Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

Spending on medications is expected to grow from $344 billion in 2018 to $420 billion in 2023, largely driven by the introduction of new branded drugs.¹ These costs place substantial financial burden on patients, with nearly 30% of patients not taking their prescriptions as directed because of costs. Although many new medications have transformed how we care for patients, others may not offer meaningful benefit over existing less-costly alternatives that are supported by declining effect sizes of conventional placebo-controlled trials.² Most medications are approved based on placebo-controlled trial data that does not include an arm comparing the new drug to standard of care, leaving clinicians and patients unable to make meaningful comparisons when deciding on the most appropriate or cost-effective treatment. We consider ways in which clinicians, patients, payers, and regulators could compel more meaningful trials from industry.

Although we often look to the US Food and Drug Administration (FDA) to ensure rigorous and appropriate testing of new medications, the primary mission of the FDA is to ensure efficacy and safety. As a result, pharmaceutical companies seeking approval in the United States have little incentive to go beyond providing the minimal level of evidence required: placebo-controlled randomized trials. Although these trials provide important data on whether a treatment works and its associated risks, they do not provide data on comparative effectiveness. When relevant inexpensive medications are already on the market for the same indication, these placebo-controlled trials provide inadequate evidence to guide clinical decision-making. This issue is particularly relevant in dermatology given how easily topical medications can be combined or reformulated to pursue additional market exclusivity. The addition of an active comparator arm represents an important opportunity to improve the value of these studies.

In the pivotal trials of clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel for the treatment of acne, the experimental group was not only compared to vehicle but also the active comparator arms of clindamycin alone and benzoyl peroxide alone. The mean percentage change in total lesions was 47.9% with clindamycin phosphate 1.2%–benzoyl peroxide 2.5% gel, 41.6% with the active comparator arm of benzoyl peroxide alone, 40.4% with the active comparator arm of clindamycin alone, and 26.2% for vehicle.³ With these data in mind, clinicians and patients can decide whether the additional benefit of this new product over benzoyl peroxide alone is worth the increased cost.

In contrast, the trials of dapsone gel 7.5% for the treatment of acne did not include an active comparator. The mean percentage change in total lesions was 48.9% for dapsone gel and 43.2% for vehicle.⁴ Given these data, it is possible that dapsone gel may be no more effective, or possibly less effective, than alternatives such as benzoyl peroxide or other topical antibiotics. Nevertheless, dapsone annual sales were more than $200 million in 2016,⁵ suggesting that effectively marketed new products can achieve high sales even without convincing evidence of their value compared to standard of care. Although dapsone may be a useful treatment, we cannot effectively make patient-centered clinical decisions given the lack of an active comparator trial design.

This issue is not limited to acne. Phase 3 trials of halobetasol propionate foam 0.05% for psoriasis and crisaborole for atopic dermatitis also did not include an active comparator arm.^6,7 Given that topical steroids—and calcineurin inhibitors for atopic dermatitis—are mainstays of treatment for each condition, it is difficult to determine whether these new treatments offer meaningful advantages over existing options and how to incorporate them into our management strategies.

Unfortunately, expensive new medications that are adopted without convincing evidence of their benefit above standard of care can put patients at risk for financial toxicity, either directly through higher out-of-pocket costs or indirectly through higher premiums. Given the impact of rising medication costs on clinicians, patients, and payers, we propose several approaches these stakeholders could adopt to encourage the use of active comparator trial designs.

Clinicians and patients can encourage these trials by remaining skeptical of new treatments that were only compared to vehicle or placebo. Because new medications often are more expensive, clinicians and patients could avoid using these treatments without evidence of either increased efficacy or improved safety and tolerability. In addition, health care institutions should consider reducing pharmaceutical representatives’ access to clinicians to encourage treatment decisions based on the published literature and comparative effectiveness data rather than marketing.

Payers, such as Medicare, also could play a role by requiring active comparator trials for coverage of new medications, particularly when there are already other effective treatments available or other medications in the same class. Payers also could give preferred coverage tier or step therapy status to medications that demonstrate value over existing options.

Although regulatory approaches to increase use of active comparator designs may be more politically challenging to introduce, these options would be more administratively robust. The FDA or a novel regulatory body could require that new treatments demonstrate value in addition to safety and efficacy. This approach would be similar to the role of The National Institute for Health and Care Excellence in the United Kingdom or the recommendations of the European Medicines Agency. Such a group also could provide independent adjudication to ensure appropriate selection of a relevant active comparator. Another approach would be to give extended market exclusivity to medications that are approved based on trials including an additional active comparator arm, an approach used by the European Medicines Agency.

Any approach that encourages increased use of active comparator trials is not without potential downsides. It will be important to avoid unintended consequences of reduced research for rare diseases with smaller markets that may not be able to support the increased cost of these trials. As a result, it would be reasonable to forgo active comparator designs for mediations indicated for rare and orphan diseases or for medications with novel mechanisms of action.

Another argument against including an active comparator arm is that it may stifle innovation by driving up the cost of conducting trials; however, if a product is so marginally innovative that it cannot demonstrate superior safety or efficacy to an existing product, such a new treatment may not be worth the increased cost. In addition, patients provide a notable contribution by participating in these trials, and it is important to ensure that their efforts result in the highest-quality data possible. Furthermore, given the adverse physical and psychosocial impact of a wide variety of dermatologic diseases, the inclusion of an active comparator arm reduces the likelihood that patients will receive placebo, which will make these trials more ethical when effective treatments are available.⁸ By raising the bar, we can encourage pharmaceutical companies to pursue novel approaches that are more likely to have a revolutionary impact rather than minor modifications or formulations that offer little to no benefit at substantially increased cost.

Although some recent clinical trials in dermatology have included active comparators, many new medications continue to be introduced without any evidence of how they compare to existing standards of care. Until clinicians, patients, payers, and regulators demand that pharmaceutical companies conduct the necessary trials to not only demonstrate whether a treatment is effective and safe but also how it provides value, there will be continued introduction of marginal innovations rather than revolutionary treatments that improve patients’ lives. The next time a new medication is approved, as clinicians, patients, and payers, we must ask ourselves, is this treatment worth it?

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

bjancin@mdedge.com

SOURCE: ECNP 2020, Session S.12.

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

bjancin@mdedge.com

SOURCE: ECNP 2020, Session S.12.

Two oral agents with novel mechanisms of action in schizophrenia generated considerable audience interest after acing large phase 2 clinical trials presented at the virtual congress of the European College of Neuropsychopharmacology.

The two successful drugs moving on to definitive phase 3 studies after their performance at ECNP 2020 are KarXT, a proprietary combination of xanomeline and trospium chloride, and an inhibitor of glycine transporter 1 (Gly-T1) known for now as BI 425809.

Pimavanserin, an oral selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors, has taken a more convoluted path through the developmental pipeline for schizophrenia. It recently failed to outperform placebo as adjunctive treatment for schizophrenia on the primary endpoint of improvement in Positive And Negative Syndrome Scale (PANSS) total score in the 6-week, phase 3 ENHANCE (Efficacy and Safety of Adjunctive Pimavanserin for the Treatment of Schizophrenia) study. The drug did, however, show significant benefit on secondary endpoints involving negative symptoms.

And in the 400-patient, 26-week, placebo-controlled, phase 2 ADVANCE trial, adjunctive pimavanserin was positive for the primary endpoint of improvement in the Negative Symptom Assessment-16 (NSA-16) score. A phase 3 program evaluating the drug specifically for negative symptoms is underway.

Another novel therapy, an investigational selective estrogen receptor beta agonist, proved reassuringly safe but completely ineffective in men with schizophrenia in a study presented at ECNP 2020.

“The results, unfortunately, were disappointing. We saw no signal on cognition, no change on brain imaging with fMRI, and no improvement in negative symptoms or PANSS total score,” reported Alan Breier, MD, professor and vice chair of the department of psychiatry at Indiana University in Indianapolis.

KarXT

KarXT combines xanomeline, a selective M1/M4 muscarinic receptor agonist exclusively licensed from Lilly to Karuna Therapeutics, with trospium chloride, a muscarinic antagonist approved for more than a decade in the United States and Europe for treatment of overactive bladder. Xanomeline was synthesized in the 1990s. It showed promising evidence of antipsychotic efficacy in schizophrenia and Alzheimer’s disease in yearlong clinical trials totaling more than 800 patients, but interest in further developing the drug cooled because of limiting GI and other cholinergic adverse events. KarXT, Karuna’s lead product candidate, is designed to maintain the efficacy of xanomeline while trospium, which doesn’t cross the blood-brain barrier, cancels out its side effects, explained Stephen Brannan, MD, a psychiatrist and chief medical officer at the company.

He presented the results of the phase 2 study, a multicenter, randomized, double-blind, placebo-controlled, 5-week trial conducted with 182 schizophrenia inpatients experiencing an acute psychotic exacerbation. All other antipsychotics were washed out before randomization to KarXT at 50 mg xanomeline/20 mg trospium twice daily, titrated to 100/20 twice daily on days 3-7 and 100/20 b.i.d. thereafter, with an optional increase to 125/30 twice daily.

The primary study endpoint was change from baseline to week 5 in PANSS total score. The results were positive at the P < .0001 level, with a mean 17.4-point reduction in the KarXT group, compared with a 5.9-point improvement in placebo-treated controls. The between-group difference was significant by the first assessment at week 2.

Four of five prespecified secondary endpoints were also positive in rapid and sustained fashion: improvement in the PANSS positive subscore, PANSS negative subscore, Marder PANSS negative subscore, and Clinical Global Impressions-Severity. The fifth secondary endpoint – the proportion of patients with a Clinical Global Impressions rating of 1 or 2, meaning normal or only mildly mentally ill – wasn’t significantly different with KarXT, compared with placebo, but Dr. Brannan shrugged that off.

“In hindsight, it was probably a little overly optimistic to think that after 5 weeks [patients with schizophrenia] would be either well or almost well,” he quipped.

An exploratory analysis of participants’ before-and-after scores on a battery of six cognitive tests showed an encouraging trend: Patients on KarXT performed numerically better than did controls on five of the six tests, albeit not significantly so. Moreover, in a further analysis stratified by baseline impairment, patients in the most impaired tertile showed a larger, statistically significant benefit in response to KarXT.

“We’re interested enough that we plan to continue to look at this in our upcoming larger and longer-term trials,” Dr. Brannan said.

As for safety and tolerability, he continued: “We were pleasantly surprised. We certainly see more side effects with KarXT than with placebo, but not by that much, and they’re much, much better than with xanomeline alone.”

The side effects, mostly cholinergic and anticholinergic, occurred 2-4 times more frequently than in controls. Notably, the rates of nausea, vomiting, and dry mouth – three of the five most common treatment-related adverse events in patients on KarXT – decreased over time to levels similar to placebo by week 5. In contrast, rates of constipation and dyspepsia remained stable over time. All side effects were mild to moderate, and none led to study discontinuation.

A key point was that the KarXT-related side effects were not the same ones that are commonly problematic and limiting with current antipsychotics. There was no weight gain or other metabolic changes, sleepiness or sedation, or extrapyramidal symptoms.

“These results show KarXT has the potential to offer patients a novel mechanism-of-action antipsychotic with a different efficacy and/or tolerability profile than current antipsychotic medications,” Dr. Brannan said.

BI 425809

BI 425809 is a once-daily oral inhibitor of glycine transporter 1 (Gly-T1) specifically designed to alleviate cognitive impairment in people with schizophrenia. Underactivity by the NMDA (N-methyl-D-aspartic acid) receptor has been implicated in this cognitive dysfunction. Glycine is an NMDA cotransmitter. By blocking glutamatergic presynaptic and astrocyte reuptake of glycine, BI 425809 results in increased glycine levels in the synaptic cleft, facilitating neurotransmission, explained W. Wolfgang Fleischhacker, MD, president of the Medical University of Innsbruck (Austria), where he is also professor of psychiatry.

He presented the results of a phase 2, randomized, double-blind, 11-country study in which 509 adults with stable schizophrenia on no more than two antipsychotics were placed on add-on BI 425809 at 2, 5, 10, or 25 mg once daily or placebo for 12 weeks.

The primary endpoint was change from baseline to 12 weeks in the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) Consensus Cognitive Battery (MCCB) score. The results were strongly positive, with patients on the two top doses of BI 425809 – 10 and 25 mg/day – showing roughly a 2-point greater improvement in MCCB overall composite T-score compared with controls. Dr. Fleischhacker drew attention to the high study completion rates in the various study arms, ranging from a low of 91% to 97.6% in the 25 mg/day group.

“That’s a very nice but also an unusual finding for a trial of this length,” he observed.

The high study completion rate was a reflection of the drug’s high-level tolerability. Indeed, the rate of adverse events leading to treatment discontinuation was 0% with BI 425809 at 10 mg/day, 2.4% at 25 mg/day, and identical at 2.4% with placebo. No increase was found in psychiatric adverse events such as suicidal ideation or behavior.

“This is a first very promising result,” Dr. Fleischhacker concluded. “Basically, this is the first study that has really shown in a convincing fashion an effect of any novel compound on cognitive impairment in people suffering from schizophrenia.”

A separate ongoing phase 2 study is evaluating BI 425809 in combination with adjunctive computerized cognitive training in an effort to increase cognitive stimulation. The company is awaiting those study results before designing its phase 3 program.
 

Pimavanserin

It has been a busy year for pimavanserin, with both successes and disappointments in clinical trials addressing a range of psychotic disorders, according to Dragana Bugarski-Kirola, MD, MBA, MSc, vice president for clinical development at Acadia Pharmaceuticals in San Diego.

At present, pimavanserin is Food and Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. But in July 2020, on the strength of the positive results of the pivotal phase 3 HARMONY trial, Acadia filed an application with the FDA for marketing approval of the drug for treatment of dementia-related psychosis. In HARMONY, patients on placebo proved to be 2.8-fold more likely to experience a relapse of delusions or hallucinations than with pimavanserin.

A big recent disappointment was that pimavanserin failed to meet its primary endpoint in the phase 3 CLARITY I and CLARITY II trials as adjunctive therapy for major depressive disorder inadequately responsive to a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor. The change in Hamilton Depression Rating Scale–17 scores in patients on the atypical antipsychotic wasn’t significantly better than with placebo. However, pimavanserin did outperform placebo on the secondary endpoint of Clinical Global Impression–Severity. Additional clinical trials of the drug for treatment of major depression are planned, Dr. Bugarski-Kirola said.
 

LY500307

Although schizophrenia is equally common in men and women, the disease has a later onset and more benign course in women. This suggests a possible protective effect of estrogen, and indeed, extensive literature supports the use of exogenous estrogen in schizophrenia, where it reduces relapses and improves cognitive impairment and negative symptoms.

“We have no other agents that do that,” noted Dr. Breier, also chief of the psychotic disorders program and director of the Prevention and Recovery Center at Indiana University.

What he considers the best-executed clinical trial of estradiol in schizophrenia, an 8-week, double-blind, randomized study of a 200-mcg estradiol patch or placebo in 200 women aged 19-46 on antipsychotics, was published last year (JAMA Psychiatry. 2019 Jul 31;76[10]:1-9).

The results were impressive. However, estrogen may not be a viable treatment for men and premenopausal women because of its side effects, including feminization, and increased thrombotic and malignancy risks.

This was the impetus for the placebo-controlled randomized trial of LY500307, a highly selective estrogen receptor beta agonist originally developed by Eli Lilly as a potential treatment for benign prostatic hypertrophy, for which it proved ineffective. In animal models, estrogen receptor beta is responsible for a range of effects, including enhanced cognition, social behavior, and an anxiolytic action, whereas the alpha receptor affects the sex organs, skeletal and metabolic homeostasis, and is responsible for estrogen’s problematic side effects.

All three doses studied in the phase 2 randomized trial, which included 94 men with schizophrenia, proved safe, well-tolerated – and ineffective.

“I think one potential conclusion one could consider from these data is that estrogen receptor alpha engagement may be necessary for the estrogenic therapeutics in schizophrenia,” Dr. Breier said.

He reported having no financial conflicts regarding the trial, funded by Indiana University. Outside the scope of the study, he serves as a consultant to Karuna Therapeutics, BioXcel, and Perception Neuroscience.

Dr. Fleischhacker serves as a consultant to Boehringer Ingelheim, which sponsored the phase 2 study of BI 425809, as well as to Angelini, Richter, and Recordati.
 

bjancin@mdedge.com

SOURCE: ECNP 2020, Session S.12.

The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

bjancin@mdedge.com

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

bjancin@mdedge.com

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

The disinhibited binge eating style often seen in individuals with high ADHD symptoms is attributable to a heightened neural reward response to food rather than to the impulsivity that’s a core feature of ADHD, Elizabeth Martin, MSc, reported at the virtual congress of the European College of Neuropsychopharmacology.

She presented a functional MRI brain-imaging study designed to help pin down the mechanism involved in the disordered eating patterns that often accompany ADHD.

“Determining the underlying mechanism between binge eating and ADHD may be helpful in developing novel therapies for both ADHD and binge eating disorder. Our research suggests that further investigation of the role of altered reward processing in ADHD may be an avenue for this,” said Ms. Martin, a doctoral researcher in the department of psychology at the University of Birmingham (England).

She and her coinvestigators recruited 31 university student volunteers with high ADHD symptoms as evidenced by their mean score of 29.3 on the 0-54 Conners’ Adult ADHD Rating Scale, and 27 others with low ADHD symptoms and a mean Conners’ score of 6.8. The two groups didn’t differ in age or BMI. However, not surprisingly, the high-ADHD group exhibited greater impulsivity, with a mean score of 72 on the Barratt Impulsiveness Scale, versus 56.5 in the low ADHD group.

A battery of eating disorder scales was applied to assess participants in terms of binge/disinhibited or restrictive eating patterns. The high- and low–ADHD symptom groups didn’t differ in terms of prevalence of a restrictive eating style, which was low, but the high-ADHD participants scored on average roughly 50% higher on the binge/disinhibited eating style measure, compared with the low-ADHD group.

Each study participant underwent a 1-hour BOLD (blood oxygen level dependent) functional MRI scan while performing two sets of tasks. One task entailed quickly looking at 120 photos of food items and an equal number of nonfood items and rating how appealing the pictures were. The other challenge was what psychologists call a go/no-go task, a computerized cognitive test used to assess inhibitory control based upon reaction times and error rates.

On the go/no-go task, there were no between-group differences in rates of errors of omission or commission or reaction time. Moreover, the MRI results indicated there were no between-group differences in neural circuitry activation during this task. The investigators therefore concluded that the tendency toward binge eating in the high–ADHD symptoms group was not tied to greater impulsivity as reflected in less effective inhibitory processes.

The food picture rating task told a different story. The MRIs demonstrated increased responses to food versus nonfood images in the high-ADHD subjects, compared with the low-ADHD subjects in reward-related brain areas, including the ventromedial prefrontal cortex, caudate nucleus, and ventral tegmental area.

“This is the first evidence that ADHD symptoms in young adults are associated with enhanced neural activation in key reward-related brain areas in response to viewing food pictures,” according to Ms. Martin. “This suggests that enhanced responsiveness to food cues may be a mediating mechanism underlying overeating in ADHD.”

Of note, only one drug – lisdexamfetamine dimesylate (Vyvanse) is Food and Drug Administration-approved for the treatment of both ADHD and binge-eating disorder.

“Until now it’s been unclear how lisdexamfetamine dimesylate reduces binge eating, but our results suggest that one mechanism worthy of further investigation is the potential effect of the drug on food reward processes,” Ms. Martin said.

She reported having no financial conflicts regarding the study, which was supported by university funding.

bjancin@mdedge.com

SOURCE: Martin E. ECNP 2020. Abstr. P.041.

Romosozumab is a novel osteoporosis treatment agent that stimulates bone formation and inhibits bone resorption. Due to concerns for adverse cardiovascular effects, this medication is generally reserved for patients with severe osteoporosis despite multiple previous treatments. However, the influence of previous osteoporosis pharmacotherapy on romosozumab’s skeletal efficacy remains poorly studied, especially in real world clinical scenarios. In a prospective non-randomized study of 130 patients treated with romosozumab in Japan, the effects of romosozumab treatment on bone turnover markers and bone mineral density (BMD) was assessed based on previous treatment with either no osteoporosis medication, bisphosphonates, denosumab, or teriparatide. In general, treatment-naïve individuals experienced superior spine BMD and bone turnover marker gains versus patients who had previously received osteoporosis pharmacotherapy. Notably, prior treatment with the potent anti-resorptive agent denosumab was associated with suboptimal spine BMD response to romosozumab. These results highlight the potential impact of previous anti-resorptive treatment on romosozumab efficacy and indicate that careful consideration of treatment sequence is warranted when deciding amongst the multiple osteoporosis agents that are currently available.

Denosumab is a potent anti-resorptive osteoporosis agent that works by neutralizing RANKL, the key cytokine that drives osteoclast differentiation. While effective at suppressing bone resorption, increasing BMD, and preventing fragility fractures when administered every 6 months, rapid discontinuation of denosumab has been associated with an increased risk of vertebral compression fractures. In routine clinical practice, denosumab injection delays are common. However, risks of vertebral fractures associated with such injection delays remain unknown. In this study of a UK population-based cohort of 2,594 patients, a large electronic database was used to assess the relationship between denosumab dosing intervals (defined as ‘on time’, ‘short delay’, and ‘long delay’) and fractures in the 6 month window after the recommended treatment date. Compared with ‘on time’ denosumab treatment, individuals who received delayed denosumab injections showed an increased risk of interval vertebral fractures. Notably, the delay time was associated with fracture risk. This powerful study design further underscores the importance of timely (every 6 months) denosumab injections. Given current health care delivery challenges associated with the COVID-19 pandemic, these results should be considered when selecting initial osteoporosis treatment agents and in management of patients currently receiving denosumab. 

Abaloparatide, a synthetic analog of parathyroid hormone related peptide (PTHrP) is a bone anabolic osteoporosis treatment agent. In the ACTIVE study, abaloparatide increased bone mineral density and reduced fracture risk compared to both placebo and teriparatide. Although abaloparatide is generally well-tolerated, non-serious adverse events have been reported such as dizziness and palpitations. PTHrP can act in a paracrine manner to cause vasodilation. Therefore, in this post hoc drug safety study, the effects of abaloparatide on blood pressure, pulse, and cardiovascular adverse events were assessed in detail in subjects from the ACTIVE study (one hour post treatment) plus an additional group of 55 subjects for more detailed hemodynamic assessment. Compared to placebo injection, both abaloparatide and teriparatide treatment caused mild and transient increases in pulse and decreases in systolic blood pressure. These mild hemodynamic changes were not associated with an increased risk of adverse cardiovascular events. In general, these data are reassuring and support the cardiac safety of PTH analogs for osteoporosis. However, the transient hemodynamic changes observed should be considered for patients with cardiovascular comorbidities or baseline problems with orthostasis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Romosozumab is a novel osteoporosis treatment agent that stimulates bone formation and inhibits bone resorption. Due to concerns for adverse cardiovascular effects, this medication is generally reserved for patients with severe osteoporosis despite multiple previous treatments. However, the influence of previous osteoporosis pharmacotherapy on romosozumab’s skeletal efficacy remains poorly studied, especially in real world clinical scenarios. In a prospective non-randomized study of 130 patients treated with romosozumab in Japan, the effects of romosozumab treatment on bone turnover markers and bone mineral density (BMD) was assessed based on previous treatment with either no osteoporosis medication, bisphosphonates, denosumab, or teriparatide. In general, treatment-naïve individuals experienced superior spine BMD and bone turnover marker gains versus patients who had previously received osteoporosis pharmacotherapy. Notably, prior treatment with the potent anti-resorptive agent denosumab was associated with suboptimal spine BMD response to romosozumab. These results highlight the potential impact of previous anti-resorptive treatment on romosozumab efficacy and indicate that careful consideration of treatment sequence is warranted when deciding amongst the multiple osteoporosis agents that are currently available.

Denosumab is a potent anti-resorptive osteoporosis agent that works by neutralizing RANKL, the key cytokine that drives osteoclast differentiation. While effective at suppressing bone resorption, increasing BMD, and preventing fragility fractures when administered every 6 months, rapid discontinuation of denosumab has been associated with an increased risk of vertebral compression fractures. In routine clinical practice, denosumab injection delays are common. However, risks of vertebral fractures associated with such injection delays remain unknown. In this study of a UK population-based cohort of 2,594 patients, a large electronic database was used to assess the relationship between denosumab dosing intervals (defined as ‘on time’, ‘short delay’, and ‘long delay’) and fractures in the 6 month window after the recommended treatment date. Compared with ‘on time’ denosumab treatment, individuals who received delayed denosumab injections showed an increased risk of interval vertebral fractures. Notably, the delay time was associated with fracture risk. This powerful study design further underscores the importance of timely (every 6 months) denosumab injections. Given current health care delivery challenges associated with the COVID-19 pandemic, these results should be considered when selecting initial osteoporosis treatment agents and in management of patients currently receiving denosumab. 

Abaloparatide, a synthetic analog of parathyroid hormone related peptide (PTHrP) is a bone anabolic osteoporosis treatment agent. In the ACTIVE study, abaloparatide increased bone mineral density and reduced fracture risk compared to both placebo and teriparatide. Although abaloparatide is generally well-tolerated, non-serious adverse events have been reported such as dizziness and palpitations. PTHrP can act in a paracrine manner to cause vasodilation. Therefore, in this post hoc drug safety study, the effects of abaloparatide on blood pressure, pulse, and cardiovascular adverse events were assessed in detail in subjects from the ACTIVE study (one hour post treatment) plus an additional group of 55 subjects for more detailed hemodynamic assessment. Compared to placebo injection, both abaloparatide and teriparatide treatment caused mild and transient increases in pulse and decreases in systolic blood pressure. These mild hemodynamic changes were not associated with an increased risk of adverse cardiovascular events. In general, these data are reassuring and support the cardiac safety of PTH analogs for osteoporosis. However, the transient hemodynamic changes observed should be considered for patients with cardiovascular comorbidities or baseline problems with orthostasis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Romosozumab is a novel osteoporosis treatment agent that stimulates bone formation and inhibits bone resorption. Due to concerns for adverse cardiovascular effects, this medication is generally reserved for patients with severe osteoporosis despite multiple previous treatments. However, the influence of previous osteoporosis pharmacotherapy on romosozumab’s skeletal efficacy remains poorly studied, especially in real world clinical scenarios. In a prospective non-randomized study of 130 patients treated with romosozumab in Japan, the effects of romosozumab treatment on bone turnover markers and bone mineral density (BMD) was assessed based on previous treatment with either no osteoporosis medication, bisphosphonates, denosumab, or teriparatide. In general, treatment-naïve individuals experienced superior spine BMD and bone turnover marker gains versus patients who had previously received osteoporosis pharmacotherapy. Notably, prior treatment with the potent anti-resorptive agent denosumab was associated with suboptimal spine BMD response to romosozumab. These results highlight the potential impact of previous anti-resorptive treatment on romosozumab efficacy and indicate that careful consideration of treatment sequence is warranted when deciding amongst the multiple osteoporosis agents that are currently available.

Denosumab is a potent anti-resorptive osteoporosis agent that works by neutralizing RANKL, the key cytokine that drives osteoclast differentiation. While effective at suppressing bone resorption, increasing BMD, and preventing fragility fractures when administered every 6 months, rapid discontinuation of denosumab has been associated with an increased risk of vertebral compression fractures. In routine clinical practice, denosumab injection delays are common. However, risks of vertebral fractures associated with such injection delays remain unknown. In this study of a UK population-based cohort of 2,594 patients, a large electronic database was used to assess the relationship between denosumab dosing intervals (defined as ‘on time’, ‘short delay’, and ‘long delay’) and fractures in the 6 month window after the recommended treatment date. Compared with ‘on time’ denosumab treatment, individuals who received delayed denosumab injections showed an increased risk of interval vertebral fractures. Notably, the delay time was associated with fracture risk. This powerful study design further underscores the importance of timely (every 6 months) denosumab injections. Given current health care delivery challenges associated with the COVID-19 pandemic, these results should be considered when selecting initial osteoporosis treatment agents and in management of patients currently receiving denosumab. 

Abaloparatide, a synthetic analog of parathyroid hormone related peptide (PTHrP) is a bone anabolic osteoporosis treatment agent. In the ACTIVE study, abaloparatide increased bone mineral density and reduced fracture risk compared to both placebo and teriparatide. Although abaloparatide is generally well-tolerated, non-serious adverse events have been reported such as dizziness and palpitations. PTHrP can act in a paracrine manner to cause vasodilation. Therefore, in this post hoc drug safety study, the effects of abaloparatide on blood pressure, pulse, and cardiovascular adverse events were assessed in detail in subjects from the ACTIVE study (one hour post treatment) plus an additional group of 55 subjects for more detailed hemodynamic assessment. Compared to placebo injection, both abaloparatide and teriparatide treatment caused mild and transient increases in pulse and decreases in systolic blood pressure. These mild hemodynamic changes were not associated with an increased risk of adverse cardiovascular events. In general, these data are reassuring and support the cardiac safety of PTH analogs for osteoporosis. However, the transient hemodynamic changes observed should be considered for patients with cardiovascular comorbidities or baseline problems with orthostasis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.

Not only the prevalence, but the impact of nonalcoholic fatty liver disease (NAFLD) is increasing in much of the world, Arun J. Sanyal, MD, said in a virtual presentation at the meeting jointly provided by Rutgers and Global Academy for Medical Education. “It is currently estimated that the number of people living with cirrhosis or with decompensated cirrhosis will increase two- to threefold from 2015 to 2030,” which underlines the public health impact and the need for improved treatment paradigms, he emphasized.

“The thing to remember about NAFLD is that it does not exist in a vacuum,” Dr. Sanyal said. NAFLD is a multisystem disorder. Most patients have concomitant cardiovascular disease, but others may have type 2 diabetes, hypertension, and dyslipidemia, all of which are now accepted as risk factors for nonalcoholic steatohepatitis (NASH), he said.

“What ties these conditions together is metabolic stress leading to systemic inflammation and fibrosis. This is primarily due to diet-induced obesity. If you think about treating all of these competing risks to the patient’s life, the optimal way is to treat the root cause,” he said.

Various options exist to manage the conditions that can lead to NASH, but several of these also appear promising as a treatment of NASH, Dr. Sanyal said. Glucagonlike peptide–1 agonists and sodium-glucose transporter 2 inhibitors have been shown to improve multiple outcomes of interest in type 2 diabetes. However, insulin can cause weight gain at the expense of controlling HbA1C levels, he said.

Bariatric surgery can improve histology, but many patients with advanced fibrosis do not demonstrate improvement in fibrosis. Also, bariatric surgery has its own associated morbidity, including an increased suicide rate across multiple studies, Dr. Sanyal noted.

A new and interesting option is duodenal mucosal resurfacing (DMR) “a novel, minimally invasive outpatient upper-endoscopic procedure,” said Dr. Sanyal. DMR involves use of a catheter to perform a submucosal lift and hydrothermal mucosal ablation, prompting healthy epithelial regrowth, he explained. “The mucosa sloughs off, fresh epithelium grows in, and the hormonal signal from the gut to the rest of the body is restored to a more normal pattern,” he noted.

In the REVITA-2 study of patients with diabetes and NAFLD, the average fat loss was 5.4% in those randomized to DMR vs. 2.4% in sham-procedure patients and represented “quite significant defatting of the liver,” Dr. Sanyal said.

Dr. Sanyal then focused on fatty liver disease. “The first step when you see a patient with fatty liver disease is to see how scarred is the liver, and whether the patient has silent cirrhosis. The more scarred the liver, the greater risk of liver-related outcomes,” he said. The goal of therapy for these patients is to reduce the risk of progression to cirrhosis, he added. Dr. Sanyal recommended evaluating fibrosis using the Fibrosis 4 score (Fib4). “If the Fib4 is less than 1.3, the likelihood of significant scarring in the liver is less than 10%,” he said. On the other hand, a Fib4 greater than 2.67 suggests advanced fibrosis, he noted.

Overall, the goals of treatment for NASH patients are to prevent cirrhosis, reduce decompensation, and prevent hepatocellular carcinoma, said Dr. Sanyal.

“The ideal drug for NASH should also help other end organs, or at least be neutral,” said Dr. Sanyal.

Current frontline therapies for precirrhotic NASH include thiazolidinediones (TZD), farnesoid X receptor (FXR)/fibroblast growth factor 19 (FGF-19), FGF21, thyroxine B-R, and glucagonlike peptide-1. Clinical evidence varies based on different populations, endpoints, assessment methods, and treatment duration, he said.

Looking ahead to the next decade, a NASH management paradigm will likely play out that can be applied in the clinic today, Dr. Sanyal said. First, make an initial assessment of the status of the end organs. Start with a weight-loss regimen; use statins and GLP-1 and SGLT2 inhibitors as needed. Follow and reassess, and if the patient still has disease, progress to targeted therapy for active NASH while continuing to encourage weight loss and healthy living, he said.

“The ultimate proof that what we are doing is working is that we are improving mortality, reducing health care costs, and improving patients’ function and quality of life,” he concluded.

Dr. Sanyal is president of Sanyal Biotechnologies. He also disclosed stock options for Durect, Exhalenz, Galmed, Genfit, Immuton, Indalo, and Tiziana, as well as various relationships with Allergan, AMRA, Astra Zeneca-Medimmune, Birdrock, Boehringer Ingelheim, Bristol Myers, Echosense, GE, Genentech, Gilead, Hemoshear, IFMO, Innovate, Intercept, Lilly, Lipocine, Merck, Novartis, Novo Nordisk, OWL, Pfizer, RedX, Sundise, Tern, and Zydus.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Help your patients understand their risks for NASH by sharing AGA patient education at http://ow.ly/5AAk30rbK5y.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

A global analysis of premature deaths from noncommunicable diseases (NCDs) has shown mixed results for gastrointestinal (GI) cancers.

The data suggest fewer people are dying from stomach cancer, but in some countries, the risk of colorectal cancer death is increasing or declining much more slowly than other causes of premature death.

As for other cancers, in more than half of the countries analyzed, the risk of liver and prostate cancer death is on the rise in men, and the risk of lung cancer death is on the rise in women.

The global decrease in the risk of stomach cancer death may be explained by the fact that stomach cancer’s main cause is Helicobacter pylori infection, which correlates with general food hygiene, the study’s corresponding author Majid Ezzati, PhD, professor of global environmental health at Imperial College London, said in an interview.

“Factors such as more widespread electrification and refrigeration tend to drive the rates down,” he explained.

Dr. Ezzati and colleagues detailed their findings in the second edition of the NCD Countdown 2030 report, recently published in The Lancet.

The report revolves around the Sustainable Development Goal (SDG) target 3.4, which is to reduce premature deaths from NCDs by one-third between 2015 and 2030. The causes of death include cancer, cardiovascular disease, chronic respiratory disease, and diabetes, which are collectively known as NCD4. “Premature” deaths are defined as deaths in people aged 30-70 years.

SDG target 3.4 is still attainable, according to Dr. Ezzati and colleagues. However, their report showed that many countries are falling short of this goal.

The findings come from an analysis of 2016 World Health Organization global estimate data on age-, sex-, and cause-specific mortality for 176 countries and territories with at least 200,000 inhabitants. Mathematical modeling was used to assess the number of approaches countries used to accelerate declines in mortality.
 

Results of the analysis

“Trends in the risk of death from 2010 to 2016 varied considerably among NCD4 causes of death,” Dr. Ezzati and colleagues wrote.

Stomach cancer, ischemic and hemorrhagic stroke, ischemic heart disease, and chronic respiratory diseases had the fastest rates of decline among risks of premature death.

In fact, stomach cancer was the fastest declining cause of death in 45 countries (25.6%) among men and in 40 countries (22.7%) among women.

On the other hand, the risk of premature death from colorectal, liver, breast, prostate, and other cancers declined more slowly than the risk of premature death from other NCDs.

The risk of death from colorectal, liver, and prostate cancers in men and lung cancer in women rose in more than 50% of the countries surveyed.

“The median annual rate of change in the probability of dying prematurely from various causes ranged from +0.2% per year for lung cancer to –2.5% per year for hemorrhagic stroke in women, and from +0.5% per year for colorectal cancer to –1.8% per year for hemorrhagic stroke in men,” the investigators summarized.
 

Explaining the GI cancer results

“There are dramatic differences between the upper and lower GI tract, both in terms of anatomy/embryologic origin but also in terms of exposures,” observed Mark Lewis, MD, medical director of the gastrointestinal oncology program at Intermountain Healthcare in Salt Lake City, in an interview.

H. pylori infection, family history, and diet factor into stomach cancer risk, Dr. Lewis said.

While family history isn’t modifiable, “we are much better now at identifying and eradicating the potentially carcinogenic H. pylori bacterium. In terms of diet, the advent of modern refrigeration has made the prevalence of heavily salted/preserved foods decline,” he added.

A 14-day course of treatment (with a proton pump inhibitor and antibiotics) can eliminate H. pylori, Dr. Lewis continued. “The prophylactic effect against gastric cancer is massive, cutting risk by roughly half,” he said.

At least in the United States, colorectal cancer rates have declined in people 50 years and older, but rates have risen sharply in younger age groups, increasing by 2% annually in the last decade, according to statistics in CA: A Cancer Journal for Clinicians.

“One prevailing theory is prior antibiotic prescriptions [even in childhood] might perturb the microbiome of the lower GI tract and predispose to cancer,” Dr. Lewis said, pointing to a recent study in the British Journal of Cancer that identified an association between repeated antibiotic use and colorectal cancer.
 

Reducing NCD deaths

Dr. Ezzati and colleagues said six high-income countries – Denmark, Luxembourg, New Zealand, Norway, Singapore, and South Korea – are likely to meet SDG target 3.4 if they maintain or exceed average rates of decline seen during 2010-2016. Seventeen countries are on track to reach the target for women, and 15 countries are on track for men.

High-income countries in Asia-Pacific, western Europe, Australasia, and Canada have seen the lowest NCD4 mortality risk, whereas low- and middle-income countries in sub-Saharan Africa and men in central Asia and eastern Europe have seen the highest risk.

“To move forward, we must learn from those countries that are doing well and replicate their strategies to NCD prevention and healthcare,” Dr. Ezzati said in a statement. “Our analysis shows that every country still has options to achieve SDG target 3.4, but they need to address multiple diseases and have strong health systems.”

Increasing access to effective cancer screening and diagnosing and treating cancers earlier could help reduce long-term health consequences and premature deaths from cancer, according to Dr. Ezzati and colleagues. Screening would help even the playing field on cancer diagnosis and survival rates between higher-income countries and low- and middle-income countries.

“This approach will allow earlier diagnosis during precancerous or early stages of disease, followed by treatment of those cancers with effective treatment,” the authors stated.

Tobacco and alcohol interventions and increasing access to quality primary care would also help tamp down on NCD-related deaths.

The authors acknowledged that low-income countries, which may be struggling with other health crises such as COVID-19 and Ebola, may find it a challenge to stage such interventions.

“COVID-19 has exposed how a failure to invest in effective public health to prevent NCDs and provide health care for people living with NCDs can come back to bite us,” said Katie Dain, CEO of the NCD Alliance.

“The good news is that all countries can still meet the 2030 targets, with sound policies and smart investments. NCD prevention and treatment can no longer be seen a ‘nice to have.’ It must be considered as part of pandemic preparedness,” she added.

COVID-19 should serve as an impetus for governments to invest in healthier lifestyle and diet habits and curb alcohol and tobacco use, according to an editorial in The Lancet related to the analysis.

The current report updates 2018’s first NCD Countdown Report, which linked NCD4 conditions to approximately 32 million or 80% of NCD deaths. Unlike the recent report, 2018’s data didn’t focus on specific diseases.

The current report was funded by Research England. Dr. Ezzati received a charitable grant from the AstraZeneca Young Health Programme and personal fees from Prudential and Scor, outside of this report. None of the other authors reported competing interests. Dr. Lewis has no relevant disclosures except that he is a commentator for Medscape, which is owned by the same parent company as MDedge.
 

SOURCE: Bennett JE et al. Lancet. 2020 Sep 3. doi: 10.1016/S0140-6736(20)31761-X.

A systematic review of nine studies provided limited evidence that off-label oral nonselective beta-blockers can be an effective treatment for facial erythema and flushing in rosacea, while at the same time underscoring the paucity of evidence supporting their use, investigators reported.

“The evidence was highest for carvedilol and propranolol, two nonselective beta-blockers,” wrote the authors of the review, Jade G.M. Logger, MD, of the department of dermatology, Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. Their review is in the Journal of the American Academy of Dermatology.

The systematic review included a case control study of 53,927 patients and an equal number of controls that evaluated beta-blockers in general, but the remaining studies and case reports included only 106 patients in total. The largest was a prospective cohort study of propranolol in 63 patients. Other studies included a 15-patient randomized clinical trial of nadolol published 31 years ago and three single-patient case reports.

The studies included patients with a history of failed therapies; only a small number of beta-blockers were evaluated. Outcomes reported in the studies varied widely, which ruled out doing a meta-analysis. “Erythema and flushing were assessed by using a wide spectrum of mostly subjective clinical and patient-based scores, and method standardization was often missing,” the researchers stated.

“Most studies showed improved erythema and flushing after initiation of oral beta-blockers,” Dr. Logger and colleagues wrote. Treatment of facial erythema and flushing remains a clinical challenge despite approved therapies, for which poor response and reactivation are common. “Diminishing erythema and flushing in rosacea is challenging because it hardly responds to conventional anti-inflammatory treatment,” they noted.

“The study adds no new evidence to support the use of beta-blockers,” Diane M. Thiboutot, MD, professor of dermatology at Penn State University, Hershey, said in an interview. “As the authors point out, the nine studies reviewed were of low quality with a variety of outcome measures that precluded generation of a meta-analysis, which would have represented new information.”

Dr. Thiboutot is lead author of a 2019 update of management options for rosacea published by the National Rosacea Society Expert Committee last year.. Beta blockers are among the drugs that are sometimes prescribed off label to help rosacea-associated flushing, along with nonsteroidal anti-inflammatory drugs, antihistamines, and clonidine, according to the update.

Dr. Logger and coauthors noted that beta-blockers come with risks, and can aggravate asthma and psoriasis and are contraindicated in patients with heart failure, cardiogenic shock, and other cardiovascular diseases, along with hyperactive airway and Raynaud’s disease. “It is important to monitor patients for adverse effects, especially blood pressure and heart rate,” they stated. Carvedilol and propranolol may have more antioxidant and anti-inflammatory properties than other nonselective beta-blockers that may curtail rosacea manifestations, they wrote.

They called for large, prospective clinical trials to more accurately assess the efficacy of beta-blockers in rosacea patients. “Researchers should further focus on the determination of the optimal dosage, treatment duration, and long-term therapeutic effects for adequate treatment of erythema and flushing in rosacea,” they said.

Getting those trials is challenging, Dr. Thiboutot said. “Objective and even subjective measurement of transient and persistent facial erythema is extremely challenging, particularly in the setting of a prospective clinical trial.” The trials would have to control for a number of variables, including room conditions, patient diet, and timing of medication, and large trials require multiple sites,” which could add to the variability of the data,” she said in the interview. Funding such trials would be difficult because adding an indication for rosacea-related symptoms would have limited commercial potential, she added.

Nonetheless, the studies would be welcome, Dr. Thiboutot said. “If standardized outcome measures for facial erythema were to be developed, a study would be more feasible.”

Dr. Logger disclosed financial relationships with Galderma, AbbVie, Novartis, Janssen, and LEO Pharma; one author disclosed conducting clinical trials for AbbVie and Novartis; the third author disclosed relationships with Galderma, Cutanea Life Sciences, AbbVie, Novartis, and Janssen, with fees paid to his institution. Dr. Thiboutot disclosed a financial relationship with Galderma.
 

SOURCE: Logger JGM et al. J Am Acad Dermatol. 2020 Oct;83(4):1088-97.

A systematic review of nine studies provided limited evidence that off-label oral nonselective beta-blockers can be an effective treatment for facial erythema and flushing in rosacea, while at the same time underscoring the paucity of evidence supporting their use, investigators reported.

“The evidence was highest for carvedilol and propranolol, two nonselective beta-blockers,” wrote the authors of the review, Jade G.M. Logger, MD, of the department of dermatology, Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. Their review is in the Journal of the American Academy of Dermatology.

The systematic review included a case control study of 53,927 patients and an equal number of controls that evaluated beta-blockers in general, but the remaining studies and case reports included only 106 patients in total. The largest was a prospective cohort study of propranolol in 63 patients. Other studies included a 15-patient randomized clinical trial of nadolol published 31 years ago and three single-patient case reports.

The studies included patients with a history of failed therapies; only a small number of beta-blockers were evaluated. Outcomes reported in the studies varied widely, which ruled out doing a meta-analysis. “Erythema and flushing were assessed by using a wide spectrum of mostly subjective clinical and patient-based scores, and method standardization was often missing,” the researchers stated.

“Most studies showed improved erythema and flushing after initiation of oral beta-blockers,” Dr. Logger and colleagues wrote. Treatment of facial erythema and flushing remains a clinical challenge despite approved therapies, for which poor response and reactivation are common. “Diminishing erythema and flushing in rosacea is challenging because it hardly responds to conventional anti-inflammatory treatment,” they noted.

“The study adds no new evidence to support the use of beta-blockers,” Diane M. Thiboutot, MD, professor of dermatology at Penn State University, Hershey, said in an interview. “As the authors point out, the nine studies reviewed were of low quality with a variety of outcome measures that precluded generation of a meta-analysis, which would have represented new information.”

Dr. Thiboutot is lead author of a 2019 update of management options for rosacea published by the National Rosacea Society Expert Committee last year.. Beta blockers are among the drugs that are sometimes prescribed off label to help rosacea-associated flushing, along with nonsteroidal anti-inflammatory drugs, antihistamines, and clonidine, according to the update.

Dr. Logger and coauthors noted that beta-blockers come with risks, and can aggravate asthma and psoriasis and are contraindicated in patients with heart failure, cardiogenic shock, and other cardiovascular diseases, along with hyperactive airway and Raynaud’s disease. “It is important to monitor patients for adverse effects, especially blood pressure and heart rate,” they stated. Carvedilol and propranolol may have more antioxidant and anti-inflammatory properties than other nonselective beta-blockers that may curtail rosacea manifestations, they wrote.

They called for large, prospective clinical trials to more accurately assess the efficacy of beta-blockers in rosacea patients. “Researchers should further focus on the determination of the optimal dosage, treatment duration, and long-term therapeutic effects for adequate treatment of erythema and flushing in rosacea,” they said.

Getting those trials is challenging, Dr. Thiboutot said. “Objective and even subjective measurement of transient and persistent facial erythema is extremely challenging, particularly in the setting of a prospective clinical trial.” The trials would have to control for a number of variables, including room conditions, patient diet, and timing of medication, and large trials require multiple sites,” which could add to the variability of the data,” she said in the interview. Funding such trials would be difficult because adding an indication for rosacea-related symptoms would have limited commercial potential, she added.

Nonetheless, the studies would be welcome, Dr. Thiboutot said. “If standardized outcome measures for facial erythema were to be developed, a study would be more feasible.”

Dr. Logger disclosed financial relationships with Galderma, AbbVie, Novartis, Janssen, and LEO Pharma; one author disclosed conducting clinical trials for AbbVie and Novartis; the third author disclosed relationships with Galderma, Cutanea Life Sciences, AbbVie, Novartis, and Janssen, with fees paid to his institution. Dr. Thiboutot disclosed a financial relationship with Galderma.
 

SOURCE: Logger JGM et al. J Am Acad Dermatol. 2020 Oct;83(4):1088-97.

A systematic review of nine studies provided limited evidence that off-label oral nonselective beta-blockers can be an effective treatment for facial erythema and flushing in rosacea, while at the same time underscoring the paucity of evidence supporting their use, investigators reported.

“The evidence was highest for carvedilol and propranolol, two nonselective beta-blockers,” wrote the authors of the review, Jade G.M. Logger, MD, of the department of dermatology, Radboud University Medical Center in Nijmegen, the Netherlands, and coauthors. Their review is in the Journal of the American Academy of Dermatology.

The systematic review included a case control study of 53,927 patients and an equal number of controls that evaluated beta-blockers in general, but the remaining studies and case reports included only 106 patients in total. The largest was a prospective cohort study of propranolol in 63 patients. Other studies included a 15-patient randomized clinical trial of nadolol published 31 years ago and three single-patient case reports.

The studies included patients with a history of failed therapies; only a small number of beta-blockers were evaluated. Outcomes reported in the studies varied widely, which ruled out doing a meta-analysis. “Erythema and flushing were assessed by using a wide spectrum of mostly subjective clinical and patient-based scores, and method standardization was often missing,” the researchers stated.

“Most studies showed improved erythema and flushing after initiation of oral beta-blockers,” Dr. Logger and colleagues wrote. Treatment of facial erythema and flushing remains a clinical challenge despite approved therapies, for which poor response and reactivation are common. “Diminishing erythema and flushing in rosacea is challenging because it hardly responds to conventional anti-inflammatory treatment,” they noted.

“The study adds no new evidence to support the use of beta-blockers,” Diane M. Thiboutot, MD, professor of dermatology at Penn State University, Hershey, said in an interview. “As the authors point out, the nine studies reviewed were of low quality with a variety of outcome measures that precluded generation of a meta-analysis, which would have represented new information.”

Dr. Thiboutot is lead author of a 2019 update of management options for rosacea published by the National Rosacea Society Expert Committee last year.. Beta blockers are among the drugs that are sometimes prescribed off label to help rosacea-associated flushing, along with nonsteroidal anti-inflammatory drugs, antihistamines, and clonidine, according to the update.

Dr. Logger and coauthors noted that beta-blockers come with risks, and can aggravate asthma and psoriasis and are contraindicated in patients with heart failure, cardiogenic shock, and other cardiovascular diseases, along with hyperactive airway and Raynaud’s disease. “It is important to monitor patients for adverse effects, especially blood pressure and heart rate,” they stated. Carvedilol and propranolol may have more antioxidant and anti-inflammatory properties than other nonselective beta-blockers that may curtail rosacea manifestations, they wrote.

They called for large, prospective clinical trials to more accurately assess the efficacy of beta-blockers in rosacea patients. “Researchers should further focus on the determination of the optimal dosage, treatment duration, and long-term therapeutic effects for adequate treatment of erythema and flushing in rosacea,” they said.

Getting those trials is challenging, Dr. Thiboutot said. “Objective and even subjective measurement of transient and persistent facial erythema is extremely challenging, particularly in the setting of a prospective clinical trial.” The trials would have to control for a number of variables, including room conditions, patient diet, and timing of medication, and large trials require multiple sites,” which could add to the variability of the data,” she said in the interview. Funding such trials would be difficult because adding an indication for rosacea-related symptoms would have limited commercial potential, she added.

Nonetheless, the studies would be welcome, Dr. Thiboutot said. “If standardized outcome measures for facial erythema were to be developed, a study would be more feasible.”

Dr. Logger disclosed financial relationships with Galderma, AbbVie, Novartis, Janssen, and LEO Pharma; one author disclosed conducting clinical trials for AbbVie and Novartis; the third author disclosed relationships with Galderma, Cutanea Life Sciences, AbbVie, Novartis, and Janssen, with fees paid to his institution. Dr. Thiboutot disclosed a financial relationship with Galderma.
 

SOURCE: Logger JGM et al. J Am Acad Dermatol. 2020 Oct;83(4):1088-97.

Condom use among sexually active high school students rose slightly in 2019, but the longer-term trend has been one of decline since 2003, according to data from the Youth Risk Behavior Survey (YRBS).

Nonuse of birth control in this population dropped to 11.9% in 2019, but the overall trend is one of no significant change since 2003. Meanwhile, the use of birth control pills has taken a different path, with prevalence rising significantly from 16.0% in 2007 to 23.0% in 2019, the Centers for Disease Control and Prevention reported.

The prevalence of condom use among sexually active students was 54.3% in 2019, up from 53.8% in 2017 – the survey is conducted every 2 years – but down from a high of 63.0% in 2003, the YRBS data show.

Condoms were the most prevalent method of contraception, but the finding that “only approximately half of sexually active students reported any condom use at last sexual intercourse … is concerning given the high risk for STDs among this population,” Leigh E. Szucs, PhD, and associates said in the Morbidity and Mortality Weekly Report.

In 2019, White (55.8%) and Hispanic (56.2%) students were more likely than Blacks (48.2%) to have used a condom during their last sexual intercourse, but use of birth control pills was much higher among Whites (29.1%) than Hispanics (15.4%) or Blacks (12.9%).The Black respondents were much more likely (23.0%) to use no contraceptive method, compared with Whites (8.4%) or Hispanics (13.3%), they said.

“Meeting the unintended pregnancy and STD/HIV prevention needs of black and Hispanic youths is vital,” wrote Dr. Szucs of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention and associates. “Understanding and addressing structural barriers that might contribute to the observed differences are important next steps.”

The high school students taking the YRBS were considered sexually active if they had intercourse with at least one person in the previous 3 months. Overall, 3,226 (27.4%) of respondents in 2019 reported being sexually active: 52.2% were female and 47.8% were male, the CDC said.

rfranki@mdedge.com

SOURCE: Szucs LE et al. MMWR. 2019 Aug 21;69(SS-01)11-8.

Condom use among sexually active high school students rose slightly in 2019, but the longer-term trend has been one of decline since 2003, according to data from the Youth Risk Behavior Survey (YRBS).

Nonuse of birth control in this population dropped to 11.9% in 2019, but the overall trend is one of no significant change since 2003. Meanwhile, the use of birth control pills has taken a different path, with prevalence rising significantly from 16.0% in 2007 to 23.0% in 2019, the Centers for Disease Control and Prevention reported.

The prevalence of condom use among sexually active students was 54.3% in 2019, up from 53.8% in 2017 – the survey is conducted every 2 years – but down from a high of 63.0% in 2003, the YRBS data show.

Condoms were the most prevalent method of contraception, but the finding that “only approximately half of sexually active students reported any condom use at last sexual intercourse … is concerning given the high risk for STDs among this population,” Leigh E. Szucs, PhD, and associates said in the Morbidity and Mortality Weekly Report.

In 2019, White (55.8%) and Hispanic (56.2%) students were more likely than Blacks (48.2%) to have used a condom during their last sexual intercourse, but use of birth control pills was much higher among Whites (29.1%) than Hispanics (15.4%) or Blacks (12.9%).The Black respondents were much more likely (23.0%) to use no contraceptive method, compared with Whites (8.4%) or Hispanics (13.3%), they said.

“Meeting the unintended pregnancy and STD/HIV prevention needs of black and Hispanic youths is vital,” wrote Dr. Szucs of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention and associates. “Understanding and addressing structural barriers that might contribute to the observed differences are important next steps.”

The high school students taking the YRBS were considered sexually active if they had intercourse with at least one person in the previous 3 months. Overall, 3,226 (27.4%) of respondents in 2019 reported being sexually active: 52.2% were female and 47.8% were male, the CDC said.

rfranki@mdedge.com

SOURCE: Szucs LE et al. MMWR. 2019 Aug 21;69(SS-01)11-8.

Condom use among sexually active high school students rose slightly in 2019, but the longer-term trend has been one of decline since 2003, according to data from the Youth Risk Behavior Survey (YRBS).

Nonuse of birth control in this population dropped to 11.9% in 2019, but the overall trend is one of no significant change since 2003. Meanwhile, the use of birth control pills has taken a different path, with prevalence rising significantly from 16.0% in 2007 to 23.0% in 2019, the Centers for Disease Control and Prevention reported.

The prevalence of condom use among sexually active students was 54.3% in 2019, up from 53.8% in 2017 – the survey is conducted every 2 years – but down from a high of 63.0% in 2003, the YRBS data show.

Condoms were the most prevalent method of contraception, but the finding that “only approximately half of sexually active students reported any condom use at last sexual intercourse … is concerning given the high risk for STDs among this population,” Leigh E. Szucs, PhD, and associates said in the Morbidity and Mortality Weekly Report.

In 2019, White (55.8%) and Hispanic (56.2%) students were more likely than Blacks (48.2%) to have used a condom during their last sexual intercourse, but use of birth control pills was much higher among Whites (29.1%) than Hispanics (15.4%) or Blacks (12.9%).The Black respondents were much more likely (23.0%) to use no contraceptive method, compared with Whites (8.4%) or Hispanics (13.3%), they said.

“Meeting the unintended pregnancy and STD/HIV prevention needs of black and Hispanic youths is vital,” wrote Dr. Szucs of the CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention and associates. “Understanding and addressing structural barriers that might contribute to the observed differences are important next steps.”

The high school students taking the YRBS were considered sexually active if they had intercourse with at least one person in the previous 3 months. Overall, 3,226 (27.4%) of respondents in 2019 reported being sexually active: 52.2% were female and 47.8% were male, the CDC said.

rfranki@mdedge.com

SOURCE: Szucs LE et al. MMWR. 2019 Aug 21;69(SS-01)11-8.

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

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

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

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

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

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

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

mzoler@mdedge.com

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

mzoler@mdedge.com

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.

The dramatically positive safety and efficacy results from the DAPA-CKD trial, which showed that treatment with the sodium-glucose transporter 2 (SGLT2) inhibitor dapagliflozin significantly cut both chronic kidney disease progression and all-cause death in patients with or without type 2 diabetes, were also notable for broadening the population of patients eligible for this treatment to those in the upper range of stage 4 CKD.

Courtesy European Society of Cardiology

Of the 4,304 CKD patients enrolled in DAPA-CKD, 624 (14%) had an estimated glomerular filtration rate (eGFR) of 25-29 mL/min per 1.73m², an unprecedented population to receive a drug from the SGLT2 inhibitor class in a reported study. The results provided definitive evidence for efficacy and safety in this range of renal function, said Hiddo J.L. Heerspink, Ph.D., at the virtual annual meeting of the European Association for the Study of Diabetes.

Until now, the widely accepted lowest level for starting an SGLT2 inhibitor in routine practice has been an eGFR as low as 30 mL/min per 1.73 m².
 

Using SGLT2 inhibitors when eGFR is as low as 25

“It’s time to reduce the eGFR level for initiating an SGLT2 inhibitor to as low as 25,” said Dr. Heerspink, a professor of clinical pharmacology at the University of Groningen (the Netherlands).

While conceding that this is primarily a decision to be made by guideline writers and regulatory bodies, he declared what he believed was established by the DAPA-CKD findings: “We’ve shown that dapagliflozin can be safely used in these patients. It is effective across the spectrum of kidney function.”

Other experts not associated with the study agreed.

Sara Freeman/MDedge News

The trial researchers were “brave” to enroll patients with eGFRs as low as 25 mL/min per 1.73 m², and “we urgently need these agents in patients with an eGFR this low,” commented Chantal Mathieu, MD, an endocrinologist and professor of medicine at Catholic University in Leuven, Belgium, and designated discussant for the report. Overall, she called the findings “spectacular,” a “landmark trial,” and a “winner.”

The study also set an new, lower floor for the level of albuminuria that can be usefully treated with dapagliflozin (Farxiga) by enrolling patients with a urinary albumin-to-creatinine ratio as low as 200 mg/g; the previous lower limit had been 300 mg/g, noted Dr. Mathieu. The new findings pose challenges to guideline writers, regulators who approve drug labels, and payers to a quickly make changes that will bring dapagliflozin to a wider number of patients with CKD.

Once the full DAPA-CKD results are reported, “it will change practice, and push the eGFR needle down” to as low as 25. It will also lower the albuminuria threshold for using dapagliflozin or other drugs in the class, commented David Z.I. Cherney, MD, a nephrologist at the University of Toronto. “It’s just one study,” he admitted, but the consistent renal benefits seen across several studies involving all four drugs in the SGLT2 inhibitor class will help hasten this change in identifying treatable patients, as well as expand the drug class to patients with CKD but no type 2 diabetes (T2D).

“I don’t think we’ve ever had stronger evidence” for drugs that can benefit both heart and renal function, plus the drug class is “very safe, and really easy to start” and maintain in patients, Dr. Cherney said in an interview. “It’s wonderful for these patients that we now have something new for treatment,” a drug with a “very favorable benefit-to-risk ratio.”
 

Results show many dapagliflozin benefits

While this broadening of the range of patients proven to tolerate and benefit from an SGLT2 inhibitor was an important consequence of DAPA-CKD, the study’s primary finding – that dapagliflozin was as safe and effective for slowing CKD progression in patients regardless of whether they also had T2D – will have an even bigger impact on expanding the target patient population. Showing efficacy in patients with CKD but without a T2D etiology, the status of about a third of the enrolled 4,304 patients, makes this treatment an option for “millions” of additional patients worldwide, said Dr. Heerspink. “These are the most common patients nephrologists see.” A major challenge now will be to do a better job finding patients with CKD who could benefit from dapagliflozin.

DAPA-CKD enrolled CKD patients based primarily on prespecified albuminuria and eGFR levels at more than 300 centers in 34 countries, including the United States. Virtually all patients, 97%, were on the only treatment now available with proven efficacy for slowing CKD, either an ACE inhibitor or an angiotensin receptor blocker. The small number of patients not on one of these drugs was because of poor tolerance.

The study’s primary endpoint was the combined rate of cardiovascular death, renal death, end-stage renal disease, or a drop in eGFR of at least 50% from baseline. This occurred in 14.5% of patients who received placebo and in 9.2% of those who received dapagliflozin during a median follow-up of 2.4 years, a highly significant 39% relative risk reduction. Concurrently with the report at the virtual meeting the results also appeared online in the New England Journal of Medicine. This 5.3% cut in the absolute rate of the combined, primary adverse outcome converted into a number needed to treat of 19 to prevent 1 event during 2.4 years, a “much lower” number needed to treat than reported for renin-angiotensin system inhibitors in these types of patients, Dr. Heerspink said.

Notable positive secondary outcomes included a significant 31% relative cut (a 2% absolute decline) in all-cause mortality, “a major highlight” of the findings, Dr. Heerspink said. Dapagliflozin treatment also linked with a significant 29% relative cut in the incidence of cardiovascular death or hospitalization for heart failure.

“Cardiovascular disease is the most common cause of death in patients with CKD,” explained David C. Wheeler, MD, a coinvestigator on the study and professor of kidney medicine at University College London. “The heart and kidney are intertwined. This is about cardiorenal disease.”

DAPA-CKD was funded by AstraZeneca, the company that markets dapagliflozin. Dr. Heerspink has been a consultant to and received research funding from AstraZeneca. He has also received personal fees from Mundipharma and Novo Nordisk, and he has also served as consultant to several other companies with the honoraria being paid to his institution. Dr. Mathieu has had relationships with AstraZeneca and several other companies. Dr. Cherney has been a consultant to and has received research funding from AstraZeneca and several other companies. Dr. Wheeler has received personal fees from AstraZeneca and from several other companies.

mzoler@mdedge.com

SOURCE: Heerspink HJL et al. EASD 2020 and N Engl J Med. 2020 Sep 24. doi: 10.1056/NEJMoa2024816.