individuals taking very high doses of the supplement, in some cases up to six times the recommended dose.

“It is probably not a real problem in people who take the recommended doses of glucosamine/chondroitin, but patients taking warfarin should be careful,” he said, adding that this message holds true for almost any drug or supplement added on top of warfarin.

Glucosamine has a “heparinoid” structure, which could explain a plausible mechanism for a mild anticoagulant effect, but data to support this notion are pretty weak, Dr. Gregory noted. Another possible explanation is that the supplement somehow modifies gastrointestinal tract flora, thus altering warfarin pharmacokinetics, but again, this is theoretical.

▸ Calcium and cardiovascular risk. Findings from a large study suggested that older women taking more than 1 g/day of calcium citrate had a twofold increase in myocardial infarctions and significant increases in coronary artery calcification over a 5-year period (BMJ 2008;336:262–6).

These are worrisome findings, given how many postmenopausal women are taking calcium to prevent or attenuate osteoporosis, but this study was riddled with confounding variables and unanswered questions that make it difficult to draw a firm conclusion that calcium is problematic, Dr. Gregory said.

The study gives no data on the patients' magnesium levels, and since calcium and magnesium are antagonistic, the problems observed in the study may reflect the fact that patients were given unopposed calcium without mitigation from magnesium. In those with already low baseline magnesium, that could be dangerous.

The observed increase in heart problems also may be related to low levels of vitamin D and vitamin K, which play a role in calcium metabolism and bone formation, he suggested.

“This study is an alert, not absolute proof, and the finding has not shown up in other calcium studies. So it is not appropriate to conclude that calcium is causing the problem. Do not dissuade patients from taking calcium, but don't overdo it: 1,200 mg/day is fine.” He added that it's a very good idea to make sure patients are also getting enough magnesium.

▸ Selenium and type 2 diabetes. Selenium has been recommended as a possible preventive for several different conditions, including Alzheimer's disease, prostate cancer (though its merits in this context were challenged by the Selenium and Vitamin E Cancer Prevention Trial [SELECT]), and type 2 diabetes. The latter recommendation is based on epidemiologic data showing a strong inverse correlation between incidence of diabetes and selenium intake.

But a secondary analysis of data from the Nutritional Prevention of Cancer Trial indicated that individuals taking 200 mcg of supplemental selenium daily had a significant increase of type 2 diabetes over an 8-year period (Ann. Intern. Med. 2007;147:217–23).

This unexpected finding was corroborated by SELECT, which also showed an increased rate of diabetes in those taking selenium alone, though the difference was not statistically significant.

Complicating matters, there was no diabetes increase in SELECT among patients taking selenium plus vitamin E, compared with those taking placebo. In fact, the incidence actually went down slightly, though, again, the difference was not significant.

“When selenium is taken by itself, it may be oxidative rather than antioxidative. So taking high doses of selenium or any other independent antioxidant may not be so healthy,” Dr. Gregory hypothesized. He added that selenium may also stimulate glucagon release.

Though the picture is hardly clear, he advised against recommending selenium alone, especially for individuals prone to insulin resistance and diabetes. “The diabetes finding is a signal. We can't draw definitive conclusions from it, but we do need to be aware of it,” he concluded.

Dr. Gregory reported having no financial conflicts of interest related to his presentation.

Glucosamine should be used with care by patients also taking warfarin.

Source ©Lamiel/Istockphoto.com