Michele G. Sullivan

A three-component polypill designed to reduce cardiovascular risk could merit consideration for approval in the United States if it was determined to be both safe and effective, a Food and Drug Administration advisory committee has agreed.

Just what form that determination would take remains a big unknown, however.

No such pill exists in the United States. But at a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the committee members considered a hypothetical polypill that would include at least one antihypertensive, a statin, and aspirin. The members envisioned it to be used as a secondary prevention measure in patients who are both hyperlipidemic and hypertensive. Some committee members suggested that the indication should be restricted to high-risk patients, including those who have had a heart attack.

The strongest reason for such a pill would be to improve compliance in patients who are taking cardiovascular drugs but aren’t reaching their goals. A polypill could also be useful for patients who can’t or won’t comply with follow-up visits necessary for titrating blood pressure medications.

"The concept is very appealing, but the current body of evidence doesn’t appear to guarantee" that the benefits of such a pill would outweigh the benefits of the individual components, committee member Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said at the meeting. "A key question to me is to make sure that there would not be pharmacokinetic or pharmacodynamics issues" in the combination that might affect the proven safety of each ingredient. "We are interested not just in improving outcomes, but in maintaining safety."

Many patients are already taking all of these individual drugs simultaneously, and no pharmaceutical company has brought a combination pill forward to the FDA. Some companies have told the agency, however, that they might create one if there were a good chance of approval.

Similar drugs are available in other countries – including India, where a large phase II trial showed that it resulted in significant reductions in blood pressure and lipids, compared with the individual components alone (Lancet 2009;373:1341-51).

A U.S. observational study of a similar concept found very encouraging results. The 2010 Kaiser Permanente ALL/PHASE protocol utilized a bundle of aspirin, lisinopril, and a statin, said Dr. James Dudl, an endocrinologist at Kaiser. More than 170,000 patients, 78% of whom had diabetes and 50% of whom had coronary artery disease, were followed for 3 years. Full data were available on 47,000. The patients were split into a high-exposure group, with a mean compliance of 68%, and a low-exposure group.

Cardiovascular events were reduced by 15/1,000 patients in the high-exposure group. The outcome was driven by stroke alone, with no benefit in heart attack. Since then, Kaiser has continued the bundle recommendation, which Dr. Dudl said costs about 25 cents per day.

The American Heart Association supports the concept of a polypill – with some caveats. "It might be aneffective way to improve adherence and reduce cardiovascular disease," Dr. Niteesh Choudhry of the AHA told the committee. "But we do have lingering concerns about the efficacy and safety of a combined agent. We believe more data are needed from a clinical trial of sufficient duration and power to identify clinically relevant outcomes – particularly blood pressure and LDL cholesterol – and safety, and to identify subgroups" that might particularly benefit from the pill, or who might experience some untoward effects of it. Postmarketing surveillance should be a requirement, added Dr. Choudhry, of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.

Although many patients are already taking all the components of a polypill simultaneously, many of the committee members believed strongly that safety and efficacy studies would be a requirement. Some thought those data could be gathered from existing studies conducted in the United States and other countries; others felt that a prospective, or even a randomized, study should be part of any approval request.

"I want to see an observational trial in a real-world setting," said Dr. Stuart Rich, professor of medicine at the University of Chicago. "A clinical trial is not a real-world setting, and what might be shown in a clinical trial won’t translate in terms of the most meaningful outcome: adherence. I would also ask that there be a measure of health care cost savings."

Dr. James DeLemos, professor of medicine at the University of Texas Southwestern, Dallas, disagreed. "It would be a mistake to demand outcomes studies that would be small, underpowered, and maybe give incorrect answers. The way to do this would be to license it and get it out there and evaluate it."

There would likely be very little up-front financial support for any studies, said FDA pharmacology adviser Sudharshan Hariharan, Ph.D. No pharmaceutical companies have volunteered, and they probably won’t, because there is very little money to be made from a medication consisting of three very inexpensive generic drugs. Any company that did market such a pill would have exclusivity for 3 years, after which the prospect of any profit virtually disappears.

"There is no commercial backing for this at all. Doing these trials would consist entirely of writing grants and pleading with friends to do them for next to nothing. Drug companies have said that if they thought something like this could make it through regulatory hurdles, then they might start to invest in creating it. But right now it’s a chicken-or-egg situation," Dr. Hariharan explained.

No committee member had any relevant financial disclosures.

[email protected]

On Twitter @alz_gal

A three-component polypill designed to reduce cardiovascular risk could merit consideration for approval in the United States if it was determined to be both safe and effective, a Food and Drug Administration advisory committee has agreed.

Just what form that determination would take remains a big unknown, however.

No such pill exists in the United States. But at a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the committee members considered a hypothetical polypill that would include at least one antihypertensive, a statin, and aspirin. The members envisioned it to be used as a secondary prevention measure in patients who are both hyperlipidemic and hypertensive. Some committee members suggested that the indication should be restricted to high-risk patients, including those who have had a heart attack.

The strongest reason for such a pill would be to improve compliance in patients who are taking cardiovascular drugs but aren’t reaching their goals. A polypill could also be useful for patients who can’t or won’t comply with follow-up visits necessary for titrating blood pressure medications.

"The concept is very appealing, but the current body of evidence doesn’t appear to guarantee" that the benefits of such a pill would outweigh the benefits of the individual components, committee member Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said at the meeting. "A key question to me is to make sure that there would not be pharmacokinetic or pharmacodynamics issues" in the combination that might affect the proven safety of each ingredient. "We are interested not just in improving outcomes, but in maintaining safety."

Many patients are already taking all of these individual drugs simultaneously, and no pharmaceutical company has brought a combination pill forward to the FDA. Some companies have told the agency, however, that they might create one if there were a good chance of approval.

Similar drugs are available in other countries – including India, where a large phase II trial showed that it resulted in significant reductions in blood pressure and lipids, compared with the individual components alone (Lancet 2009;373:1341-51).

A U.S. observational study of a similar concept found very encouraging results. The 2010 Kaiser Permanente ALL/PHASE protocol utilized a bundle of aspirin, lisinopril, and a statin, said Dr. James Dudl, an endocrinologist at Kaiser. More than 170,000 patients, 78% of whom had diabetes and 50% of whom had coronary artery disease, were followed for 3 years. Full data were available on 47,000. The patients were split into a high-exposure group, with a mean compliance of 68%, and a low-exposure group.

Cardiovascular events were reduced by 15/1,000 patients in the high-exposure group. The outcome was driven by stroke alone, with no benefit in heart attack. Since then, Kaiser has continued the bundle recommendation, which Dr. Dudl said costs about 25 cents per day.

The American Heart Association supports the concept of a polypill – with some caveats. "It might be aneffective way to improve adherence and reduce cardiovascular disease," Dr. Niteesh Choudhry of the AHA told the committee. "But we do have lingering concerns about the efficacy and safety of a combined agent. We believe more data are needed from a clinical trial of sufficient duration and power to identify clinically relevant outcomes – particularly blood pressure and LDL cholesterol – and safety, and to identify subgroups" that might particularly benefit from the pill, or who might experience some untoward effects of it. Postmarketing surveillance should be a requirement, added Dr. Choudhry, of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.

Although many patients are already taking all the components of a polypill simultaneously, many of the committee members believed strongly that safety and efficacy studies would be a requirement. Some thought those data could be gathered from existing studies conducted in the United States and other countries; others felt that a prospective, or even a randomized, study should be part of any approval request.

"I want to see an observational trial in a real-world setting," said Dr. Stuart Rich, professor of medicine at the University of Chicago. "A clinical trial is not a real-world setting, and what might be shown in a clinical trial won’t translate in terms of the most meaningful outcome: adherence. I would also ask that there be a measure of health care cost savings."

Dr. James DeLemos, professor of medicine at the University of Texas Southwestern, Dallas, disagreed. "It would be a mistake to demand outcomes studies that would be small, underpowered, and maybe give incorrect answers. The way to do this would be to license it and get it out there and evaluate it."

There would likely be very little up-front financial support for any studies, said FDA pharmacology adviser Sudharshan Hariharan, Ph.D. No pharmaceutical companies have volunteered, and they probably won’t, because there is very little money to be made from a medication consisting of three very inexpensive generic drugs. Any company that did market such a pill would have exclusivity for 3 years, after which the prospect of any profit virtually disappears.

"There is no commercial backing for this at all. Doing these trials would consist entirely of writing grants and pleading with friends to do them for next to nothing. Drug companies have said that if they thought something like this could make it through regulatory hurdles, then they might start to invest in creating it. But right now it’s a chicken-or-egg situation," Dr. Hariharan explained.

No committee member had any relevant financial disclosures.

[email protected]

On Twitter @alz_gal

A three-component polypill designed to reduce cardiovascular risk could merit consideration for approval in the United States if it was determined to be both safe and effective, a Food and Drug Administration advisory committee has agreed.

Just what form that determination would take remains a big unknown, however.

No such pill exists in the United States. But at a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee, the committee members considered a hypothetical polypill that would include at least one antihypertensive, a statin, and aspirin. The members envisioned it to be used as a secondary prevention measure in patients who are both hyperlipidemic and hypertensive. Some committee members suggested that the indication should be restricted to high-risk patients, including those who have had a heart attack.

The strongest reason for such a pill would be to improve compliance in patients who are taking cardiovascular drugs but aren’t reaching their goals. A polypill could also be useful for patients who can’t or won’t comply with follow-up visits necessary for titrating blood pressure medications.

"The concept is very appealing, but the current body of evidence doesn’t appear to guarantee" that the benefits of such a pill would outweigh the benefits of the individual components, committee member Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, said at the meeting. "A key question to me is to make sure that there would not be pharmacokinetic or pharmacodynamics issues" in the combination that might affect the proven safety of each ingredient. "We are interested not just in improving outcomes, but in maintaining safety."

Many patients are already taking all of these individual drugs simultaneously, and no pharmaceutical company has brought a combination pill forward to the FDA. Some companies have told the agency, however, that they might create one if there were a good chance of approval.

Similar drugs are available in other countries – including India, where a large phase II trial showed that it resulted in significant reductions in blood pressure and lipids, compared with the individual components alone (Lancet 2009;373:1341-51).

A U.S. observational study of a similar concept found very encouraging results. The 2010 Kaiser Permanente ALL/PHASE protocol utilized a bundle of aspirin, lisinopril, and a statin, said Dr. James Dudl, an endocrinologist at Kaiser. More than 170,000 patients, 78% of whom had diabetes and 50% of whom had coronary artery disease, were followed for 3 years. Full data were available on 47,000. The patients were split into a high-exposure group, with a mean compliance of 68%, and a low-exposure group.

Cardiovascular events were reduced by 15/1,000 patients in the high-exposure group. The outcome was driven by stroke alone, with no benefit in heart attack. Since then, Kaiser has continued the bundle recommendation, which Dr. Dudl said costs about 25 cents per day.

The American Heart Association supports the concept of a polypill – with some caveats. "It might be aneffective way to improve adherence and reduce cardiovascular disease," Dr. Niteesh Choudhry of the AHA told the committee. "But we do have lingering concerns about the efficacy and safety of a combined agent. We believe more data are needed from a clinical trial of sufficient duration and power to identify clinically relevant outcomes – particularly blood pressure and LDL cholesterol – and safety, and to identify subgroups" that might particularly benefit from the pill, or who might experience some untoward effects of it. Postmarketing surveillance should be a requirement, added Dr. Choudhry, of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.

Although many patients are already taking all the components of a polypill simultaneously, many of the committee members believed strongly that safety and efficacy studies would be a requirement. Some thought those data could be gathered from existing studies conducted in the United States and other countries; others felt that a prospective, or even a randomized, study should be part of any approval request.

"I want to see an observational trial in a real-world setting," said Dr. Stuart Rich, professor of medicine at the University of Chicago. "A clinical trial is not a real-world setting, and what might be shown in a clinical trial won’t translate in terms of the most meaningful outcome: adherence. I would also ask that there be a measure of health care cost savings."

Dr. James DeLemos, professor of medicine at the University of Texas Southwestern, Dallas, disagreed. "It would be a mistake to demand outcomes studies that would be small, underpowered, and maybe give incorrect answers. The way to do this would be to license it and get it out there and evaluate it."

There would likely be very little up-front financial support for any studies, said FDA pharmacology adviser Sudharshan Hariharan, Ph.D. No pharmaceutical companies have volunteered, and they probably won’t, because there is very little money to be made from a medication consisting of three very inexpensive generic drugs. Any company that did market such a pill would have exclusivity for 3 years, after which the prospect of any profit virtually disappears.

"There is no commercial backing for this at all. Doing these trials would consist entirely of writing grants and pleading with friends to do them for next to nothing. Drug companies have said that if they thought something like this could make it through regulatory hurdles, then they might start to invest in creating it. But right now it’s a chicken-or-egg situation," Dr. Hariharan explained.

No committee member had any relevant financial disclosures.

[email protected]

On Twitter @alz_gal

After a delay of more than 3 years, the Food and Drug Administration has approved the nation’s third weight-loss drug, a combination of naltrexone and bupropion.

The extended release tablets (Contrave; Orexigen and Takeda) are approved for use in adults who have a body mass index of at least 30 kg/m², or those with a BMI of at least 27 kg/m² and at least one additional weight-related condition such as hypertension, type 2 diabetes, or dyslipidemia. The agency recommended that Contrave be used in addition to caloric restriction and increased physical activity.

Naseem Miller/Frontline Medical News

Dr. Timothy Garvey, chair of the American Association of Clinical Endocrinologists’ scientific committee, lauded the approval.

"We have a new tool now to treat obesity – and that is very good news," he said in an interview.

He said Contrave will be a valuable addition to the existing weight-loss medications: the phentermine/topiramate combo (Qsymia; Vivus) and lorcaserin (Belviq; Arena).

"There are no head-to-head trials with the other drugs, so we really can’t say much about relative efficacy," said Dr. Garvey. "But when you look at the placebo-subtracted weight loss in all the phase III data, it looks like Contrave is in the middle, with about a 6% loss over lifestyle interventions alone. So it’s not as effective as the topiramate combination, but more effective than lorcaserin."

In the pivotal, 56-week phase III trials, those taking Contrave lost 5%-8% of their baseline body weight, compared with a loss of 1%-2% in those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45%-56% of those on the proposed dose, compared with 16%-43% of those on placebo.

The FDA guidance on weight-loss drugs suggests a 12-week efficacy evaluation – if the patient has not lost at least 5% of total body weight by then, the drug should be discontinued and another started.

It’s not possible to predict who will respond best to which drug, although there are some things to consider when choosing, said Dr. Garvey, who is chair of the department of nutrition at the University of Alabama at Birmingham.

"For example, women of childbearing age need to take precautions against becoming pregnant if they take the topiramate combination, and should stop it right away if they do become pregnant. And since lorcaserin is a serotonergic drug, it has to be used very cautiously in patients who are on other serotonergic medications. We definitely need more safety data there."

Additionally, none of the weight-loss drugs should be used in children or teens until more studies confirm their safety for those patients, "All of the companies are planning these trials, and we hope they will complete them expeditiously," Dr. Garvey said. "Childhood and adolescent obesity is a huge problem, and we really need some good treatment options there."

Because it contains bupropion, an antidepressant that has been associated with an increased risk of suicidal thoughts and actions, the drug carries a black box warning. Bupropion is also known to lower seizure threshold, so the drug should not be used in patients with seizure disorders. If a seizure occurs while taking on the medication, it should be permanently discontinued. Nor should it be used in patients with uncontrolled hypertension.

Orexigen and Takeda originally brought the drug forward in December 2011. It was not approved at that time because of concerns about its effect on blood pressure – an unexpected move, and one that Orexigen management called "a big setback."

About a quarter of those in the 56-week pivotal phase III trial experienced significant blood pressure increases of at least 10% above their baseline, compared with about 20% of those in the control arm. Increases of diastolic blood pressure of at least 5 mm Hg over baseline occurred in 37% of those on the combination, compared with 29% of those on placebo. About a quarter in the active arm also had heart rate increases of at least 10 beats per minute, compared with 19% of those taking placebo.

Because of these concerns, the FDA required the drug companies to conduct a large, double-blinded, randomized, placebo-controlled trial to investigate the risk of major cardiovascular events. Takeda and Orexigen then launched the 4-year, 8,900 patient Light study, which is still ongoing. Endpoints are major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in overweight and obese subjects who have concomitant diabetes and/or other cardiovascular risk factors.

In June, citing encouraging preliminary results, Takeda and Orexigen brought Contrave to the FDA once more – only to be shot down again, at least temporarily. The agency required a review extension in order to come to agreement on the final form of postmarketing surveillance, said Denise Powell, a spokeswoman for Orexigen.

"At that time, FDA said the data looked good," she said in an interview. "We just needed more time to work out the postmarketing requirements."

Those will include:

• A cardiovascular outcomes trial to assess the cardiovascular risk associated with Contrave use.

• Two efficacy, safety, and clinical pharmacology studies in pediatric patients (one in patients 12-17 years old, and one in patients 7-11 years old).

• A juvenile animal toxicity study with a particular focus on growth and development as well as behavior, learning, and memory.

• A cardiac conduction study.

• Clinical trials to evaluate dosing in patients with hepatic or renal impairment.

• A clinical trial to evaluate the potential for interactions between the medication and other drugs.

Contrave contains an extended-release formulation of 8 mg naltrexone and 90 mg bupropion. It is to be administered in an in a 4-week upward titration schedule, with a single morning tablet during week 1; a single tablet at morning and evening during week 2; two tablets in the morning and one in the evening during week 3; and two tablets both morning and evening from week 4 and onward.

Dr. Garvey is a consultant for Daiichi Sankyo, LipoScience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, AstraZeneca, Weight Watchers, Eisai, and Sanofi.

[email protected]

On Twitter @alz_gal

After a delay of more than 3 years, the Food and Drug Administration has approved the nation’s third weight-loss drug, a combination of naltrexone and bupropion.

The extended release tablets (Contrave; Orexigen and Takeda) are approved for use in adults who have a body mass index of at least 30 kg/m², or those with a BMI of at least 27 kg/m² and at least one additional weight-related condition such as hypertension, type 2 diabetes, or dyslipidemia. The agency recommended that Contrave be used in addition to caloric restriction and increased physical activity.

Naseem Miller/Frontline Medical News

Dr. Timothy Garvey, chair of the American Association of Clinical Endocrinologists’ scientific committee, lauded the approval.

"We have a new tool now to treat obesity – and that is very good news," he said in an interview.

He said Contrave will be a valuable addition to the existing weight-loss medications: the phentermine/topiramate combo (Qsymia; Vivus) and lorcaserin (Belviq; Arena).

"There are no head-to-head trials with the other drugs, so we really can’t say much about relative efficacy," said Dr. Garvey. "But when you look at the placebo-subtracted weight loss in all the phase III data, it looks like Contrave is in the middle, with about a 6% loss over lifestyle interventions alone. So it’s not as effective as the topiramate combination, but more effective than lorcaserin."

In the pivotal, 56-week phase III trials, those taking Contrave lost 5%-8% of their baseline body weight, compared with a loss of 1%-2% in those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45%-56% of those on the proposed dose, compared with 16%-43% of those on placebo.

The FDA guidance on weight-loss drugs suggests a 12-week efficacy evaluation – if the patient has not lost at least 5% of total body weight by then, the drug should be discontinued and another started.

It’s not possible to predict who will respond best to which drug, although there are some things to consider when choosing, said Dr. Garvey, who is chair of the department of nutrition at the University of Alabama at Birmingham.

"For example, women of childbearing age need to take precautions against becoming pregnant if they take the topiramate combination, and should stop it right away if they do become pregnant. And since lorcaserin is a serotonergic drug, it has to be used very cautiously in patients who are on other serotonergic medications. We definitely need more safety data there."

Additionally, none of the weight-loss drugs should be used in children or teens until more studies confirm their safety for those patients, "All of the companies are planning these trials, and we hope they will complete them expeditiously," Dr. Garvey said. "Childhood and adolescent obesity is a huge problem, and we really need some good treatment options there."

Because it contains bupropion, an antidepressant that has been associated with an increased risk of suicidal thoughts and actions, the drug carries a black box warning. Bupropion is also known to lower seizure threshold, so the drug should not be used in patients with seizure disorders. If a seizure occurs while taking on the medication, it should be permanently discontinued. Nor should it be used in patients with uncontrolled hypertension.

Orexigen and Takeda originally brought the drug forward in December 2011. It was not approved at that time because of concerns about its effect on blood pressure – an unexpected move, and one that Orexigen management called "a big setback."

About a quarter of those in the 56-week pivotal phase III trial experienced significant blood pressure increases of at least 10% above their baseline, compared with about 20% of those in the control arm. Increases of diastolic blood pressure of at least 5 mm Hg over baseline occurred in 37% of those on the combination, compared with 29% of those on placebo. About a quarter in the active arm also had heart rate increases of at least 10 beats per minute, compared with 19% of those taking placebo.

Because of these concerns, the FDA required the drug companies to conduct a large, double-blinded, randomized, placebo-controlled trial to investigate the risk of major cardiovascular events. Takeda and Orexigen then launched the 4-year, 8,900 patient Light study, which is still ongoing. Endpoints are major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in overweight and obese subjects who have concomitant diabetes and/or other cardiovascular risk factors.

In June, citing encouraging preliminary results, Takeda and Orexigen brought Contrave to the FDA once more – only to be shot down again, at least temporarily. The agency required a review extension in order to come to agreement on the final form of postmarketing surveillance, said Denise Powell, a spokeswoman for Orexigen.

"At that time, FDA said the data looked good," she said in an interview. "We just needed more time to work out the postmarketing requirements."

Those will include:

• A cardiovascular outcomes trial to assess the cardiovascular risk associated with Contrave use.

• Two efficacy, safety, and clinical pharmacology studies in pediatric patients (one in patients 12-17 years old, and one in patients 7-11 years old).

• A juvenile animal toxicity study with a particular focus on growth and development as well as behavior, learning, and memory.

• A cardiac conduction study.

• Clinical trials to evaluate dosing in patients with hepatic or renal impairment.

• A clinical trial to evaluate the potential for interactions between the medication and other drugs.

Contrave contains an extended-release formulation of 8 mg naltrexone and 90 mg bupropion. It is to be administered in an in a 4-week upward titration schedule, with a single morning tablet during week 1; a single tablet at morning and evening during week 2; two tablets in the morning and one in the evening during week 3; and two tablets both morning and evening from week 4 and onward.

Dr. Garvey is a consultant for Daiichi Sankyo, LipoScience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, AstraZeneca, Weight Watchers, Eisai, and Sanofi.

[email protected]

On Twitter @alz_gal

After a delay of more than 3 years, the Food and Drug Administration has approved the nation’s third weight-loss drug, a combination of naltrexone and bupropion.

The extended release tablets (Contrave; Orexigen and Takeda) are approved for use in adults who have a body mass index of at least 30 kg/m², or those with a BMI of at least 27 kg/m² and at least one additional weight-related condition such as hypertension, type 2 diabetes, or dyslipidemia. The agency recommended that Contrave be used in addition to caloric restriction and increased physical activity.

Naseem Miller/Frontline Medical News

Dr. Timothy Garvey, chair of the American Association of Clinical Endocrinologists’ scientific committee, lauded the approval.

"We have a new tool now to treat obesity – and that is very good news," he said in an interview.

He said Contrave will be a valuable addition to the existing weight-loss medications: the phentermine/topiramate combo (Qsymia; Vivus) and lorcaserin (Belviq; Arena).

"There are no head-to-head trials with the other drugs, so we really can’t say much about relative efficacy," said Dr. Garvey. "But when you look at the placebo-subtracted weight loss in all the phase III data, it looks like Contrave is in the middle, with about a 6% loss over lifestyle interventions alone. So it’s not as effective as the topiramate combination, but more effective than lorcaserin."

In the pivotal, 56-week phase III trials, those taking Contrave lost 5%-8% of their baseline body weight, compared with a loss of 1%-2% in those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45%-56% of those on the proposed dose, compared with 16%-43% of those on placebo.

The FDA guidance on weight-loss drugs suggests a 12-week efficacy evaluation – if the patient has not lost at least 5% of total body weight by then, the drug should be discontinued and another started.

It’s not possible to predict who will respond best to which drug, although there are some things to consider when choosing, said Dr. Garvey, who is chair of the department of nutrition at the University of Alabama at Birmingham.

"For example, women of childbearing age need to take precautions against becoming pregnant if they take the topiramate combination, and should stop it right away if they do become pregnant. And since lorcaserin is a serotonergic drug, it has to be used very cautiously in patients who are on other serotonergic medications. We definitely need more safety data there."

Additionally, none of the weight-loss drugs should be used in children or teens until more studies confirm their safety for those patients, "All of the companies are planning these trials, and we hope they will complete them expeditiously," Dr. Garvey said. "Childhood and adolescent obesity is a huge problem, and we really need some good treatment options there."

Because it contains bupropion, an antidepressant that has been associated with an increased risk of suicidal thoughts and actions, the drug carries a black box warning. Bupropion is also known to lower seizure threshold, so the drug should not be used in patients with seizure disorders. If a seizure occurs while taking on the medication, it should be permanently discontinued. Nor should it be used in patients with uncontrolled hypertension.

Orexigen and Takeda originally brought the drug forward in December 2011. It was not approved at that time because of concerns about its effect on blood pressure – an unexpected move, and one that Orexigen management called "a big setback."

About a quarter of those in the 56-week pivotal phase III trial experienced significant blood pressure increases of at least 10% above their baseline, compared with about 20% of those in the control arm. Increases of diastolic blood pressure of at least 5 mm Hg over baseline occurred in 37% of those on the combination, compared with 29% of those on placebo. About a quarter in the active arm also had heart rate increases of at least 10 beats per minute, compared with 19% of those taking placebo.

Because of these concerns, the FDA required the drug companies to conduct a large, double-blinded, randomized, placebo-controlled trial to investigate the risk of major cardiovascular events. Takeda and Orexigen then launched the 4-year, 8,900 patient Light study, which is still ongoing. Endpoints are major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in overweight and obese subjects who have concomitant diabetes and/or other cardiovascular risk factors.

In June, citing encouraging preliminary results, Takeda and Orexigen brought Contrave to the FDA once more – only to be shot down again, at least temporarily. The agency required a review extension in order to come to agreement on the final form of postmarketing surveillance, said Denise Powell, a spokeswoman for Orexigen.

"At that time, FDA said the data looked good," she said in an interview. "We just needed more time to work out the postmarketing requirements."

Those will include:

• A cardiovascular outcomes trial to assess the cardiovascular risk associated with Contrave use.

• Two efficacy, safety, and clinical pharmacology studies in pediatric patients (one in patients 12-17 years old, and one in patients 7-11 years old).

• A juvenile animal toxicity study with a particular focus on growth and development as well as behavior, learning, and memory.

• A cardiac conduction study.

• Clinical trials to evaluate dosing in patients with hepatic or renal impairment.

• A clinical trial to evaluate the potential for interactions between the medication and other drugs.

Contrave contains an extended-release formulation of 8 mg naltrexone and 90 mg bupropion. It is to be administered in an in a 4-week upward titration schedule, with a single morning tablet during week 1; a single tablet at morning and evening during week 2; two tablets in the morning and one in the evening during week 3; and two tablets both morning and evening from week 4 and onward.

Dr. Garvey is a consultant for Daiichi Sankyo, LipoScience, Takeda, Vivus, Boehringer Ingelheim, Janssen, Eisai, and Novo Nordisk. He has received research funding from Merck, AstraZeneca, Weight Watchers, Eisai, and Sanofi.

[email protected]

On Twitter @alz_gal

A Food and Drug Administration advisory committee has withheld its recommendation of approval for a fixed-dose combination hypertension drug, saying that it offered no significant benefits over its individual components.

The Cardiovascular and Renal Drugs Advisory Committee voted 6-4 against recommending the drug, a combination of nebivolol 20 mg and valsartan 320 mg.

In a large, well-powered study, the combination lowered systolic blood pressure by a mean of 17 mm Hg, and diastolic BP by 12.5 mm Hg, for a mean benefit of 1.2 mm Hg diastolic and 2.9 mm Hg systolic over nebivolol 40 mg alone. But while the systolic endpoint was statistically significant, neither it nor the diastolic endpoint were clinically meaningful, the committee said.

About 5% more of those who took the combination than those who took nebivolol alone achieved the target systolic goals of 140 and 130 mm Hg – another nonsignificant finding.

In discussing their decisions, several committee members said that approving a minimally effective combination antihypertensive available could be counterproductive.

"Approving a drug with this small effect could lead to physicians choosing this over other combinations that work better," extending even further the time it takes patients to reach blood pressure goals, said Dr. James DeLemos, professor of medicine at the University of Texas Southwestern, Dallas. "We don’t need more combinations. We need fewer, which offer clear advantages over their individual components."

The pivotal 8-week, double-blind efficacy trial randomized 4,161 patients to five doses of the combination of nebivolol and valsartan or to the highest approved doses of the individual components, following a 4- to 6-week single-blind, placebo run-in phase. Forest Laboratories brought the 20/320 fixed dose forward to the FDA. The primary comparator was nebivolol 40 mg; the primary endpoint was change in diastolic blood pressure.

The comparison was a sticking point from the beginning, however, as committee members pointed out that nebivolol 40 mg is not an approved dose in the United States, and the likelihood of a clinician prescribing two 20-mg tablets is small. Forest considered using the 20-mg dose as the primary comparator, but went with 40 mg because FDA regulatory standards require using the highest available dose.

Dr. Stuart Rich said the comparison was unfortunate.

"We were asked to make a judgment on a combination compared to a monotherapy that isn’t even available. My sense is it works better than valsartan alone and better than the lower dose of nebivolol alone, but we’re left with this hypothetical comparison. If we had clear-cut data for the 20-mg nebivolol, the decision would be easier," said Dr. Rich, professor of medicine at the University of Chicago.

The combination was safe, with a very low rate of serious adverse events (0.2%). There were significantly fewer adverse events leading to discontinuation in the combination group than in the nebivolol-alone group (1.6% vs. 4%). These were driven by bradycardia, which occurred in three patients taking the combination (0.5%) and eight taking only nebivolol (1.3%).

However, all of the bradycardia cases were asymptomatic, a finding that led the committee chairman reviewer to question the events’ clinical significance.

"They have not provided any compelling evidence that these were clinically important events," said Dr. Michael Lincoff of the Cleveland Clinic. "It was an artificial measurement that didn’t demonstrate better tolerability of the combination."

Members of the committee had no financial disclosures.

[email protected]

A Food and Drug Administration advisory committee has withheld its recommendation of approval for a fixed-dose combination hypertension drug, saying that it offered no significant benefits over its individual components.

The Cardiovascular and Renal Drugs Advisory Committee voted 6-4 against recommending the drug, a combination of nebivolol 20 mg and valsartan 320 mg.

In a large, well-powered study, the combination lowered systolic blood pressure by a mean of 17 mm Hg, and diastolic BP by 12.5 mm Hg, for a mean benefit of 1.2 mm Hg diastolic and 2.9 mm Hg systolic over nebivolol 40 mg alone. But while the systolic endpoint was statistically significant, neither it nor the diastolic endpoint were clinically meaningful, the committee said.

About 5% more of those who took the combination than those who took nebivolol alone achieved the target systolic goals of 140 and 130 mm Hg – another nonsignificant finding.

In discussing their decisions, several committee members said that approving a minimally effective combination antihypertensive available could be counterproductive.

"Approving a drug with this small effect could lead to physicians choosing this over other combinations that work better," extending even further the time it takes patients to reach blood pressure goals, said Dr. James DeLemos, professor of medicine at the University of Texas Southwestern, Dallas. "We don’t need more combinations. We need fewer, which offer clear advantages over their individual components."

The pivotal 8-week, double-blind efficacy trial randomized 4,161 patients to five doses of the combination of nebivolol and valsartan or to the highest approved doses of the individual components, following a 4- to 6-week single-blind, placebo run-in phase. Forest Laboratories brought the 20/320 fixed dose forward to the FDA. The primary comparator was nebivolol 40 mg; the primary endpoint was change in diastolic blood pressure.

The comparison was a sticking point from the beginning, however, as committee members pointed out that nebivolol 40 mg is not an approved dose in the United States, and the likelihood of a clinician prescribing two 20-mg tablets is small. Forest considered using the 20-mg dose as the primary comparator, but went with 40 mg because FDA regulatory standards require using the highest available dose.

Dr. Stuart Rich said the comparison was unfortunate.

"We were asked to make a judgment on a combination compared to a monotherapy that isn’t even available. My sense is it works better than valsartan alone and better than the lower dose of nebivolol alone, but we’re left with this hypothetical comparison. If we had clear-cut data for the 20-mg nebivolol, the decision would be easier," said Dr. Rich, professor of medicine at the University of Chicago.

The combination was safe, with a very low rate of serious adverse events (0.2%). There were significantly fewer adverse events leading to discontinuation in the combination group than in the nebivolol-alone group (1.6% vs. 4%). These were driven by bradycardia, which occurred in three patients taking the combination (0.5%) and eight taking only nebivolol (1.3%).

However, all of the bradycardia cases were asymptomatic, a finding that led the committee chairman reviewer to question the events’ clinical significance.

"They have not provided any compelling evidence that these were clinically important events," said Dr. Michael Lincoff of the Cleveland Clinic. "It was an artificial measurement that didn’t demonstrate better tolerability of the combination."

Members of the committee had no financial disclosures.

[email protected]

A Food and Drug Administration advisory committee has withheld its recommendation of approval for a fixed-dose combination hypertension drug, saying that it offered no significant benefits over its individual components.

The Cardiovascular and Renal Drugs Advisory Committee voted 6-4 against recommending the drug, a combination of nebivolol 20 mg and valsartan 320 mg.

In a large, well-powered study, the combination lowered systolic blood pressure by a mean of 17 mm Hg, and diastolic BP by 12.5 mm Hg, for a mean benefit of 1.2 mm Hg diastolic and 2.9 mm Hg systolic over nebivolol 40 mg alone. But while the systolic endpoint was statistically significant, neither it nor the diastolic endpoint were clinically meaningful, the committee said.

About 5% more of those who took the combination than those who took nebivolol alone achieved the target systolic goals of 140 and 130 mm Hg – another nonsignificant finding.

In discussing their decisions, several committee members said that approving a minimally effective combination antihypertensive available could be counterproductive.

"Approving a drug with this small effect could lead to physicians choosing this over other combinations that work better," extending even further the time it takes patients to reach blood pressure goals, said Dr. James DeLemos, professor of medicine at the University of Texas Southwestern, Dallas. "We don’t need more combinations. We need fewer, which offer clear advantages over their individual components."

The pivotal 8-week, double-blind efficacy trial randomized 4,161 patients to five doses of the combination of nebivolol and valsartan or to the highest approved doses of the individual components, following a 4- to 6-week single-blind, placebo run-in phase. Forest Laboratories brought the 20/320 fixed dose forward to the FDA. The primary comparator was nebivolol 40 mg; the primary endpoint was change in diastolic blood pressure.

The comparison was a sticking point from the beginning, however, as committee members pointed out that nebivolol 40 mg is not an approved dose in the United States, and the likelihood of a clinician prescribing two 20-mg tablets is small. Forest considered using the 20-mg dose as the primary comparator, but went with 40 mg because FDA regulatory standards require using the highest available dose.

Dr. Stuart Rich said the comparison was unfortunate.

"We were asked to make a judgment on a combination compared to a monotherapy that isn’t even available. My sense is it works better than valsartan alone and better than the lower dose of nebivolol alone, but we’re left with this hypothetical comparison. If we had clear-cut data for the 20-mg nebivolol, the decision would be easier," said Dr. Rich, professor of medicine at the University of Chicago.

The combination was safe, with a very low rate of serious adverse events (0.2%). There were significantly fewer adverse events leading to discontinuation in the combination group than in the nebivolol-alone group (1.6% vs. 4%). These were driven by bradycardia, which occurred in three patients taking the combination (0.5%) and eight taking only nebivolol (1.3%).

However, all of the bradycardia cases were asymptomatic, a finding that led the committee chairman reviewer to question the events’ clinical significance.

"They have not provided any compelling evidence that these were clinically important events," said Dr. Michael Lincoff of the Cleveland Clinic. "It was an artificial measurement that didn’t demonstrate better tolerability of the combination."

Members of the committee had no financial disclosures.

[email protected]

Two simple recommendations for older patients with asthma – keeping medication in the bathroom and integrating its use into a daily routine – can significantly improve adherence to inhaled corticosteroids.

When patients consistently did either of those, adherence rose threefold, compared with patients who didn’t, Dr. Alex Federman and his associates wrote in the August issue of the Journal of Internal Medicine.

©CandyBoxImages/thinkstockphotos.com

The findings suggest that clinicians might help improve adherence by suggesting that their patients store the medication in their bathroom cabinet, and take it, for example, when they brush their teeth every day.

"Because adherence strategies are modifiable, the findings in this study may provide clinicians and care coaches with straightforward and useful messages to help older patients improve their medication adherence," wrote Dr. Federman of Icahn School of Medicine at Mount Sinai, New York, and his coauthors (J. Intern. Med. 2014 Aug. 5 [doi:10.1007/s11606-014-2940-8]).

The team investigated adherence to inhaled corticosteroids among 358 elderly patients with asthma. They were a mean of 67 years old, with 31% older than 70 years. Most (84%) were women and many were Latino (38%). Black patients comprised 31% of the cohort and the others were non-Hispanic whites.

The majority had a low monthly income ($1,350 or less), and 25% were not fully literate in English. Many had comorbid psychological conditions, including depression (20%) and anxiety (21%).

Low health literacy was common (34%), although most (71%) did understand that they would always have asthma and that it could not be cured (81%). But half believed that they had the disease only when they were symptomatic. In a survey of medication beliefs, most did believe that the steroids were good for them and that their benefits outweighed the risks.

However, only 37% of the cohort reported good medication adherence. This proportion was significantly worse among blacks and Hispanics; those with lower incomes and lower education; those born in Puerto Rico and the Dominican Republic; and those with poor physical health, anxiety, or depression.

The authors identified six medication adherence strategies among the group: keeping the medication in a usual location (44%); integrating it into their daily routine (33%); taking it at a specific time of day (22%); taking it with other medications (13%); using it only when needed; (13%) and using other reminders (12%). Less than 2% reported using written notes as a reminder or having someone else remind them; 4% had no specific strategy.

The most common places to keep medicine were at the bedside (20%) and in the bathroom (9%). Those who integrated taking it with other daily routines did in the morning (12%) and at bedtime (8%).

Only three of the strategies were significantly associated with good adherence: keeping medication in the bathroom (16% adherent vs. 5% nonadherent); integrating it into a daily routine (morning 25% vs. 5%; evening 13% vs. 6%); and taking it at a specific time of day (29% vs. 17%).

Taking the medication only when needed was associated with significantly worse adherence.

After controlling for other variables, only leaving the medication in the bathroom significantly predicted good adherence (odds ratio, 3), compared with those who kept it somewhere else).

Those who integrated medication into other daily routines were also significantly more likely to be adherent (OR, 3.7) in a partially adjusted model, but not in a fully adjusted model. Still, the authors noted, this recommendation would be a good suggestion toward improving adherence.

Patients who used these two strategies were more likely to be white, have at least a partial education, and to have been born in the United States. Low income, limited English proficiency, low health literacy, poor physical and psychological health, and erroneous beliefs about asthma predicted poor adherence.

The team postulated that there are two types of nonadherence: simple forgetfulness or lack of understanding about its importance and deliberate nonadherence.

"The bathroom and daily routine strategies may address forgetful nonadherence. ... Taking the medication only as needed, on the other hand, may indicate faulty disease or medication beliefs. ... Taken together, these findings provide further evidence of the value of patient-centered care: Clinicians need to understand why patients do not use their medications appropriately before counseling patients on ways to improve adherence."

The study was supported by a grant from the National Heart, Lung, and Blood Institute. None of the authors had any financial disclosures.

[email protected]

Two simple recommendations for older patients with asthma – keeping medication in the bathroom and integrating its use into a daily routine – can significantly improve adherence to inhaled corticosteroids.

When patients consistently did either of those, adherence rose threefold, compared with patients who didn’t, Dr. Alex Federman and his associates wrote in the August issue of the Journal of Internal Medicine.

©CandyBoxImages/thinkstockphotos.com

The findings suggest that clinicians might help improve adherence by suggesting that their patients store the medication in their bathroom cabinet, and take it, for example, when they brush their teeth every day.

"Because adherence strategies are modifiable, the findings in this study may provide clinicians and care coaches with straightforward and useful messages to help older patients improve their medication adherence," wrote Dr. Federman of Icahn School of Medicine at Mount Sinai, New York, and his coauthors (J. Intern. Med. 2014 Aug. 5 [doi:10.1007/s11606-014-2940-8]).

The team investigated adherence to inhaled corticosteroids among 358 elderly patients with asthma. They were a mean of 67 years old, with 31% older than 70 years. Most (84%) were women and many were Latino (38%). Black patients comprised 31% of the cohort and the others were non-Hispanic whites.

The majority had a low monthly income ($1,350 or less), and 25% were not fully literate in English. Many had comorbid psychological conditions, including depression (20%) and anxiety (21%).

Low health literacy was common (34%), although most (71%) did understand that they would always have asthma and that it could not be cured (81%). But half believed that they had the disease only when they were symptomatic. In a survey of medication beliefs, most did believe that the steroids were good for them and that their benefits outweighed the risks.

However, only 37% of the cohort reported good medication adherence. This proportion was significantly worse among blacks and Hispanics; those with lower incomes and lower education; those born in Puerto Rico and the Dominican Republic; and those with poor physical health, anxiety, or depression.

The authors identified six medication adherence strategies among the group: keeping the medication in a usual location (44%); integrating it into their daily routine (33%); taking it at a specific time of day (22%); taking it with other medications (13%); using it only when needed; (13%) and using other reminders (12%). Less than 2% reported using written notes as a reminder or having someone else remind them; 4% had no specific strategy.

The most common places to keep medicine were at the bedside (20%) and in the bathroom (9%). Those who integrated taking it with other daily routines did in the morning (12%) and at bedtime (8%).

Only three of the strategies were significantly associated with good adherence: keeping medication in the bathroom (16% adherent vs. 5% nonadherent); integrating it into a daily routine (morning 25% vs. 5%; evening 13% vs. 6%); and taking it at a specific time of day (29% vs. 17%).

Taking the medication only when needed was associated with significantly worse adherence.

After controlling for other variables, only leaving the medication in the bathroom significantly predicted good adherence (odds ratio, 3), compared with those who kept it somewhere else).

Those who integrated medication into other daily routines were also significantly more likely to be adherent (OR, 3.7) in a partially adjusted model, but not in a fully adjusted model. Still, the authors noted, this recommendation would be a good suggestion toward improving adherence.

Patients who used these two strategies were more likely to be white, have at least a partial education, and to have been born in the United States. Low income, limited English proficiency, low health literacy, poor physical and psychological health, and erroneous beliefs about asthma predicted poor adherence.

The team postulated that there are two types of nonadherence: simple forgetfulness or lack of understanding about its importance and deliberate nonadherence.

"The bathroom and daily routine strategies may address forgetful nonadherence. ... Taking the medication only as needed, on the other hand, may indicate faulty disease or medication beliefs. ... Taken together, these findings provide further evidence of the value of patient-centered care: Clinicians need to understand why patients do not use their medications appropriately before counseling patients on ways to improve adherence."

The study was supported by a grant from the National Heart, Lung, and Blood Institute. None of the authors had any financial disclosures.

[email protected]

Two simple recommendations for older patients with asthma – keeping medication in the bathroom and integrating its use into a daily routine – can significantly improve adherence to inhaled corticosteroids.

When patients consistently did either of those, adherence rose threefold, compared with patients who didn’t, Dr. Alex Federman and his associates wrote in the August issue of the Journal of Internal Medicine.

©CandyBoxImages/thinkstockphotos.com

The findings suggest that clinicians might help improve adherence by suggesting that their patients store the medication in their bathroom cabinet, and take it, for example, when they brush their teeth every day.

"Because adherence strategies are modifiable, the findings in this study may provide clinicians and care coaches with straightforward and useful messages to help older patients improve their medication adherence," wrote Dr. Federman of Icahn School of Medicine at Mount Sinai, New York, and his coauthors (J. Intern. Med. 2014 Aug. 5 [doi:10.1007/s11606-014-2940-8]).

The team investigated adherence to inhaled corticosteroids among 358 elderly patients with asthma. They were a mean of 67 years old, with 31% older than 70 years. Most (84%) were women and many were Latino (38%). Black patients comprised 31% of the cohort and the others were non-Hispanic whites.

The majority had a low monthly income ($1,350 or less), and 25% were not fully literate in English. Many had comorbid psychological conditions, including depression (20%) and anxiety (21%).

Low health literacy was common (34%), although most (71%) did understand that they would always have asthma and that it could not be cured (81%). But half believed that they had the disease only when they were symptomatic. In a survey of medication beliefs, most did believe that the steroids were good for them and that their benefits outweighed the risks.

However, only 37% of the cohort reported good medication adherence. This proportion was significantly worse among blacks and Hispanics; those with lower incomes and lower education; those born in Puerto Rico and the Dominican Republic; and those with poor physical health, anxiety, or depression.

The authors identified six medication adherence strategies among the group: keeping the medication in a usual location (44%); integrating it into their daily routine (33%); taking it at a specific time of day (22%); taking it with other medications (13%); using it only when needed; (13%) and using other reminders (12%). Less than 2% reported using written notes as a reminder or having someone else remind them; 4% had no specific strategy.

The most common places to keep medicine were at the bedside (20%) and in the bathroom (9%). Those who integrated taking it with other daily routines did in the morning (12%) and at bedtime (8%).

Only three of the strategies were significantly associated with good adherence: keeping medication in the bathroom (16% adherent vs. 5% nonadherent); integrating it into a daily routine (morning 25% vs. 5%; evening 13% vs. 6%); and taking it at a specific time of day (29% vs. 17%).

Taking the medication only when needed was associated with significantly worse adherence.

After controlling for other variables, only leaving the medication in the bathroom significantly predicted good adherence (odds ratio, 3), compared with those who kept it somewhere else).

Those who integrated medication into other daily routines were also significantly more likely to be adherent (OR, 3.7) in a partially adjusted model, but not in a fully adjusted model. Still, the authors noted, this recommendation would be a good suggestion toward improving adherence.

Patients who used these two strategies were more likely to be white, have at least a partial education, and to have been born in the United States. Low income, limited English proficiency, low health literacy, poor physical and psychological health, and erroneous beliefs about asthma predicted poor adherence.

The team postulated that there are two types of nonadherence: simple forgetfulness or lack of understanding about its importance and deliberate nonadherence.

"The bathroom and daily routine strategies may address forgetful nonadherence. ... Taking the medication only as needed, on the other hand, may indicate faulty disease or medication beliefs. ... Taken together, these findings provide further evidence of the value of patient-centered care: Clinicians need to understand why patients do not use their medications appropriately before counseling patients on ways to improve adherence."

The study was supported by a grant from the National Heart, Lung, and Blood Institute. None of the authors had any financial disclosures.

[email protected]

Coronary artery disease may develop at a younger age in patients with inflammatory bowel disease, even when they have fewer traditional risk factors for heart problems.

A database review of patients with CAD has determined that those with IBD were significantly younger, less heavy, and less likely to smoke than matched controls, Dr. Ashish Aggarwal and his colleagues reported in the August issue of Inflammatory Bowel Diseases (Inflamm. Bowel Dis. 2014;20:1593-601).

"These findings support the theory that traditional risk factors may not be sufficient to predict the risk of coronary artery disease in patients with IBD, and that inflammation may play a key role in the pathogenesis of atherosclerosis," wrote Dr. Aggarwal of the Cleveland Clinic and his coauthors.

The team reviewed both CAD risk factors and the outcomes of percutaneous interventions in a group of 655 patients with CAD: 131 of these had an IBD, including 54 with Crohn’s and 77 with ulcerative colitis.

The most common phenotypes among those with Crohn’s were ileocolonic disease location (39%) and nonstricturing, nonpenetrating disease (48%). Among patients with ulcerative colitis, half had extensive or pancolitis. About two-thirds of those with IBD had taken steroids at some point.

Patients with IBD were significantly younger than the control patients (65 vs. 68 years). They were also less likely to be smokers (11% vs. 19%), and had a lower mean body mass index (28 vs. 29.4 kg/m²).

However, there were no significant between-group differences in hypertension, diabetes, or hyperlipidemia. Platelet counts were similar, as were C-reactive protein levels.

The mean Framingham risk scores were 7.3 for those with IBD and 7.7 for those without – not a significant difference.

Despite their similarities in Framingham risk, the IBD patients were significantly less likely to have severe left anterior descending (LAD) disease (56% vs. 73%). They were also less likely – though not significantly so – to have multivessel disease (71% vs. 79%) and had fewer involved vessels (two vs. three).

Percutaneous coronary intervention was necessary for 28% of those with IBD and 35% of those without. Again, IBD patients were younger, had lower BMI, and were less often smokers.

The overall PCI success rate was similar, but patients with IBD were half as likely to have a major cardiac adverse event (13% vs. 24%) or die during follow-up (6.5% vs. 13.4%) – although again, these differences did not reach significance (P = .28).

Two patients with IBD and 16 without needed a repeat revascularization. IBD exercised no significant increase in the risk of any post-PCI major cardiovascular outcome.

The authors suggested that anti-inflammatory drugs based on salicylic acid compounds may offer IBD patients some cardioprotection – an idea supported by a large Danish cohort study (PLoS One 2013;8:e56944). It concluded that CAD incidence was significantly lower among those who took salicylic-based medications (relative risks, 1.16 vs. 1.36).

"Furthermore, patients with IBD were less likely to be active smokers or obese as found in our study, which again could lower the risk for future cardiovascular events," they added.

The authors had no financial disclosures; the study sponsor was not indicated.

[email protected]

Coronary artery disease may develop at a younger age in patients with inflammatory bowel disease, even when they have fewer traditional risk factors for heart problems.

A database review of patients with CAD has determined that those with IBD were significantly younger, less heavy, and less likely to smoke than matched controls, Dr. Ashish Aggarwal and his colleagues reported in the August issue of Inflammatory Bowel Diseases (Inflamm. Bowel Dis. 2014;20:1593-601).

"These findings support the theory that traditional risk factors may not be sufficient to predict the risk of coronary artery disease in patients with IBD, and that inflammation may play a key role in the pathogenesis of atherosclerosis," wrote Dr. Aggarwal of the Cleveland Clinic and his coauthors.

The team reviewed both CAD risk factors and the outcomes of percutaneous interventions in a group of 655 patients with CAD: 131 of these had an IBD, including 54 with Crohn’s and 77 with ulcerative colitis.

The most common phenotypes among those with Crohn’s were ileocolonic disease location (39%) and nonstricturing, nonpenetrating disease (48%). Among patients with ulcerative colitis, half had extensive or pancolitis. About two-thirds of those with IBD had taken steroids at some point.

Patients with IBD were significantly younger than the control patients (65 vs. 68 years). They were also less likely to be smokers (11% vs. 19%), and had a lower mean body mass index (28 vs. 29.4 kg/m²).

However, there were no significant between-group differences in hypertension, diabetes, or hyperlipidemia. Platelet counts were similar, as were C-reactive protein levels.

The mean Framingham risk scores were 7.3 for those with IBD and 7.7 for those without – not a significant difference.

Despite their similarities in Framingham risk, the IBD patients were significantly less likely to have severe left anterior descending (LAD) disease (56% vs. 73%). They were also less likely – though not significantly so – to have multivessel disease (71% vs. 79%) and had fewer involved vessels (two vs. three).

Percutaneous coronary intervention was necessary for 28% of those with IBD and 35% of those without. Again, IBD patients were younger, had lower BMI, and were less often smokers.

The overall PCI success rate was similar, but patients with IBD were half as likely to have a major cardiac adverse event (13% vs. 24%) or die during follow-up (6.5% vs. 13.4%) – although again, these differences did not reach significance (P = .28).

Two patients with IBD and 16 without needed a repeat revascularization. IBD exercised no significant increase in the risk of any post-PCI major cardiovascular outcome.

The authors suggested that anti-inflammatory drugs based on salicylic acid compounds may offer IBD patients some cardioprotection – an idea supported by a large Danish cohort study (PLoS One 2013;8:e56944). It concluded that CAD incidence was significantly lower among those who took salicylic-based medications (relative risks, 1.16 vs. 1.36).

"Furthermore, patients with IBD were less likely to be active smokers or obese as found in our study, which again could lower the risk for future cardiovascular events," they added.

The authors had no financial disclosures; the study sponsor was not indicated.

[email protected]

Coronary artery disease may develop at a younger age in patients with inflammatory bowel disease, even when they have fewer traditional risk factors for heart problems.

A database review of patients with CAD has determined that those with IBD were significantly younger, less heavy, and less likely to smoke than matched controls, Dr. Ashish Aggarwal and his colleagues reported in the August issue of Inflammatory Bowel Diseases (Inflamm. Bowel Dis. 2014;20:1593-601).

"These findings support the theory that traditional risk factors may not be sufficient to predict the risk of coronary artery disease in patients with IBD, and that inflammation may play a key role in the pathogenesis of atherosclerosis," wrote Dr. Aggarwal of the Cleveland Clinic and his coauthors.

The team reviewed both CAD risk factors and the outcomes of percutaneous interventions in a group of 655 patients with CAD: 131 of these had an IBD, including 54 with Crohn’s and 77 with ulcerative colitis.

The most common phenotypes among those with Crohn’s were ileocolonic disease location (39%) and nonstricturing, nonpenetrating disease (48%). Among patients with ulcerative colitis, half had extensive or pancolitis. About two-thirds of those with IBD had taken steroids at some point.

Patients with IBD were significantly younger than the control patients (65 vs. 68 years). They were also less likely to be smokers (11% vs. 19%), and had a lower mean body mass index (28 vs. 29.4 kg/m²).

However, there were no significant between-group differences in hypertension, diabetes, or hyperlipidemia. Platelet counts were similar, as were C-reactive protein levels.

The mean Framingham risk scores were 7.3 for those with IBD and 7.7 for those without – not a significant difference.

Despite their similarities in Framingham risk, the IBD patients were significantly less likely to have severe left anterior descending (LAD) disease (56% vs. 73%). They were also less likely – though not significantly so – to have multivessel disease (71% vs. 79%) and had fewer involved vessels (two vs. three).

Percutaneous coronary intervention was necessary for 28% of those with IBD and 35% of those without. Again, IBD patients were younger, had lower BMI, and were less often smokers.

The overall PCI success rate was similar, but patients with IBD were half as likely to have a major cardiac adverse event (13% vs. 24%) or die during follow-up (6.5% vs. 13.4%) – although again, these differences did not reach significance (P = .28).

Two patients with IBD and 16 without needed a repeat revascularization. IBD exercised no significant increase in the risk of any post-PCI major cardiovascular outcome.

The authors suggested that anti-inflammatory drugs based on salicylic acid compounds may offer IBD patients some cardioprotection – an idea supported by a large Danish cohort study (PLoS One 2013;8:e56944). It concluded that CAD incidence was significantly lower among those who took salicylic-based medications (relative risks, 1.16 vs. 1.36).

"Furthermore, patients with IBD were less likely to be active smokers or obese as found in our study, which again could lower the risk for future cardiovascular events," they added.

The authors had no financial disclosures; the study sponsor was not indicated.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

© Michal Rózewski/Thinkstock

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

© Michal Rózewski/Thinkstock

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

© Michal Rózewski/Thinkstock

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

© Michal Rózewski/Thinkstock

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

© Michal Rózewski/Thinkstock

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

Serious liver injury from herbal and dietary supplements – including those used by bodybuilders – has risen significantly over the past decade.

According to findings from a review, herbal supplement–related injures increased from 2% to 20% of all nonacetaminophen drug-related liver injuries. Injuries from bodybuilding supplements rose from 2% to 8%, while those related to nonbodybuilding supplements increased from 5% to 12%, Dr. Victor J. Navarro, chair of the hepatology division at the Einstein Medical Center, Philadelphia, and his coauthors reported in the September issue of Hepatology (Hepatol. 2014 Aug. 25 [doi: 10.1002/hep.27317]).

© Michal Rózewski/Thinkstock

The investigators reviewed 839 cases included in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2013. Of these, 709 were caused by nonacetaminophen medications, 85 by nonbodybuilding supplements, and 45 by bodybuilding supplements.

Overall, the injuries from supplements rose from 7% to 20%. Those related to nonbodybuilding supplements increased from 5% to 12%, and those from bodybuilding supplements from 2% to 8%.

There were no transplants or deaths among those with bodybuilding supplement–related injuries. These occurred exclusively in men and were characterized by prolonged jaundice. Injures from nonbodybuilding supplements occurred most often in middle-aged women (65%). Among these, there were 11 transplants and 4 deaths; 1 of these was a patient who died after transplant. Two of the other deaths were related to a cholestatic or mixed injury, and one resulted from a complication of endoscopy.

Most patients were using multiple supplements, which included multiple ingredients (vitamins, minerals, and botanical extracts). The entire group of 130 patients had taken a total of 217 such products. Among these, 12% of the bodybuilding supplements and 22% of the nonbodybuilding supplements were labeled as having a single ingredient. However, 10% of the bodybuilding and 13% of the nonbodybuilding supplements had at least 20 ingredients.

It’s nearly impossible to identify the specific culprit ingredients, wrote Dr. Navarro and his coauthors.

"The numerous products that frequently contain multiple ingredients, often with unclear chemical descriptors and variable common names, can confound pinpointing the specific toxic agent. Furthermore, some products may seem quite innocuous, such as multivitamins, making it difficult to conceive of any toxic potential."

Sometimes, such supplements are contaminated with microbials, drugs, mycotoxins, and heavy metals, the authors noted. "Also, unidentified interactions with medications used concomitantly may be responsible for toxicity, yet are difficult to establish."

The authors urged an increased understanding and sense of responsibility for the issue.

"All stakeholders, including the dietary supplement industry, regulatory agencies, health care providers, and consumers must take note of these findings if a culture of safety for herbal dietary supplements use is to be established."

Dr. Navarro did not make any financial disclosures. Three coauthors disclosed ties with pharmaceutical companies.

[email protected]

The Food and Drug Administration has granted an accelerated approval to pembrolizumab, a PD-1 inhibitor, for the treatment of patients with advanced or unresectable melanoma that is no longer responding to other drugs.

Pembrolizumab (Keytruda; Merck) is intended for use following treatment with ipilimumab. For BRAF V600-positive patients, the drug should be used after treatment with both ipilimumab and a BRAF inhibitor, according to an FDA press statement.

The approved dose is 2 mg/kg every 3 weeks for patients with unresectable or metastatic melanoma and disease progression following the initial treatments.

According to a Merck press statement, "This indication is approved ... based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established." Additional studies are underway, and continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials, the statement noted.

The pivotal trial comprised 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with pembrolizumab, either at the recommended dose of 2 mg/kg or at a higher dose of 10 mg/kg. In the half of the participants who received pembrolizumab at the recommended dose of 2 mg/kg, approximately 24% had their tumors shrink. This effect lasted at least 1.4-8.5 months and continued beyond this period in most patients, the FDA statement said.

The drug was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving pembrolizumab. The most common serious adverse reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis. Adverse reactions occurring in at least 20% of the 411 patients across doses were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The FDA cautions that pembrolizumab also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands, and liver, occurred uncommonly, they said.

It is the sixth drug to be approved for melanoma since 2011, joining ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

The Melanoma Research Alliance applauded FDA’s action in a press statement.

"The news of FDA’s first approval of an anti-PD-1 drug is extremely exciting and shows just how far the field has come in the last few years," said Debra Black, MRA cofounder. "When we started MRA there was little hope for melanoma patients. Today we are seeing a real sea change, with several new therapies and proof of concept that these new treatments can save lives."

[email protected]

The Food and Drug Administration has granted an accelerated approval to pembrolizumab, a PD-1 inhibitor, for the treatment of patients with advanced or unresectable melanoma that is no longer responding to other drugs.

Pembrolizumab (Keytruda; Merck) is intended for use following treatment with ipilimumab. For BRAF V600-positive patients, the drug should be used after treatment with both ipilimumab and a BRAF inhibitor, according to an FDA press statement.

The approved dose is 2 mg/kg every 3 weeks for patients with unresectable or metastatic melanoma and disease progression following the initial treatments.

According to a Merck press statement, "This indication is approved ... based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established." Additional studies are underway, and continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials, the statement noted.

The pivotal trial comprised 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with pembrolizumab, either at the recommended dose of 2 mg/kg or at a higher dose of 10 mg/kg. In the half of the participants who received pembrolizumab at the recommended dose of 2 mg/kg, approximately 24% had their tumors shrink. This effect lasted at least 1.4-8.5 months and continued beyond this period in most patients, the FDA statement said.

The drug was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving pembrolizumab. The most common serious adverse reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis. Adverse reactions occurring in at least 20% of the 411 patients across doses were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The FDA cautions that pembrolizumab also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands, and liver, occurred uncommonly, they said.

It is the sixth drug to be approved for melanoma since 2011, joining ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

The Melanoma Research Alliance applauded FDA’s action in a press statement.

"The news of FDA’s first approval of an anti-PD-1 drug is extremely exciting and shows just how far the field has come in the last few years," said Debra Black, MRA cofounder. "When we started MRA there was little hope for melanoma patients. Today we are seeing a real sea change, with several new therapies and proof of concept that these new treatments can save lives."

[email protected]

The Food and Drug Administration has granted an accelerated approval to pembrolizumab, a PD-1 inhibitor, for the treatment of patients with advanced or unresectable melanoma that is no longer responding to other drugs.

Pembrolizumab (Keytruda; Merck) is intended for use following treatment with ipilimumab. For BRAF V600-positive patients, the drug should be used after treatment with both ipilimumab and a BRAF inhibitor, according to an FDA press statement.

The approved dose is 2 mg/kg every 3 weeks for patients with unresectable or metastatic melanoma and disease progression following the initial treatments.

According to a Merck press statement, "This indication is approved ... based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established." Additional studies are underway, and continued approval may be contingent upon verification and description of clinical benefit in the confirmatory trials, the statement noted.

The pivotal trial comprised 173 clinical trial participants with advanced melanoma whose disease progressed after prior treatment. All participants were treated with pembrolizumab, either at the recommended dose of 2 mg/kg or at a higher dose of 10 mg/kg. In the half of the participants who received pembrolizumab at the recommended dose of 2 mg/kg, approximately 24% had their tumors shrink. This effect lasted at least 1.4-8.5 months and continued beyond this period in most patients, the FDA statement said.

The drug was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving pembrolizumab. The most common serious adverse reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis. Adverse reactions occurring in at least 20% of the 411 patients across doses were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The FDA cautions that pembrolizumab also has the potential for severe immune-mediated side effects. In the 411 participants with advanced melanoma, severe immune-mediated side effects involving healthy organs, including the lung, colon, hormone-producing glands, and liver, occurred uncommonly, they said.

It is the sixth drug to be approved for melanoma since 2011, joining ipilimumab (2011), peginterferon alfa-2b (2011), vemurafenib (2011), dabrafenib (2013), and trametinib (2013).

The Melanoma Research Alliance applauded FDA’s action in a press statement.

"The news of FDA’s first approval of an anti-PD-1 drug is extremely exciting and shows just how far the field has come in the last few years," said Debra Black, MRA cofounder. "When we started MRA there was little hope for melanoma patients. Today we are seeing a real sea change, with several new therapies and proof of concept that these new treatments can save lives."

[email protected]

Fecal microbiota transplant improved or alleviated symptoms in 70% of patients with refractory irritable bowel syndrome, a small retrospective study has determined.

A single transfusion of fresh donor feces improved abdominal pain, bowel habits, dyspepsia, bloating, and flatulence, Dr. Olga Aroniadis reported at the meeting sponsored by the American Gastroenterological Association.

For some patients, noticeable improvement occurred within days, Dr. Aroniadis of Montefiore Medical Center, New York, said in an interview. "For others it took longer, but in those who felt better, they did so within a matter of weeks."

The study followed 13 patients for an average of 11 months. All had irritable bowel syndrome (IBS) that was refractory to diet, probiotic, antibiotic, and/or antidepressant therapy.

The main outcome was assessed by a 41-item questionnaire that evaluated severity of abdominal pain, bloating, flatus, diarrhea, constipation, and overall quality of life.

Most of the patients (7/13) were women. The diagnoses were diarrhea-predominant IBS (nine), constipation-predominant IBS (three), and mixed IBS (one).

The donor pool comprised patients’ relatives, spouses, or close friends. The transfusion was delivered once by upper endoscopy.

Overall, 9 patients of 13 experienced symptom resolution or improvement.

At baseline, 11 patients had abdominal pain. This resolved in three, improved in five, and remained unchanged in three.

Abdominal bloating was present in 12 patients at baseline. This resolved in two, improved in four, and remained unchanged in six.

Flatus, present in 12 at baseline, resolved in one, improved in four, did not change in six, and worsened in one.

Of six patients with dyspepsia, two reported resolution, two noted improvement, and two had no change.

Before the transplant, none of the patients scored their quality of life as "good;" four scored it as "acceptable" and nine as "poor." After fecal transplant, status changed to "good" in three, "acceptable" in six, and "poor" in four.

There has been speculation about whether a family member, household member, or someone else is the ideal donor for fecal transplant; however, this study wasn’t powered to address this, Dr. Aroniadis said. "That’s an important question but we didn’t have a sufficient number of patients to make those inferences. It’s something we do need to look at in the future, although I suspect that use of a standard donor will become commonplace."

Picking the optimal donor probably depends on accurately detailing the microbiome of both donor and recipient. "In the future, we hope to develop an individual approach to FMT [fecal microbiota transplant], but to do this, we need to know which specific bacterial populations need to be restored in each patient, and that is several years away."

Patients responded to FMT regardless of IBS subtype, however, the numbers of patients in each group were too few to perform a statistical comparison. Dr. Aroniadis and her colleagues are planning a randomized controlled trial that will enroll only patients with diarrhea-predominant IBS. "We will have a much better sense of the efficacy of FMT for the treatment of diarrhea-predominant IBS after we conduct our clinical trial."

The present study is the first to track fecal transplant response exclusively in IBS patients, Dr. Aroniadis said. Two other observational studies that looked at the efficacy of FMT for functional gastrointestinal diseases included a study of patients with inflammatory bowel disease and IBS, and another study of patients with chronic constipation. "The results were promising in both of these studies." she said.

She and her colleagues are planning a randomized controlled trial that will focus exclusively on patients with diarrhea-predominant IBS. Participants enrolled in the trial will undergo microbiome analyses before and after fecal transplant, which she hopes will shed some light on how alteration of the intestinal microbiota correlates with symptoms.

Dr. Aroniadis had no financial disclosures.

[email protected]

Fecal microbiota transplant improved or alleviated symptoms in 70% of patients with refractory irritable bowel syndrome, a small retrospective study has determined.

A single transfusion of fresh donor feces improved abdominal pain, bowel habits, dyspepsia, bloating, and flatulence, Dr. Olga Aroniadis reported at the meeting sponsored by the American Gastroenterological Association.

For some patients, noticeable improvement occurred within days, Dr. Aroniadis of Montefiore Medical Center, New York, said in an interview. "For others it took longer, but in those who felt better, they did so within a matter of weeks."

The study followed 13 patients for an average of 11 months. All had irritable bowel syndrome (IBS) that was refractory to diet, probiotic, antibiotic, and/or antidepressant therapy.

The main outcome was assessed by a 41-item questionnaire that evaluated severity of abdominal pain, bloating, flatus, diarrhea, constipation, and overall quality of life.

Most of the patients (7/13) were women. The diagnoses were diarrhea-predominant IBS (nine), constipation-predominant IBS (three), and mixed IBS (one).

The donor pool comprised patients’ relatives, spouses, or close friends. The transfusion was delivered once by upper endoscopy.

Overall, 9 patients of 13 experienced symptom resolution or improvement.

At baseline, 11 patients had abdominal pain. This resolved in three, improved in five, and remained unchanged in three.

Abdominal bloating was present in 12 patients at baseline. This resolved in two, improved in four, and remained unchanged in six.

Flatus, present in 12 at baseline, resolved in one, improved in four, did not change in six, and worsened in one.

Of six patients with dyspepsia, two reported resolution, two noted improvement, and two had no change.

Before the transplant, none of the patients scored their quality of life as "good;" four scored it as "acceptable" and nine as "poor." After fecal transplant, status changed to "good" in three, "acceptable" in six, and "poor" in four.

There has been speculation about whether a family member, household member, or someone else is the ideal donor for fecal transplant; however, this study wasn’t powered to address this, Dr. Aroniadis said. "That’s an important question but we didn’t have a sufficient number of patients to make those inferences. It’s something we do need to look at in the future, although I suspect that use of a standard donor will become commonplace."

Picking the optimal donor probably depends on accurately detailing the microbiome of both donor and recipient. "In the future, we hope to develop an individual approach to FMT [fecal microbiota transplant], but to do this, we need to know which specific bacterial populations need to be restored in each patient, and that is several years away."

Patients responded to FMT regardless of IBS subtype, however, the numbers of patients in each group were too few to perform a statistical comparison. Dr. Aroniadis and her colleagues are planning a randomized controlled trial that will enroll only patients with diarrhea-predominant IBS. "We will have a much better sense of the efficacy of FMT for the treatment of diarrhea-predominant IBS after we conduct our clinical trial."

The present study is the first to track fecal transplant response exclusively in IBS patients, Dr. Aroniadis said. Two other observational studies that looked at the efficacy of FMT for functional gastrointestinal diseases included a study of patients with inflammatory bowel disease and IBS, and another study of patients with chronic constipation. "The results were promising in both of these studies." she said.

She and her colleagues are planning a randomized controlled trial that will focus exclusively on patients with diarrhea-predominant IBS. Participants enrolled in the trial will undergo microbiome analyses before and after fecal transplant, which she hopes will shed some light on how alteration of the intestinal microbiota correlates with symptoms.

Dr. Aroniadis had no financial disclosures.

[email protected]

Fecal microbiota transplant improved or alleviated symptoms in 70% of patients with refractory irritable bowel syndrome, a small retrospective study has determined.

A single transfusion of fresh donor feces improved abdominal pain, bowel habits, dyspepsia, bloating, and flatulence, Dr. Olga Aroniadis reported at the meeting sponsored by the American Gastroenterological Association.

For some patients, noticeable improvement occurred within days, Dr. Aroniadis of Montefiore Medical Center, New York, said in an interview. "For others it took longer, but in those who felt better, they did so within a matter of weeks."

The study followed 13 patients for an average of 11 months. All had irritable bowel syndrome (IBS) that was refractory to diet, probiotic, antibiotic, and/or antidepressant therapy.

The main outcome was assessed by a 41-item questionnaire that evaluated severity of abdominal pain, bloating, flatus, diarrhea, constipation, and overall quality of life.

Most of the patients (7/13) were women. The diagnoses were diarrhea-predominant IBS (nine), constipation-predominant IBS (three), and mixed IBS (one).

The donor pool comprised patients’ relatives, spouses, or close friends. The transfusion was delivered once by upper endoscopy.

Overall, 9 patients of 13 experienced symptom resolution or improvement.

At baseline, 11 patients had abdominal pain. This resolved in three, improved in five, and remained unchanged in three.

Abdominal bloating was present in 12 patients at baseline. This resolved in two, improved in four, and remained unchanged in six.

Flatus, present in 12 at baseline, resolved in one, improved in four, did not change in six, and worsened in one.

Of six patients with dyspepsia, two reported resolution, two noted improvement, and two had no change.

Before the transplant, none of the patients scored their quality of life as "good;" four scored it as "acceptable" and nine as "poor." After fecal transplant, status changed to "good" in three, "acceptable" in six, and "poor" in four.

There has been speculation about whether a family member, household member, or someone else is the ideal donor for fecal transplant; however, this study wasn’t powered to address this, Dr. Aroniadis said. "That’s an important question but we didn’t have a sufficient number of patients to make those inferences. It’s something we do need to look at in the future, although I suspect that use of a standard donor will become commonplace."

Picking the optimal donor probably depends on accurately detailing the microbiome of both donor and recipient. "In the future, we hope to develop an individual approach to FMT [fecal microbiota transplant], but to do this, we need to know which specific bacterial populations need to be restored in each patient, and that is several years away."

Patients responded to FMT regardless of IBS subtype, however, the numbers of patients in each group were too few to perform a statistical comparison. Dr. Aroniadis and her colleagues are planning a randomized controlled trial that will enroll only patients with diarrhea-predominant IBS. "We will have a much better sense of the efficacy of FMT for the treatment of diarrhea-predominant IBS after we conduct our clinical trial."

The present study is the first to track fecal transplant response exclusively in IBS patients, Dr. Aroniadis said. Two other observational studies that looked at the efficacy of FMT for functional gastrointestinal diseases included a study of patients with inflammatory bowel disease and IBS, and another study of patients with chronic constipation. "The results were promising in both of these studies." she said.

She and her colleagues are planning a randomized controlled trial that will focus exclusively on patients with diarrhea-predominant IBS. Participants enrolled in the trial will undergo microbiome analyses before and after fecal transplant, which she hopes will shed some light on how alteration of the intestinal microbiota correlates with symptoms.

Dr. Aroniadis had no financial disclosures.

[email protected]