Pharmacology

A handful of studies have suggested that for newly infected COVID-19 patients, risk for serious illness may be reduced with a short course of fluvoxamine (Luvox), a decades-old pill typically prescribed for depression or obsessive-compulsive disorder (OCD). But those were small studies involving just a few hundred people.

This week, researchers reported promising data from a large, randomized phase 3 trial that enrolled COVID-19 patients from 11 sites in Brazil. In this study, in which 1,472 people were assigned to receive either a 10-day course of fluvoxamine or placebo pills, the antidepressant cut emergency department and hospital admissions by 29%.

Findings from the new study, which have not yet been peer reviewed, were published August 23 in MedRxiv.

Around the globe, particularly in countries without access to vaccines, “treatment options that are cheap and available and supported by good-quality evidence are the only hope we’ve got to reduce mortality within high-risk populations,” said Edward Mills, PhD, professor in the department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont.

The new findings came from TOGETHER, a large platform trial coordinated by Dr. Mills and colleagues to evaluate the use of fluvoxamine and other repurposed drug candidates for symptomatic, high-risk, adult outpatients with confirmed cases of COVID-19.

The trial’s adaptive format allows multiple agents to be added and tested alongside placebo in a single master protocol – similar to the United Kingdom’s Recovery trial, which found that the common steroid dexamethasone could reduce deaths among hospitalized COVID-19 patients.

In platform trials, treatment arms can be dropped for futility, as was the case with hydroxychloroquine and lopinavir-ritonavir, neither of which did better than placebo at preventing hospitalization in an earlier TOGETHER trial analysis.
 

Study details

In the newly reported analysis, patients were randomly assigned to receive fluvoxamine or placebo between January and August 2021. Participants took fluvoxamine 100 mg twice daily for 10 days. By comparison, the U.S. Food and Drug Administration recommends a maximum daily dose of 300 mg of fluvoxamine for patients with OCD; full psychiatric benefits occur after 6 weeks.

For the primary outcome, the investigators assessed whether the conditions of patients with COVID worsened over a 28-day period so as to require either hospitalization or observation in the emergency department for more than 6 hours. In the placebo group, 108 of 733 patients’ conditions deteriorated to this extent (14.7%); by contrast, only 77 of 739 patients in the fluvoxamine group (10.4%) met these primary criteria – a relative risk reduction of 29%.

The treatment effect was greater (34%) in the per protocol analysis of participants who completed their course of pills.

The investigators also collected data on vital signs, including temperature and oxygen saturation, as well as adverse events reported at clinic visits or through video conferencing, phone calls, or social media applications. Side effects were mild, most commonly nausea and fatigue, and did not differ significantly between active treatment and control groups, Dr. Mills said in an interview.

Amid scores of studies evaluating repurposed drugs for COVID-19, the data on fluvoxamine are “looking much more favorable than anyone could have guessed – at least anyone in infectious disease,” said Paul Sax, MD, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

The new TOGETHER trial results augment supportive data published in JAMA last November from a phase 2 randomized trial that was small but “very well done,” Dr. Sax told this news organization.

Those results got a boost from a subsequent study of 65 racetrack workers who chose to take fluvoxamine during a COVID-19 outbreak in the San Francisco Bay area. Forty-eight persons opted against taking the drug. In this small, nonrandomized study, “the people who chose to be treated with fluvoxamine were sicker [at baseline] than the people who didn’t go on it, and yet the [treated group] ended up better,” said Dr. Sax, who discussed accumulating data on the use of fluvoxamine for COVID-19 in a recent New England Journal of Medicine blog post.
 

Anti-inflammatory effect?

After reviewing the new findings, Frank Domino, MD, professor of family medicine and community health at the University of Massachusetts, Worcester, said he would encourage patients with high-risk COVID-19 to consider taking fluvoxamine to lower their risk of being hospitalized. “But I would make it clear this was not a ‘cure,’ “ he said, “and we are unsure how it helps.”

At this point, U.S. treatment guidelines do not recommend fluvoxamine as the standard of care for nonhospitalized COVID-19 patients, but the National Institutes of Health is “very aware of the data,” Dr. Sax told this news organization.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) – a class of drugs that includes the more commonly prescribed antidepressant fluoxetine (Prozac). If prescribed off-label to COVID-19 patients, fluvoxamine should not be used within 2 weeks of starting treatment with other SSRI or monoamine oxidase inhibitor antidepressants and should be used with caution with other QT-interval prolonging medications, Dr. Sax said.

In addition, fluvoxamine can enhance the effect of antiplatelet and anticoagulant drugs, potentially triggering bleeding.

On the basis of in vitro and mouse studies of fluvoxamine, “we think it has an anti-inflammatory effect,” said child psychiatrist Angela Reiersen, MD, of Washington University, St. Louis, who came up with the idea for testing fluvoxamine in last year’s phase 2 trial and coauthored a recent article describing the drug’s potential mechanisms of action in COVID-19.

She and other researchers believe fluvoxamine’s anti-inflammatory effects derive from the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, which regulates cellular responses to stress and infection.

Fluvoxamine also inhibits the activation of platelets. “In COVID-19, there does seem to be a problem with hyperactivation of platelets and excessive blood clots forming, so it is possible this could be another mechanism where it might be helping,” Dr. Reiersen said.

If sigma-1 activation turns out to be the main mechanism underlying fluvoxamine’s benefits in COVID-19, other sigma-1 agonists, such as fluoxetine, may also help. In a retrospective analysis of thousands of adults hospitalized for COVID-19 in France early in the pandemic, those who were taking antidepressants had a 44% lower risk for intubation or death.

And in a study under review, researchers at Stanford (Calif.) University and the University of California, San Francisco, analyzed electronic health records to explore a potential link between fluoxetine use and COVID outcomes among more than 80,000 patients from over 80 institutions across the United States. Other research suggests that antipsychotics could also have protective effects for patients with COVID-19.
 

Long COVID, long-term challenges

On the basis of its potential mechanisms of action, fluvoxamine may be able to prevent or treat long COVID, Dr. Reiersen said. That possibility will be assessed among other secondary endpoints in two ongoing studies of repurposed drugs: the NIH’s ACTIV-6, and the University of Minnesota’s COVID-OUT, an at-home trial of ivermectin, metformin, and fluvoxamine.

Dr. Reiersen and Washington University colleagues are also analyzing longer-term outcomes of participants in their own phase 3 trial of fluvoxamine (Stop COVID 2), which was discontinued when enrollment slowed to a trickle during the U.S. vaccine rollout. Logistical hurdles and scant funding have greatly hampered efforts to test the use of off-patent drugs for COVID-19 outpatients during the pandemic.

U.S. efforts face other obstacles as well. Elsewhere in the world – including Brazil, where the TOGETHER trial was run – vaccines are scarce, and there are no monoclonal antibodies.

“People have a great sense of community duty, and they’re participating in the trials,” Dr. Mills said. “You’re in a much more political environment in the U.S. on these outpatient trials.”

The TOGETHER trial was funded by Fast Grants and the Rainwater Foundation. Dr. Reiersen is an inventor on a patent application related to methods of treating COVID-19, which was filed by Washington University, St. Louis. Dr. Mills, Dr. Domino, and Dr. Sax report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A handful of studies have suggested that for newly infected COVID-19 patients, risk for serious illness may be reduced with a short course of fluvoxamine (Luvox), a decades-old pill typically prescribed for depression or obsessive-compulsive disorder (OCD). But those were small studies involving just a few hundred people.

This week, researchers reported promising data from a large, randomized phase 3 trial that enrolled COVID-19 patients from 11 sites in Brazil. In this study, in which 1,472 people were assigned to receive either a 10-day course of fluvoxamine or placebo pills, the antidepressant cut emergency department and hospital admissions by 29%.

Findings from the new study, which have not yet been peer reviewed, were published August 23 in MedRxiv.

Around the globe, particularly in countries without access to vaccines, “treatment options that are cheap and available and supported by good-quality evidence are the only hope we’ve got to reduce mortality within high-risk populations,” said Edward Mills, PhD, professor in the department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont.

The new findings came from TOGETHER, a large platform trial coordinated by Dr. Mills and colleagues to evaluate the use of fluvoxamine and other repurposed drug candidates for symptomatic, high-risk, adult outpatients with confirmed cases of COVID-19.

The trial’s adaptive format allows multiple agents to be added and tested alongside placebo in a single master protocol – similar to the United Kingdom’s Recovery trial, which found that the common steroid dexamethasone could reduce deaths among hospitalized COVID-19 patients.

In platform trials, treatment arms can be dropped for futility, as was the case with hydroxychloroquine and lopinavir-ritonavir, neither of which did better than placebo at preventing hospitalization in an earlier TOGETHER trial analysis.
 

Study details

In the newly reported analysis, patients were randomly assigned to receive fluvoxamine or placebo between January and August 2021. Participants took fluvoxamine 100 mg twice daily for 10 days. By comparison, the U.S. Food and Drug Administration recommends a maximum daily dose of 300 mg of fluvoxamine for patients with OCD; full psychiatric benefits occur after 6 weeks.

For the primary outcome, the investigators assessed whether the conditions of patients with COVID worsened over a 28-day period so as to require either hospitalization or observation in the emergency department for more than 6 hours. In the placebo group, 108 of 733 patients’ conditions deteriorated to this extent (14.7%); by contrast, only 77 of 739 patients in the fluvoxamine group (10.4%) met these primary criteria – a relative risk reduction of 29%.

The treatment effect was greater (34%) in the per protocol analysis of participants who completed their course of pills.

The investigators also collected data on vital signs, including temperature and oxygen saturation, as well as adverse events reported at clinic visits or through video conferencing, phone calls, or social media applications. Side effects were mild, most commonly nausea and fatigue, and did not differ significantly between active treatment and control groups, Dr. Mills said in an interview.

Amid scores of studies evaluating repurposed drugs for COVID-19, the data on fluvoxamine are “looking much more favorable than anyone could have guessed – at least anyone in infectious disease,” said Paul Sax, MD, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

The new TOGETHER trial results augment supportive data published in JAMA last November from a phase 2 randomized trial that was small but “very well done,” Dr. Sax told this news organization.

Those results got a boost from a subsequent study of 65 racetrack workers who chose to take fluvoxamine during a COVID-19 outbreak in the San Francisco Bay area. Forty-eight persons opted against taking the drug. In this small, nonrandomized study, “the people who chose to be treated with fluvoxamine were sicker [at baseline] than the people who didn’t go on it, and yet the [treated group] ended up better,” said Dr. Sax, who discussed accumulating data on the use of fluvoxamine for COVID-19 in a recent New England Journal of Medicine blog post.
 

Anti-inflammatory effect?

After reviewing the new findings, Frank Domino, MD, professor of family medicine and community health at the University of Massachusetts, Worcester, said he would encourage patients with high-risk COVID-19 to consider taking fluvoxamine to lower their risk of being hospitalized. “But I would make it clear this was not a ‘cure,’ “ he said, “and we are unsure how it helps.”

At this point, U.S. treatment guidelines do not recommend fluvoxamine as the standard of care for nonhospitalized COVID-19 patients, but the National Institutes of Health is “very aware of the data,” Dr. Sax told this news organization.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) – a class of drugs that includes the more commonly prescribed antidepressant fluoxetine (Prozac). If prescribed off-label to COVID-19 patients, fluvoxamine should not be used within 2 weeks of starting treatment with other SSRI or monoamine oxidase inhibitor antidepressants and should be used with caution with other QT-interval prolonging medications, Dr. Sax said.

In addition, fluvoxamine can enhance the effect of antiplatelet and anticoagulant drugs, potentially triggering bleeding.

On the basis of in vitro and mouse studies of fluvoxamine, “we think it has an anti-inflammatory effect,” said child psychiatrist Angela Reiersen, MD, of Washington University, St. Louis, who came up with the idea for testing fluvoxamine in last year’s phase 2 trial and coauthored a recent article describing the drug’s potential mechanisms of action in COVID-19.

She and other researchers believe fluvoxamine’s anti-inflammatory effects derive from the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, which regulates cellular responses to stress and infection.

Fluvoxamine also inhibits the activation of platelets. “In COVID-19, there does seem to be a problem with hyperactivation of platelets and excessive blood clots forming, so it is possible this could be another mechanism where it might be helping,” Dr. Reiersen said.

If sigma-1 activation turns out to be the main mechanism underlying fluvoxamine’s benefits in COVID-19, other sigma-1 agonists, such as fluoxetine, may also help. In a retrospective analysis of thousands of adults hospitalized for COVID-19 in France early in the pandemic, those who were taking antidepressants had a 44% lower risk for intubation or death.

And in a study under review, researchers at Stanford (Calif.) University and the University of California, San Francisco, analyzed electronic health records to explore a potential link between fluoxetine use and COVID outcomes among more than 80,000 patients from over 80 institutions across the United States. Other research suggests that antipsychotics could also have protective effects for patients with COVID-19.
 

Long COVID, long-term challenges

On the basis of its potential mechanisms of action, fluvoxamine may be able to prevent or treat long COVID, Dr. Reiersen said. That possibility will be assessed among other secondary endpoints in two ongoing studies of repurposed drugs: the NIH’s ACTIV-6, and the University of Minnesota’s COVID-OUT, an at-home trial of ivermectin, metformin, and fluvoxamine.

Dr. Reiersen and Washington University colleagues are also analyzing longer-term outcomes of participants in their own phase 3 trial of fluvoxamine (Stop COVID 2), which was discontinued when enrollment slowed to a trickle during the U.S. vaccine rollout. Logistical hurdles and scant funding have greatly hampered efforts to test the use of off-patent drugs for COVID-19 outpatients during the pandemic.

U.S. efforts face other obstacles as well. Elsewhere in the world – including Brazil, where the TOGETHER trial was run – vaccines are scarce, and there are no monoclonal antibodies.

“People have a great sense of community duty, and they’re participating in the trials,” Dr. Mills said. “You’re in a much more political environment in the U.S. on these outpatient trials.”

The TOGETHER trial was funded by Fast Grants and the Rainwater Foundation. Dr. Reiersen is an inventor on a patent application related to methods of treating COVID-19, which was filed by Washington University, St. Louis. Dr. Mills, Dr. Domino, and Dr. Sax report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A handful of studies have suggested that for newly infected COVID-19 patients, risk for serious illness may be reduced with a short course of fluvoxamine (Luvox), a decades-old pill typically prescribed for depression or obsessive-compulsive disorder (OCD). But those were small studies involving just a few hundred people.

This week, researchers reported promising data from a large, randomized phase 3 trial that enrolled COVID-19 patients from 11 sites in Brazil. In this study, in which 1,472 people were assigned to receive either a 10-day course of fluvoxamine or placebo pills, the antidepressant cut emergency department and hospital admissions by 29%.

Findings from the new study, which have not yet been peer reviewed, were published August 23 in MedRxiv.

Around the globe, particularly in countries without access to vaccines, “treatment options that are cheap and available and supported by good-quality evidence are the only hope we’ve got to reduce mortality within high-risk populations,” said Edward Mills, PhD, professor in the department of health research methods, evidence, and impact, McMaster University, Hamilton, Ont.

The new findings came from TOGETHER, a large platform trial coordinated by Dr. Mills and colleagues to evaluate the use of fluvoxamine and other repurposed drug candidates for symptomatic, high-risk, adult outpatients with confirmed cases of COVID-19.

The trial’s adaptive format allows multiple agents to be added and tested alongside placebo in a single master protocol – similar to the United Kingdom’s Recovery trial, which found that the common steroid dexamethasone could reduce deaths among hospitalized COVID-19 patients.

In platform trials, treatment arms can be dropped for futility, as was the case with hydroxychloroquine and lopinavir-ritonavir, neither of which did better than placebo at preventing hospitalization in an earlier TOGETHER trial analysis.
 

Study details

In the newly reported analysis, patients were randomly assigned to receive fluvoxamine or placebo between January and August 2021. Participants took fluvoxamine 100 mg twice daily for 10 days. By comparison, the U.S. Food and Drug Administration recommends a maximum daily dose of 300 mg of fluvoxamine for patients with OCD; full psychiatric benefits occur after 6 weeks.

For the primary outcome, the investigators assessed whether the conditions of patients with COVID worsened over a 28-day period so as to require either hospitalization or observation in the emergency department for more than 6 hours. In the placebo group, 108 of 733 patients’ conditions deteriorated to this extent (14.7%); by contrast, only 77 of 739 patients in the fluvoxamine group (10.4%) met these primary criteria – a relative risk reduction of 29%.

The treatment effect was greater (34%) in the per protocol analysis of participants who completed their course of pills.

The investigators also collected data on vital signs, including temperature and oxygen saturation, as well as adverse events reported at clinic visits or through video conferencing, phone calls, or social media applications. Side effects were mild, most commonly nausea and fatigue, and did not differ significantly between active treatment and control groups, Dr. Mills said in an interview.

Amid scores of studies evaluating repurposed drugs for COVID-19, the data on fluvoxamine are “looking much more favorable than anyone could have guessed – at least anyone in infectious disease,” said Paul Sax, MD, clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

The new TOGETHER trial results augment supportive data published in JAMA last November from a phase 2 randomized trial that was small but “very well done,” Dr. Sax told this news organization.

Those results got a boost from a subsequent study of 65 racetrack workers who chose to take fluvoxamine during a COVID-19 outbreak in the San Francisco Bay area. Forty-eight persons opted against taking the drug. In this small, nonrandomized study, “the people who chose to be treated with fluvoxamine were sicker [at baseline] than the people who didn’t go on it, and yet the [treated group] ended up better,” said Dr. Sax, who discussed accumulating data on the use of fluvoxamine for COVID-19 in a recent New England Journal of Medicine blog post.
 

Anti-inflammatory effect?

After reviewing the new findings, Frank Domino, MD, professor of family medicine and community health at the University of Massachusetts, Worcester, said he would encourage patients with high-risk COVID-19 to consider taking fluvoxamine to lower their risk of being hospitalized. “But I would make it clear this was not a ‘cure,’ “ he said, “and we are unsure how it helps.”

At this point, U.S. treatment guidelines do not recommend fluvoxamine as the standard of care for nonhospitalized COVID-19 patients, but the National Institutes of Health is “very aware of the data,” Dr. Sax told this news organization.

Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) – a class of drugs that includes the more commonly prescribed antidepressant fluoxetine (Prozac). If prescribed off-label to COVID-19 patients, fluvoxamine should not be used within 2 weeks of starting treatment with other SSRI or monoamine oxidase inhibitor antidepressants and should be used with caution with other QT-interval prolonging medications, Dr. Sax said.

In addition, fluvoxamine can enhance the effect of antiplatelet and anticoagulant drugs, potentially triggering bleeding.

On the basis of in vitro and mouse studies of fluvoxamine, “we think it has an anti-inflammatory effect,” said child psychiatrist Angela Reiersen, MD, of Washington University, St. Louis, who came up with the idea for testing fluvoxamine in last year’s phase 2 trial and coauthored a recent article describing the drug’s potential mechanisms of action in COVID-19.

She and other researchers believe fluvoxamine’s anti-inflammatory effects derive from the molecule’s binding to the sigma-1 receptor in the endoplasmic reticulum, which regulates cellular responses to stress and infection.

Fluvoxamine also inhibits the activation of platelets. “In COVID-19, there does seem to be a problem with hyperactivation of platelets and excessive blood clots forming, so it is possible this could be another mechanism where it might be helping,” Dr. Reiersen said.

If sigma-1 activation turns out to be the main mechanism underlying fluvoxamine’s benefits in COVID-19, other sigma-1 agonists, such as fluoxetine, may also help. In a retrospective analysis of thousands of adults hospitalized for COVID-19 in France early in the pandemic, those who were taking antidepressants had a 44% lower risk for intubation or death.

And in a study under review, researchers at Stanford (Calif.) University and the University of California, San Francisco, analyzed electronic health records to explore a potential link between fluoxetine use and COVID outcomes among more than 80,000 patients from over 80 institutions across the United States. Other research suggests that antipsychotics could also have protective effects for patients with COVID-19.
 

Long COVID, long-term challenges

On the basis of its potential mechanisms of action, fluvoxamine may be able to prevent or treat long COVID, Dr. Reiersen said. That possibility will be assessed among other secondary endpoints in two ongoing studies of repurposed drugs: the NIH’s ACTIV-6, and the University of Minnesota’s COVID-OUT, an at-home trial of ivermectin, metformin, and fluvoxamine.

Dr. Reiersen and Washington University colleagues are also analyzing longer-term outcomes of participants in their own phase 3 trial of fluvoxamine (Stop COVID 2), which was discontinued when enrollment slowed to a trickle during the U.S. vaccine rollout. Logistical hurdles and scant funding have greatly hampered efforts to test the use of off-patent drugs for COVID-19 outpatients during the pandemic.

U.S. efforts face other obstacles as well. Elsewhere in the world – including Brazil, where the TOGETHER trial was run – vaccines are scarce, and there are no monoclonal antibodies.

“People have a great sense of community duty, and they’re participating in the trials,” Dr. Mills said. “You’re in a much more political environment in the U.S. on these outpatient trials.”

The TOGETHER trial was funded by Fast Grants and the Rainwater Foundation. Dr. Reiersen is an inventor on a patent application related to methods of treating COVID-19, which was filed by Washington University, St. Louis. Dr. Mills, Dr. Domino, and Dr. Sax report no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.

European Society of Cardiology

“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.

In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.

This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.

“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
 

More than 100 centers in 12 countries involved

In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).

In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”

The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.

In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
 

No significant difference on primary endpoint

At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).

As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.

This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.

In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
 

Cancer drugs can increase CV risk

Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.

It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.

This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.

“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.

“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.

The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.

The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.

The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.

European Society of Cardiology

“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.

In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.

This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.

“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
 

More than 100 centers in 12 countries involved

In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).

In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”

The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.

In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
 

No significant difference on primary endpoint

At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).

As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.

This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.

In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
 

Cancer drugs can increase CV risk

Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.

It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.

This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.

“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.

“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.

The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.

The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.

The first global trial to compare the cardiovascular (CV) safety of two therapies for prostate cancer proved inconclusive because of inadequate enrollment and events, but the study is a harbinger of growth in the emerging specialty of cardio-oncology, according to experts.

European Society of Cardiology

“Many new cancer agents have extended patient survival, yet some of these agents have significant potential cardiovascular toxicity,” said Renato D. Lopes, MD, in presenting a study at the annual congress of the European Society of Cardiology.

In the context of improving survival in patients with or at risk for both cancer and cardiovascular disease, he suggested that the prostate cancer study he led could be “a model for interdisciplinary collaboration” needed to address the relative and sometimes competing risks of these disease states.

This point was seconded by several pioneers in cardio-oncology who participated in the discussion of the results of the trial, called PRONOUNCE.

“We know many drugs in oncology increase cardiovascular risk, so these are the types of trials we need,” according Thomas M. Suter, MD, who leads the cardio-oncology service at the University Hospital, Berne, Switzerland. He was the ESC-invited discussant for PRONOUNCE.
 

More than 100 centers in 12 countries involved

In PRONOUNCE, 545 patients with prostate cancer and established atherosclerotic cardiovascular disease were randomized to degarelix, a gonadotropin-releasing hormone antagonist, or leuprolide, a GnRH agonist. The patients were enrolled at 113 participating centers in 12 countries. All of the patients had an indication for an androgen-deprivation therapy (ADT).

In numerous previous studies, “ADT has been associated with higher CV morbidity and mortality, particularly in men with preexisting CV disease,” explained Dr. Lopes, but the relative cardiovascular safety of GnRH agonists relative to GnRH antagonists has been “controversial.”

The PRONOUNCE study was designed to resolve this issue, but the study was terminated early because of slow enrollment (not related to the COVID-19 pandemic). The planned enrollment was 900 patients.

In addition, the rate of major adverse cardiovascular events (MACE), defined as myocardial infarction, stroke, or death, was lower over the course of follow-up than anticipated in the study design.
 

No significant difference on primary endpoint

At the end of 12 months, MACE occurred in 11 (4.1%) of patients randomized to leuprolide and 15 (5.5%) of those randomized to degarelix. The greater hazard ratio for MACE in the degarelix group did not approach statistical significance (hazard ratio, 1.28; P = .53).

As a result, the question of the relative CV safety of these drugs “remains unresolved,” according to Dr. Lopes, professor of medicine at Duke University Medical Center, Durham, N.C.

This does not diminish the need to answer this question. In the addition to the fact that cancer is a malignancy primarily of advancing age when CV disease is prevalent – the mean age in this study was 73 years and 44% were over age 75 – it is often an indolent disease with long periods of survival, according to Dr. Lopes. About half of prostate cancer patients have concomitant CV disease, and about half will receive ADT at some point in their treatment.

In patients receiving ADT, leuprolide is far more commonly used than GnRH antagonists, which are offered in only about 4% of patients, according to data cited by Dr. Lopes. The underlying hypothesis of this study was that leuprolide is associated with greater CV risk, which might have been relevant to a risk-benefit calculation, if the hypothesis had been confirmed.
 

Cancer drugs can increase CV risk

Based on experimental data, “there is concern the leuprolide is involved in plaque destabilization,” said Dr. Lopes, but he noted that ADTs in general are associated with adverse metabolic changes, including increases in LDL cholesterol, insulin resistance, and body fat, all of which could be relevant to CV risk.

It is the improving rates of survival for prostate cancer as well for other types of cancer that have increased attention to the potential for cancer drugs to increase CV risk, another major cause of early mortality. For these competing risks, objective data are needed to evaluate a relative risk-to-benefit ratio for treatment choices.

This dilemma led the ESC to recently establish its Council on Cardio-Oncology, and many centers around the world are also creating interdisciplinary groups to guide treatment choices for patients with both diseases.

“You will certainly get a lot of referrals,” said Rudolf de Boer, MD, professor of translational cardiology, University Medical Center, Groningen, Netherlands. Basing his remark on his own experience starting a cardio-oncology clinic at his institution, he called this work challenging and agreed that the need for objective data is urgent.

“We need data to provide common ground on which to judge relative risks,” Dr. de Boer said. He also praised the PRONOUNCE investigators for their efforts even if the data failed to answer the question posed.

The PRONOUNCE results were published online in Circulation at the time of Dr. Lopes’s presentation.

The study received funding from Ferring Pharmaceuticals. Dr. Lopes reports financial relationships with Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi. Dr. Suter reports financial relationships with Boehringer Ingelheim, GlaxoSmithKline, and Roche. Dr. de Boer reports financial relationships with AstraZeneca, Abbott, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Roche.

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

mzoler@mdedge.com

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

mzoler@mdedge.com

The Food and Drug Administration has approved difelikefalin for treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis, the first agent approved from a novel class of kappa opioid receptor agonists.

Olivier Le Moal/Getty Images

Some nephrologists welcomed the Aug. 23 approval of this new option for treating pruritus, a relatively common and often hard-to-resolve complication of dialysis in patients with chronic kidney disease (CKD) that can substantially impinge on quality of life for some patients, but also voiced uncertainty about the role of a new agent with a modest trial track record that may be expensive and face insurance-coverage hurdles.

“Uptake of difelikefalin will depend on awareness of itch among patients dependent on hemodialysis, and on payment policies,” predicted Daniel E. Weiner, MD, a nephrologist at Tufts Medical Center in Boston. “Pruritus is underdiagnosed among people with kidney failure, and in some patients ongoing pruritus can be highly impactful on sleep and quality of life. The clinical trial results were very encouraging that difelikefalin is effective and safe,” which makes recognition of pruritus as a significant issue for patients a key factor in uptake of the new drug, Dr. Weiner, an investigator in a difelikefalin clinical study, said in an interview.

Other nephrologists acknowledged the substantial problem that itch can pose for many patients with CKD on dialysis but questioned the weight of evidence behind difelikefalin’s approval.
 

Two pivotal trials with fewer than 900 total randomized patients

The data considered by the FDA primarily featured results from two pivotal trials, KALM-1 and KALM-2. KALM-1 randomized 378 patients with CKD and on hemodialysis and with moderate to severe pruritus to intravenous treatment with difelikefalin or placebo three times a week for 12 weeks with a primary endpoint of an improvement (decrease) of at least 3 points from baseline in their Worst Itching Intensity Numerical Rating Scale (WI-NRS) score, which averaged just over 7 points at baseline. After 12 weeks on treatment, 52% of patients who received difelikefalin had at least a 3-point drop, compared with 31% of patients who received placebo, a significant difference. The results appeared in a 2020 report in the New England Journal of Medicine.

Confirmatory results came in the second pivotal trial, KALM-2, a similarly designed, 12-week study that randomized 473 patients, with 54% of those in the active arm achieving at least a 3-point cut in their baseline WI-NRS score, compared with 42% of patients who received placebo, a significant difference. A report at the Kidney Week meeting sponsored by the National Kidney Foundation in October 2020 presented the KALM-2 results, but the findings have not yet appeared in a published article.

In sum, the data suggest that treatment with difelikefalin will, on average, produce a clinically meaningful effect on itch compared with placebo in about 20% of patients, with nearly half the patients who receive the active drug having a less robust response and many patients who receive no active treatment also show a meaningful cut in their pruritus severity in a trial setting, noted Paul Palevsky, MD, professor of medicine at the University of Pittsburgh and chief of the renal section at the Veterans Affairs Pittsburgh Healthcare System.

The upshot is that questions linger over which patients are the best candidates for this drug and how it might perform in real-world practice given difelikefalin’s limited track record, Dr. Palevsky said in an interview.

In addition, the labeling specifies the indication is for patients with moderate to severe pruritus, but itching severity is not routinely quantified in these patients in current practice, added Dr. Palevsky, who is also president of the National Kidney Foundation.

Dr. Weiner noted that another unknown is the appropriate duration of treatment in real-world use.
 

What will it cost, and will it be covered?

The drug’s price and insurance coverage will likely be a major factor in uptake of the new drug, agreed both Dr. Weiner and Dr. Palevsky, especially the coverage decision for Medicare patients by the Centers for Medicare & Medicaid Services. A corollary is whether or not coverage for difelikefalin, which patients receive as an intravenous infusion during each of their usual three-times-a-week dialysis sessions, will lie outside of the bundled dialysis reimbursement payment. If is no mechanism exists to pay for difelikefalin separately beyond the current bundled dialysis rate, “I suspect it will not get used very much unless it is very inexpensive,” predicted Dr. Weiner.

Another issue is where difelikefalin fits within the lineup of standard treatment options. “A lot of people receiving hemodialysis suffer from pruritus and have not been successfully treated. For these individuals difelikefalin could be a game changer,” Dr. Weiner said.

Other nephrologists have a more positive take on the existing treatment options.

“Start systemic therapy for patients with itch that is significantly affecting quality of life; stepping up from topical therapy just delays effective treatment,” advised Hugh C. Rayner, MD, a nephrologist affiliated with Birmingham (England) Heartland’s Hospital who was lead author on a review of pruritus treatments for patients with CKD on hemodialysis.

“Standard systemic therapy is gabapentin or pregabalin,” an approach “supported by robust evidence confirmed in a Cochrane review,” he said in an interview. The impact of difelikefalin “will be limited as its effectiveness in reducing itch is modest at best and far inferior to gabapentin and pregabalin,” Dr. Rayner added. Difelikefalin’s “main downsides will be its cost, compared with gabapentin, and its gastrointestinal side effects.”
 

Adverse-event profiles

In KALM-1, the most frequent adverse effects from difelikefalin treatment was diarrhea, in 10% of patients, compared with a 4% rate among patients who received placebo. Vomiting occurred at a 5% incidence on difelikefalin and in 3% of patients on placebo. All serious adverse events occurred in 26% of patients on difelikefalin and in 22% of those who received placebo. Discontinuations because of an adverse event occurred in 8% of patients on difelikefalin and in 5% of the placebo patients.

An editorial that accompanied the published KALM-1 report in 2020 said “the findings are compelling, although diarrhea, dizziness, and vomiting were frequent side effects.”

Both Dr. Weiner and Dr. Palevsky were more reserved than Dr. Rayner in their appraisal of gabapentin and pregabalin, although Dr. Palevsky admitted that he has prescribed one or the other of these two drugs to “lots of patients,” especially gabapentin. “But they are not completely benign drugs,” he cautioned, a concern echoed by Dr. Weiner.

“Antihistamines, gabapentin, and pregabalin have a high side-effect burden in patients on hemodialysis and limited efficacy, and are poor options for chronic pruritus management,” explained Dr. Weiner. “I would favor difelikefalin to chronic prescription of these other agents” because difelikefalin “appears effective and has a very low side effect burden. Very few effective treatments for pruritus do not have side effects.”

Difelikefalin is a peripherally restricted, selective kappa opioid receptor agonist that exerts antipruritic effects by activating kappa opioid receptors on peripheral neurons and immune cells. The drug’s hydrophilic, small-peptide structure restricts passive diffusion across membranes, which limits the drug’s access to kappa opioid receptors in the central nervous system and hence reduces potential adverse effects.

The FDA made this approval decision without consulting an advisory committee. The companies that will market difelikefalin (Korsuva), Cara Therapeutics and Vifor Pharma, announced that their U.S. promotional launch of the drug starts early in 2022.

The KALM-1 and KALM-2 studies were sponsored by Cara Therapeutics and Vifor Pharma, the two companies that have been jointly developing difelikefalin. Dr. Pavelsky and Dr. Rayner had no relevant disclosures. Dr. Weiner was previously an adviser to Cara and Vifor and participated as an investigator in a difelikefalin clinical study, but more recently has had no relationships with the companies.

mzoler@mdedge.com

In medical school, I remember thinking that telling a patient “you have cancer” would be the most professionally challenging phrase I would ever utter. And don’t get me wrong – it certainly isn’t easy; but, compared with telling someone “you are infertile,” it’s a cakewalk.

Maybe it’s because people “have” cancer and cancer is something you “fight.” Or maybe because, unlike infertility, cancer has become a part of public life (think lapel pins and support groups) and is now easier to accept. On the other hand, someone “is” infertile. The condition is a source of embarrassment for the couple and is often hidden from society.

Here’s another concerning point of contrast: While the overall rate of cancer death has declined since the early 1990s, infertility is increasing. Reports now show that one in six couples have problems conceiving and the use of assisted reproductive technologies is increasing by 5%-10% per year. Many theories exist to explain these trends, chief among them the rise in average maternal age and the increasing incidence of obesity, as well as various other male- and female-specific factors.

But interestingly, recent data suggest that the most male of all male-specific factors – total sperm count – may be specifically to blame.

According to a recent meta-analysis, the average total sperm count in men declined by 59.3% between 1973 and 2011. While these data certainly have limitations – including the exclusion of non-English publications, the reliance on total sperm count and not sperm motility, and the potential bias of those patients willing to give a semen sample – the overall trend nevertheless seems to be clearly downward. What’s more concerning, if you believe the data presented, is that there does not appear to be a leveling off of the downward curve in total sperm count.

Think about that last statement. At the current rate of decline, the average sperm count will be zero in 2045. One of the lead authors on the meta-analysis, Hagai Levine, MD, MPH, goes so far as to state, “We should hope for the best and prepare for the worst.”

As a matter of personal philosophy, I’m not a huge fan of end-of-the-world predictions because they tend not to come true (think Montanism back in the 2nd century; the 2012 Mayan calendar scare; or my personal favorite, the Prophet Hen of Leeds). On the other hand, the overall trend of decreased total sperm count in the English-speaking world seems to be true and it raises the interesting question of why.

According to the Mayo Clinic, causes of decreased sperm count include everything from anatomical factors (like varicoceles and ejaculatory issues) and lifestyle issues (such as recreational drugs, weight gain, and emotional stress) to environmental exposures (heavy metal or radiation). The senior author of the aforementioned meta-analysis, Shanna Swan, PhD, has championed another theory: the widespread exposure to endocrine-disrupting chemicals in everyday plastics.

It turns out that at least two chemicals used in the plastics industry, bisphenol A and phthalates, can mimic the effect of estrogen when ingested into the body. Even low levels of these chemicals in our bodies can lead to health problems.

Consider for a moment the presence of plastics in your life: the plastic wrappings on your food, plastic containers for shampoos and beauty products, and even the coatings of our oral supplements. A study by the Centers for Disease Control and Prevention looked at the urine of people participating in the National Health and Nutrition Examination Survey and found detectable concentrations of both of these chemicals in nearly all participants.

In 2045, I intend to be retired. But in the meantime, I think we all need to be aware of the potential impact that various endocrine-disrupting chemicals could be having on humanity. We need more research. If indeed the connection between endocrine disruptors and decreased sperm count is borne out, changes in our environmental exposure to these chemicals need to be made.

Henry Rosevear, MD, is a private-practice urologist based in Colorado Springs. He comes from a long line of doctors, but before entering medicine he served in the U.S. Navy as an officer aboard the USS Pittsburgh, a fast-attack submarine based out of New London, Conn. During his time in the Navy, he served in two deployments to the Persian Gulf, including combat experience as part of Operation Iraqi Freedom. Dr. Rosevear disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

In medical school, I remember thinking that telling a patient “you have cancer” would be the most professionally challenging phrase I would ever utter. And don’t get me wrong – it certainly isn’t easy; but, compared with telling someone “you are infertile,” it’s a cakewalk.

Maybe it’s because people “have” cancer and cancer is something you “fight.” Or maybe because, unlike infertility, cancer has become a part of public life (think lapel pins and support groups) and is now easier to accept. On the other hand, someone “is” infertile. The condition is a source of embarrassment for the couple and is often hidden from society.

Here’s another concerning point of contrast: While the overall rate of cancer death has declined since the early 1990s, infertility is increasing. Reports now show that one in six couples have problems conceiving and the use of assisted reproductive technologies is increasing by 5%-10% per year. Many theories exist to explain these trends, chief among them the rise in average maternal age and the increasing incidence of obesity, as well as various other male- and female-specific factors.

But interestingly, recent data suggest that the most male of all male-specific factors – total sperm count – may be specifically to blame.

According to a recent meta-analysis, the average total sperm count in men declined by 59.3% between 1973 and 2011. While these data certainly have limitations – including the exclusion of non-English publications, the reliance on total sperm count and not sperm motility, and the potential bias of those patients willing to give a semen sample – the overall trend nevertheless seems to be clearly downward. What’s more concerning, if you believe the data presented, is that there does not appear to be a leveling off of the downward curve in total sperm count.

Think about that last statement. At the current rate of decline, the average sperm count will be zero in 2045. One of the lead authors on the meta-analysis, Hagai Levine, MD, MPH, goes so far as to state, “We should hope for the best and prepare for the worst.”

As a matter of personal philosophy, I’m not a huge fan of end-of-the-world predictions because they tend not to come true (think Montanism back in the 2nd century; the 2012 Mayan calendar scare; or my personal favorite, the Prophet Hen of Leeds). On the other hand, the overall trend of decreased total sperm count in the English-speaking world seems to be true and it raises the interesting question of why.

According to the Mayo Clinic, causes of decreased sperm count include everything from anatomical factors (like varicoceles and ejaculatory issues) and lifestyle issues (such as recreational drugs, weight gain, and emotional stress) to environmental exposures (heavy metal or radiation). The senior author of the aforementioned meta-analysis, Shanna Swan, PhD, has championed another theory: the widespread exposure to endocrine-disrupting chemicals in everyday plastics.

It turns out that at least two chemicals used in the plastics industry, bisphenol A and phthalates, can mimic the effect of estrogen when ingested into the body. Even low levels of these chemicals in our bodies can lead to health problems.

Consider for a moment the presence of plastics in your life: the plastic wrappings on your food, plastic containers for shampoos and beauty products, and even the coatings of our oral supplements. A study by the Centers for Disease Control and Prevention looked at the urine of people participating in the National Health and Nutrition Examination Survey and found detectable concentrations of both of these chemicals in nearly all participants.

In 2045, I intend to be retired. But in the meantime, I think we all need to be aware of the potential impact that various endocrine-disrupting chemicals could be having on humanity. We need more research. If indeed the connection between endocrine disruptors and decreased sperm count is borne out, changes in our environmental exposure to these chemicals need to be made.

Henry Rosevear, MD, is a private-practice urologist based in Colorado Springs. He comes from a long line of doctors, but before entering medicine he served in the U.S. Navy as an officer aboard the USS Pittsburgh, a fast-attack submarine based out of New London, Conn. During his time in the Navy, he served in two deployments to the Persian Gulf, including combat experience as part of Operation Iraqi Freedom. Dr. Rosevear disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

In medical school, I remember thinking that telling a patient “you have cancer” would be the most professionally challenging phrase I would ever utter. And don’t get me wrong – it certainly isn’t easy; but, compared with telling someone “you are infertile,” it’s a cakewalk.

Maybe it’s because people “have” cancer and cancer is something you “fight.” Or maybe because, unlike infertility, cancer has become a part of public life (think lapel pins and support groups) and is now easier to accept. On the other hand, someone “is” infertile. The condition is a source of embarrassment for the couple and is often hidden from society.

Here’s another concerning point of contrast: While the overall rate of cancer death has declined since the early 1990s, infertility is increasing. Reports now show that one in six couples have problems conceiving and the use of assisted reproductive technologies is increasing by 5%-10% per year. Many theories exist to explain these trends, chief among them the rise in average maternal age and the increasing incidence of obesity, as well as various other male- and female-specific factors.

But interestingly, recent data suggest that the most male of all male-specific factors – total sperm count – may be specifically to blame.

According to a recent meta-analysis, the average total sperm count in men declined by 59.3% between 1973 and 2011. While these data certainly have limitations – including the exclusion of non-English publications, the reliance on total sperm count and not sperm motility, and the potential bias of those patients willing to give a semen sample – the overall trend nevertheless seems to be clearly downward. What’s more concerning, if you believe the data presented, is that there does not appear to be a leveling off of the downward curve in total sperm count.

Think about that last statement. At the current rate of decline, the average sperm count will be zero in 2045. One of the lead authors on the meta-analysis, Hagai Levine, MD, MPH, goes so far as to state, “We should hope for the best and prepare for the worst.”

As a matter of personal philosophy, I’m not a huge fan of end-of-the-world predictions because they tend not to come true (think Montanism back in the 2nd century; the 2012 Mayan calendar scare; or my personal favorite, the Prophet Hen of Leeds). On the other hand, the overall trend of decreased total sperm count in the English-speaking world seems to be true and it raises the interesting question of why.

According to the Mayo Clinic, causes of decreased sperm count include everything from anatomical factors (like varicoceles and ejaculatory issues) and lifestyle issues (such as recreational drugs, weight gain, and emotional stress) to environmental exposures (heavy metal or radiation). The senior author of the aforementioned meta-analysis, Shanna Swan, PhD, has championed another theory: the widespread exposure to endocrine-disrupting chemicals in everyday plastics.

It turns out that at least two chemicals used in the plastics industry, bisphenol A and phthalates, can mimic the effect of estrogen when ingested into the body. Even low levels of these chemicals in our bodies can lead to health problems.

Consider for a moment the presence of plastics in your life: the plastic wrappings on your food, plastic containers for shampoos and beauty products, and even the coatings of our oral supplements. A study by the Centers for Disease Control and Prevention looked at the urine of people participating in the National Health and Nutrition Examination Survey and found detectable concentrations of both of these chemicals in nearly all participants.

In 2045, I intend to be retired. But in the meantime, I think we all need to be aware of the potential impact that various endocrine-disrupting chemicals could be having on humanity. We need more research. If indeed the connection between endocrine disruptors and decreased sperm count is borne out, changes in our environmental exposure to these chemicals need to be made.

Henry Rosevear, MD, is a private-practice urologist based in Colorado Springs. He comes from a long line of doctors, but before entering medicine he served in the U.S. Navy as an officer aboard the USS Pittsburgh, a fast-attack submarine based out of New London, Conn. During his time in the Navy, he served in two deployments to the Persian Gulf, including combat experience as part of Operation Iraqi Freedom. Dr. Rosevear disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

Childhood exposure to parental smoking appears to greatly boost the risk of confirmed cases of rheumatoid arthritis in adult women, although the overall rate is small, a new study reports. The findings, published Aug. 18, 2021, in Arthritis & Rheumatology, follows other evidence that early second-hand smoke exposure can trigger lifelong damage to the immune system.

pmphoto/iStockphoto.com

“We estimated that there is 75% increased risk of adult seropositive RA due to the direct impact of childhood parental smoking,” said study lead author and Brigham & Women’s Hospital epidemiologist Kazuki Yoshida, MD, ScD, referring to an adjusted analysis conducted in the study. “Passive smoking is likely harmful throughout an individual’s life course regarding rheumatoid arthritis but potentially more harmful during the childhood period.”

The researchers launched the study to fill an evidence gap, Dr. Yoshida said in an interview. “Active smoking is a well-established risk factor for RA. However, studies on passive smoking’s impact on RA are sparse, and few studies had a well-characterized cohort of participants with comprehensive data of passive smoking during life course – in utero exposure, childhood exposure, adult exposure – and chart review–adjudicated RA outcomes.”

The study authors retrospectively tracked 90,923 subjects who joined the Nurses’ Health Study II in 1989 when they were aged 25-42. At the study’s start, the average age of subjects was 34.5, 93% were White, and 98% were premenopausal. Almost two-thirds had never smoked themselves, and 65% said their parents had smoked during their childhoods.

Of the subjects, the researchers found that 532 were identified as having RA over a median follow-up period of 27.7 years. Two-thirds of those cases (n = 352) were confirmed as seropositive by clinical testing.

The study linked maternal smoking during pregnancy to confirmed RA in adulthood via a confounder-adjusted analysis (hazard ratio, 1.25; 95% confidence interval, 1.03-1.52), but the connection vanished after researchers adjusted their statistics to reflect possible influences by later exposures to smoke.

After adjustment for confounders, the study linked childhood exposure to parental smoking to a 41% in increase in risk of confirmed adulthood RA (HR, 1.41; 95% CI, 1.08-1.83). A controlled direct effect analysis boosted the excess risk to 75% (HR, 1.75; 95% CI, 1.03-2.98).

This analysis reveals that “childhood parental smoking seems to be associated with adult rheumatoid arthritis beyond what is explained by the fact that childhood passive smoking can promote personal smoking uptake, a known risk factor for rheumatoid arthritis,” Dr. Yoshida said.

The overall rate of RA in the study population – roughly 0.6% – aligns with risk levels in the general population, he said. As a result, “the absolute risk increase may not be extremely high. But the concept that early life exposure may affect immunological health later in life is important.”

Potential pathophysiological mechanisms

Why might parental smoking boost the risk of RA? Exposure to secondhand smoke may irritate the lungs and cause abnormal proteins to form, Dr. Yoshida said. “The immune system produces antibodies in an attempt to attack such abnormal proteins. This immune reaction can spread to other body sites and attack normal tissues, including the joints.”

In addition, “smoking increases the risk of infections, which could in turn increase the risk of RA. Smoking is also known to result in epigenetic changes which could trigger RA in susceptible people,” University of California, San Francisco, autoimmune disease epidemiologist Milena A. Gianfrancesco, PhD, MPH, said in an interview. She cowrote a commentary accompanying the new study.

Other studies have linked smoking exposure to autoimmune disorders. Earlier this year, researchers who tracked 79,806 French women reported at the EULAR 2021 annual meeting that they found a link between exposure to second-hand smoking during childhood or adulthood and higher rates of RA.

Dr. Yoshida and colleagues noted their study’s limitations, including the inability to track cases of RA in subjects up to the age when they entered the nurses research project. Also, only one questionnaire over the entire period of the Nurses’ Health Study II asks subjects about whether they were exposed to secondhand smoke as adults.

The study also says nothing about whether a similar risk exists for males, and the nurse subjects are overwhelmingly White.

Still, Dr. Gianfrancesco praised the study and said it relies on extensive data and strong statistical methods. “The findings are important because they drive home the importance of reducing cigarette smoke exposure to reduce risk of disease,” she said. “They highlight the need to not only focus on one’s personal smoking habits, but also other sources of secondhand smoke exposure.”

She added that children with a family history of RA or other autoimmune diseases are especially vulnerable to the effects of secondhand smoke because they may be more susceptible to developing the diseases themselves. “Rheumatologists and other health care providers should be sure to discuss the risks of smoking with their patients, as well as the risk of secondhand smoke,” she said. “And parents should keep their children away from secondhand smoke in the home or other environments in which smoke is prevalent, such as the home of another caregiver or a workplace if the child accompanies their parent to work.”

The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Institutes of Health. The study and commentary authors, including Dr. Yoshida and Dr. Gianfrancesco, reported having no relevant disclosures.

Childhood exposure to parental smoking appears to greatly boost the risk of confirmed cases of rheumatoid arthritis in adult women, although the overall rate is small, a new study reports. The findings, published Aug. 18, 2021, in Arthritis & Rheumatology, follows other evidence that early second-hand smoke exposure can trigger lifelong damage to the immune system.

pmphoto/iStockphoto.com

“We estimated that there is 75% increased risk of adult seropositive RA due to the direct impact of childhood parental smoking,” said study lead author and Brigham & Women’s Hospital epidemiologist Kazuki Yoshida, MD, ScD, referring to an adjusted analysis conducted in the study. “Passive smoking is likely harmful throughout an individual’s life course regarding rheumatoid arthritis but potentially more harmful during the childhood period.”

The researchers launched the study to fill an evidence gap, Dr. Yoshida said in an interview. “Active smoking is a well-established risk factor for RA. However, studies on passive smoking’s impact on RA are sparse, and few studies had a well-characterized cohort of participants with comprehensive data of passive smoking during life course – in utero exposure, childhood exposure, adult exposure – and chart review–adjudicated RA outcomes.”

The study authors retrospectively tracked 90,923 subjects who joined the Nurses’ Health Study II in 1989 when they were aged 25-42. At the study’s start, the average age of subjects was 34.5, 93% were White, and 98% were premenopausal. Almost two-thirds had never smoked themselves, and 65% said their parents had smoked during their childhoods.

Of the subjects, the researchers found that 532 were identified as having RA over a median follow-up period of 27.7 years. Two-thirds of those cases (n = 352) were confirmed as seropositive by clinical testing.

The study linked maternal smoking during pregnancy to confirmed RA in adulthood via a confounder-adjusted analysis (hazard ratio, 1.25; 95% confidence interval, 1.03-1.52), but the connection vanished after researchers adjusted their statistics to reflect possible influences by later exposures to smoke.

After adjustment for confounders, the study linked childhood exposure to parental smoking to a 41% in increase in risk of confirmed adulthood RA (HR, 1.41; 95% CI, 1.08-1.83). A controlled direct effect analysis boosted the excess risk to 75% (HR, 1.75; 95% CI, 1.03-2.98).

This analysis reveals that “childhood parental smoking seems to be associated with adult rheumatoid arthritis beyond what is explained by the fact that childhood passive smoking can promote personal smoking uptake, a known risk factor for rheumatoid arthritis,” Dr. Yoshida said.

The overall rate of RA in the study population – roughly 0.6% – aligns with risk levels in the general population, he said. As a result, “the absolute risk increase may not be extremely high. But the concept that early life exposure may affect immunological health later in life is important.”

Potential pathophysiological mechanisms

Why might parental smoking boost the risk of RA? Exposure to secondhand smoke may irritate the lungs and cause abnormal proteins to form, Dr. Yoshida said. “The immune system produces antibodies in an attempt to attack such abnormal proteins. This immune reaction can spread to other body sites and attack normal tissues, including the joints.”

In addition, “smoking increases the risk of infections, which could in turn increase the risk of RA. Smoking is also known to result in epigenetic changes which could trigger RA in susceptible people,” University of California, San Francisco, autoimmune disease epidemiologist Milena A. Gianfrancesco, PhD, MPH, said in an interview. She cowrote a commentary accompanying the new study.

Other studies have linked smoking exposure to autoimmune disorders. Earlier this year, researchers who tracked 79,806 French women reported at the EULAR 2021 annual meeting that they found a link between exposure to second-hand smoking during childhood or adulthood and higher rates of RA.

Dr. Yoshida and colleagues noted their study’s limitations, including the inability to track cases of RA in subjects up to the age when they entered the nurses research project. Also, only one questionnaire over the entire period of the Nurses’ Health Study II asks subjects about whether they were exposed to secondhand smoke as adults.

The study also says nothing about whether a similar risk exists for males, and the nurse subjects are overwhelmingly White.

Still, Dr. Gianfrancesco praised the study and said it relies on extensive data and strong statistical methods. “The findings are important because they drive home the importance of reducing cigarette smoke exposure to reduce risk of disease,” she said. “They highlight the need to not only focus on one’s personal smoking habits, but also other sources of secondhand smoke exposure.”

She added that children with a family history of RA or other autoimmune diseases are especially vulnerable to the effects of secondhand smoke because they may be more susceptible to developing the diseases themselves. “Rheumatologists and other health care providers should be sure to discuss the risks of smoking with their patients, as well as the risk of secondhand smoke,” she said. “And parents should keep their children away from secondhand smoke in the home or other environments in which smoke is prevalent, such as the home of another caregiver or a workplace if the child accompanies their parent to work.”

The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Institutes of Health. The study and commentary authors, including Dr. Yoshida and Dr. Gianfrancesco, reported having no relevant disclosures.

Childhood exposure to parental smoking appears to greatly boost the risk of confirmed cases of rheumatoid arthritis in adult women, although the overall rate is small, a new study reports. The findings, published Aug. 18, 2021, in Arthritis & Rheumatology, follows other evidence that early second-hand smoke exposure can trigger lifelong damage to the immune system.

pmphoto/iStockphoto.com

“We estimated that there is 75% increased risk of adult seropositive RA due to the direct impact of childhood parental smoking,” said study lead author and Brigham & Women’s Hospital epidemiologist Kazuki Yoshida, MD, ScD, referring to an adjusted analysis conducted in the study. “Passive smoking is likely harmful throughout an individual’s life course regarding rheumatoid arthritis but potentially more harmful during the childhood period.”

The researchers launched the study to fill an evidence gap, Dr. Yoshida said in an interview. “Active smoking is a well-established risk factor for RA. However, studies on passive smoking’s impact on RA are sparse, and few studies had a well-characterized cohort of participants with comprehensive data of passive smoking during life course – in utero exposure, childhood exposure, adult exposure – and chart review–adjudicated RA outcomes.”

The study authors retrospectively tracked 90,923 subjects who joined the Nurses’ Health Study II in 1989 when they were aged 25-42. At the study’s start, the average age of subjects was 34.5, 93% were White, and 98% were premenopausal. Almost two-thirds had never smoked themselves, and 65% said their parents had smoked during their childhoods.

Of the subjects, the researchers found that 532 were identified as having RA over a median follow-up period of 27.7 years. Two-thirds of those cases (n = 352) were confirmed as seropositive by clinical testing.

The study linked maternal smoking during pregnancy to confirmed RA in adulthood via a confounder-adjusted analysis (hazard ratio, 1.25; 95% confidence interval, 1.03-1.52), but the connection vanished after researchers adjusted their statistics to reflect possible influences by later exposures to smoke.

After adjustment for confounders, the study linked childhood exposure to parental smoking to a 41% in increase in risk of confirmed adulthood RA (HR, 1.41; 95% CI, 1.08-1.83). A controlled direct effect analysis boosted the excess risk to 75% (HR, 1.75; 95% CI, 1.03-2.98).

This analysis reveals that “childhood parental smoking seems to be associated with adult rheumatoid arthritis beyond what is explained by the fact that childhood passive smoking can promote personal smoking uptake, a known risk factor for rheumatoid arthritis,” Dr. Yoshida said.

The overall rate of RA in the study population – roughly 0.6% – aligns with risk levels in the general population, he said. As a result, “the absolute risk increase may not be extremely high. But the concept that early life exposure may affect immunological health later in life is important.”

Potential pathophysiological mechanisms

Why might parental smoking boost the risk of RA? Exposure to secondhand smoke may irritate the lungs and cause abnormal proteins to form, Dr. Yoshida said. “The immune system produces antibodies in an attempt to attack such abnormal proteins. This immune reaction can spread to other body sites and attack normal tissues, including the joints.”

In addition, “smoking increases the risk of infections, which could in turn increase the risk of RA. Smoking is also known to result in epigenetic changes which could trigger RA in susceptible people,” University of California, San Francisco, autoimmune disease epidemiologist Milena A. Gianfrancesco, PhD, MPH, said in an interview. She cowrote a commentary accompanying the new study.

Other studies have linked smoking exposure to autoimmune disorders. Earlier this year, researchers who tracked 79,806 French women reported at the EULAR 2021 annual meeting that they found a link between exposure to second-hand smoking during childhood or adulthood and higher rates of RA.

Dr. Yoshida and colleagues noted their study’s limitations, including the inability to track cases of RA in subjects up to the age when they entered the nurses research project. Also, only one questionnaire over the entire period of the Nurses’ Health Study II asks subjects about whether they were exposed to secondhand smoke as adults.

The study also says nothing about whether a similar risk exists for males, and the nurse subjects are overwhelmingly White.

Still, Dr. Gianfrancesco praised the study and said it relies on extensive data and strong statistical methods. “The findings are important because they drive home the importance of reducing cigarette smoke exposure to reduce risk of disease,” she said. “They highlight the need to not only focus on one’s personal smoking habits, but also other sources of secondhand smoke exposure.”

She added that children with a family history of RA or other autoimmune diseases are especially vulnerable to the effects of secondhand smoke because they may be more susceptible to developing the diseases themselves. “Rheumatologists and other health care providers should be sure to discuss the risks of smoking with their patients, as well as the risk of secondhand smoke,” she said. “And parents should keep their children away from secondhand smoke in the home or other environments in which smoke is prevalent, such as the home of another caregiver or a workplace if the child accompanies their parent to work.”

The study was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Rheumatology Research Foundation, and the National Institutes of Health. The study and commentary authors, including Dr. Yoshida and Dr. Gianfrancesco, reported having no relevant disclosures.

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at COVID@rheumatology.org.

A version of this article first appeared on Medscape.com.

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at COVID@rheumatology.org.

A version of this article first appeared on Medscape.com.

With worldwide supplies of tocilizumab dwindling as the COVID-19 pandemic rages on, a shortage of the agent will persist “for at least the next several weeks,” according to Genentech, the Roche unit that manufactures tocilizumab under the trade name Actemra IV.

The World Health Organization and Unitaid have called on Genentech to guarantee equitable distribution of the biologic agent globally and to ease up on technology transfer restrictions to make the treatment more accessible.

At this point, supplies of tocilizumab for subcutaneous use to treat rheumatoid arthritis and its other approved indications for inflammatory conditions aren’t as dire, but Genentech is watching them as well, the company says.

In June, the Food and Drug Administration issued an emergency use authorization for intravenous tocilizumab for hospitalized COVID-19 patients. Since then, it has been included in the WHO Therapeutics and COVID-19: living guideline. And on the same day Genentech and Roche reported the tocilizumab shortage, the European Medicines Agency posted a statement that it had started evaluating RoActemra, the European brand name for tocilizumab, for hospitalized COVID-19 patients.

The FDA authorization has caused an unprecedented run on supplies for the biologic agent, which is FDA approved to treat RA, giant cell arteritis, systemic sclerosis–associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. 
 

Depleted stocks

In the United States, stocks of the 200- and 400-mg units were unavailable, according to an FDA update in mid-August on its website, and the 80-mg/4-mL unit is available by drop ship only. Supplies of 80-mg units were expected to be depleted by the end of the third week in August, Genentech said in a press release.

The company expects to resupply stocks by the end of August. “However,” the Genentech statement added, “if the pandemic continues to spread at its current pace, we anticipate additional periods of stockout in the weeks and months ahead.”

For patients with RA or other approved indications taking the subcutaneous formulation – pens and prefilled syringes – supplies continue to be available, but, the company added, “the supply situation continues to evolve.” The subcutaneous formulations aren’t authorized for use in COVID-19 patients. However, the American Society of Health-System Pharmacists’ website lists the 162-mg/0.9-mL prefilled syringe as one of the products affected by the shortage.

In a separate statement, Roche said that demand for tocilizumab increased 300% in developing countries over prepandemic orders, and that U.S. demand spiked more than 400% in the first 2 weeks of August.

Roche laid out four reasons for the shortage: global manufacturing capacity limits; raw material shortages; the overall complex process of manufacturing biologic agents; and “the dynamically evolving nature of the pandemic.”

The Roche statement noted the company ramped up manufacturing of tocilizumab more than 100% over prepandemic capacity.

With regard to issues WHO and Unitaid raised in their statement, Roche stated that about 60% of its COVID-19 supplies have gone to developing countries, and that Roche and partner Chugai – both of whom hold tocilizumab-related patents – won’t assert any patents over its use for COVID-19 in low- and middle-income countries (LMICs) during the pandemic.

“Roche is in the midst of discussions with WHO and we are committed to support access in LMICs as much as we can,” a Roche spokesperson said in an interview.

Blair Solow, MD, chair of the American College of Rheumatology’s government affairs committee, said the organization supports the equitable distribution of tocilizumab. “We will work to ensure that our patients continue to have access to the medications they need,” she said. “We will continue to engage with the FDA and others to address shortages and ensure patient access to critical therapies.”

The ACR said that any health care professionals having difficulty getting tocilizumab IV or any other COVID-19-related issues can contact the organization at COVID@rheumatology.org.

A version of this article first appeared on Medscape.com.

Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

A version of this article first appeared on Medscape.com.

Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

A version of this article first appeared on Medscape.com.

Pfizer has recalled four more lots of the smoking cessation drug varenicline (Chantix), according to an Aug. 16 update on the U.S. Food and Drug Administration website.

In a new FDA MedWatch, the agency notes that these 0.5 mg/1 mg tablets are being recalled because of the presence of N-nitroso-varenicline, a nitrosamine impurity, at a level higher than Pfizer’s acceptable intake limit.

On July 2, the FDA reported that Pfizer had voluntarily recalled nine lots of the drug for this reason. As reported by this news organization, the company added three more lots to the recall a few weeks later. The new recall now brings to 16 the number of lots that have been recalled.

In the update, the FDA noted that, although long-term ingestion of the impurity “may be associated with a theoretical potential increased cancer risk in humans,” there is no immediate risk in taking this medication. The agency added that no related adverse events (AEs) have been reported.

The four additional lots included in the newest recall are as follows:

• 00018522 (expiration date: August 2021).
• 00018523 (expiration date: August 2021).
• 00018739 (expiration date: August 2021).
• 00018740 (expiration date: August 2021).

The recalled lots were distributed in the United States and Puerto Rico from June 2019 to June 2021.

As before, the FDA noted that the benefits of stopping smoking “outweigh the theoretical potential cancer risk” from varenicline’s impurity.

It added that, although the impurities may increase risk for cancer if a high level of exposure continues over a long period, the drug is intended as a short-term treatment to aid in smoking cessation.

For now, clinicians should report any AEs from varenicline to the FDA’s MedWatch program, and patients taking this treatment should consult with their health care practitioner or pharmacy, the update notes.

A version of this article first appeared on Medscape.com.

Second-generation antipsychotics (SGAs) taken by pregnant women are linked to a low rate of adverse effects in their children, new research suggests.

monkeybusinessimages/Thinkstock

Data from a large registry study of almost 2,000 women showed that 2.5% of the live births in a group that had been exposed to antipsychotics had confirmed major malformations compared with 2% of the live births in a non-exposed group. This translated into an estimated odds ratio of 1.5 for major malformations.

“The 2.5% absolute risk for major malformations is consistent with the estimates of the Centers for Disease Control and Prevention’s national baseline rate of major malformations in the general population,” lead author Adele Viguera, MD, MPH, director of research for women’s mental health, Cleveland Clinic Neurological Institute, told this news organization.

“Our results are reassuring and suggest that second-generation antipsychotics, as a class, do not substantially increase the risk of major malformations,” Dr. Viguera said.

The findings were published online August 3 in the Journal of Clinical Psychiatry.
 

Safety data scarce

Despite the increasing use of SGAs to treat a “spectrum of psychiatric disorders,” relatively little data are available on the reproductive safety of these agents, Dr. Viguera said.

The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established in 2008 to determine risk for major malformation among infants exposed to these medications during the first trimester, relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.

The NPRAA follows pregnant women (aged 18 to 45 years) with psychiatric illness who are exposed or unexposed to SGAs during pregnancy. Participants are recruited through nationwide provider referral, self-referral, and advertisement through the Massachusetts General Hospital Center for Women’s Mental Health website.

The women are interviewed by phone at three timepoints: Enrollment, 7 months, and 3 months postpartum. Specific data collected are shown in the following table.

Demographic differences

Of the 1,906 women who enrolled as of April 2020, 1,311 (mean age, 32.6 years; 81.3% White) completed the study and were eligible for inclusion in the analysis.

Although the groups had a virtually identical mean age, fewer women in the exposure group were married compared with those in the non-exposure group (77% vs. 90%, respectively) and fewer had a college education (71.2% vs. 87.8%). There was also a higher percentage of first-trimester cigarette smokers in the exposure group (18.4% vs. 5.1%).

On the other hand, more women in the non-exposure group used alcohol than in the exposure group (28.6% vs. 21.4%, respectively).

The most frequent psychiatric disorder in the exposure group was bipolar disorder (63.9%), followed by major depression (12.9%), anxiety (5.8%), and schizophrenia (4.5%). Only 11.4% of women in the non-exposure group were diagnosed with bipolar disorder, whereas 34.1% were diagnosed with major depression, 31.3% with anxiety, and none with schizophrenia.

Notably, a large percentage of women in both groups had a history of postpartum depression and/or psychosis (41.4% and 35.5%, respectively).

The most frequently used SGAs in the exposure group were quetiapine (Seroquel), aripiprazole (Abilify), and lurasidone (Latuda).

Participants in the exposure group had a higher age at initial onset of primary psychiatric diagnosis and a lower proportion of lifetime illness compared with those in the non-exposure group.
 

Major clinical implication?

Among 640 live births in the exposure group, which included 17 twin pregnancies and 1 triplet pregnancy, 2.5% reported major malformations. Among 704 live births in the control group, which included 14 twin pregnancies, 1.99% reported major malformations.

The estimated OR for major malformations comparing exposed and unexposed infants was 1.48 (95% confidence interval, 0.625-3.517).

The authors note that their findings were consistent with one of the largest studies to date, which included a nationwide sample of more than 1 million women. Its results showed that, among infants exposed to SGAs versus those who were not exposed, the estimated risk ratio after adjusting for psychiatric conditions was 1.05 (95% CI, 0.96-1.16).

Additionally, “a hallmark of a teratogen is that it tends to cause a specific type or pattern of malformations, and we found no preponderance of one single type of major malformation or specific pattern of malformations among the exposed and unexposed groups,” Dr. Viguera said

“A major clinical implication of these findings is that for women with major mood and/or psychotic disorders, treatment with an atypical antipsychotic during pregnancy may be the most prudent clinical decision, much as continued treatment is recommended for pregnant women with other serious and chronic medical conditions, such as epilepsy,” she added.
 

The concept of ‘satisficing’

Commenting on the study, Vivien Burt, MD, PhD, founder and director/consultant of the Women’s Life Center at the Resnick University of California, Los Angeles (UCLA) Neuropsychiatric Hospital, called the findings “reassuring.”

The results “support the conclusion that in pregnant women with serious psychiatric illnesses, the use of SGAs is often a better option than avoiding these medications and exposing both the women and their offspring to the adverse consequences of maternal mental illness,” she said.

An accompanying editorial co-authored by Dr. Burt and colleague Sonya Rasminsky, MD, introduced the concept of “satisficing” – a term coined by Herbert Simon, a behavioral economist and Nobel Laureate. “Satisficing” is a “decision-making strategy that aims for a satisfactory (‘good enough’) outcome rather than a perfect one.”

The concept applies to decision-making beyond the field of economics “and is critical to how physicians help patients make decisions when they are faced with multiple treatment options,” said Dr. Burt, a professor emeritus of psychiatry at UCLA.

“The goal of ‘satisficing’ is to plan for the most satisfactory outcome, knowing that there are always unknowns, so in an uncertain world, clinicians should carefully help their patients make decisions that will allow them to achieve an outcome they can best live with,” she noted.

The investigators note that their findings may not be generalizable to the larger population of women taking SGAs, given that their participants were “overwhelmingly White, married, and well-educated women.”

They add that enrollment into the NPRAA registry is ongoing and larger sample sizes will “further narrow the confidence interval around the risk estimates and allow for adjustment of likely sources of confounding.”

The NPRAA is supported by Alkermes, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, SAGE Therapeutics, Teva Pharmaceuticals, and Aurobindo Pharma. Past sponsors of the NPRAA are listed in the original paper. Dr. Viguera receives research support from the NPRAA, Alkermes Biopharmaceuticals, Aurobindo Pharma, Janssen Pharmaceuticals, Otsuka Pharmaceutical, Sunovion Pharmaceuticals, Teva Pharmaceuticals, and SAGE Therapeutics and receives adviser/consulting fees from Up-to-Date. Dr. Burt has been a consultant/speaker for Sage Therapeutics. Dr. Rasminsky has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Second-generation antipsychotics (SGAs) taken by pregnant women are linked to a low rate of adverse effects in their children, new research suggests.

monkeybusinessimages/Thinkstock

Data from a large registry study of almost 2,000 women showed that 2.5% of the live births in a group that had been exposed to antipsychotics had confirmed major malformations compared with 2% of the live births in a non-exposed group. This translated into an estimated odds ratio of 1.5 for major malformations.

“The 2.5% absolute risk for major malformations is consistent with the estimates of the Centers for Disease Control and Prevention’s national baseline rate of major malformations in the general population,” lead author Adele Viguera, MD, MPH, director of research for women’s mental health, Cleveland Clinic Neurological Institute, told this news organization.

“Our results are reassuring and suggest that second-generation antipsychotics, as a class, do not substantially increase the risk of major malformations,” Dr. Viguera said.

The findings were published online August 3 in the Journal of Clinical Psychiatry.
 

Safety data scarce

Despite the increasing use of SGAs to treat a “spectrum of psychiatric disorders,” relatively little data are available on the reproductive safety of these agents, Dr. Viguera said.

The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established in 2008 to determine risk for major malformation among infants exposed to these medications during the first trimester, relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.

The NPRAA follows pregnant women (aged 18 to 45 years) with psychiatric illness who are exposed or unexposed to SGAs during pregnancy. Participants are recruited through nationwide provider referral, self-referral, and advertisement through the Massachusetts General Hospital Center for Women’s Mental Health website.

The women are interviewed by phone at three timepoints: Enrollment, 7 months, and 3 months postpartum. Specific data collected are shown in the following table.

Demographic differences

Of the 1,906 women who enrolled as of April 2020, 1,311 (mean age, 32.6 years; 81.3% White) completed the study and were eligible for inclusion in the analysis.

Although the groups had a virtually identical mean age, fewer women in the exposure group were married compared with those in the non-exposure group (77% vs. 90%, respectively) and fewer had a college education (71.2% vs. 87.8%). There was also a higher percentage of first-trimester cigarette smokers in the exposure group (18.4% vs. 5.1%).

On the other hand, more women in the non-exposure group used alcohol than in the exposure group (28.6% vs. 21.4%, respectively).

The most frequent psychiatric disorder in the exposure group was bipolar disorder (63.9%), followed by major depression (12.9%), anxiety (5.8%), and schizophrenia (4.5%). Only 11.4% of women in the non-exposure group were diagnosed with bipolar disorder, whereas 34.1% were diagnosed with major depression, 31.3% with anxiety, and none with schizophrenia.

Notably, a large percentage of women in both groups had a history of postpartum depression and/or psychosis (41.4% and 35.5%, respectively).

The most frequently used SGAs in the exposure group were quetiapine (Seroquel), aripiprazole (Abilify), and lurasidone (Latuda).

Participants in the exposure group had a higher age at initial onset of primary psychiatric diagnosis and a lower proportion of lifetime illness compared with those in the non-exposure group.
 

Major clinical implication?

Among 640 live births in the exposure group, which included 17 twin pregnancies and 1 triplet pregnancy, 2.5% reported major malformations. Among 704 live births in the control group, which included 14 twin pregnancies, 1.99% reported major malformations.

The estimated OR for major malformations comparing exposed and unexposed infants was 1.48 (95% confidence interval, 0.625-3.517).

The authors note that their findings were consistent with one of the largest studies to date, which included a nationwide sample of more than 1 million women. Its results showed that, among infants exposed to SGAs versus those who were not exposed, the estimated risk ratio after adjusting for psychiatric conditions was 1.05 (95% CI, 0.96-1.16).

Additionally, “a hallmark of a teratogen is that it tends to cause a specific type or pattern of malformations, and we found no preponderance of one single type of major malformation or specific pattern of malformations among the exposed and unexposed groups,” Dr. Viguera said

“A major clinical implication of these findings is that for women with major mood and/or psychotic disorders, treatment with an atypical antipsychotic during pregnancy may be the most prudent clinical decision, much as continued treatment is recommended for pregnant women with other serious and chronic medical conditions, such as epilepsy,” she added.
 

The concept of ‘satisficing’

Commenting on the study, Vivien Burt, MD, PhD, founder and director/consultant of the Women’s Life Center at the Resnick University of California, Los Angeles (UCLA) Neuropsychiatric Hospital, called the findings “reassuring.”

The results “support the conclusion that in pregnant women with serious psychiatric illnesses, the use of SGAs is often a better option than avoiding these medications and exposing both the women and their offspring to the adverse consequences of maternal mental illness,” she said.

An accompanying editorial co-authored by Dr. Burt and colleague Sonya Rasminsky, MD, introduced the concept of “satisficing” – a term coined by Herbert Simon, a behavioral economist and Nobel Laureate. “Satisficing” is a “decision-making strategy that aims for a satisfactory (‘good enough’) outcome rather than a perfect one.”

The concept applies to decision-making beyond the field of economics “and is critical to how physicians help patients make decisions when they are faced with multiple treatment options,” said Dr. Burt, a professor emeritus of psychiatry at UCLA.

“The goal of ‘satisficing’ is to plan for the most satisfactory outcome, knowing that there are always unknowns, so in an uncertain world, clinicians should carefully help their patients make decisions that will allow them to achieve an outcome they can best live with,” she noted.

The investigators note that their findings may not be generalizable to the larger population of women taking SGAs, given that their participants were “overwhelmingly White, married, and well-educated women.”

They add that enrollment into the NPRAA registry is ongoing and larger sample sizes will “further narrow the confidence interval around the risk estimates and allow for adjustment of likely sources of confounding.”

The NPRAA is supported by Alkermes, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, SAGE Therapeutics, Teva Pharmaceuticals, and Aurobindo Pharma. Past sponsors of the NPRAA are listed in the original paper. Dr. Viguera receives research support from the NPRAA, Alkermes Biopharmaceuticals, Aurobindo Pharma, Janssen Pharmaceuticals, Otsuka Pharmaceutical, Sunovion Pharmaceuticals, Teva Pharmaceuticals, and SAGE Therapeutics and receives adviser/consulting fees from Up-to-Date. Dr. Burt has been a consultant/speaker for Sage Therapeutics. Dr. Rasminsky has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Second-generation antipsychotics (SGAs) taken by pregnant women are linked to a low rate of adverse effects in their children, new research suggests.

monkeybusinessimages/Thinkstock

Data from a large registry study of almost 2,000 women showed that 2.5% of the live births in a group that had been exposed to antipsychotics had confirmed major malformations compared with 2% of the live births in a non-exposed group. This translated into an estimated odds ratio of 1.5 for major malformations.

“The 2.5% absolute risk for major malformations is consistent with the estimates of the Centers for Disease Control and Prevention’s national baseline rate of major malformations in the general population,” lead author Adele Viguera, MD, MPH, director of research for women’s mental health, Cleveland Clinic Neurological Institute, told this news organization.

“Our results are reassuring and suggest that second-generation antipsychotics, as a class, do not substantially increase the risk of major malformations,” Dr. Viguera said.

The findings were published online August 3 in the Journal of Clinical Psychiatry.
 

Safety data scarce

Despite the increasing use of SGAs to treat a “spectrum of psychiatric disorders,” relatively little data are available on the reproductive safety of these agents, Dr. Viguera said.

The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established in 2008 to determine risk for major malformation among infants exposed to these medications during the first trimester, relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.

The NPRAA follows pregnant women (aged 18 to 45 years) with psychiatric illness who are exposed or unexposed to SGAs during pregnancy. Participants are recruited through nationwide provider referral, self-referral, and advertisement through the Massachusetts General Hospital Center for Women’s Mental Health website.

The women are interviewed by phone at three timepoints: Enrollment, 7 months, and 3 months postpartum. Specific data collected are shown in the following table.

Demographic differences

Of the 1,906 women who enrolled as of April 2020, 1,311 (mean age, 32.6 years; 81.3% White) completed the study and were eligible for inclusion in the analysis.

Although the groups had a virtually identical mean age, fewer women in the exposure group were married compared with those in the non-exposure group (77% vs. 90%, respectively) and fewer had a college education (71.2% vs. 87.8%). There was also a higher percentage of first-trimester cigarette smokers in the exposure group (18.4% vs. 5.1%).

On the other hand, more women in the non-exposure group used alcohol than in the exposure group (28.6% vs. 21.4%, respectively).

The most frequent psychiatric disorder in the exposure group was bipolar disorder (63.9%), followed by major depression (12.9%), anxiety (5.8%), and schizophrenia (4.5%). Only 11.4% of women in the non-exposure group were diagnosed with bipolar disorder, whereas 34.1% were diagnosed with major depression, 31.3% with anxiety, and none with schizophrenia.

Notably, a large percentage of women in both groups had a history of postpartum depression and/or psychosis (41.4% and 35.5%, respectively).

The most frequently used SGAs in the exposure group were quetiapine (Seroquel), aripiprazole (Abilify), and lurasidone (Latuda).

Participants in the exposure group had a higher age at initial onset of primary psychiatric diagnosis and a lower proportion of lifetime illness compared with those in the non-exposure group.
 

Major clinical implication?

Among 640 live births in the exposure group, which included 17 twin pregnancies and 1 triplet pregnancy, 2.5% reported major malformations. Among 704 live births in the control group, which included 14 twin pregnancies, 1.99% reported major malformations.

The estimated OR for major malformations comparing exposed and unexposed infants was 1.48 (95% confidence interval, 0.625-3.517).

The authors note that their findings were consistent with one of the largest studies to date, which included a nationwide sample of more than 1 million women. Its results showed that, among infants exposed to SGAs versus those who were not exposed, the estimated risk ratio after adjusting for psychiatric conditions was 1.05 (95% CI, 0.96-1.16).

Additionally, “a hallmark of a teratogen is that it tends to cause a specific type or pattern of malformations, and we found no preponderance of one single type of major malformation or specific pattern of malformations among the exposed and unexposed groups,” Dr. Viguera said

“A major clinical implication of these findings is that for women with major mood and/or psychotic disorders, treatment with an atypical antipsychotic during pregnancy may be the most prudent clinical decision, much as continued treatment is recommended for pregnant women with other serious and chronic medical conditions, such as epilepsy,” she added.
 

The concept of ‘satisficing’

Commenting on the study, Vivien Burt, MD, PhD, founder and director/consultant of the Women’s Life Center at the Resnick University of California, Los Angeles (UCLA) Neuropsychiatric Hospital, called the findings “reassuring.”

The results “support the conclusion that in pregnant women with serious psychiatric illnesses, the use of SGAs is often a better option than avoiding these medications and exposing both the women and their offspring to the adverse consequences of maternal mental illness,” she said.

An accompanying editorial co-authored by Dr. Burt and colleague Sonya Rasminsky, MD, introduced the concept of “satisficing” – a term coined by Herbert Simon, a behavioral economist and Nobel Laureate. “Satisficing” is a “decision-making strategy that aims for a satisfactory (‘good enough’) outcome rather than a perfect one.”

The concept applies to decision-making beyond the field of economics “and is critical to how physicians help patients make decisions when they are faced with multiple treatment options,” said Dr. Burt, a professor emeritus of psychiatry at UCLA.

“The goal of ‘satisficing’ is to plan for the most satisfactory outcome, knowing that there are always unknowns, so in an uncertain world, clinicians should carefully help their patients make decisions that will allow them to achieve an outcome they can best live with,” she noted.

The investigators note that their findings may not be generalizable to the larger population of women taking SGAs, given that their participants were “overwhelmingly White, married, and well-educated women.”

They add that enrollment into the NPRAA registry is ongoing and larger sample sizes will “further narrow the confidence interval around the risk estimates and allow for adjustment of likely sources of confounding.”

The NPRAA is supported by Alkermes, Johnson & Johnson/Janssen Pharmaceuticals, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, SAGE Therapeutics, Teva Pharmaceuticals, and Aurobindo Pharma. Past sponsors of the NPRAA are listed in the original paper. Dr. Viguera receives research support from the NPRAA, Alkermes Biopharmaceuticals, Aurobindo Pharma, Janssen Pharmaceuticals, Otsuka Pharmaceutical, Sunovion Pharmaceuticals, Teva Pharmaceuticals, and SAGE Therapeutics and receives adviser/consulting fees from Up-to-Date. Dr. Burt has been a consultant/speaker for Sage Therapeutics. Dr. Rasminsky has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

There is currently no evidence that newer antiseizure medications increase the risk for suicide among patients with epilepsy, new research shows. “There appears to be no justification for the FDA to label every new antiseizure medication with a warning that it may increase risk of suicidality,” said study investigator Michael R. Sperling, MD, professor of neurology, Thomas Jefferson University, Philadelphia.

“How many patients are afraid of their medication and do not take it because of the warning – and are consequently at risk because of that? We do not know, but have anecdotal experience that this is certainly an issue,” Dr. Sperling, who is director of the Jefferson Comprehensive Epilepsy Center, added.

The study was published online August 2 in JAMA Neurology.
 

Blanket warning

In 2008, the FDA issued an alert stating that antiseizure medications increase suicidality. The alert was based on pooled data from placebo-controlled clinical trials that included 11 antiseizure medications – carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.

The meta-analytic review showed that, compared with placebo, antiseizure medications nearly doubled suicide risk among patients treated for epilepsy, psychiatric disorders, and other diseases. As a result of the FDA study, all antiseizure medications that have been approved since 2008 carry a warning for suicidality.

However, subsequent analyses did not show the same results, Dr. Sperling and colleagues noted.

“Pivotal” antiseizure medication epilepsy trials since 2008 have evaluated suicidality prospectively. Since 2011, trials have included the validated Columbia Suicidality Severity Rating Scale, they noted.
 

Meta analysis showed no increased risk

Dr. Sperling and colleagues conducted a meta-analysis of 17 randomized placebo-controlled epilepsy trials of five antiseizure medications approved since 2008. These antiseizure medications were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. The trials involved 5,996 patients, including 4,000 who were treated with antiseizure medications and 1,996 who were treated with placebo.

Confining the analysis to epilepsy trials avoids potential confounders, such as possible differences in suicidality risks between different diseases, the researchers noted.

They found no evidence of increased risk for suicidal ideation (overall risk ratio, antiseizure medications vs. placebo: 0.75; 95% confidence interval: 0.35-1.60) or suicide attempt (risk ratio, 0.75; 95% CI: 0.30-1.87) overall or for any individual antiseizure medication.

Suicidal ideation occurred in 12 of 4,000 patients treated with antiseizure medications (0.30%), versus 7 of 1,996 patients treated with placebo (0.35%) (P = .74). Three patients who were treated with antiseizure medications attempted suicide; no patients who were treated with placebo attempted suicide (P = .22). There were no completed suicides.

“There is no current evidence that the five antiseizure medications evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning,” the investigators wrote. When prescribed for epilepsy, “evidence does not support the FDA’s labeling practice of a blanket assumption of increased suicidality,” said Dr. Sperling.

“Our findings indicate the nonspecific suicide warning for all epilepsy drugs is simply not justifiable,” he said. “The results are not surprising. Different drugs affect cells in different ways. So there’s no reason to expect that every drug would increase suicide risk for every patient,” Dr. Sperling said in a statement.

“It’s important to recognize that epilepsy has many causes – perinatal injury, stroke, tumor, head trauma, developmental malformations, genetic causes, and others – and these underlying etiologies may well contribute to the presence of depression and suicidality in this population,” he said in an interview. “Psychodynamic influences also may occur as a consequence of having seizures. This is a complicated area, and drugs are simply one piece of the puzzle,” he added.

Dr. Sperling said the FDA has accomplished “one useful thing with its warning – it highlighted that physicians and other health care providers must pay attention to their patients’ psychological state, ask questions, and treat accordingly.”

The study had no specific funding. Dr. Sperling has received grants from Eisai, Medtronic, Neurelis, SK Life Science, Sunovion, Takeda, Xenon, Cerevel Therapeutics, UCB Pharma, and Engage Pharma; personal fees from Neurelis, Medscape, Neurology Live, International Medical Press, UCB Pharma, Eisai, Oxford University Press, and Projects in Knowledge. He has also consulted for Medtronic outside the submitted work; payments went to Thomas Jefferson University. A complete list of authors’ disclosures is available with the original article.

A version of this article first appeared on Medscape.com.

There is currently no evidence that newer antiseizure medications increase the risk for suicide among patients with epilepsy, new research shows. “There appears to be no justification for the FDA to label every new antiseizure medication with a warning that it may increase risk of suicidality,” said study investigator Michael R. Sperling, MD, professor of neurology, Thomas Jefferson University, Philadelphia.

“How many patients are afraid of their medication and do not take it because of the warning – and are consequently at risk because of that? We do not know, but have anecdotal experience that this is certainly an issue,” Dr. Sperling, who is director of the Jefferson Comprehensive Epilepsy Center, added.

The study was published online August 2 in JAMA Neurology.
 

Blanket warning

In 2008, the FDA issued an alert stating that antiseizure medications increase suicidality. The alert was based on pooled data from placebo-controlled clinical trials that included 11 antiseizure medications – carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.

The meta-analytic review showed that, compared with placebo, antiseizure medications nearly doubled suicide risk among patients treated for epilepsy, psychiatric disorders, and other diseases. As a result of the FDA study, all antiseizure medications that have been approved since 2008 carry a warning for suicidality.

However, subsequent analyses did not show the same results, Dr. Sperling and colleagues noted.

“Pivotal” antiseizure medication epilepsy trials since 2008 have evaluated suicidality prospectively. Since 2011, trials have included the validated Columbia Suicidality Severity Rating Scale, they noted.
 

Meta analysis showed no increased risk

Dr. Sperling and colleagues conducted a meta-analysis of 17 randomized placebo-controlled epilepsy trials of five antiseizure medications approved since 2008. These antiseizure medications were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. The trials involved 5,996 patients, including 4,000 who were treated with antiseizure medications and 1,996 who were treated with placebo.

Confining the analysis to epilepsy trials avoids potential confounders, such as possible differences in suicidality risks between different diseases, the researchers noted.

They found no evidence of increased risk for suicidal ideation (overall risk ratio, antiseizure medications vs. placebo: 0.75; 95% confidence interval: 0.35-1.60) or suicide attempt (risk ratio, 0.75; 95% CI: 0.30-1.87) overall or for any individual antiseizure medication.

Suicidal ideation occurred in 12 of 4,000 patients treated with antiseizure medications (0.30%), versus 7 of 1,996 patients treated with placebo (0.35%) (P = .74). Three patients who were treated with antiseizure medications attempted suicide; no patients who were treated with placebo attempted suicide (P = .22). There were no completed suicides.

“There is no current evidence that the five antiseizure medications evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning,” the investigators wrote. When prescribed for epilepsy, “evidence does not support the FDA’s labeling practice of a blanket assumption of increased suicidality,” said Dr. Sperling.

“Our findings indicate the nonspecific suicide warning for all epilepsy drugs is simply not justifiable,” he said. “The results are not surprising. Different drugs affect cells in different ways. So there’s no reason to expect that every drug would increase suicide risk for every patient,” Dr. Sperling said in a statement.

“It’s important to recognize that epilepsy has many causes – perinatal injury, stroke, tumor, head trauma, developmental malformations, genetic causes, and others – and these underlying etiologies may well contribute to the presence of depression and suicidality in this population,” he said in an interview. “Psychodynamic influences also may occur as a consequence of having seizures. This is a complicated area, and drugs are simply one piece of the puzzle,” he added.

Dr. Sperling said the FDA has accomplished “one useful thing with its warning – it highlighted that physicians and other health care providers must pay attention to their patients’ psychological state, ask questions, and treat accordingly.”

The study had no specific funding. Dr. Sperling has received grants from Eisai, Medtronic, Neurelis, SK Life Science, Sunovion, Takeda, Xenon, Cerevel Therapeutics, UCB Pharma, and Engage Pharma; personal fees from Neurelis, Medscape, Neurology Live, International Medical Press, UCB Pharma, Eisai, Oxford University Press, and Projects in Knowledge. He has also consulted for Medtronic outside the submitted work; payments went to Thomas Jefferson University. A complete list of authors’ disclosures is available with the original article.

A version of this article first appeared on Medscape.com.

There is currently no evidence that newer antiseizure medications increase the risk for suicide among patients with epilepsy, new research shows. “There appears to be no justification for the FDA to label every new antiseizure medication with a warning that it may increase risk of suicidality,” said study investigator Michael R. Sperling, MD, professor of neurology, Thomas Jefferson University, Philadelphia.

“How many patients are afraid of their medication and do not take it because of the warning – and are consequently at risk because of that? We do not know, but have anecdotal experience that this is certainly an issue,” Dr. Sperling, who is director of the Jefferson Comprehensive Epilepsy Center, added.

The study was published online August 2 in JAMA Neurology.
 

Blanket warning

In 2008, the FDA issued an alert stating that antiseizure medications increase suicidality. The alert was based on pooled data from placebo-controlled clinical trials that included 11 antiseizure medications – carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide.

The meta-analytic review showed that, compared with placebo, antiseizure medications nearly doubled suicide risk among patients treated for epilepsy, psychiatric disorders, and other diseases. As a result of the FDA study, all antiseizure medications that have been approved since 2008 carry a warning for suicidality.

However, subsequent analyses did not show the same results, Dr. Sperling and colleagues noted.

“Pivotal” antiseizure medication epilepsy trials since 2008 have evaluated suicidality prospectively. Since 2011, trials have included the validated Columbia Suicidality Severity Rating Scale, they noted.
 

Meta analysis showed no increased risk

Dr. Sperling and colleagues conducted a meta-analysis of 17 randomized placebo-controlled epilepsy trials of five antiseizure medications approved since 2008. These antiseizure medications were eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. The trials involved 5,996 patients, including 4,000 who were treated with antiseizure medications and 1,996 who were treated with placebo.

Confining the analysis to epilepsy trials avoids potential confounders, such as possible differences in suicidality risks between different diseases, the researchers noted.

They found no evidence of increased risk for suicidal ideation (overall risk ratio, antiseizure medications vs. placebo: 0.75; 95% confidence interval: 0.35-1.60) or suicide attempt (risk ratio, 0.75; 95% CI: 0.30-1.87) overall or for any individual antiseizure medication.

Suicidal ideation occurred in 12 of 4,000 patients treated with antiseizure medications (0.30%), versus 7 of 1,996 patients treated with placebo (0.35%) (P = .74). Three patients who were treated with antiseizure medications attempted suicide; no patients who were treated with placebo attempted suicide (P = .22). There were no completed suicides.

“There is no current evidence that the five antiseizure medications evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning,” the investigators wrote. When prescribed for epilepsy, “evidence does not support the FDA’s labeling practice of a blanket assumption of increased suicidality,” said Dr. Sperling.

“Our findings indicate the nonspecific suicide warning for all epilepsy drugs is simply not justifiable,” he said. “The results are not surprising. Different drugs affect cells in different ways. So there’s no reason to expect that every drug would increase suicide risk for every patient,” Dr. Sperling said in a statement.

“It’s important to recognize that epilepsy has many causes – perinatal injury, stroke, tumor, head trauma, developmental malformations, genetic causes, and others – and these underlying etiologies may well contribute to the presence of depression and suicidality in this population,” he said in an interview. “Psychodynamic influences also may occur as a consequence of having seizures. This is a complicated area, and drugs are simply one piece of the puzzle,” he added.

Dr. Sperling said the FDA has accomplished “one useful thing with its warning – it highlighted that physicians and other health care providers must pay attention to their patients’ psychological state, ask questions, and treat accordingly.”

The study had no specific funding. Dr. Sperling has received grants from Eisai, Medtronic, Neurelis, SK Life Science, Sunovion, Takeda, Xenon, Cerevel Therapeutics, UCB Pharma, and Engage Pharma; personal fees from Neurelis, Medscape, Neurology Live, International Medical Press, UCB Pharma, Eisai, Oxford University Press, and Projects in Knowledge. He has also consulted for Medtronic outside the submitted work; payments went to Thomas Jefferson University. A complete list of authors’ disclosures is available with the original article.

A version of this article first appeared on Medscape.com.

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

SDI Productions/E+

The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

A version of this article first appeared on Medscape.com.

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

SDI Productions/E+

The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

A version of this article first appeared on Medscape.com.

Nearly half of adults prescribed metformin after a new diagnosis of type 2 diabetes have stopped taking it by 1 year, new data show.

SDI Productions/E+

The findings, from a retrospective analysis of administrative data from Alberta, Canada, during 2012-2017, also show that the fall-off in metformin adherence was most dramatic during the first 30 days, and in most cases, there was no concomitant substitution of another glucose-lowering drug.

While the majority with newly diagnosed type 2 diabetes were prescribed metformin as first-line therapy, patients started on other agents incurred far higher medication and health care costs.

The data were recently published online in Diabetic Medicine by David J. T. Campbell, MD, PhD, of the University of Calgary (Alta.), and colleagues.

“We realized that even if someone is prescribed metformin that doesn’t mean they’re staying on metformin even for a year ... the drop-off rate is really quite abrupt,” Dr. Campbell said in an interview. Most who discontinued had A1c levels above 7.5%, so it wasn’t that they no longer needed glucose-lowering medication, he noted.
 

People don’t understand chronic use; meds don’t make you feel better

One reason for the discontinuations, he said, is that patients might not realize they need to keep taking the medication.

“When a physician is seeing a person with newly diagnosed diabetes, I think it’s important to remember that they might not know the implications of having a chronic condition. A lot of times we’re quick to prescribe metformin and forget about it. ... Physicians might write a script for 3 months and three refills and not see the patient again for a year ... We may need to keep a closer eye on these folks and have more regular follow-up, and make sure they’re getting early diabetes education.”

Side effects are an issue, but not for most. “Any clinician who prescribes metformin knows there are side effects, such as upset stomach, diarrhea, and nausea. But certainly, it’s not half [who experience these]. ... A lot of people just aren’t accepting of having to take it lifelong, especially since they probably don’t feel any better on it,” Dr. Campbell said.  

James Flory, MD, an endocrinologist at Memorial Sloan Kettering Cancer Center, New York, said in an interview that about 25% of patients taking metformin experience gastrointestinal side effects.

Moreover, he noted that the drop-off in adherence is also seen with antihypertensive and lipid-lowering drugs that have fewer side effects than those of metformin. He pointed to a “striking example” of this, a 2011 randomized trial published in the New England Journal of Medicine, and as reported by this news organization, showing overall rates of adherence to these medications was around 50%, even among people who had already had a myocardial infarction.   

“People really don’t want to be on these medications. ... They have an aversion to being medicalized and taking pills. If they’re not being pretty consistently prompted and reminded and urged to take them, I think people will find rationalizations, reasons for stopping. ... I think people want to handle things through lifestyle and not be on a drug,” noted Dr. Flory, who has published on the subject of metformin adherence.

“These drugs don’t make people feel better. None of them do. At best they don’t make you feel worse. You have to really believe in the chronic condition and believe that it’s hurting you and that you can’t handle it without the drugs to motivate you to keep taking them,” Dr. Flory explained.

Communication with the patient is key, he added.

“I don’t have empirical data to support this, but I feel it’s helpful to acknowledge the downsides to patients. I tell them to let me know [if they’re having side effects] and we’ll work on it. Don’t just stop taking the drug and never circle back.” At the same time, he added, “I think it’s important to emphasize metformin’s safety and effectiveness.”

For patients experiencing gastrointestinal side effects, options including switching to extended-release metformin or lowering the dose.

Also, while patients are typically advised to take metformin with food, some experience diarrhea when they do that and prefer to take it at bedtime than with dinner. “If that’s what works for people, that’s what they should do,” Dr. Flory advised.

“It doesn’t take a lot of time to emphasize to patients the safety and this level of flexibility and control they should be able to exercise over how much they take and when. These things should really help.”  
 

Metformin usually prescribed, but not always taken

Dr. Campbell and colleagues analyzed 17,932 individuals with incident type 2 diabetes diagnosed between April 1, 2012, and March 31, 2017. Overall, 89% received metformin monotherapy as their initial diabetes prescription, 7.6% started metformin in combination with another glucose-lowering drug, and 3.3% were prescribed a nonmetformin diabetes medication. (Those prescribed insulin as their first diabetes medication were excluded.) 

The most commonly coprescribed drugs with metformin were sulfonylureas (in 47%) and DPP-4 inhibitors (28%). Of those initiated with only nonmetformin medications, sulfonylureas were also the most common (53%) and dipeptidyl peptidase-4 (DPP-4) inhibitors second (21%).

The metformin prescribing rate of 89% reflects current guidelines, Dr. Campbell noted.

“In hypertension, clinicians weren’t really following the guidelines ... they were prescribing more expensive drugs than the guidelines say. ... We showed that in diabetes, contrary to hypertension, clinicians really are generally following the clinical practice guidelines. ... The vast majority who are started on metformin are started on monotherapy. That was reassuring to us. We’re not paying for a bunch of expensive drugs when metformin would do just as well,” he said.

However, the proportion who had been dispensed metformin to cover the prescribed number of days dropped by about 10% after 30 days, by a further 10% after 90 days, and yet again after 100 days, resulting in just 54% remaining on the drug by 1 year.

Factors associated with higher adherence included older age, presence of comorbidities, and highest versus lowest neighborhood income quintile.

Those who had been prescribed nonmetformin monotherapy had about twice the total health care costs of those initially prescribed metformin monotherapy. Higher health care costs were seen among patients who were younger, had lower incomes, had higher baseline A1c, had more comorbidities, and were men.

How will the newer type 2 diabetes drugs change prescribing?

Dr. Campbell noted that “a lot has changed since 2017. ... At least in Canada, the sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists were supposed to be reserved as second-line agents in patients with cardiovascular disease, but more and more they’re being thought of as first-line agents in high-risk patients.”

“I suspect as those guidelines are transmitted to primary care colleagues who are doing the bulk of the prescribing we’ll see more and more uptake of these agents.”

Indeed, Dr. Flory said, “The metformin data at this point are very dated and the body of trials showing health benefits for it is actually very weak compared to the big trials that have been done for the newer agents, to the point where you can imagine a consensus gradually forming where people start to recommend something other than metformin for nearly everybody with type 2 diabetes. The cost implications are just huge, and I think the safety implications as well.”

According to Dr. Flory, the SGLT2 inhibitors “are fundamentally not as safe as metformin. I think they’re very safe drugs – large good studies have established that – but if you’re going to give drugs to a large number of people who are pretty healthy at baseline the safety standards have to be pretty high.”

Just the elevated risk of euglycemic diabetic ketoacidosis alone is reason for pause, Dr. Flory said. “Even though it’s manageable ... metformin just doesn’t have a safety problem like that. I’m very comfortable prescribing SGLT2 inhibitors, but If I’m going to give a drug to a million people and have nothing go wrong with any of them, that would be metformin, not an SGLT2 [inhibitor].”

Dr. Campbell and colleagues will be conducting a follow-up of prescribing data through 2019, which will of course include the newer agents. They’ll also investigate reasons for drug discontinuation and outcomes of those who discontinue versus continue metformin.

Dr. Campbell has reported no relevant financial relationships. Dr. Flory consults for a legal firm on litigation related to insulin analog pricing issues, not for or pertaining to a specific company.

A version of this article first appeared on Medscape.com.