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Doug Brunk is a San Diego-based award-winning reporter who began covering health care in 1991. Before joining the company, he wrote for the health sciences division of Columbia University and was an associate editor at Contemporary Long Term Care magazine when it won a Jesse H. Neal Award. His work has been syndicated by the Los Angeles Times and he is the author of two books related to the University of Kentucky Wildcats men's basketball program. Doug has a master’s degree in magazine journalism from the S.I. Newhouse School of Public Communications at Syracuse University. Follow him on Twitter @dougbrunk.
Ideal agent for insomnia not always clear cut
LAS VEGAS – Many patients with insomnia reach for certain dietary supplements and herbal preparations for relief, but their efficacies have not been established in well-controlled studies.
"Dietary supplements and herbal preparations not regulated by the FDA [Food and Drug Administration]," Dr. Karl Doghramji said at the annual psychopharmacology update held by the Nevada Psychiatric Association. "There is some question about the purity of these agents, and also about the active ingredient. There are many ingredients in these so-called nutraceutical compounds. Which is the active ingredient? We’re not quite sure."
If clinicians recommend agents whose effectiveness is not well established, "are we delaying treatment for insomnia and other conditions, which may have a negative impact in daytime performance and may impair mood?" asked Dr. Doghramji, professor of psychiatry, neurology, and medicine at Thomas Jefferson University, Philadelphia. "That’s a concern."
One of the more commonly used natural supplements for insomnia is valerian in a dose of 400-450 mg/day. This herb is believed to have some anxiolytic, muscle relaxant, and sleep-promoting properties, "yet data regarding efficacy are mixed," said Dr. Doghramji, who also directs the university’s Sleep Disorders Center. "Safety data are scant, yet side effects appear to be rare and mild, primarily GI irritation and headache. There are case reports of hepatotoxicity in persons taking herbal products containing valerian."
He described melatonin as the most commonly used natural supplement for insomnia. A review of 139 published studies commissioned by the Agency for Healthcare Research and Quality suggests that melatonin has no effectiveness in the treatment of everyday regular insomnia (AHRQ Publication No. 05-E002-2;2004). "But, some evidence suggests that it is effective in treating delayed sleep-phase syndrome with short-term use," Dr. Doghramji noted. "On the other hand, evidence suggests that melatonin is not effective in treating most secondary sleep disorders with short-term use, and no evidence suggests that melatonin is effective in alleviating the sleep disturbance aspect of jet lag and shift-work disorder."
Certain prescription agents might benefit patients with insomnia, he continued. FDA-nonapproved agents for insomnia include sedating antidepressants, antipsychotics, and anticonvulsants. FDA-approved hypnotics include benzodiazepine-receptor agonists, melatonin-receptor agonists, and H1-receptor antagonists.
"At appropriate doses, sedating antidepressants are effective for mood and anxiety disorders; there is a low abuse risk, low cost, and there is a large dose range," Dr. Doghramji said.
"One of the disadvantages is that they tend to be long acting and have anticholinergic and antihistaminic side effects." A 42-day controlled study of doxepin 25-50 mg found that the agent did not produce any change in terms of sleep latency (J. Clin. Psychiatry 2001;62:453-63). However, "it did increase their total sleep time, suggesting that they didn’t necessarily fall asleep more quickly, but they had fewer awakenings after they did fall asleep," he said. "So, if doxepin is to be used for insomnia, it seems to be best suited for the insomnia characterized by middle of the night awakening and late morning insomnia."
A 2-week study that compared trazodone with zolpidem in primary insomnia demonstrated that trazodone did seem to help people fall asleep more quickly in the first week or so (Hum. Psychopharmacol. 1998;13:191-8). "It also helped them feel as though they had slept longer," said Dr. Doghramji, who was not involved with the study. "The problem was, tolerance occurred within 2 weeks. The issue there is, should you increase the dosage or keep the same dosage for a while? We don’t have a lot of data on this."
From a pharmacokinetic standpoint, trazodone has a long half-life (5-12 hours) and features a complex set of pharmacodynamics. "It not only has some serotonergic potential, it has some histaminic potential, making it an agent that can have multiple side effects, so be careful with it," he said.
Clinicians likely use benzodiazepine-receptor agonists more than any other agent for insomnia. These include the benzodiazepines, such as estazolam, flurazepam, quazepam, temazepam, and triazolam; and the nonbenzodiazepines (also known as selective benzodiazepine-receptor agonists) such as zaleplon, zolpidem and its various preparations (oral, sublingual, and oral spray); and eszopiclone. Adverse effects may include daytime sedation, psychomotor and cognitive impairment (depending on dose and half-life), rebound insomnia, and respiratory depression in vulnerable populations. All of these are classified as schedule IV controlled substance by the Drug Enforcement Administration. New drugs, which do not have a DEA schedule classification, include ramelteon, a melatonin-receptor agonist, and low-dose doxepin.
Choosing which antidepressant agent to use for a patient with depression and comorbid insomnia poses a certain clinical dilemma, Dr. Doghramji concluded. "Do you start with a sedating agent when your patient is both depressed and cannot sleep? Or do you put them on any old agent, regardless of whether it’s sedating or not? Unfortunately, at this point, there are not a lot of data guiding us on this."
Dr. Doghramji disclosed that he is a consultant for UCB, Teva Pharmaceuticals, Vanda Pharmaceuticals, and Jazz Pharmaceuticals, and that he holds stock in Merck.
Dr. Paul A. Selecky, FCCP, comments: This is a well written and concise review of the common medications and other agents used in the treatment of insomnia to guide clinicians, pointing out the caution that the non-prescription items have limited scientific evidence to support their regular use. Some of the prescription medications are reviewed as well.
LAS VEGAS – Many patients with insomnia reach for certain dietary supplements and herbal preparations for relief, but their efficacies have not been established in well-controlled studies.
"Dietary supplements and herbal preparations not regulated by the FDA [Food and Drug Administration]," Dr. Karl Doghramji said at the annual psychopharmacology update held by the Nevada Psychiatric Association. "There is some question about the purity of these agents, and also about the active ingredient. There are many ingredients in these so-called nutraceutical compounds. Which is the active ingredient? We’re not quite sure."
If clinicians recommend agents whose effectiveness is not well established, "are we delaying treatment for insomnia and other conditions, which may have a negative impact in daytime performance and may impair mood?" asked Dr. Doghramji, professor of psychiatry, neurology, and medicine at Thomas Jefferson University, Philadelphia. "That’s a concern."
One of the more commonly used natural supplements for insomnia is valerian in a dose of 400-450 mg/day. This herb is believed to have some anxiolytic, muscle relaxant, and sleep-promoting properties, "yet data regarding efficacy are mixed," said Dr. Doghramji, who also directs the university’s Sleep Disorders Center. "Safety data are scant, yet side effects appear to be rare and mild, primarily GI irritation and headache. There are case reports of hepatotoxicity in persons taking herbal products containing valerian."
He described melatonin as the most commonly used natural supplement for insomnia. A review of 139 published studies commissioned by the Agency for Healthcare Research and Quality suggests that melatonin has no effectiveness in the treatment of everyday regular insomnia (AHRQ Publication No. 05-E002-2;2004). "But, some evidence suggests that it is effective in treating delayed sleep-phase syndrome with short-term use," Dr. Doghramji noted. "On the other hand, evidence suggests that melatonin is not effective in treating most secondary sleep disorders with short-term use, and no evidence suggests that melatonin is effective in alleviating the sleep disturbance aspect of jet lag and shift-work disorder."
Certain prescription agents might benefit patients with insomnia, he continued. FDA-nonapproved agents for insomnia include sedating antidepressants, antipsychotics, and anticonvulsants. FDA-approved hypnotics include benzodiazepine-receptor agonists, melatonin-receptor agonists, and H1-receptor antagonists.
"At appropriate doses, sedating antidepressants are effective for mood and anxiety disorders; there is a low abuse risk, low cost, and there is a large dose range," Dr. Doghramji said.
"One of the disadvantages is that they tend to be long acting and have anticholinergic and antihistaminic side effects." A 42-day controlled study of doxepin 25-50 mg found that the agent did not produce any change in terms of sleep latency (J. Clin. Psychiatry 2001;62:453-63). However, "it did increase their total sleep time, suggesting that they didn’t necessarily fall asleep more quickly, but they had fewer awakenings after they did fall asleep," he said. "So, if doxepin is to be used for insomnia, it seems to be best suited for the insomnia characterized by middle of the night awakening and late morning insomnia."
A 2-week study that compared trazodone with zolpidem in primary insomnia demonstrated that trazodone did seem to help people fall asleep more quickly in the first week or so (Hum. Psychopharmacol. 1998;13:191-8). "It also helped them feel as though they had slept longer," said Dr. Doghramji, who was not involved with the study. "The problem was, tolerance occurred within 2 weeks. The issue there is, should you increase the dosage or keep the same dosage for a while? We don’t have a lot of data on this."
From a pharmacokinetic standpoint, trazodone has a long half-life (5-12 hours) and features a complex set of pharmacodynamics. "It not only has some serotonergic potential, it has some histaminic potential, making it an agent that can have multiple side effects, so be careful with it," he said.
Clinicians likely use benzodiazepine-receptor agonists more than any other agent for insomnia. These include the benzodiazepines, such as estazolam, flurazepam, quazepam, temazepam, and triazolam; and the nonbenzodiazepines (also known as selective benzodiazepine-receptor agonists) such as zaleplon, zolpidem and its various preparations (oral, sublingual, and oral spray); and eszopiclone. Adverse effects may include daytime sedation, psychomotor and cognitive impairment (depending on dose and half-life), rebound insomnia, and respiratory depression in vulnerable populations. All of these are classified as schedule IV controlled substance by the Drug Enforcement Administration. New drugs, which do not have a DEA schedule classification, include ramelteon, a melatonin-receptor agonist, and low-dose doxepin.
Choosing which antidepressant agent to use for a patient with depression and comorbid insomnia poses a certain clinical dilemma, Dr. Doghramji concluded. "Do you start with a sedating agent when your patient is both depressed and cannot sleep? Or do you put them on any old agent, regardless of whether it’s sedating or not? Unfortunately, at this point, there are not a lot of data guiding us on this."
Dr. Doghramji disclosed that he is a consultant for UCB, Teva Pharmaceuticals, Vanda Pharmaceuticals, and Jazz Pharmaceuticals, and that he holds stock in Merck.
Dr. Paul A. Selecky, FCCP, comments: This is a well written and concise review of the common medications and other agents used in the treatment of insomnia to guide clinicians, pointing out the caution that the non-prescription items have limited scientific evidence to support their regular use. Some of the prescription medications are reviewed as well.
LAS VEGAS – Many patients with insomnia reach for certain dietary supplements and herbal preparations for relief, but their efficacies have not been established in well-controlled studies.
"Dietary supplements and herbal preparations not regulated by the FDA [Food and Drug Administration]," Dr. Karl Doghramji said at the annual psychopharmacology update held by the Nevada Psychiatric Association. "There is some question about the purity of these agents, and also about the active ingredient. There are many ingredients in these so-called nutraceutical compounds. Which is the active ingredient? We’re not quite sure."
If clinicians recommend agents whose effectiveness is not well established, "are we delaying treatment for insomnia and other conditions, which may have a negative impact in daytime performance and may impair mood?" asked Dr. Doghramji, professor of psychiatry, neurology, and medicine at Thomas Jefferson University, Philadelphia. "That’s a concern."
One of the more commonly used natural supplements for insomnia is valerian in a dose of 400-450 mg/day. This herb is believed to have some anxiolytic, muscle relaxant, and sleep-promoting properties, "yet data regarding efficacy are mixed," said Dr. Doghramji, who also directs the university’s Sleep Disorders Center. "Safety data are scant, yet side effects appear to be rare and mild, primarily GI irritation and headache. There are case reports of hepatotoxicity in persons taking herbal products containing valerian."
He described melatonin as the most commonly used natural supplement for insomnia. A review of 139 published studies commissioned by the Agency for Healthcare Research and Quality suggests that melatonin has no effectiveness in the treatment of everyday regular insomnia (AHRQ Publication No. 05-E002-2;2004). "But, some evidence suggests that it is effective in treating delayed sleep-phase syndrome with short-term use," Dr. Doghramji noted. "On the other hand, evidence suggests that melatonin is not effective in treating most secondary sleep disorders with short-term use, and no evidence suggests that melatonin is effective in alleviating the sleep disturbance aspect of jet lag and shift-work disorder."
Certain prescription agents might benefit patients with insomnia, he continued. FDA-nonapproved agents for insomnia include sedating antidepressants, antipsychotics, and anticonvulsants. FDA-approved hypnotics include benzodiazepine-receptor agonists, melatonin-receptor agonists, and H1-receptor antagonists.
"At appropriate doses, sedating antidepressants are effective for mood and anxiety disorders; there is a low abuse risk, low cost, and there is a large dose range," Dr. Doghramji said.
"One of the disadvantages is that they tend to be long acting and have anticholinergic and antihistaminic side effects." A 42-day controlled study of doxepin 25-50 mg found that the agent did not produce any change in terms of sleep latency (J. Clin. Psychiatry 2001;62:453-63). However, "it did increase their total sleep time, suggesting that they didn’t necessarily fall asleep more quickly, but they had fewer awakenings after they did fall asleep," he said. "So, if doxepin is to be used for insomnia, it seems to be best suited for the insomnia characterized by middle of the night awakening and late morning insomnia."
A 2-week study that compared trazodone with zolpidem in primary insomnia demonstrated that trazodone did seem to help people fall asleep more quickly in the first week or so (Hum. Psychopharmacol. 1998;13:191-8). "It also helped them feel as though they had slept longer," said Dr. Doghramji, who was not involved with the study. "The problem was, tolerance occurred within 2 weeks. The issue there is, should you increase the dosage or keep the same dosage for a while? We don’t have a lot of data on this."
From a pharmacokinetic standpoint, trazodone has a long half-life (5-12 hours) and features a complex set of pharmacodynamics. "It not only has some serotonergic potential, it has some histaminic potential, making it an agent that can have multiple side effects, so be careful with it," he said.
Clinicians likely use benzodiazepine-receptor agonists more than any other agent for insomnia. These include the benzodiazepines, such as estazolam, flurazepam, quazepam, temazepam, and triazolam; and the nonbenzodiazepines (also known as selective benzodiazepine-receptor agonists) such as zaleplon, zolpidem and its various preparations (oral, sublingual, and oral spray); and eszopiclone. Adverse effects may include daytime sedation, psychomotor and cognitive impairment (depending on dose and half-life), rebound insomnia, and respiratory depression in vulnerable populations. All of these are classified as schedule IV controlled substance by the Drug Enforcement Administration. New drugs, which do not have a DEA schedule classification, include ramelteon, a melatonin-receptor agonist, and low-dose doxepin.
Choosing which antidepressant agent to use for a patient with depression and comorbid insomnia poses a certain clinical dilemma, Dr. Doghramji concluded. "Do you start with a sedating agent when your patient is both depressed and cannot sleep? Or do you put them on any old agent, regardless of whether it’s sedating or not? Unfortunately, at this point, there are not a lot of data guiding us on this."
Dr. Doghramji disclosed that he is a consultant for UCB, Teva Pharmaceuticals, Vanda Pharmaceuticals, and Jazz Pharmaceuticals, and that he holds stock in Merck.
Dr. Paul A. Selecky, FCCP, comments: This is a well written and concise review of the common medications and other agents used in the treatment of insomnia to guide clinicians, pointing out the caution that the non-prescription items have limited scientific evidence to support their regular use. Some of the prescription medications are reviewed as well.
Asthma may increase risk of cardiovascular events
SAN DIEGO – Having asthma appears to significantly increase a patient’s risk for cardiovascular events, while having allergic rhinitis appears to lower a patient’s risk of some such events, results from a large cohort study demonstrated.
Studies of mouse models have suggested that Th1 inflammation "is associated with atherosclerosis and plaque development, while the Th2 or general allergic response seems to be protective against atherosclerosis," Dr. Angelina Crans Yoon said during a press briefing at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. At the same time, results from human studies regarding the association between allergic rhinitis and cardiovascular events are mixed, said Dr. Crans Yoon, a first-year allergy fellow at Kaiser Permanente Los Angeles Medical Center.
In an effort to assess the relationship between cardiovascular disease and allergic rhinitis, she and her associates used the Kaiser Permanente Southern California regional database and ICD-9 codes to compare the incidence of cardiovascular and cerebrovascular events and all-cause mortality in a cohort of 109,229 allergic rhinitis patients and 92,775 asthma patients who were seen between Jan. 1, 1995, and Dec. 31, 2012. The cohorts were matched by age, sex, and ethnicity to reference cohorts and followed for a median of 8 years.
Patients with allergic rhinitis had a significantly lower risk of myocardial infarction (hazard ratio, 0.75), cerebrovascular disease (HR, 0.81), and all-cause mortality (HR, 0.51), yet their risk of all cardiovascular events was equal to that of the control cohort (HR, 0.97). At the same time, patients with asthma had a significantly higher risk of all cardiovascular disease (HR, 1.36), yet no significantly higher risk of cerebrovascular disease (HR, 1.03) or all-cause mortality (HR, 1.00).
The findings "led us to think of more questions," Dr. Crans Yoon said. "Why is there this decreased risk of events in patients with allergic rhinitis? What explains the risk of cardiovascular events in patients with asthma? Is atopy related to these differences? We started some secondary analyses looking at medication use. It looks like if you use any medications for allergic rhinitis or asthma, you have a decreased risk of some of these events, except for long-acting beta-agonists, which is consistent with previous reports."We’re also starting to look at specific IgE data on these patients. It also looks like positive IgE testing may be associated with a decreased risk of these events., she said".
She speculated that asthma physiology may explain why patients with asthma had significantly higher risk of cardiovascular disease but not cerebrovascular disease. "The interesting point is that, potentially, atopic asthmatics may not have the same increased risk," she said.
Dr. Crans Yoon reported she had no relevant financial conflicts.
Dr. Jun Chiong, FCCP, comments: Clinicians have yet to sort out a clear connection between asthma and heart disease, but the link is a statistical fact. In some studies, the link persist even after adjusting the smoking history and other risk factors. A variety of theories about the possible link such as genetics and inflammation has come up, as that's also what makes the arteries harden.
A more defined and directed study is necessary in order to better don’t understand exactly what the connection is. People who are having heart failure, angina, or heart pain such as tightness in the chest may mistake those symptoms for breathing difficulty and other asthma symptoms. Heart failure can cause fluid to build up in the lungs and airways, and can lead to symptoms that resemble asthma symptoms such as wheezing, coughing, and shortness of breath.
SAN DIEGO – Having asthma appears to significantly increase a patient’s risk for cardiovascular events, while having allergic rhinitis appears to lower a patient’s risk of some such events, results from a large cohort study demonstrated.
Studies of mouse models have suggested that Th1 inflammation "is associated with atherosclerosis and plaque development, while the Th2 or general allergic response seems to be protective against atherosclerosis," Dr. Angelina Crans Yoon said during a press briefing at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. At the same time, results from human studies regarding the association between allergic rhinitis and cardiovascular events are mixed, said Dr. Crans Yoon, a first-year allergy fellow at Kaiser Permanente Los Angeles Medical Center.
In an effort to assess the relationship between cardiovascular disease and allergic rhinitis, she and her associates used the Kaiser Permanente Southern California regional database and ICD-9 codes to compare the incidence of cardiovascular and cerebrovascular events and all-cause mortality in a cohort of 109,229 allergic rhinitis patients and 92,775 asthma patients who were seen between Jan. 1, 1995, and Dec. 31, 2012. The cohorts were matched by age, sex, and ethnicity to reference cohorts and followed for a median of 8 years.
Patients with allergic rhinitis had a significantly lower risk of myocardial infarction (hazard ratio, 0.75), cerebrovascular disease (HR, 0.81), and all-cause mortality (HR, 0.51), yet their risk of all cardiovascular events was equal to that of the control cohort (HR, 0.97). At the same time, patients with asthma had a significantly higher risk of all cardiovascular disease (HR, 1.36), yet no significantly higher risk of cerebrovascular disease (HR, 1.03) or all-cause mortality (HR, 1.00).
The findings "led us to think of more questions," Dr. Crans Yoon said. "Why is there this decreased risk of events in patients with allergic rhinitis? What explains the risk of cardiovascular events in patients with asthma? Is atopy related to these differences? We started some secondary analyses looking at medication use. It looks like if you use any medications for allergic rhinitis or asthma, you have a decreased risk of some of these events, except for long-acting beta-agonists, which is consistent with previous reports."We’re also starting to look at specific IgE data on these patients. It also looks like positive IgE testing may be associated with a decreased risk of these events., she said".
She speculated that asthma physiology may explain why patients with asthma had significantly higher risk of cardiovascular disease but not cerebrovascular disease. "The interesting point is that, potentially, atopic asthmatics may not have the same increased risk," she said.
Dr. Crans Yoon reported she had no relevant financial conflicts.
Dr. Jun Chiong, FCCP, comments: Clinicians have yet to sort out a clear connection between asthma and heart disease, but the link is a statistical fact. In some studies, the link persist even after adjusting the smoking history and other risk factors. A variety of theories about the possible link such as genetics and inflammation has come up, as that's also what makes the arteries harden.
A more defined and directed study is necessary in order to better don’t understand exactly what the connection is. People who are having heart failure, angina, or heart pain such as tightness in the chest may mistake those symptoms for breathing difficulty and other asthma symptoms. Heart failure can cause fluid to build up in the lungs and airways, and can lead to symptoms that resemble asthma symptoms such as wheezing, coughing, and shortness of breath.
SAN DIEGO – Having asthma appears to significantly increase a patient’s risk for cardiovascular events, while having allergic rhinitis appears to lower a patient’s risk of some such events, results from a large cohort study demonstrated.
Studies of mouse models have suggested that Th1 inflammation "is associated with atherosclerosis and plaque development, while the Th2 or general allergic response seems to be protective against atherosclerosis," Dr. Angelina Crans Yoon said during a press briefing at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. At the same time, results from human studies regarding the association between allergic rhinitis and cardiovascular events are mixed, said Dr. Crans Yoon, a first-year allergy fellow at Kaiser Permanente Los Angeles Medical Center.
In an effort to assess the relationship between cardiovascular disease and allergic rhinitis, she and her associates used the Kaiser Permanente Southern California regional database and ICD-9 codes to compare the incidence of cardiovascular and cerebrovascular events and all-cause mortality in a cohort of 109,229 allergic rhinitis patients and 92,775 asthma patients who were seen between Jan. 1, 1995, and Dec. 31, 2012. The cohorts were matched by age, sex, and ethnicity to reference cohorts and followed for a median of 8 years.
Patients with allergic rhinitis had a significantly lower risk of myocardial infarction (hazard ratio, 0.75), cerebrovascular disease (HR, 0.81), and all-cause mortality (HR, 0.51), yet their risk of all cardiovascular events was equal to that of the control cohort (HR, 0.97). At the same time, patients with asthma had a significantly higher risk of all cardiovascular disease (HR, 1.36), yet no significantly higher risk of cerebrovascular disease (HR, 1.03) or all-cause mortality (HR, 1.00).
The findings "led us to think of more questions," Dr. Crans Yoon said. "Why is there this decreased risk of events in patients with allergic rhinitis? What explains the risk of cardiovascular events in patients with asthma? Is atopy related to these differences? We started some secondary analyses looking at medication use. It looks like if you use any medications for allergic rhinitis or asthma, you have a decreased risk of some of these events, except for long-acting beta-agonists, which is consistent with previous reports."We’re also starting to look at specific IgE data on these patients. It also looks like positive IgE testing may be associated with a decreased risk of these events., she said".
She speculated that asthma physiology may explain why patients with asthma had significantly higher risk of cardiovascular disease but not cerebrovascular disease. "The interesting point is that, potentially, atopic asthmatics may not have the same increased risk," she said.
Dr. Crans Yoon reported she had no relevant financial conflicts.
Dr. Jun Chiong, FCCP, comments: Clinicians have yet to sort out a clear connection between asthma and heart disease, but the link is a statistical fact. In some studies, the link persist even after adjusting the smoking history and other risk factors. A variety of theories about the possible link such as genetics and inflammation has come up, as that's also what makes the arteries harden.
A more defined and directed study is necessary in order to better don’t understand exactly what the connection is. People who are having heart failure, angina, or heart pain such as tightness in the chest may mistake those symptoms for breathing difficulty and other asthma symptoms. Heart failure can cause fluid to build up in the lungs and airways, and can lead to symptoms that resemble asthma symptoms such as wheezing, coughing, and shortness of breath.
AT THE 2014 AAAAI ANNUAL MEETING
Major finding: Compared with matched controls, patients with asthma had a significantly higher risk of all cardiovascular disease (HR, 1.36) while patients with allergic rhinitis had a significantly lower risk for myocardial infarction (HR, 0.75).
Data source: A study of 109,229 patients with allergic rhinitis and 92,775 patients with asthma who were treated at Kaiser Permanente Southern California and followed for a median of 8 years.
Disclosures: Dr. Crans Yoon said that she had no relevant financial conflicts to disclose.
‘Extremely exciting’ results from phase I trial of novel cancer metabolism agent
SAN DIEGO – Five of seven evaluable patients with advanced hematologic malignancies demonstrated complete remission or complete remission with partial platelet count recovery after treatment with AG-221, an oral first-in-class drug that exploits cancer metabolism, according to preliminary findings from a phase I trial.
"This data is kind of unheard of," Dr. Eytan M. Stein said during a press briefing at the annual meeting of the American Association for Cancer Research. "It’s early clinical data – we’ll have to see what happens to the other patients who are on study – but I would say that this is an extremely exciting result."
A novel agent being developed by Cambridge, Mass.–based Agios Pharmaceuticals, AG-221 acts by interfering with cancer metabolism to halt tumor growth. It is an oral inhibitor of the isocitrate dehydrogenase-2 (IDH2) protein and is administered once or twice daily in a 28-day cycle.
IDH2 mutations are found in 10%-15% of acute myelogenous leukemias (AML), 5% of myelodysplastic syndromes/multiple primary neoplasms (MDS/MPN), and 25% of angioimmunoblastic non-Hodgkin lymphomas.
Mutations in the genes for the metabolic enzyme are thought to be the drivers of distinct subsets of AML, by allowing increased production of 2-hydroxyglutarate, an oncometabolite. Researchers hypothesized that blocking production of the enzyme may lead to clinical benefit in patients with these mutations.
In September 2013, Dr. Stein and his associates conducted a single-arm, phase I, open-label study of AG-221 as single-agent therapy with continuous oral daily dosing in 28-day cycles. Patients received the drug at a dose of 30 mg b.i.d., 50 mg b.i.d., 75 mg b.i.d., or 100 mg b.i.d. The median age of the population was 62.5 years, and participants included those with relapsed or refractory AML and MDS, or patients over age 60 who were unable to be treated with conventional therapy because of comorbid medical conditions.
"They had to be IDH2 mutation positive to get into the trial," Dr. Stein explained. "The key objectives were to assess the safety and tolerability; determine maximum tolerated dose and recommended phase II dose; determine dose-limiting toxicity, pharmacokinetics, and pharmacodynamics; and characterize differentiation effect and clinical activity."
As of March 20, 2014, there were 22 patients enrolled and 16 patients remain on study. Dr. Stein reported that there have been two possible treatment-related serious adverse events to date: one grade 2 hyperleukocytosis and differentiation syndrome, and one case of grade 3 confusion in the setting of respiratory failure in a patient with sepsis. There have been four deaths within 30 days of study drug termination, all stemming from complications of disease-related sepsis. "This is not unusual for patients with refractory AML, who are often very ill," Dr. Stein said.
The researchers observed a greater than 90% plasma 2-hydroxyglutarate reduction after multiple doses, providing proof of concept for the drug mechanism. In the 30-mg b.i.d. cohort, there was one complete remission and one complete remission with incomplete platelet recovery. In the 50-mg b.i.d. cohort, there were two complete remissions and one complete remission with an incomplete platelet count recovery, one partial remission, and one patient with progressive disease.
"Overall, this shows that out of the seven patients who were evaluable for efficacy, five of the patients achieved complete remission or complete remission with partial platelet count recovery," Dr. Stein said. "What that means is that there is no more leukemia in the bone marrow; their platelet count just has not risen to above 100,000/mcL."
Preliminary analysis of pharmacokinetics at the 30- and 50-mg dose levels showed a mean plasma half-life of greater than 40 hours. Moving forward, dose escalation will continue, he said, as the maximum tolerated dose has not yet been realized. Expansion cohorts are scheduled to begin in late 2014.
"These data provide early validation of mutant IDH-2 as a therapeutic target in AML and MDS," Dr. Stein said. "We’re going to be further characterizing the safety, pharmacokinetics/pharmacodynamics, and response rate of AG-221 in AML. Down the road, we’re hoping to evaluate this agent in combinations and in earlier lines to treatment. We’re also going to be exploring the activity of AG-221 in other IDH2-mutation-positive hematologic malignancies and solid tumors."
In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, said that she was impressed by the study’s findings in the context of refractory AML. "To be able to get responses with a drug that’s not nearly as toxic as chemotherapy, that is much more tolerable than chemotherapy, is exciting," she said.
"We don’t have long enough follow-up to know what those complete responses mean in terms of long-term survival. It is a phase I trial, but to see these kinds of responses in an AML refractory population with a selective drug against a mutated target, it’s a sign that there are some pretty exciting things happening in oncology these days."
Agios Pharmaceuticals funded the study. Dr. Stein disclosed that he has been a consultant for Janssen.
Agios Pharmaceuticals, halt tumor growth, oral inhibitor, isocitrate dehydrogenase-2 (IDH2) protein,
SAN DIEGO – Five of seven evaluable patients with advanced hematologic malignancies demonstrated complete remission or complete remission with partial platelet count recovery after treatment with AG-221, an oral first-in-class drug that exploits cancer metabolism, according to preliminary findings from a phase I trial.
"This data is kind of unheard of," Dr. Eytan M. Stein said during a press briefing at the annual meeting of the American Association for Cancer Research. "It’s early clinical data – we’ll have to see what happens to the other patients who are on study – but I would say that this is an extremely exciting result."
A novel agent being developed by Cambridge, Mass.–based Agios Pharmaceuticals, AG-221 acts by interfering with cancer metabolism to halt tumor growth. It is an oral inhibitor of the isocitrate dehydrogenase-2 (IDH2) protein and is administered once or twice daily in a 28-day cycle.
IDH2 mutations are found in 10%-15% of acute myelogenous leukemias (AML), 5% of myelodysplastic syndromes/multiple primary neoplasms (MDS/MPN), and 25% of angioimmunoblastic non-Hodgkin lymphomas.
Mutations in the genes for the metabolic enzyme are thought to be the drivers of distinct subsets of AML, by allowing increased production of 2-hydroxyglutarate, an oncometabolite. Researchers hypothesized that blocking production of the enzyme may lead to clinical benefit in patients with these mutations.
In September 2013, Dr. Stein and his associates conducted a single-arm, phase I, open-label study of AG-221 as single-agent therapy with continuous oral daily dosing in 28-day cycles. Patients received the drug at a dose of 30 mg b.i.d., 50 mg b.i.d., 75 mg b.i.d., or 100 mg b.i.d. The median age of the population was 62.5 years, and participants included those with relapsed or refractory AML and MDS, or patients over age 60 who were unable to be treated with conventional therapy because of comorbid medical conditions.
"They had to be IDH2 mutation positive to get into the trial," Dr. Stein explained. "The key objectives were to assess the safety and tolerability; determine maximum tolerated dose and recommended phase II dose; determine dose-limiting toxicity, pharmacokinetics, and pharmacodynamics; and characterize differentiation effect and clinical activity."
As of March 20, 2014, there were 22 patients enrolled and 16 patients remain on study. Dr. Stein reported that there have been two possible treatment-related serious adverse events to date: one grade 2 hyperleukocytosis and differentiation syndrome, and one case of grade 3 confusion in the setting of respiratory failure in a patient with sepsis. There have been four deaths within 30 days of study drug termination, all stemming from complications of disease-related sepsis. "This is not unusual for patients with refractory AML, who are often very ill," Dr. Stein said.
The researchers observed a greater than 90% plasma 2-hydroxyglutarate reduction after multiple doses, providing proof of concept for the drug mechanism. In the 30-mg b.i.d. cohort, there was one complete remission and one complete remission with incomplete platelet recovery. In the 50-mg b.i.d. cohort, there were two complete remissions and one complete remission with an incomplete platelet count recovery, one partial remission, and one patient with progressive disease.
"Overall, this shows that out of the seven patients who were evaluable for efficacy, five of the patients achieved complete remission or complete remission with partial platelet count recovery," Dr. Stein said. "What that means is that there is no more leukemia in the bone marrow; their platelet count just has not risen to above 100,000/mcL."
Preliminary analysis of pharmacokinetics at the 30- and 50-mg dose levels showed a mean plasma half-life of greater than 40 hours. Moving forward, dose escalation will continue, he said, as the maximum tolerated dose has not yet been realized. Expansion cohorts are scheduled to begin in late 2014.
"These data provide early validation of mutant IDH-2 as a therapeutic target in AML and MDS," Dr. Stein said. "We’re going to be further characterizing the safety, pharmacokinetics/pharmacodynamics, and response rate of AG-221 in AML. Down the road, we’re hoping to evaluate this agent in combinations and in earlier lines to treatment. We’re also going to be exploring the activity of AG-221 in other IDH2-mutation-positive hematologic malignancies and solid tumors."
In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, said that she was impressed by the study’s findings in the context of refractory AML. "To be able to get responses with a drug that’s not nearly as toxic as chemotherapy, that is much more tolerable than chemotherapy, is exciting," she said.
"We don’t have long enough follow-up to know what those complete responses mean in terms of long-term survival. It is a phase I trial, but to see these kinds of responses in an AML refractory population with a selective drug against a mutated target, it’s a sign that there are some pretty exciting things happening in oncology these days."
Agios Pharmaceuticals funded the study. Dr. Stein disclosed that he has been a consultant for Janssen.
SAN DIEGO – Five of seven evaluable patients with advanced hematologic malignancies demonstrated complete remission or complete remission with partial platelet count recovery after treatment with AG-221, an oral first-in-class drug that exploits cancer metabolism, according to preliminary findings from a phase I trial.
"This data is kind of unheard of," Dr. Eytan M. Stein said during a press briefing at the annual meeting of the American Association for Cancer Research. "It’s early clinical data – we’ll have to see what happens to the other patients who are on study – but I would say that this is an extremely exciting result."
A novel agent being developed by Cambridge, Mass.–based Agios Pharmaceuticals, AG-221 acts by interfering with cancer metabolism to halt tumor growth. It is an oral inhibitor of the isocitrate dehydrogenase-2 (IDH2) protein and is administered once or twice daily in a 28-day cycle.
IDH2 mutations are found in 10%-15% of acute myelogenous leukemias (AML), 5% of myelodysplastic syndromes/multiple primary neoplasms (MDS/MPN), and 25% of angioimmunoblastic non-Hodgkin lymphomas.
Mutations in the genes for the metabolic enzyme are thought to be the drivers of distinct subsets of AML, by allowing increased production of 2-hydroxyglutarate, an oncometabolite. Researchers hypothesized that blocking production of the enzyme may lead to clinical benefit in patients with these mutations.
In September 2013, Dr. Stein and his associates conducted a single-arm, phase I, open-label study of AG-221 as single-agent therapy with continuous oral daily dosing in 28-day cycles. Patients received the drug at a dose of 30 mg b.i.d., 50 mg b.i.d., 75 mg b.i.d., or 100 mg b.i.d. The median age of the population was 62.5 years, and participants included those with relapsed or refractory AML and MDS, or patients over age 60 who were unable to be treated with conventional therapy because of comorbid medical conditions.
"They had to be IDH2 mutation positive to get into the trial," Dr. Stein explained. "The key objectives were to assess the safety and tolerability; determine maximum tolerated dose and recommended phase II dose; determine dose-limiting toxicity, pharmacokinetics, and pharmacodynamics; and characterize differentiation effect and clinical activity."
As of March 20, 2014, there were 22 patients enrolled and 16 patients remain on study. Dr. Stein reported that there have been two possible treatment-related serious adverse events to date: one grade 2 hyperleukocytosis and differentiation syndrome, and one case of grade 3 confusion in the setting of respiratory failure in a patient with sepsis. There have been four deaths within 30 days of study drug termination, all stemming from complications of disease-related sepsis. "This is not unusual for patients with refractory AML, who are often very ill," Dr. Stein said.
The researchers observed a greater than 90% plasma 2-hydroxyglutarate reduction after multiple doses, providing proof of concept for the drug mechanism. In the 30-mg b.i.d. cohort, there was one complete remission and one complete remission with incomplete platelet recovery. In the 50-mg b.i.d. cohort, there were two complete remissions and one complete remission with an incomplete platelet count recovery, one partial remission, and one patient with progressive disease.
"Overall, this shows that out of the seven patients who were evaluable for efficacy, five of the patients achieved complete remission or complete remission with partial platelet count recovery," Dr. Stein said. "What that means is that there is no more leukemia in the bone marrow; their platelet count just has not risen to above 100,000/mcL."
Preliminary analysis of pharmacokinetics at the 30- and 50-mg dose levels showed a mean plasma half-life of greater than 40 hours. Moving forward, dose escalation will continue, he said, as the maximum tolerated dose has not yet been realized. Expansion cohorts are scheduled to begin in late 2014.
"These data provide early validation of mutant IDH-2 as a therapeutic target in AML and MDS," Dr. Stein said. "We’re going to be further characterizing the safety, pharmacokinetics/pharmacodynamics, and response rate of AG-221 in AML. Down the road, we’re hoping to evaluate this agent in combinations and in earlier lines to treatment. We’re also going to be exploring the activity of AG-221 in other IDH2-mutation-positive hematologic malignancies and solid tumors."
In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, said that she was impressed by the study’s findings in the context of refractory AML. "To be able to get responses with a drug that’s not nearly as toxic as chemotherapy, that is much more tolerable than chemotherapy, is exciting," she said.
"We don’t have long enough follow-up to know what those complete responses mean in terms of long-term survival. It is a phase I trial, but to see these kinds of responses in an AML refractory population with a selective drug against a mutated target, it’s a sign that there are some pretty exciting things happening in oncology these days."
Agios Pharmaceuticals funded the study. Dr. Stein disclosed that he has been a consultant for Janssen.
Agios Pharmaceuticals, halt tumor growth, oral inhibitor, isocitrate dehydrogenase-2 (IDH2) protein,
Agios Pharmaceuticals, halt tumor growth, oral inhibitor, isocitrate dehydrogenase-2 (IDH2) protein,
AT THE AACR ANNUAL MEETING
Major finding: Among seven patients evaluable for efficacy, five achieved complete remission or complete remission with partial platelet count recovery after treatment.
Data source: Preliminary results from a phase I trial of the novel agent AG-221 in patients with advanced hematologic malignancies with an isocitrate dehydrogenase-2 mutation.
Disclosures: Agios Pharmaceuticals funded the study. Dr. Stein disclosed that he has been a consultant for Janssen.
Patients with PD-L1–positive tumors had better response to immune checkpoint inhibitor
SAN DIEGO – Preliminary findings from two studies presented at the annual meeting of the American Association for Cancer Research suggest that cancer patients whose tumors contained the protein PD-L1 responded favorably to treatment with the investigational checkpoint inhibitor MK-3475.
A highly selective anti–PD-1 immunotherapy being developed by Merck, MK-3475 is designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein.
Both studies are analyses from the ongoing phase 1B KEYNOTE-001 study. In the first analysis, researchers led by Dr. Adil I. Daud evaluated tumor samples from 195 patients with late-stage melanoma who received MK-3475 at three different doses: 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks. Some of the patients had received prior treatment with ipilimumab.
Dr. Daud, codirector of the University of California, San Francisco, melanoma center and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, and his associates measured the amount of PD-L1 in the tumor samples and considered them PD-L1 positive if at least 1 cell/100 tumors cells stained by immunohistochemistry contained the protein. They also used multiplex flow cytometry to assess absolute CD4 and CD8 T-cell counts and the percentage of activated CD4 and CD8 T-cell counts in peripheral blood.
All study participants had a new tumor biopsy within 2 months before the first dose of MK-3475. Their mean age was 63 years, 76% were male, and 76% had BRAF wild-type tumors. Of the 125 evaluable tumor samples, 89 (71%) were PD-L1 positive and 36 were PD-L1 negative. Disease did not progress for about 50 weeks among patients with PD-L1–positive tumors, compared with about 12 weeks among those with PD-L1–negative tumors. Among the entire study population, the overall response rate was 40%, "which is high for immunotherapy," Dr. Daud said during a press briefing.
Based on cut point of at least 1 cell/100 tumors cells, the response rate among patients with PD-L1–positive tumors was 49%, compared with 13% among patients with PD-L1–negative tumors (P = .0007). At 6 months, 57% of patients with PD-L1–positive tumors had no disease progression, compared with 35% of those whose tumors were PD-L1 negative (P = 0.0051).
Between baseline and week 6, the researchers observed a significant median increase in the percentage of CD8-positive CD4-positive T cells (14.6% vs. 15.7%, respectively) though no significant change in the absolute numbers of circulating T cells was observed.
"Given the high prevalence of PD-L1–positive tumors, the clinical utility of PD-L1 expression in melanoma is not clear at this point, because unselected patients have such a high level of response," Dr. Daud said. Changes in T-cell subtype distribution as a pharmacodynamic marker "supports the proposed MK-3475 mechanism of action."
He characterized the study as "a good foundation to build on, and we think that ongoing studies looking at larger clinical trials will help clarify the role of PD-L1 expression in terms of correlating with response of patients treated with MK-3475. Clinical development of MK-3475, both as monotherapy and as part of combination strategies, is ongoing in multiple solid tumors and hematologic malignancies."
In the second study, Dr. Leena Gandhi presented extended data from an earlier trial of 38 patients with non–small cell lung cancer who were treated with MK-3475. That trial found that higher levels of PD-L1 expression "appeared to correlate with an increased response to MK-3475," Dr. Gandhi, a thoracic oncologist at the Dana-Farber Cancer Institute, Boston, said during a press briefing. The purpose of the current analysis, which included 146 patients, was to determine an optimal cut point for defining whether a tumor is likely to respond to MK-3475 therapy or not. The patients received the agent at three different doses: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. Tumors were assessed by imaging every 9 weeks and by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).
Dr. Gandhi and her associates found that PD-L1 levels of greater than 50% as measured by immunohistochemistry was the best cut-off point for determining whether a tumor is likely to respond to MK-3475. Six months after starting treatment, 41% of patients with tumors that contained high levels of PD-L1 prior to treatment had no disease progression, compared with 17% of those whose tumors contained low levels of PD-L1 (hazard ratio, 0.53; P = .004). This finding is "based on very small numbers of patients with long-term follow-up, so we expect that the final progression-free survival differences may change over time with additional patients," Dr. Gandhi noted.
As for overall survival, 72% of patients with tumors that contained high levels of PD-L1 were alive at 6 months, compared with 53% of those whose tumors contained low levels of PD-L1. This difference trended toward statistical significance (HR, 0.65; P = .134) and may also change as data from additional patients are realized, she said.
Dr. Gandhi noted that data from two ongoing studies will be used to "further explore the relationship between tumor PD-L1 expression and MK-3475 activity in NSCLC patients."
In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the MK-3475 biomarker as "maturing, but I still think it’s under investigation. I still think we have a ways to go in identifying the best predictive biomarker. I don’t think it’s 100% foolproof by any means."
Both studies were funded by Merck. Dr. Daud disclosed that he has served on the advisory board of Merck and GlaxoSmithKline. Dr. Gandhi said that she had no relevant financial conflicts to disclose.
Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.
SAN DIEGO – Preliminary findings from two studies presented at the annual meeting of the American Association for Cancer Research suggest that cancer patients whose tumors contained the protein PD-L1 responded favorably to treatment with the investigational checkpoint inhibitor MK-3475.
A highly selective anti–PD-1 immunotherapy being developed by Merck, MK-3475 is designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein.
Both studies are analyses from the ongoing phase 1B KEYNOTE-001 study. In the first analysis, researchers led by Dr. Adil I. Daud evaluated tumor samples from 195 patients with late-stage melanoma who received MK-3475 at three different doses: 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks. Some of the patients had received prior treatment with ipilimumab.
Dr. Daud, codirector of the University of California, San Francisco, melanoma center and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, and his associates measured the amount of PD-L1 in the tumor samples and considered them PD-L1 positive if at least 1 cell/100 tumors cells stained by immunohistochemistry contained the protein. They also used multiplex flow cytometry to assess absolute CD4 and CD8 T-cell counts and the percentage of activated CD4 and CD8 T-cell counts in peripheral blood.
All study participants had a new tumor biopsy within 2 months before the first dose of MK-3475. Their mean age was 63 years, 76% were male, and 76% had BRAF wild-type tumors. Of the 125 evaluable tumor samples, 89 (71%) were PD-L1 positive and 36 were PD-L1 negative. Disease did not progress for about 50 weeks among patients with PD-L1–positive tumors, compared with about 12 weeks among those with PD-L1–negative tumors. Among the entire study population, the overall response rate was 40%, "which is high for immunotherapy," Dr. Daud said during a press briefing.
Based on cut point of at least 1 cell/100 tumors cells, the response rate among patients with PD-L1–positive tumors was 49%, compared with 13% among patients with PD-L1–negative tumors (P = .0007). At 6 months, 57% of patients with PD-L1–positive tumors had no disease progression, compared with 35% of those whose tumors were PD-L1 negative (P = 0.0051).
Between baseline and week 6, the researchers observed a significant median increase in the percentage of CD8-positive CD4-positive T cells (14.6% vs. 15.7%, respectively) though no significant change in the absolute numbers of circulating T cells was observed.
"Given the high prevalence of PD-L1–positive tumors, the clinical utility of PD-L1 expression in melanoma is not clear at this point, because unselected patients have such a high level of response," Dr. Daud said. Changes in T-cell subtype distribution as a pharmacodynamic marker "supports the proposed MK-3475 mechanism of action."
He characterized the study as "a good foundation to build on, and we think that ongoing studies looking at larger clinical trials will help clarify the role of PD-L1 expression in terms of correlating with response of patients treated with MK-3475. Clinical development of MK-3475, both as monotherapy and as part of combination strategies, is ongoing in multiple solid tumors and hematologic malignancies."
In the second study, Dr. Leena Gandhi presented extended data from an earlier trial of 38 patients with non–small cell lung cancer who were treated with MK-3475. That trial found that higher levels of PD-L1 expression "appeared to correlate with an increased response to MK-3475," Dr. Gandhi, a thoracic oncologist at the Dana-Farber Cancer Institute, Boston, said during a press briefing. The purpose of the current analysis, which included 146 patients, was to determine an optimal cut point for defining whether a tumor is likely to respond to MK-3475 therapy or not. The patients received the agent at three different doses: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. Tumors were assessed by imaging every 9 weeks and by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).
Dr. Gandhi and her associates found that PD-L1 levels of greater than 50% as measured by immunohistochemistry was the best cut-off point for determining whether a tumor is likely to respond to MK-3475. Six months after starting treatment, 41% of patients with tumors that contained high levels of PD-L1 prior to treatment had no disease progression, compared with 17% of those whose tumors contained low levels of PD-L1 (hazard ratio, 0.53; P = .004). This finding is "based on very small numbers of patients with long-term follow-up, so we expect that the final progression-free survival differences may change over time with additional patients," Dr. Gandhi noted.
As for overall survival, 72% of patients with tumors that contained high levels of PD-L1 were alive at 6 months, compared with 53% of those whose tumors contained low levels of PD-L1. This difference trended toward statistical significance (HR, 0.65; P = .134) and may also change as data from additional patients are realized, she said.
Dr. Gandhi noted that data from two ongoing studies will be used to "further explore the relationship between tumor PD-L1 expression and MK-3475 activity in NSCLC patients."
In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the MK-3475 biomarker as "maturing, but I still think it’s under investigation. I still think we have a ways to go in identifying the best predictive biomarker. I don’t think it’s 100% foolproof by any means."
Both studies were funded by Merck. Dr. Daud disclosed that he has served on the advisory board of Merck and GlaxoSmithKline. Dr. Gandhi said that she had no relevant financial conflicts to disclose.
Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.
SAN DIEGO – Preliminary findings from two studies presented at the annual meeting of the American Association for Cancer Research suggest that cancer patients whose tumors contained the protein PD-L1 responded favorably to treatment with the investigational checkpoint inhibitor MK-3475.
A highly selective anti–PD-1 immunotherapy being developed by Merck, MK-3475 is designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein.
Both studies are analyses from the ongoing phase 1B KEYNOTE-001 study. In the first analysis, researchers led by Dr. Adil I. Daud evaluated tumor samples from 195 patients with late-stage melanoma who received MK-3475 at three different doses: 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 2 mg/kg every 3 weeks. Some of the patients had received prior treatment with ipilimumab.
Dr. Daud, codirector of the University of California, San Francisco, melanoma center and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center, and his associates measured the amount of PD-L1 in the tumor samples and considered them PD-L1 positive if at least 1 cell/100 tumors cells stained by immunohistochemistry contained the protein. They also used multiplex flow cytometry to assess absolute CD4 and CD8 T-cell counts and the percentage of activated CD4 and CD8 T-cell counts in peripheral blood.
All study participants had a new tumor biopsy within 2 months before the first dose of MK-3475. Their mean age was 63 years, 76% were male, and 76% had BRAF wild-type tumors. Of the 125 evaluable tumor samples, 89 (71%) were PD-L1 positive and 36 were PD-L1 negative. Disease did not progress for about 50 weeks among patients with PD-L1–positive tumors, compared with about 12 weeks among those with PD-L1–negative tumors. Among the entire study population, the overall response rate was 40%, "which is high for immunotherapy," Dr. Daud said during a press briefing.
Based on cut point of at least 1 cell/100 tumors cells, the response rate among patients with PD-L1–positive tumors was 49%, compared with 13% among patients with PD-L1–negative tumors (P = .0007). At 6 months, 57% of patients with PD-L1–positive tumors had no disease progression, compared with 35% of those whose tumors were PD-L1 negative (P = 0.0051).
Between baseline and week 6, the researchers observed a significant median increase in the percentage of CD8-positive CD4-positive T cells (14.6% vs. 15.7%, respectively) though no significant change in the absolute numbers of circulating T cells was observed.
"Given the high prevalence of PD-L1–positive tumors, the clinical utility of PD-L1 expression in melanoma is not clear at this point, because unselected patients have such a high level of response," Dr. Daud said. Changes in T-cell subtype distribution as a pharmacodynamic marker "supports the proposed MK-3475 mechanism of action."
He characterized the study as "a good foundation to build on, and we think that ongoing studies looking at larger clinical trials will help clarify the role of PD-L1 expression in terms of correlating with response of patients treated with MK-3475. Clinical development of MK-3475, both as monotherapy and as part of combination strategies, is ongoing in multiple solid tumors and hematologic malignancies."
In the second study, Dr. Leena Gandhi presented extended data from an earlier trial of 38 patients with non–small cell lung cancer who were treated with MK-3475. That trial found that higher levels of PD-L1 expression "appeared to correlate with an increased response to MK-3475," Dr. Gandhi, a thoracic oncologist at the Dana-Farber Cancer Institute, Boston, said during a press briefing. The purpose of the current analysis, which included 146 patients, was to determine an optimal cut point for defining whether a tumor is likely to respond to MK-3475 therapy or not. The patients received the agent at three different doses: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks. Tumors were assessed by imaging every 9 weeks and by RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).
Dr. Gandhi and her associates found that PD-L1 levels of greater than 50% as measured by immunohistochemistry was the best cut-off point for determining whether a tumor is likely to respond to MK-3475. Six months after starting treatment, 41% of patients with tumors that contained high levels of PD-L1 prior to treatment had no disease progression, compared with 17% of those whose tumors contained low levels of PD-L1 (hazard ratio, 0.53; P = .004). This finding is "based on very small numbers of patients with long-term follow-up, so we expect that the final progression-free survival differences may change over time with additional patients," Dr. Gandhi noted.
As for overall survival, 72% of patients with tumors that contained high levels of PD-L1 were alive at 6 months, compared with 53% of those whose tumors contained low levels of PD-L1. This difference trended toward statistical significance (HR, 0.65; P = .134) and may also change as data from additional patients are realized, she said.
Dr. Gandhi noted that data from two ongoing studies will be used to "further explore the relationship between tumor PD-L1 expression and MK-3475 activity in NSCLC patients."
In an interview, Dr. Patricia M. LoRusso, director of the Center for Translational Therapeutics at Wayne State University’s Karmanos Cancer Institute, Detroit, characterized the MK-3475 biomarker as "maturing, but I still think it’s under investigation. I still think we have a ways to go in identifying the best predictive biomarker. I don’t think it’s 100% foolproof by any means."
Both studies were funded by Merck. Dr. Daud disclosed that he has served on the advisory board of Merck and GlaxoSmithKline. Dr. Gandhi said that she had no relevant financial conflicts to disclose.
Dr. LoRusso disclosed that she has received research funding from Agios Pharmaceuticals.
AT THE AACR ANNUAL MEETING
Major finding: Overall response to MK-3475 among melanoma patients with PD-L1–positive tumors was 49%, compared with 13% among patients with PD-L1–negative tumors (P = .0007). In a separate study, 41% of NSCLC patients with tumors that contained high levels of PD-L1 prior to treatment had no disease progression, compared with 17% of those whose tumors contained low levels of PD-L1 (P = .004).
Data source: Two studies of 341 patients from the ongoing phase 1B KEYNOTE-001 study.
Disclosures: The studies were funded by Merck. Dr. Daud disclosed that he has served on the advisory board of Merck and GlaxoSmithKline. Dr. Gandhi said that she had no relevant financial conflicts to disclose.
Investigational acne treatment targets the sebaceous gland
DENVER – In the not-so-distant future, a treatment option for patients with moderate to severe acne may involve destruction of the sebaceous gland, according to Dr. R. Rox Anderson, director of the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston.
"If you look at the existing devices that are available for treating acne, none of them are really targeting the sebaceous gland itself," said Dr. Anderson. "They’re having secondary effects by eating skin or changing inflammatory reactions."
At the annual meeting of the American Academy of Dermatology, Dr. Anderson presented findings from a randomized phase I study of an investigational technique to target the sebaceous gland that consists of externally delivered plasmonic microparticles followed by pulsed laser irradiation, much like laser hair removal.
From a physiologic standpoint, Dr. Anderson likened the sebaceous gland to a small version of a lung. "It has an outflow tract that puts sebum out, but it doesn’t know how to inhale; it only exhales sebum," he explained. "The question is, can we make [the sebaceous gland] inhale and drive material into the gland itself? The strategy is to come up with a light-absorbing material, force it into the gland, then once the gland is made to absorb light, do selective photothermolysis – the same principles that were developed for hair removal."
Dr. Anderson and his associates randomized 48 adult patients with moderate to severe acne to treatment using a technology being developed by Duluth, Ga.–based company Sebacia, or to a control treatment. The 23 patients in the treatment arm received massage of 3 mL of a topical gold nanoparticle suspension and 800-nm laser irradiation without anesthesia for 12 weeks. In the control group, 25 patients used an over-the-counter face wash that contained salicylic acid, followed by laser treatment for 12 weeks, and then were crossed over to treatment with gold nanoparticles. The laser treatments occurred three times, two weeks apart, and consisted of two passes on a 9-mm square spot delivered at a fluence of 25-35 J/cm3 with a 30-second pulse duration. The study was conducted at two sites in Poland.
At 12 weeks, patients in the nanoparticle group had a 34% reduction in inflammatory lesion counts, compared with 16% in the salicylic acid group, a difference that reached significance (P = .02). At 7 months, patients in the treatment group had a 61% reduction in inflammatory lesion counts, compared with a 50% reduction among patients in the crossover group. "What was interesting to me is the lack of side effects," Dr. Anderson said. The treatment "was very well tolerated, very much like laser hair removal. You don’t have the pustulation and side effects of photodynamic therapy."
The gold nanoparticles used in the study were 150-300 nanometers in diameter and "are basically like a tattoo," Dr. Anderson said. "Once they get into the glands, do they stay there? Or do they come out?" To answer this question, the researchers measured the number of nanograms of material inserted, and observed that the sebaceus gland "constantly spits these particles out," even after laser exposure, he said.
Dr. Anderson characterized selective photothermolysis of the sebaceous gland as a technology "at the beginning, but we’ll see how this goes. It’s not available clinically yet, but maybe we’ll see it in our hands someday."
Dr. Anderson disclosed that he is a consultant for numerous pharmaceutical and device companies, including Sebacia.
DENVER – In the not-so-distant future, a treatment option for patients with moderate to severe acne may involve destruction of the sebaceous gland, according to Dr. R. Rox Anderson, director of the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston.
"If you look at the existing devices that are available for treating acne, none of them are really targeting the sebaceous gland itself," said Dr. Anderson. "They’re having secondary effects by eating skin or changing inflammatory reactions."
At the annual meeting of the American Academy of Dermatology, Dr. Anderson presented findings from a randomized phase I study of an investigational technique to target the sebaceous gland that consists of externally delivered plasmonic microparticles followed by pulsed laser irradiation, much like laser hair removal.
From a physiologic standpoint, Dr. Anderson likened the sebaceous gland to a small version of a lung. "It has an outflow tract that puts sebum out, but it doesn’t know how to inhale; it only exhales sebum," he explained. "The question is, can we make [the sebaceous gland] inhale and drive material into the gland itself? The strategy is to come up with a light-absorbing material, force it into the gland, then once the gland is made to absorb light, do selective photothermolysis – the same principles that were developed for hair removal."
Dr. Anderson and his associates randomized 48 adult patients with moderate to severe acne to treatment using a technology being developed by Duluth, Ga.–based company Sebacia, or to a control treatment. The 23 patients in the treatment arm received massage of 3 mL of a topical gold nanoparticle suspension and 800-nm laser irradiation without anesthesia for 12 weeks. In the control group, 25 patients used an over-the-counter face wash that contained salicylic acid, followed by laser treatment for 12 weeks, and then were crossed over to treatment with gold nanoparticles. The laser treatments occurred three times, two weeks apart, and consisted of two passes on a 9-mm square spot delivered at a fluence of 25-35 J/cm3 with a 30-second pulse duration. The study was conducted at two sites in Poland.
At 12 weeks, patients in the nanoparticle group had a 34% reduction in inflammatory lesion counts, compared with 16% in the salicylic acid group, a difference that reached significance (P = .02). At 7 months, patients in the treatment group had a 61% reduction in inflammatory lesion counts, compared with a 50% reduction among patients in the crossover group. "What was interesting to me is the lack of side effects," Dr. Anderson said. The treatment "was very well tolerated, very much like laser hair removal. You don’t have the pustulation and side effects of photodynamic therapy."
The gold nanoparticles used in the study were 150-300 nanometers in diameter and "are basically like a tattoo," Dr. Anderson said. "Once they get into the glands, do they stay there? Or do they come out?" To answer this question, the researchers measured the number of nanograms of material inserted, and observed that the sebaceus gland "constantly spits these particles out," even after laser exposure, he said.
Dr. Anderson characterized selective photothermolysis of the sebaceous gland as a technology "at the beginning, but we’ll see how this goes. It’s not available clinically yet, but maybe we’ll see it in our hands someday."
Dr. Anderson disclosed that he is a consultant for numerous pharmaceutical and device companies, including Sebacia.
DENVER – In the not-so-distant future, a treatment option for patients with moderate to severe acne may involve destruction of the sebaceous gland, according to Dr. R. Rox Anderson, director of the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston.
"If you look at the existing devices that are available for treating acne, none of them are really targeting the sebaceous gland itself," said Dr. Anderson. "They’re having secondary effects by eating skin or changing inflammatory reactions."
At the annual meeting of the American Academy of Dermatology, Dr. Anderson presented findings from a randomized phase I study of an investigational technique to target the sebaceous gland that consists of externally delivered plasmonic microparticles followed by pulsed laser irradiation, much like laser hair removal.
From a physiologic standpoint, Dr. Anderson likened the sebaceous gland to a small version of a lung. "It has an outflow tract that puts sebum out, but it doesn’t know how to inhale; it only exhales sebum," he explained. "The question is, can we make [the sebaceous gland] inhale and drive material into the gland itself? The strategy is to come up with a light-absorbing material, force it into the gland, then once the gland is made to absorb light, do selective photothermolysis – the same principles that were developed for hair removal."
Dr. Anderson and his associates randomized 48 adult patients with moderate to severe acne to treatment using a technology being developed by Duluth, Ga.–based company Sebacia, or to a control treatment. The 23 patients in the treatment arm received massage of 3 mL of a topical gold nanoparticle suspension and 800-nm laser irradiation without anesthesia for 12 weeks. In the control group, 25 patients used an over-the-counter face wash that contained salicylic acid, followed by laser treatment for 12 weeks, and then were crossed over to treatment with gold nanoparticles. The laser treatments occurred three times, two weeks apart, and consisted of two passes on a 9-mm square spot delivered at a fluence of 25-35 J/cm3 with a 30-second pulse duration. The study was conducted at two sites in Poland.
At 12 weeks, patients in the nanoparticle group had a 34% reduction in inflammatory lesion counts, compared with 16% in the salicylic acid group, a difference that reached significance (P = .02). At 7 months, patients in the treatment group had a 61% reduction in inflammatory lesion counts, compared with a 50% reduction among patients in the crossover group. "What was interesting to me is the lack of side effects," Dr. Anderson said. The treatment "was very well tolerated, very much like laser hair removal. You don’t have the pustulation and side effects of photodynamic therapy."
The gold nanoparticles used in the study were 150-300 nanometers in diameter and "are basically like a tattoo," Dr. Anderson said. "Once they get into the glands, do they stay there? Or do they come out?" To answer this question, the researchers measured the number of nanograms of material inserted, and observed that the sebaceus gland "constantly spits these particles out," even after laser exposure, he said.
Dr. Anderson characterized selective photothermolysis of the sebaceous gland as a technology "at the beginning, but we’ll see how this goes. It’s not available clinically yet, but maybe we’ll see it in our hands someday."
Dr. Anderson disclosed that he is a consultant for numerous pharmaceutical and device companies, including Sebacia.
EXPERT ANALYSIS FROM THE AAD ANNUAL MEETING
Major Finding: At 12 weeks, patients in the treatment group had a 34% reduction in inflammatory lesion counts, compared with 16% in the salicylic acid group, a significant difference.
Data Source: A randomized study of 48 patients with moderate to severe acne.
Disclosures: Dr. Anderson disclosed that he is a consultant for numerous pharmaceutical and device companies, including Sebacia.
What’s Old is New Again for Actinic Keratoses Treatment
DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.
Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.
Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."
As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."
Other topical preparations for actinic keratoses on the market include:
• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."
Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.
• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.
Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.
"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."
Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.
• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.
In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."
Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."
Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.
DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.
Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.
Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."
As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."
Other topical preparations for actinic keratoses on the market include:
• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."
Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.
• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.
Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.
"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."
Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.
• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.
In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."
Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."
Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.
DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.
Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.
Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."
As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."
Other topical preparations for actinic keratoses on the market include:
• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."
Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.
• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.
Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.
"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."
Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.
• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.
In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."
Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."
Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.
EXPERT ANALYSIS FROM THE AAD ANNUAL MEETING
What’s old is new again for actinic keratoses treatment
DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.
Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.
Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."
As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."
Other topical preparations for actinic keratoses on the market include:
• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."
Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.
• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.
Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.
"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."
Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.
• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.
In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."
Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."
Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.
DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.
Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.
Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."
As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."
Other topical preparations for actinic keratoses on the market include:
• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."
Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.
• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.
Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.
"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."
Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.
• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.
In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."
Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."
Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.
DENVER – Changes in health insurance coverage are prompting a resurgence in the use of 5-fluorouracil to treat actinic keratoses, according to Dr. Linda Susan Marcus.
Not only is 5-fluorouracil (5-FU) effective, "but it has become increasingly difficult to get some of the newer topical agents covered by health insurance plans, especially Medicare. This is the reality now," Dr. Marcus said at the annual meeting of the American Academy of Dermatology.
Dr. Marcus, a dermatologist in Wyckoff, N.J., noted that 5-FU blocks methylation of deoxyuridylic acid to thymidylic acid in DNA, altering only fast-dividing cancerous cells. The agent is available in 1%, 2%, and 5% solutions, and in 1% and 5% creams. "We don’t really use the solutions much anymore; they’re very irritating," Dr. Marcus said. "The 1% cream is less irritating, but 5% cream is really the gold standard." Her approach is to have patients apply the 5% 5-FU cream to the affected area twice a day for 3 weeks. Another option is a 0.5% 5-FU cream with a microsphere delivery system "that traps the active ingredients in the skin surface to increase efficacy and decrease irritancy," she said. "Some people use this for maintenance or cycle therapy prior to cryosurgery."
As for side effects, 5-FU elicits erythema, scaliness, and crusting (which can be avoided with the milder preparations); but these conditions are self-limited, Dr. Marcus noted. Some dermatologists use topical steroids or hyaluronic acid gels "to make the erythema go away faster," she added. "There are studies that say if you use these topical steroids, it curtails efficacy and you might lose some efficacy. That might be true. However, you have to make it user-friendly for the patient. Use your clinical judgment."
Other topical preparations for actinic keratoses on the market include:
• Diclofenac sodium 3% in 2.5% hyaluronic acid gel. This colorless agent is designed to be applied twice a day for 2-3 months. "That can pose a compliance issue for some patients," Dr. Marcus said. "The mechanism is unknown, but it probably functions as an NSAID that may involve prostaglandin levels in UV exposed skin and upregulation of COX-2, which may promote proliferation. Cyclooxygenase is the rate-limiting enzyme step in prostaglandin synthesis."
Dr. Marcus said that that diclofenac sodium 3% in 2.5% hyaluronic acid gel may be best suited for patients with mild lesions and for pre- or post cryosurgery.
• Imiquimod. A 5% formulation of imiquimod "is becoming the new gold standard of topical therapies, but it can be irritating," Dr. Marcus said. A 3.75% formulation is available that is designed to be used for 2 weeks, followed by a 2-week break, and then the patient repeats the cycle, Dr. Marcus said, adding that she uses the 3.75% formulation most often for her patients with actinic keratoses.
Dr. Marcus described imiquimod as an immune response modifier that induces mRNA encoding cytokines like alpha-interferon, TNF, and interleukin-12 for a cytotoxic T-lymphocyte response.
"There’s a direct proapoptotic effect in changing cancerous cells as a result of bypassing transduction paths activating caspase-3 downstream of membrane-bound death receptor activation," she said. "You can get a severe reaction, but there shouldn’t be a lot of pain. You get excellent cosmetic results upon healing."
Dermatologists often tweak the frequency of application, she added, and results from some studies suggest that outcomes with imiquimod are similar to those obtained with 5-FU, while others hint that imiquimod may provide longer-lasting results. "Field-directed therapy is the advantage since it brings out subclinical lesions, but you need a lot of hand holding to encourage patients with this phenomenon," Dr. Marcus said.
• Ingenol mebutate (PEP005). Approved as a gel in January of 2012, ingenol mebutate is a natural diterpene from the Euphorbia peplus flowering plant in Southeast Asia. The agent is believed to augment neutrophil-killing ability on abnormal cells via damaging mitochondria, and its antiangiogenic properties promote healing and skin regeneration. "It’s proven histologically in superficial basal cell epithelioma, which is interesting, because this drug is approved only in the United States and the indication is only for actinic keratosis and not for superficial basal cells," Dr. Marcus said.
In early studies, a 0.0025% preparation resulted in 38% clearance and was tolerable, while a 0.125% preparation gave 100% clearance but was too irritating. The approved form of ingenol mebutate gel is a 0.015% formulation applied daily for 3 days to head areas and ingenol mebutate gel 0.05% applied daily for 2 days to body areas. "You apply it for 3 days, but the reaction actually peaks on the 4th day, so when the patients are not applying it, they are still going to get a bit of redness before they’re into the healing phase," Dr. Marcus said. "The advantage is that you’re only applying it for 2-3 days, and then you’re done, so it increases compliance."
Photodynamic therapy is useful for field therapy, and it is done in one office visit, so compliance is not an issue, Dr. Marcus said. Photodynamic therapy also is covered by Medicare. "It may illicit some burning and require hand holding, but is effective," she said. "The key is combination therapy."
Dr. Marcus disclosed that she has received honoraria, grants, and research support from numerous pharmaceutical companies.
EXPERT ANALYSIS FROM THE AAD ANNUAL MEETING
Put to Rest the Calcium Supplement Controversy
SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).
Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.
Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."
Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."
Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D3 and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D3 and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.
The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).
Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.
Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.
Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.
"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."
"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."
Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."
Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.
SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).
Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.
Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."
Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."
Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D3 and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D3 and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.
The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).
Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.
Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.
Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.
"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."
"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."
Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."
Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.
SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).
Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.
Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."
Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."
Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D3 and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D3 and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.
The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).
Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.
Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.
Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.
"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."
"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."
Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."
Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.
EXPERT ANALYSIS FROM THE NATURAL SUPPLEMENTS UPDATE
It’s time to put to rest the calcium supplement controversy
SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).
Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.
Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."
Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."
Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D3 and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D3 and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.
The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).
Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.
Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.
Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.
"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."
"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."
Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."
Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.
SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).
Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.
Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."
Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."
Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D3 and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D3 and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.
The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).
Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.
Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.
Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.
"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."
"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."
Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."
Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.
SAN DIEGO – Lingering concern over increased risk cardiovascular events and mortality associated with calcium supplementation do not outweigh the bone benefits of calcium supplements, Connie Weaver, Ph.D., said at Natural Supplements: An Evidence-Based Update, presented by Scripps Center for Integrative Medicine.
In her opinion, the best randomized, controlled trial is from the Women’s Health Initiative, which found that calcium supplementation significantly reduced the risk of hip fracture and breast cancer, said Dr. Weaver, distinguished professor and head of the department of nutrition science at Purdue University, West Lafayette, Ind. In addition, there were no significant associations observed in the risk of myocardial infarction, heart disease, cardiovascular diseases, or death (Osteoporos. Int. 2013;24:567-80).
Other studies showing that calcium supplementation increased the risk for cardiovascular events were flawed in a number of ways, she said.
Questions about the value of calcium supplementation began to surface following publication of a meta-analysis of 15 trials that found a 30% increased in the incidence of myocardial infarction and smaller, nonsignificant increased in the risk of stroke and mortality (BMJ 2010;341:c3691). According to Dr. Weaver, who is also director of the Indiana Clinical and Translational Science Institute, this and other studies on the topic are limited by the fact that they are secondary analyses of studies designed to investigate bone. "So, if myocardial infarction or any other outcome measures are not part of your original plan, you may not be taking the measurements with the same care," she explained. "If you didn’t adjudicate, your self-reported information may turn out to be gastrointestinal discomfort, and the patient might confuse indigestion with myocardial infarction. That’s the kind of trouble you can get into with secondary analysis."
Other limitations of studies on this topic include a lack of baseline cardiovascular data and lack of standards for cardiovascular event ascertainment. "Self-reported data are very problematic," she maintained." In addition, no dose-response relationship was examined in many of these analyses, there was low compliance in intent to treat analyses, but the main thing for me was there was no underlying mechanism that was demonstrated."
Even so, in 2013 the U. S. Preventive Services Task Force weighed the existing evidence and recommended against daily supplements of less than 400 IU vitamin D3 and less than 1,000 mg of calcium for the prevention of fractures in postmenopausal women (Ann. Intern. Med. 2013;159:824-34). Further, they concluded that the current evidence is insufficient to recommend greater than 400 IU vitamin D3 and greater than 1,000 mg calcium for the prevention of fractures in postmenopausal women, premenopausal women, and men. "The controversy is unlikely to be resolved by epidemiological studies or secondary analysis of randomized controlled trials," Dr. Weaver said.
The mechanism by which calcium may lessen cardiovascular health remains elusive. Some speculate that a spike in circulating calcium following excessive calcium intake exacerbates coronary artery calcification and leads to subsequent cardiovascular dysfunction. "There is no research to show that this happens, but this is the speculated mechanism," Dr. Weaver said. However, in 2013 investigators published a study that demonstrated that an increase in serum calcium following a 1,000-mg oral dose of calcium citrate did not cause harmful changes in cardiovascular function (J. Bone Miner. Res. 2013; 28:412-8).
Data from one animal study may lend support to the safety of calcium supplements. Dr. Weaver led an interdisciplinary team to study soft tissue calcification in 24 Ossabaw miniature swine. Previous studies of these pigs have demonstrated that when fed an excess calorie atherogenic diet, they develop metabolic syndrome and progress to coronary atherosclerosis.
Dr. Weaver and her associates randomized the pigs into to three dietary intake groups: control, high dairy (nonfat milk) or high supplement (calcium carbonate). After a little more than 5 months on their allocated diet, the pigs underwent jugular injection of the tracer 41Ca, which has a long half-life and can be monitored sensitively at low levels expected in tissue. The researchers collected blood and urine samples, conducted intravascular ultrasound imaging and PET-CT to assess coronary artery disease, and performed an in vitro wire myography on the proximal 1.5 cm of left anterior descending artery. This procedure "examines functional responses and vascular reactivity of arteries and is a sensitive and early indicator of compromised cell function," Dr. Weaver explained.
Intravascular ultrasound detected no significant differences in plaque wall coverage between the three dietary groups and PET-CT found that stroke volume and ejection fraction did not differ among the groups. In vitro myography also demonstrated no differences between the three groups, even when smooth muscle of the left anterior descending artery was exposed to bradykinin and sodium nitroprusside. Histology also demonstrated no differences between the three groups.
"We hope our case study puts to rest these concerns about calcium supplements so we cover our bones as well as not worry about cardiovascular effects," Dr. Weaver concluded. "Adequate intake of calcium should be below the tolerable upper limit and should be encouraged for bone health. Most dietary guidance committees recommend foods as the first choice, but supplements should be used to fill dietary shortcomings. So if the dietary guidelines recommend 3 cups/day of low-fat dairy product equivalents to get enough calcium, the addition of a 300-mg calcium supplement is recommended for every one serving missed."
"Bone health is a lifelong concern," she said. "Peak skeletal mass is achieved by ages 20-30 and the adult skeleton is remodeled and replaced every 10 years."
Milk contains enough calcium to meet dietary recommendations, but milk consumption is decreasing among Americans in all age groups, especially in children, she said. "This decline could set them up to grow lower levels of bone mass. Over life, that could position them to be in a fracture zone earlier. So we have to be concerned: How do we get these minerals needed if use of the main dietary source – milk – is declining? The controversy of calcium supplements comes to the forefront, because that is one alternative to milk. There are not that many foods that are concentrated in well-absorbed calcium."
Dr. Weaver disclosed that she serves on the boards of the National Osteoporosis Foundation, the International Life Sciences Institute, Showalter, and Pharmavite. She has also received grant support from the National Institutes of Health, the Dairy Research Institute, Nestle, and Tate & Lyle.
EXPERT ANALYSIS FROM THE NATURAL SUPPLEMENTS UPDATE
Tofacitinib found noninferior to etanercept for treating psoriasis
DENVER – Key results from a phase III trial found that an investigational Janus kinase inhibitor was noninferior to a biologic agent for treating psoriasis.
During a late-breaking session at the annual meeting of the American Academy of Dermatology, Dr. Fernando Valenzuela presented findings from a multicenter, double-dummy 12-week comparison of tofacitinib vs. etanercept or placebo for the treatment of patients with moderate to severe psoriasis. Tofacitinib is an investigational Janus kinase inhibitor being developed by Pfizer.
Twice-daily tofacitinib at 5 mg and 10 mg was effective in patients with moderate to severe psoriasis, and the efficacy of twice-daily tofacitinib at 10 mg was similar to twice-weekly etanercept at 50 mg and was superior to placebo.
"Plaque psoriasis is a chronic, immune-mediated systemic disease [that] can lead to major quality of life impairment in its moderate to severe forms," said Dr. Valenzuela of the department of dermatology at the University of Chile Clinical Hospital, Santiago. "The JAK/STAT [Janus kinase/signal transducers and activators of transcription] signaling pathway is implicated in the pathogenesis of chronic immune-mediated diseases including psoriasis. Tofacitinib has previously demonstrated significant efficacy in a placebo-controlled, phase II study in patients with moderate to severe plaque psoriasis."
In the 12-week multicenter trial known as OPT Compare, which was conducted in 23 countries outside of North America, he and his associates assessed the noninferiority/superiority of two doses of oral tofacitinib vs. high-dose etanercept or placebo. To be eligible for the trial, patients had to be at least 18 years of age; have moderate to severe chronic plaque psoriasis; be candidates for systemic therapy or phototherapy; have a Psoriasis Area and Severity Index (PASI) of 12 or greater; have a Physician’s Global Assessment (PGA) of moderate or severe; have psoriasis involvement of 10% or greater body surface area; and had failed to respond, tolerate, or have a contraindication to at least one systemic therapy. Patients previously treated with etanercept or who previously experienced failure to treatment with a tumor necrosis factor therapy were excluded from the trial.
Patients were randomized 3:3:3:1 in the following fashion over a 12-week period: 329 received tofacitinib b.i.d.; 330 received tofacitinib 10 mg b.i.d.; 335 received etanercept 50 mg subcutaneously twice weekly; and 107 received placebo. The coprimary efficacy endpoints were the proportion of patients achieving at least a 75% reduction in PASI score at week 12 from baseline and a PGA score of "clear" or "almost clear" at week 12. The researchers used a fixed sequence procedure to assess noninferiority/superiority sequentially in order to control overall type 1 error. The mean age of patients was 44 years and about 82% of patients had moderate disease.
Dr. Valenzuela reported that at 12 weeks, 39.5%, 63.6%, 58.8%, and 5.6% of patients achieved PASI 75 responses and 47.1%, 68.2%, 66.3%, and 15.0% achieved PGA responses with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, etanercept 50 mg twice weekly, and placebo, respectively. Tofacitinib 10 mg twice a day was noninferior to etanercept and superior to placebo (P less than .0001), but tofacitinib 5 mg twice a day did not meet the noninferiority criterion vs. etanercept.
Over 12 weeks, the safety and tolerability of either dose of tofacitinib was similar to that of etanercept. "The most frequent adverse events were infections, most commonly nasopharyngitis and upper respiratory tract infection," Dr. Valenzuela said. "Hypercholesterolemia and dyslipidemia were more common in tofacitinib recipients, as was an increase in creatine phosphokinase*." Injection site reactions were most frequent among etanercept recipients.
The study was sponsored by Pfizer. Dr. Valenzuela disclosed that he has been a principal investigator, member of a scientific advisory board, or speaker for Pfizer, Janssen, Eli Lilly, Merck, and Novartis.
*Correction, 3/27/2014: An earlier version of this article misstated the term creatine phosphokinase.
DENVER – Key results from a phase III trial found that an investigational Janus kinase inhibitor was noninferior to a biologic agent for treating psoriasis.
During a late-breaking session at the annual meeting of the American Academy of Dermatology, Dr. Fernando Valenzuela presented findings from a multicenter, double-dummy 12-week comparison of tofacitinib vs. etanercept or placebo for the treatment of patients with moderate to severe psoriasis. Tofacitinib is an investigational Janus kinase inhibitor being developed by Pfizer.
Twice-daily tofacitinib at 5 mg and 10 mg was effective in patients with moderate to severe psoriasis, and the efficacy of twice-daily tofacitinib at 10 mg was similar to twice-weekly etanercept at 50 mg and was superior to placebo.
"Plaque psoriasis is a chronic, immune-mediated systemic disease [that] can lead to major quality of life impairment in its moderate to severe forms," said Dr. Valenzuela of the department of dermatology at the University of Chile Clinical Hospital, Santiago. "The JAK/STAT [Janus kinase/signal transducers and activators of transcription] signaling pathway is implicated in the pathogenesis of chronic immune-mediated diseases including psoriasis. Tofacitinib has previously demonstrated significant efficacy in a placebo-controlled, phase II study in patients with moderate to severe plaque psoriasis."
In the 12-week multicenter trial known as OPT Compare, which was conducted in 23 countries outside of North America, he and his associates assessed the noninferiority/superiority of two doses of oral tofacitinib vs. high-dose etanercept or placebo. To be eligible for the trial, patients had to be at least 18 years of age; have moderate to severe chronic plaque psoriasis; be candidates for systemic therapy or phototherapy; have a Psoriasis Area and Severity Index (PASI) of 12 or greater; have a Physician’s Global Assessment (PGA) of moderate or severe; have psoriasis involvement of 10% or greater body surface area; and had failed to respond, tolerate, or have a contraindication to at least one systemic therapy. Patients previously treated with etanercept or who previously experienced failure to treatment with a tumor necrosis factor therapy were excluded from the trial.
Patients were randomized 3:3:3:1 in the following fashion over a 12-week period: 329 received tofacitinib b.i.d.; 330 received tofacitinib 10 mg b.i.d.; 335 received etanercept 50 mg subcutaneously twice weekly; and 107 received placebo. The coprimary efficacy endpoints were the proportion of patients achieving at least a 75% reduction in PASI score at week 12 from baseline and a PGA score of "clear" or "almost clear" at week 12. The researchers used a fixed sequence procedure to assess noninferiority/superiority sequentially in order to control overall type 1 error. The mean age of patients was 44 years and about 82% of patients had moderate disease.
Dr. Valenzuela reported that at 12 weeks, 39.5%, 63.6%, 58.8%, and 5.6% of patients achieved PASI 75 responses and 47.1%, 68.2%, 66.3%, and 15.0% achieved PGA responses with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, etanercept 50 mg twice weekly, and placebo, respectively. Tofacitinib 10 mg twice a day was noninferior to etanercept and superior to placebo (P less than .0001), but tofacitinib 5 mg twice a day did not meet the noninferiority criterion vs. etanercept.
Over 12 weeks, the safety and tolerability of either dose of tofacitinib was similar to that of etanercept. "The most frequent adverse events were infections, most commonly nasopharyngitis and upper respiratory tract infection," Dr. Valenzuela said. "Hypercholesterolemia and dyslipidemia were more common in tofacitinib recipients, as was an increase in creatine phosphokinase*." Injection site reactions were most frequent among etanercept recipients.
The study was sponsored by Pfizer. Dr. Valenzuela disclosed that he has been a principal investigator, member of a scientific advisory board, or speaker for Pfizer, Janssen, Eli Lilly, Merck, and Novartis.
*Correction, 3/27/2014: An earlier version of this article misstated the term creatine phosphokinase.
DENVER – Key results from a phase III trial found that an investigational Janus kinase inhibitor was noninferior to a biologic agent for treating psoriasis.
During a late-breaking session at the annual meeting of the American Academy of Dermatology, Dr. Fernando Valenzuela presented findings from a multicenter, double-dummy 12-week comparison of tofacitinib vs. etanercept or placebo for the treatment of patients with moderate to severe psoriasis. Tofacitinib is an investigational Janus kinase inhibitor being developed by Pfizer.
Twice-daily tofacitinib at 5 mg and 10 mg was effective in patients with moderate to severe psoriasis, and the efficacy of twice-daily tofacitinib at 10 mg was similar to twice-weekly etanercept at 50 mg and was superior to placebo.
"Plaque psoriasis is a chronic, immune-mediated systemic disease [that] can lead to major quality of life impairment in its moderate to severe forms," said Dr. Valenzuela of the department of dermatology at the University of Chile Clinical Hospital, Santiago. "The JAK/STAT [Janus kinase/signal transducers and activators of transcription] signaling pathway is implicated in the pathogenesis of chronic immune-mediated diseases including psoriasis. Tofacitinib has previously demonstrated significant efficacy in a placebo-controlled, phase II study in patients with moderate to severe plaque psoriasis."
In the 12-week multicenter trial known as OPT Compare, which was conducted in 23 countries outside of North America, he and his associates assessed the noninferiority/superiority of two doses of oral tofacitinib vs. high-dose etanercept or placebo. To be eligible for the trial, patients had to be at least 18 years of age; have moderate to severe chronic plaque psoriasis; be candidates for systemic therapy or phototherapy; have a Psoriasis Area and Severity Index (PASI) of 12 or greater; have a Physician’s Global Assessment (PGA) of moderate or severe; have psoriasis involvement of 10% or greater body surface area; and had failed to respond, tolerate, or have a contraindication to at least one systemic therapy. Patients previously treated with etanercept or who previously experienced failure to treatment with a tumor necrosis factor therapy were excluded from the trial.
Patients were randomized 3:3:3:1 in the following fashion over a 12-week period: 329 received tofacitinib b.i.d.; 330 received tofacitinib 10 mg b.i.d.; 335 received etanercept 50 mg subcutaneously twice weekly; and 107 received placebo. The coprimary efficacy endpoints were the proportion of patients achieving at least a 75% reduction in PASI score at week 12 from baseline and a PGA score of "clear" or "almost clear" at week 12. The researchers used a fixed sequence procedure to assess noninferiority/superiority sequentially in order to control overall type 1 error. The mean age of patients was 44 years and about 82% of patients had moderate disease.
Dr. Valenzuela reported that at 12 weeks, 39.5%, 63.6%, 58.8%, and 5.6% of patients achieved PASI 75 responses and 47.1%, 68.2%, 66.3%, and 15.0% achieved PGA responses with tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, etanercept 50 mg twice weekly, and placebo, respectively. Tofacitinib 10 mg twice a day was noninferior to etanercept and superior to placebo (P less than .0001), but tofacitinib 5 mg twice a day did not meet the noninferiority criterion vs. etanercept.
Over 12 weeks, the safety and tolerability of either dose of tofacitinib was similar to that of etanercept. "The most frequent adverse events were infections, most commonly nasopharyngitis and upper respiratory tract infection," Dr. Valenzuela said. "Hypercholesterolemia and dyslipidemia were more common in tofacitinib recipients, as was an increase in creatine phosphokinase*." Injection site reactions were most frequent among etanercept recipients.
The study was sponsored by Pfizer. Dr. Valenzuela disclosed that he has been a principal investigator, member of a scientific advisory board, or speaker for Pfizer, Janssen, Eli Lilly, Merck, and Novartis.
*Correction, 3/27/2014: An earlier version of this article misstated the term creatine phosphokinase.
AT THE AAD ANNUAL MEETING
Major finding: Twice-daily tofacitinib at 5 mg and 10 mg was effective in patients with moderate to severe psoriasis, and the efficacy of twice-daily tofacitinib at 10 mg was similar to twice-weekly etanercept at 50 mg and was superior to placebo.
Data source: A phase III, multicenter, double dummy trial in which patients with moderate to severe psoriasis were randomized 3:3:3:1 in the following fashion over a 12-week period: 329 received tofacitinib twice a day; 330 received tofacitinib 10 mg twice a day; 335 received etanercept 50 mg subcutaneously twice weekly; and 107 received placebo.
Disclosures: The study was sponsored by Pfizer. Dr. Valenzuela disclosed that he has been a principal investigator, member of a scientific advisory board, or speaker for Pfizer, Janssen, Eli Lilly, Merck, and Novartis.