Pharmacology

Machine-based learning of genetic and epigenetic characteristics of patients with rheumatoid arthritis could help to predict who is likely to benefit from the biologic drugs adalimumab and etanercept, according to results from a longitudinal, observational cohort study.

In the study, machine learning models created by researchers from Utrecht University in the Netherlands using different parameters predicted true-positive rates for response to adalimumab ranging from 76% to 90% and true-negative rates ranging from 70% to 89%, while for etanercept true-positive rates ranged from about 60% to 80% and true-negative rates ranged from about 82% to 98%.

“These results suggest that we can accurately predict the clinical response before adalimumab and etanercept treatment using molecular signatures-based machine learning models, although the prediction accuracy of these molecular signatures differs between cell types and treatments, underlining the need to study more than one drug, cell type, or epigenetic layers,” first author Weiyang Tao and colleagues wrote in Arthritis & Rheumatology. The ability to predict which tumor necrosis factor inhibitor (TNFi) is the first choice for treatment would be highly beneficial in reducing the time to effective treatment, which has been extensively proven to be a paramount factor for achieving long-sustained disease remission, they noted.

The researchers analyzed gene expression and epigenetic signatures in 80 patients with rheumatoid arthritis prior to treatment with adalimumab or etanercept and then examined patients’ response to treatment at 6 months. They then used that information to build a machine learning model to try to predict treatment response.

Overall, 47.5% of patients were treated with adalimumab, and 52.5% were treated with etanercept. Among the adalimumab group, 53% had a good or moderate response to treatment at 6 months, and among those treated with etanercept, 45% had a good or moderate response.

While there were no differences in baseline clinical parameters between responders and nonresponders, the study found significant genetic and epigenetic differences between patients.

They identified 549 genes that showed significantly different levels of expression between responders and nonresponders treated with adalimumab – in particular, genes involved in DNA and nucleotide binding – and 460 genes that were differentially expressed between etanercept responders and nonresponders, including genes involved in TNF-receptor signaling. However, only 2% of these differentially expressed genes were common in both the adalimumab and etanercept groups, suggesting treatment responses for these two medications have distinct gene signatures.

Looking at DNA methylation, researchers found 16,141 CpG positions – sites of DNA methylation – that were differentially methylated between adalimumab responders and nonresponders, 46% of which were hypermethylated among responders but not nonresponders. In the etanercept group, there were 17,026 differentially methylated sites in responders and nonresponders, 76.3% of which were hypermethylated among responders.

The researchers also noted that among the adalimumab responders, the hypermethylated sites were more likely to be found in the upstream and promoter regions of genes, and on CpG islands.

“Thus, on epigenetic level, we observed a distinct hypermethylation pattern between adalimumab and etanercept responders, suggesting the role of epigenetics in defining response towards adalimumab and to etanercept in PBMCs [peripheral blood mononuclear cells],” the authors wrote.

Given the differences in gene signatures seen in the adalimumab responders and etanercept responders, researchers speculated that different cell types might be involved in the responses to these two treatments. They undertook RNA sequencing on the variety of immune cell types known to be involved in rheumatoid arthritis, which revealed gene-expression differences between adalimumab responders and nonresponders in their CD4+ T cells but not in monocytes. However, the gene-expression differences between etanercept responders and nonresponders were seen in both CD4+ T cells and monocytes.

The study was supported by AbbVie, which manufactures adalimumab, and two authors were supported by the China Scholarship Council and the Netherlands Organization for Scientific Research. No conflicts of interest were declared.

SOURCE: Tao W et al. Arthritis Rheumatol. 2020 Sep 10. doi: 10.1002/art.41516.

Machine-based learning of genetic and epigenetic characteristics of patients with rheumatoid arthritis could help to predict who is likely to benefit from the biologic drugs adalimumab and etanercept, according to results from a longitudinal, observational cohort study.

In the study, machine learning models created by researchers from Utrecht University in the Netherlands using different parameters predicted true-positive rates for response to adalimumab ranging from 76% to 90% and true-negative rates ranging from 70% to 89%, while for etanercept true-positive rates ranged from about 60% to 80% and true-negative rates ranged from about 82% to 98%.

“These results suggest that we can accurately predict the clinical response before adalimumab and etanercept treatment using molecular signatures-based machine learning models, although the prediction accuracy of these molecular signatures differs between cell types and treatments, underlining the need to study more than one drug, cell type, or epigenetic layers,” first author Weiyang Tao and colleagues wrote in Arthritis & Rheumatology. The ability to predict which tumor necrosis factor inhibitor (TNFi) is the first choice for treatment would be highly beneficial in reducing the time to effective treatment, which has been extensively proven to be a paramount factor for achieving long-sustained disease remission, they noted.

The researchers analyzed gene expression and epigenetic signatures in 80 patients with rheumatoid arthritis prior to treatment with adalimumab or etanercept and then examined patients’ response to treatment at 6 months. They then used that information to build a machine learning model to try to predict treatment response.

Overall, 47.5% of patients were treated with adalimumab, and 52.5% were treated with etanercept. Among the adalimumab group, 53% had a good or moderate response to treatment at 6 months, and among those treated with etanercept, 45% had a good or moderate response.

While there were no differences in baseline clinical parameters between responders and nonresponders, the study found significant genetic and epigenetic differences between patients.

They identified 549 genes that showed significantly different levels of expression between responders and nonresponders treated with adalimumab – in particular, genes involved in DNA and nucleotide binding – and 460 genes that were differentially expressed between etanercept responders and nonresponders, including genes involved in TNF-receptor signaling. However, only 2% of these differentially expressed genes were common in both the adalimumab and etanercept groups, suggesting treatment responses for these two medications have distinct gene signatures.

Looking at DNA methylation, researchers found 16,141 CpG positions – sites of DNA methylation – that were differentially methylated between adalimumab responders and nonresponders, 46% of which were hypermethylated among responders but not nonresponders. In the etanercept group, there were 17,026 differentially methylated sites in responders and nonresponders, 76.3% of which were hypermethylated among responders.

The researchers also noted that among the adalimumab responders, the hypermethylated sites were more likely to be found in the upstream and promoter regions of genes, and on CpG islands.

“Thus, on epigenetic level, we observed a distinct hypermethylation pattern between adalimumab and etanercept responders, suggesting the role of epigenetics in defining response towards adalimumab and to etanercept in PBMCs [peripheral blood mononuclear cells],” the authors wrote.

Given the differences in gene signatures seen in the adalimumab responders and etanercept responders, researchers speculated that different cell types might be involved in the responses to these two treatments. They undertook RNA sequencing on the variety of immune cell types known to be involved in rheumatoid arthritis, which revealed gene-expression differences between adalimumab responders and nonresponders in their CD4+ T cells but not in monocytes. However, the gene-expression differences between etanercept responders and nonresponders were seen in both CD4+ T cells and monocytes.

The study was supported by AbbVie, which manufactures adalimumab, and two authors were supported by the China Scholarship Council and the Netherlands Organization for Scientific Research. No conflicts of interest were declared.

SOURCE: Tao W et al. Arthritis Rheumatol. 2020 Sep 10. doi: 10.1002/art.41516.

Machine-based learning of genetic and epigenetic characteristics of patients with rheumatoid arthritis could help to predict who is likely to benefit from the biologic drugs adalimumab and etanercept, according to results from a longitudinal, observational cohort study.

In the study, machine learning models created by researchers from Utrecht University in the Netherlands using different parameters predicted true-positive rates for response to adalimumab ranging from 76% to 90% and true-negative rates ranging from 70% to 89%, while for etanercept true-positive rates ranged from about 60% to 80% and true-negative rates ranged from about 82% to 98%.

“These results suggest that we can accurately predict the clinical response before adalimumab and etanercept treatment using molecular signatures-based machine learning models, although the prediction accuracy of these molecular signatures differs between cell types and treatments, underlining the need to study more than one drug, cell type, or epigenetic layers,” first author Weiyang Tao and colleagues wrote in Arthritis & Rheumatology. The ability to predict which tumor necrosis factor inhibitor (TNFi) is the first choice for treatment would be highly beneficial in reducing the time to effective treatment, which has been extensively proven to be a paramount factor for achieving long-sustained disease remission, they noted.

The researchers analyzed gene expression and epigenetic signatures in 80 patients with rheumatoid arthritis prior to treatment with adalimumab or etanercept and then examined patients’ response to treatment at 6 months. They then used that information to build a machine learning model to try to predict treatment response.

Overall, 47.5% of patients were treated with adalimumab, and 52.5% were treated with etanercept. Among the adalimumab group, 53% had a good or moderate response to treatment at 6 months, and among those treated with etanercept, 45% had a good or moderate response.

While there were no differences in baseline clinical parameters between responders and nonresponders, the study found significant genetic and epigenetic differences between patients.

They identified 549 genes that showed significantly different levels of expression between responders and nonresponders treated with adalimumab – in particular, genes involved in DNA and nucleotide binding – and 460 genes that were differentially expressed between etanercept responders and nonresponders, including genes involved in TNF-receptor signaling. However, only 2% of these differentially expressed genes were common in both the adalimumab and etanercept groups, suggesting treatment responses for these two medications have distinct gene signatures.

Looking at DNA methylation, researchers found 16,141 CpG positions – sites of DNA methylation – that were differentially methylated between adalimumab responders and nonresponders, 46% of which were hypermethylated among responders but not nonresponders. In the etanercept group, there were 17,026 differentially methylated sites in responders and nonresponders, 76.3% of which were hypermethylated among responders.

The researchers also noted that among the adalimumab responders, the hypermethylated sites were more likely to be found in the upstream and promoter regions of genes, and on CpG islands.

“Thus, on epigenetic level, we observed a distinct hypermethylation pattern between adalimumab and etanercept responders, suggesting the role of epigenetics in defining response towards adalimumab and to etanercept in PBMCs [peripheral blood mononuclear cells],” the authors wrote.

Given the differences in gene signatures seen in the adalimumab responders and etanercept responders, researchers speculated that different cell types might be involved in the responses to these two treatments. They undertook RNA sequencing on the variety of immune cell types known to be involved in rheumatoid arthritis, which revealed gene-expression differences between adalimumab responders and nonresponders in their CD4+ T cells but not in monocytes. However, the gene-expression differences between etanercept responders and nonresponders were seen in both CD4+ T cells and monocytes.

The study was supported by AbbVie, which manufactures adalimumab, and two authors were supported by the China Scholarship Council and the Netherlands Organization for Scientific Research. No conflicts of interest were declared.

SOURCE: Tao W et al. Arthritis Rheumatol. 2020 Sep 10. doi: 10.1002/art.41516.

Requests for self-managed abortion via a telemedicine service increased by 27% from March 20, 2020, to April 11, 2020, in the United States in the wake of widespread lockdowns and shelter-in-place directives because of the COVID-19 pandemic, based on data from a provider of such services.

nortonrsx/Getty Images

Access to abortion care is challenging in many areas under ordinary circumstances, but the disruption of the COVID-19 pandemic led to many states suspending or limiting in-clinic services, wrote Abigail R.A. Aiken, MD, PhD, of the University of Texas at Austin and colleagues.

“As a result, people may increasingly be seeking self-managed abortion outside the formal health care system,” they said.

In a research letter published in Obstetrics & Gynecology, the investigators reviewed request data from Aid Access, a telemedicine service that provides medication for abortion at up to 10 weeks’ gestation for users who complete an online consultation form. They also collected data on the implementation and scope of COVID-19–related abortion restrictions by state.

The analysis included all 49,935 requests made between January 1, 2019, and April 11, 2020.

Overall, the rate of requests for self-managed medical abortions increased significantly, by 27%, during the period from March 20, 2020, to April 11, 2020, which reflected the average period after clinic restrictions or closures at the state level. A total of 11 states showed individually significant increases in requests for self-managed medical abortions, with the highest of 94% in Texas and the lowest of 22% in Ohio. In these 11 states, the median time spent at home was 5% higher than in states without significant increases in requests for self-managed medical abortions during the same period. These states also had “particularly high COVID-19 rates or more severe COVID-19–related restrictions on in-clinic abortion access,” the researchers noted.

Patients want alternatives to in-person care

“Our results may reflect two distinct phenomena,” Dr. Aiken and associates wrote. “First, more people may be seeking abortion through all channels, whether due to COVID-19 risks during pregnancy, reduced access to prenatal care, or the pandemic-related economic downturn. Second, there may be shift in demand from in-clinic to self-managed abortion during the pandemic, possibly owing to fear of infection during in-person care or inability to get to a clinic because of childcare and transit disruptions,” they explained.

The study findings were limited by the inability to measure all options for women to achieve self-managed abortions and a lack of power to detect changes in states with low request numbers or where restrictions were implemented at later dates, the researchers noted. However, the results suggest that telemedicine services for medication abortion should be a policy priority because patients may continue to seek alternatives while in-clinic services remain restricted, they said.

In fact, “the World Health Organization recommends telemedicine and self-management abortion-care models during the pandemic, and the United Kingdom has temporarily implemented fully remote provision of abortion medications,” the researchers wrote. However, similar strategies in the United States “would depend on sustained changes to the U.S. Food and Drug Administration’s Risk Evaluation and Mitigation Strategy, which requires patients to collect mifepristone at a hospital or medical facility, as well as changes to state-specific laws that prohibit remote provider consultation,” Dr. Aiken and associates concluded.

Lift barriers to protect patients

“This important and timely article assesses the association between the disruptions of the coronavirus pandemic and online requests for telemedicine abortion,” Eve Espey, MD, of the University of New Mexico, Albuquerque, said in an interview.

“As background, state abortion restrictions have increased exponentially over the last decade, while research over the same time period has demonstrated the safety of telemedicine abortion – a form of self-managed abortion – with no in-person visit for appropriate candidates,” she said.

“Enter the coronavirus pandemic with safety concerns related to in-person medical visits and certain states leveraging the opportunity to enact even more stringent abortion restrictions. Unsurprisingly, the result, as documented in this excellent research report, is a significant increase in requests for telemedicine abortion in many states, particularly the most restrictive, from the single online service in the United States, Aid Access,” said Dr. Espey.

“Barriers to self-managed abortion include the [FDA] Risk Evaluation and Mitigation Strategy for mifepristone, a set of unnecessary restrictions requiring that providers meet certain qualifications and dispense the medication only in a clinic, office, or hospital,” she said. “The REMS precludes the use of telemedicine abortion; Aid Access and the FDA are in legal proceedings,” she noted.

“Most recently, the [American Civil Liberties Union] sued the FDA on behalf of a coalition of medical experts led by [American College of Obstetricians and Gynecologists] to suspend the REMS for mifepristone during the COVID public health emergency, to allow patients to receive the medications for early abortion without a visit to a health care provider,” Dr. Espey said. “Fortunately, a federal district court required the temporary suspension of the in-person dispensing restriction. Although this is a great step to improve abortion access during the pandemic, a permanent removal of the REMS would pave the way for ongoing safe, effective, and patient-centered early abortion care,” noted Dr. Espey, who was asked to comment on the research letter.

Dr. Aiken disclosed serving as a consultant for Agile Therapeutics, and a coauthor is the founder and director of Aid Access. Dr. Espey had no financial conflicts to disclose. She is a member of the Ob.Gyn. News Editorial Advisory Board.

SOURCE: Aiken ARA et al. Obstet Gynecol. 2020 Jul 21. doi: 10.1097/AOG.0000000000004081.

Requests for self-managed abortion via a telemedicine service increased by 27% from March 20, 2020, to April 11, 2020, in the United States in the wake of widespread lockdowns and shelter-in-place directives because of the COVID-19 pandemic, based on data from a provider of such services.

nortonrsx/Getty Images

Access to abortion care is challenging in many areas under ordinary circumstances, but the disruption of the COVID-19 pandemic led to many states suspending or limiting in-clinic services, wrote Abigail R.A. Aiken, MD, PhD, of the University of Texas at Austin and colleagues.

“As a result, people may increasingly be seeking self-managed abortion outside the formal health care system,” they said.

In a research letter published in Obstetrics & Gynecology, the investigators reviewed request data from Aid Access, a telemedicine service that provides medication for abortion at up to 10 weeks’ gestation for users who complete an online consultation form. They also collected data on the implementation and scope of COVID-19–related abortion restrictions by state.

The analysis included all 49,935 requests made between January 1, 2019, and April 11, 2020.

Overall, the rate of requests for self-managed medical abortions increased significantly, by 27%, during the period from March 20, 2020, to April 11, 2020, which reflected the average period after clinic restrictions or closures at the state level. A total of 11 states showed individually significant increases in requests for self-managed medical abortions, with the highest of 94% in Texas and the lowest of 22% in Ohio. In these 11 states, the median time spent at home was 5% higher than in states without significant increases in requests for self-managed medical abortions during the same period. These states also had “particularly high COVID-19 rates or more severe COVID-19–related restrictions on in-clinic abortion access,” the researchers noted.

Patients want alternatives to in-person care

“Our results may reflect two distinct phenomena,” Dr. Aiken and associates wrote. “First, more people may be seeking abortion through all channels, whether due to COVID-19 risks during pregnancy, reduced access to prenatal care, or the pandemic-related economic downturn. Second, there may be shift in demand from in-clinic to self-managed abortion during the pandemic, possibly owing to fear of infection during in-person care or inability to get to a clinic because of childcare and transit disruptions,” they explained.

The study findings were limited by the inability to measure all options for women to achieve self-managed abortions and a lack of power to detect changes in states with low request numbers or where restrictions were implemented at later dates, the researchers noted. However, the results suggest that telemedicine services for medication abortion should be a policy priority because patients may continue to seek alternatives while in-clinic services remain restricted, they said.

In fact, “the World Health Organization recommends telemedicine and self-management abortion-care models during the pandemic, and the United Kingdom has temporarily implemented fully remote provision of abortion medications,” the researchers wrote. However, similar strategies in the United States “would depend on sustained changes to the U.S. Food and Drug Administration’s Risk Evaluation and Mitigation Strategy, which requires patients to collect mifepristone at a hospital or medical facility, as well as changes to state-specific laws that prohibit remote provider consultation,” Dr. Aiken and associates concluded.

Lift barriers to protect patients

“This important and timely article assesses the association between the disruptions of the coronavirus pandemic and online requests for telemedicine abortion,” Eve Espey, MD, of the University of New Mexico, Albuquerque, said in an interview.

“As background, state abortion restrictions have increased exponentially over the last decade, while research over the same time period has demonstrated the safety of telemedicine abortion – a form of self-managed abortion – with no in-person visit for appropriate candidates,” she said.

“Enter the coronavirus pandemic with safety concerns related to in-person medical visits and certain states leveraging the opportunity to enact even more stringent abortion restrictions. Unsurprisingly, the result, as documented in this excellent research report, is a significant increase in requests for telemedicine abortion in many states, particularly the most restrictive, from the single online service in the United States, Aid Access,” said Dr. Espey.

“Barriers to self-managed abortion include the [FDA] Risk Evaluation and Mitigation Strategy for mifepristone, a set of unnecessary restrictions requiring that providers meet certain qualifications and dispense the medication only in a clinic, office, or hospital,” she said. “The REMS precludes the use of telemedicine abortion; Aid Access and the FDA are in legal proceedings,” she noted.

“Most recently, the [American Civil Liberties Union] sued the FDA on behalf of a coalition of medical experts led by [American College of Obstetricians and Gynecologists] to suspend the REMS for mifepristone during the COVID public health emergency, to allow patients to receive the medications for early abortion without a visit to a health care provider,” Dr. Espey said. “Fortunately, a federal district court required the temporary suspension of the in-person dispensing restriction. Although this is a great step to improve abortion access during the pandemic, a permanent removal of the REMS would pave the way for ongoing safe, effective, and patient-centered early abortion care,” noted Dr. Espey, who was asked to comment on the research letter.

Dr. Aiken disclosed serving as a consultant for Agile Therapeutics, and a coauthor is the founder and director of Aid Access. Dr. Espey had no financial conflicts to disclose. She is a member of the Ob.Gyn. News Editorial Advisory Board.

SOURCE: Aiken ARA et al. Obstet Gynecol. 2020 Jul 21. doi: 10.1097/AOG.0000000000004081.

Requests for self-managed abortion via a telemedicine service increased by 27% from March 20, 2020, to April 11, 2020, in the United States in the wake of widespread lockdowns and shelter-in-place directives because of the COVID-19 pandemic, based on data from a provider of such services.

nortonrsx/Getty Images

Access to abortion care is challenging in many areas under ordinary circumstances, but the disruption of the COVID-19 pandemic led to many states suspending or limiting in-clinic services, wrote Abigail R.A. Aiken, MD, PhD, of the University of Texas at Austin and colleagues.

“As a result, people may increasingly be seeking self-managed abortion outside the formal health care system,” they said.

In a research letter published in Obstetrics & Gynecology, the investigators reviewed request data from Aid Access, a telemedicine service that provides medication for abortion at up to 10 weeks’ gestation for users who complete an online consultation form. They also collected data on the implementation and scope of COVID-19–related abortion restrictions by state.

The analysis included all 49,935 requests made between January 1, 2019, and April 11, 2020.

Overall, the rate of requests for self-managed medical abortions increased significantly, by 27%, during the period from March 20, 2020, to April 11, 2020, which reflected the average period after clinic restrictions or closures at the state level. A total of 11 states showed individually significant increases in requests for self-managed medical abortions, with the highest of 94% in Texas and the lowest of 22% in Ohio. In these 11 states, the median time spent at home was 5% higher than in states without significant increases in requests for self-managed medical abortions during the same period. These states also had “particularly high COVID-19 rates or more severe COVID-19–related restrictions on in-clinic abortion access,” the researchers noted.

Patients want alternatives to in-person care

“Our results may reflect two distinct phenomena,” Dr. Aiken and associates wrote. “First, more people may be seeking abortion through all channels, whether due to COVID-19 risks during pregnancy, reduced access to prenatal care, or the pandemic-related economic downturn. Second, there may be shift in demand from in-clinic to self-managed abortion during the pandemic, possibly owing to fear of infection during in-person care or inability to get to a clinic because of childcare and transit disruptions,” they explained.

The study findings were limited by the inability to measure all options for women to achieve self-managed abortions and a lack of power to detect changes in states with low request numbers or where restrictions were implemented at later dates, the researchers noted. However, the results suggest that telemedicine services for medication abortion should be a policy priority because patients may continue to seek alternatives while in-clinic services remain restricted, they said.

In fact, “the World Health Organization recommends telemedicine and self-management abortion-care models during the pandemic, and the United Kingdom has temporarily implemented fully remote provision of abortion medications,” the researchers wrote. However, similar strategies in the United States “would depend on sustained changes to the U.S. Food and Drug Administration’s Risk Evaluation and Mitigation Strategy, which requires patients to collect mifepristone at a hospital or medical facility, as well as changes to state-specific laws that prohibit remote provider consultation,” Dr. Aiken and associates concluded.

Lift barriers to protect patients

“This important and timely article assesses the association between the disruptions of the coronavirus pandemic and online requests for telemedicine abortion,” Eve Espey, MD, of the University of New Mexico, Albuquerque, said in an interview.

“As background, state abortion restrictions have increased exponentially over the last decade, while research over the same time period has demonstrated the safety of telemedicine abortion – a form of self-managed abortion – with no in-person visit for appropriate candidates,” she said.

“Enter the coronavirus pandemic with safety concerns related to in-person medical visits and certain states leveraging the opportunity to enact even more stringent abortion restrictions. Unsurprisingly, the result, as documented in this excellent research report, is a significant increase in requests for telemedicine abortion in many states, particularly the most restrictive, from the single online service in the United States, Aid Access,” said Dr. Espey.

“Barriers to self-managed abortion include the [FDA] Risk Evaluation and Mitigation Strategy for mifepristone, a set of unnecessary restrictions requiring that providers meet certain qualifications and dispense the medication only in a clinic, office, or hospital,” she said. “The REMS precludes the use of telemedicine abortion; Aid Access and the FDA are in legal proceedings,” she noted.

“Most recently, the [American Civil Liberties Union] sued the FDA on behalf of a coalition of medical experts led by [American College of Obstetricians and Gynecologists] to suspend the REMS for mifepristone during the COVID public health emergency, to allow patients to receive the medications for early abortion without a visit to a health care provider,” Dr. Espey said. “Fortunately, a federal district court required the temporary suspension of the in-person dispensing restriction. Although this is a great step to improve abortion access during the pandemic, a permanent removal of the REMS would pave the way for ongoing safe, effective, and patient-centered early abortion care,” noted Dr. Espey, who was asked to comment on the research letter.

Dr. Aiken disclosed serving as a consultant for Agile Therapeutics, and a coauthor is the founder and director of Aid Access. Dr. Espey had no financial conflicts to disclose. She is a member of the Ob.Gyn. News Editorial Advisory Board.

SOURCE: Aiken ARA et al. Obstet Gynecol. 2020 Jul 21. doi: 10.1097/AOG.0000000000004081.

Patients with type 2 or type 1 diabetes who stay in a blood glucose range of 70-180 mg/dL at least 70% of the time have the lowest rates of major adverse coronary events, severe hypoglycemic episodes, and microvascular events, according to a post hoc analysis of data collected from 5,774 patients with type 2 diabetes.

Data collected by the DEVOTE trial showed that every additional 10% of the time that a patient with type 2 diabetes (T2D) spent in their target range for blood glucose linked with a significant 6% reduced rate for developing a major adverse cardiovascular event (MACE), Richard M. Bergenstal, MD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

For every 10% increase in time in range (TIR), patients showed an average 10% drop in their incidence of severe hypoglycemic episodes.
 

Increasing evidence from post hoc analyses

These findings confirmed a prior post hoc analysis of data collected in the DCCT trial (NCT00360815), which were published in the New England Journal of Medicine, although those results showed significant relationships between increased TIR and decreased rates of retinopathy and microalbuminuria. For every 10% drop in TIR, retinopathy rose by 64% and microalbuminuria increased by 40%, according to a post hoc analysis of the DCCT data that Dr. Bergenstal helped run and was published in Diabetes Care.

“It’s becoming clear that time in range is an important metric for diabetes management, and our new findings and those previously reported with the DCCT data make it look like time in range is becoming a good marker for clinical outcomes as well,” said Dr. Bergenstal, an endocrinologist at the Park Nicollet Clinic in Minneapolis.

“It’s a new concept, getting time-in-range data,” said Dr. Bergenstal, who was a coauthor of recommendations from Diabetes Care that were made in 2019 by an expert panel organized by the Advanced Technologies & Treatments for Diabetes Congress. “We think this will be a good marker to keep glycemia in a safe range, and the results look positive.” Patients who stay in the blood glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) at least 70% of the time generally have an hemoglobin A_1c of about 7%, which is what makes it a good target for patients and clinicians to focus on. Patients with a 50% TIR rate generally have an HbA_1c of about 8%.

But a TIR assessment can be more informative than HbA_1c, said the 2019 recommendations document. It called TIR assessments “appropriate and useful as clinical targets and outcome measurements that complement A1c for a wide range of people with diabetes.”
 

Data mining from DEVOTE

The analysis run by Dr. Bergenstal and his associates used data from 5,774 of the 7,637 patients enrolled in the DEVOTE trial, for whom adequate longitudinal blood glucose data were available to derive and track TIR. DEVOTE had the primary aim of comparing two different types of insulin in patients with T2D, according to its explanation in the New England Journal of Medicine. The DEVOTE patients did not undergo routine continuous blood glucose monitoring, so derivation of TIR was the only option with the dataset, Dr. Bergenstal said. “We’re trying to get continuous blood monitoring into T2D trials,” he said.

The post hoc analysis showed that, during the study’s follow-up of just under 2 years, patients who maintained a derived TIR of 70%-100% had about a 6% MACE rate, which peaked at nearly twice that in patients whose TIR was 30% or less. The analysis showed a roughly positive linear relationship between TIR and MACE rates across the range of TIR values. In an adjusted analysis, patients with at least a 70% TIR had a significant 31% lower rate of MACE events, compared with patients whose TIR was 50% or less.

A second analysis that looked for the association between TIR and incidence of hypoglycemic episodes showed a somewhat similar positive relationship, with incidence rates of severe hypoglycemia episodes of about 4%-5% among patients with a TIR of 70% or greater, and a rate of about 7% in patients with a TIR of 30% or less, spiking to 14% among patients with a TIR of 10% or less. In an adjusted analysis, patients with a TIR of at least 70% had a significant 46% lower rate of severe hypoglycemic events, compared with patients whose TIR was 50% or less. This finding belies a common misconception that the tighter glycemic control that produces a higher TIR will lead to increased episodes of severe hypoglycemia, Dr. Bergenstal noted.

He also reported less extensive data on microvascular events. In an adjusted analysis, patients with a TIR of at least 70% had a significant 40% cut in these events compared with patients with 50% or less TIR.

DEVOTE was funded by Novo Nordisk. Dr. Bergenstal has had financial relationships with Novo Nordisk and several other companies.

mzoler@mdedge.com

SOURCE: Bergenstal R et al. EASD 2020, abstract 159.

Patients with type 2 or type 1 diabetes who stay in a blood glucose range of 70-180 mg/dL at least 70% of the time have the lowest rates of major adverse coronary events, severe hypoglycemic episodes, and microvascular events, according to a post hoc analysis of data collected from 5,774 patients with type 2 diabetes.

Data collected by the DEVOTE trial showed that every additional 10% of the time that a patient with type 2 diabetes (T2D) spent in their target range for blood glucose linked with a significant 6% reduced rate for developing a major adverse cardiovascular event (MACE), Richard M. Bergenstal, MD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

For every 10% increase in time in range (TIR), patients showed an average 10% drop in their incidence of severe hypoglycemic episodes.
 

Increasing evidence from post hoc analyses

These findings confirmed a prior post hoc analysis of data collected in the DCCT trial (NCT00360815), which were published in the New England Journal of Medicine, although those results showed significant relationships between increased TIR and decreased rates of retinopathy and microalbuminuria. For every 10% drop in TIR, retinopathy rose by 64% and microalbuminuria increased by 40%, according to a post hoc analysis of the DCCT data that Dr. Bergenstal helped run and was published in Diabetes Care.

“It’s becoming clear that time in range is an important metric for diabetes management, and our new findings and those previously reported with the DCCT data make it look like time in range is becoming a good marker for clinical outcomes as well,” said Dr. Bergenstal, an endocrinologist at the Park Nicollet Clinic in Minneapolis.

“It’s a new concept, getting time-in-range data,” said Dr. Bergenstal, who was a coauthor of recommendations from Diabetes Care that were made in 2019 by an expert panel organized by the Advanced Technologies & Treatments for Diabetes Congress. “We think this will be a good marker to keep glycemia in a safe range, and the results look positive.” Patients who stay in the blood glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) at least 70% of the time generally have an hemoglobin A_1c of about 7%, which is what makes it a good target for patients and clinicians to focus on. Patients with a 50% TIR rate generally have an HbA_1c of about 8%.

But a TIR assessment can be more informative than HbA_1c, said the 2019 recommendations document. It called TIR assessments “appropriate and useful as clinical targets and outcome measurements that complement A1c for a wide range of people with diabetes.”
 

Data mining from DEVOTE

The analysis run by Dr. Bergenstal and his associates used data from 5,774 of the 7,637 patients enrolled in the DEVOTE trial, for whom adequate longitudinal blood glucose data were available to derive and track TIR. DEVOTE had the primary aim of comparing two different types of insulin in patients with T2D, according to its explanation in the New England Journal of Medicine. The DEVOTE patients did not undergo routine continuous blood glucose monitoring, so derivation of TIR was the only option with the dataset, Dr. Bergenstal said. “We’re trying to get continuous blood monitoring into T2D trials,” he said.

The post hoc analysis showed that, during the study’s follow-up of just under 2 years, patients who maintained a derived TIR of 70%-100% had about a 6% MACE rate, which peaked at nearly twice that in patients whose TIR was 30% or less. The analysis showed a roughly positive linear relationship between TIR and MACE rates across the range of TIR values. In an adjusted analysis, patients with at least a 70% TIR had a significant 31% lower rate of MACE events, compared with patients whose TIR was 50% or less.

A second analysis that looked for the association between TIR and incidence of hypoglycemic episodes showed a somewhat similar positive relationship, with incidence rates of severe hypoglycemia episodes of about 4%-5% among patients with a TIR of 70% or greater, and a rate of about 7% in patients with a TIR of 30% or less, spiking to 14% among patients with a TIR of 10% or less. In an adjusted analysis, patients with a TIR of at least 70% had a significant 46% lower rate of severe hypoglycemic events, compared with patients whose TIR was 50% or less. This finding belies a common misconception that the tighter glycemic control that produces a higher TIR will lead to increased episodes of severe hypoglycemia, Dr. Bergenstal noted.

He also reported less extensive data on microvascular events. In an adjusted analysis, patients with a TIR of at least 70% had a significant 40% cut in these events compared with patients with 50% or less TIR.

DEVOTE was funded by Novo Nordisk. Dr. Bergenstal has had financial relationships with Novo Nordisk and several other companies.

mzoler@mdedge.com

SOURCE: Bergenstal R et al. EASD 2020, abstract 159.

Patients with type 2 or type 1 diabetes who stay in a blood glucose range of 70-180 mg/dL at least 70% of the time have the lowest rates of major adverse coronary events, severe hypoglycemic episodes, and microvascular events, according to a post hoc analysis of data collected from 5,774 patients with type 2 diabetes.

Data collected by the DEVOTE trial showed that every additional 10% of the time that a patient with type 2 diabetes (T2D) spent in their target range for blood glucose linked with a significant 6% reduced rate for developing a major adverse cardiovascular event (MACE), Richard M. Bergenstal, MD, said at the virtual annual meeting of the European Association for the Study of Diabetes.

For every 10% increase in time in range (TIR), patients showed an average 10% drop in their incidence of severe hypoglycemic episodes.
 

Increasing evidence from post hoc analyses

These findings confirmed a prior post hoc analysis of data collected in the DCCT trial (NCT00360815), which were published in the New England Journal of Medicine, although those results showed significant relationships between increased TIR and decreased rates of retinopathy and microalbuminuria. For every 10% drop in TIR, retinopathy rose by 64% and microalbuminuria increased by 40%, according to a post hoc analysis of the DCCT data that Dr. Bergenstal helped run and was published in Diabetes Care.

“It’s becoming clear that time in range is an important metric for diabetes management, and our new findings and those previously reported with the DCCT data make it look like time in range is becoming a good marker for clinical outcomes as well,” said Dr. Bergenstal, an endocrinologist at the Park Nicollet Clinic in Minneapolis.

“It’s a new concept, getting time-in-range data,” said Dr. Bergenstal, who was a coauthor of recommendations from Diabetes Care that were made in 2019 by an expert panel organized by the Advanced Technologies & Treatments for Diabetes Congress. “We think this will be a good marker to keep glycemia in a safe range, and the results look positive.” Patients who stay in the blood glucose range of 70-180 mg/dL (3.9-10.0 mmol/L) at least 70% of the time generally have an hemoglobin A_1c of about 7%, which is what makes it a good target for patients and clinicians to focus on. Patients with a 50% TIR rate generally have an HbA_1c of about 8%.

But a TIR assessment can be more informative than HbA_1c, said the 2019 recommendations document. It called TIR assessments “appropriate and useful as clinical targets and outcome measurements that complement A1c for a wide range of people with diabetes.”
 

Data mining from DEVOTE

The analysis run by Dr. Bergenstal and his associates used data from 5,774 of the 7,637 patients enrolled in the DEVOTE trial, for whom adequate longitudinal blood glucose data were available to derive and track TIR. DEVOTE had the primary aim of comparing two different types of insulin in patients with T2D, according to its explanation in the New England Journal of Medicine. The DEVOTE patients did not undergo routine continuous blood glucose monitoring, so derivation of TIR was the only option with the dataset, Dr. Bergenstal said. “We’re trying to get continuous blood monitoring into T2D trials,” he said.

The post hoc analysis showed that, during the study’s follow-up of just under 2 years, patients who maintained a derived TIR of 70%-100% had about a 6% MACE rate, which peaked at nearly twice that in patients whose TIR was 30% or less. The analysis showed a roughly positive linear relationship between TIR and MACE rates across the range of TIR values. In an adjusted analysis, patients with at least a 70% TIR had a significant 31% lower rate of MACE events, compared with patients whose TIR was 50% or less.

A second analysis that looked for the association between TIR and incidence of hypoglycemic episodes showed a somewhat similar positive relationship, with incidence rates of severe hypoglycemia episodes of about 4%-5% among patients with a TIR of 70% or greater, and a rate of about 7% in patients with a TIR of 30% or less, spiking to 14% among patients with a TIR of 10% or less. In an adjusted analysis, patients with a TIR of at least 70% had a significant 46% lower rate of severe hypoglycemic events, compared with patients whose TIR was 50% or less. This finding belies a common misconception that the tighter glycemic control that produces a higher TIR will lead to increased episodes of severe hypoglycemia, Dr. Bergenstal noted.

He also reported less extensive data on microvascular events. In an adjusted analysis, patients with a TIR of at least 70% had a significant 40% cut in these events compared with patients with 50% or less TIR.

DEVOTE was funded by Novo Nordisk. Dr. Bergenstal has had financial relationships with Novo Nordisk and several other companies.

mzoler@mdedge.com

SOURCE: Bergenstal R et al. EASD 2020, abstract 159.

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.

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

Further data suggesting that a lower dose of rituximab seems to offer similar effectiveness with a better safety profile than higher doses commonly used in multiple sclerosis (MS), according to a new observational study. “We showed similar numbers of relapses, MRI new/active lesions, and effects on disability with a higher and lower dose of rituximab over a median follow of 16 months,” said lead author, Luciana Midaglia, MD, Multiple Sclerosis Centre of Catalonia (Cemcat) at Vall d’Hebron University Hospital, Barcelona. “But adverse effects – particularly frequency of infection – were increased in the high-dose group.”

Dr. Midaglia presented the findings at the recent Joint European Committee for Treatment and Research in Multiple Sclerosis–Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2020, this year known as MSVirtual2020.

“There haven’t been large studies of rituximab in MS as the company [Genentech/Roche] prioritized development of ocrelizumab over rituximab,” she explained. Rituximab has, therefore, never been approved for this indication. But it is available for several other conditions, and it is often used off label for MS.

“Although we now have a lot of experience with rituximab in MS, a dosage regimen has not been standardized,” Dr. Midaglia noted.

The current study was conducted to compare the efficacy and safety of two different dosage regimens of rituximab used at two different Catalan MS centers.

In the Barcelona center, 249 patients received a regimen of 2 g IV for the first three 6-month cycles followed by 1 g every 6 months thereafter (higher-dose group). In the Girona center, 54 patients received just one loading dose of 2 g followed by 500 mg every 6 months thereafter (lower-dose group).

Patients were followed up clinically every 6 months, and MRI brain scans were performed at baseline and yearly thereafter. Blood samples for safety and B cell/immunoglobulin monitoring were drawn at 3 months after rituximab infusions.

Results showed that the annualized relapse rate reduced by 87% (from 0.4 to 0.05; P < .001) in the higher-dose cohort, and by 90% (from 0.31 to 0.03; P = .018) in the lower-dose cohort.

The Expanded Disability Status Scale score remained stable or improved in 83% of the higher-dose group versus 72% of the lower-dose group (P = .09).

Contrast-enhancing lesions were reduced by 92% by 12 months and by 100% by 36 months in the higher-dose group and by 81% and 100%, respectively, in the lower-dose group.

New T2 lesions were present in 19% of patients at 12 months and in 12% at 36 months in the higher-dose group and in 16% and 0%, respectively, in the lower-dose group.

Reductions in B cell levels were similar with both doses. However, a reduced rate of adverse effects, mainly infections, was seen in the lower-dose group.

Infections were reported in 7.2% of the higher-dose group and 3.7% of the lower-dose group at 1 year, in 9.7% versus 0% in the second year, and in 9.7% versus 0% in the third year. Urinary tract infections, followed by respiratory infections, were the most prevalent.

A randomized phase 3 study is now underway testing an even lower dose of rituximab. The trial, known as RIDOSE-MS, is comparing maintenance doses of 500 mg every 6 months and 500 mg every 12 months.

Dr. Midaglia said that most centers are using higher doses of rituximab – similar to the Barcelona cohort in this study.

“After this study, we will we now start a new protocol and use the lower dose for all MS patients,” she said.

She reported that her hospital has been using rituximab extensively in MS.

“There were delays to ocrelizumab being introduced in Spain, and while we were waiting, we started using rituximab,” she said. “We believe it is similarly effective to ocrelizumab. It has exactly the same mechanism of action. The only difference is that rituximab is a chimeric antibody while ocrelizumab is fully humanized.”

While rituximab has not had the validation of a full phase 3 trial, she added, “there are data available from several smaller studies and we feel we have learned how to use it in the real world, but we don’t have an approved dosage schedule. We started off using the dose approved for use in rheumatological and hematological conditions.”

Now that ocrelizumab is approved, Dr. Midaglia said they are using that drug for the patients who meet the approved criteria, but there are many patients who don’t qualify.

“For example, in progressive MS, ocrelizumab has quite a narrow indication – it is not reimbursed for patients without any inflammatory activity. So for these patients, we tend to use rituximab,” she noted.

“While there is no good data on its efficacy in these patients, we believe it has some effect and there is no other option at present. Rituximab is an inexpensive drug and has a long safety record in other conditions, so we feel it’s worth a try,” Dr. Midaglia concluded. “And now we have better data on the optimal dosage.”

Commenting on the study, Daniel Ontaneda, MD, comoderator of the session at which the study was presented, said: “Rituximab is not an [Food and Drug Administration]–approved medication for MS, but it has been used in clinical practice quite extensively in the U.S. and also in Europe. The study is of interest as it showed that the lower dose of rituximab achieved good control of disease activity.”

Dr. Ontaneda, a neurologist at the Mellen Center for MS at the Cleveland Clinic, Ohio, added: “Many centers have been using lower doses or less frequent infusions and this study supports this practice. Some degree of residual confounding in the study in the differences in side effects may be related to the two different sites, but overall I think these results add to the real-world observational data now available for anti-CD20 therapies.”

Dr. Midaglia reported receiving travel funding from Genzyme, Roche, Biogen Idec, and Novartis, and personal fees for lectures from Roche.
 

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

Current American and European guidelines recommending long-term beta-blocker therapy following an acute MI appear to be obsolete in the modern reperfusion era, suggests an analysis of Danish registry data.

Those guidelines are based on old randomized trials of beta-blocker therapy conducted prior to introduction of routine percutaneous coronary intervention and modern multidrug optimal medical therapy for acute MI. There have been no prospective controlled studies in the reperfusion era. And a new Danish national observational study strongly suggests it’s time to reexamine the beta-blocker recommendation, Anders Holt, MD, said at the virtual annual congress of the European Society of Cardiology.

“Stable, optimally treated MI patients do not seem to benefit from beta-blocker treatment exceeding 3 months post hospitalization – bearing in mind this doesn’t apply to patients with other indications for beta-blockers, like heart failure or atrial fibrillation,” said Dr. Holt of Copenhagen University Hospital.

His analysis of Danish national registry data on more than 30,000 patients hospitalized for acute MI during 2003-2018 earned him the annual ESC Young Investigator Award in Population Science.

Frontline Medical News

“This was a crisp and clear presentation of a very creative use of observational epidemiology to try to understand the length of therapy that may or may not be appropriate,” commented award session cochair Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

Dr. Holt reported on 30,177 patients optimally treated for a first MI in Danish hospitals during 2003-2018, none of whom had a prior indication or contraindication for beta-blocker therapy. “Optimally treated” meant they underwent percutaneous coronary revascularization and were discharged on a statin and aspirin. As a study requirement, all had to be stable 90 days post hospitalization, at which point 24,770 of the patients were on long-term beta-blocker therapy, and 5,407 (18%) were not. The two groups were comparable in terms of age, sex, comorbidities, and baseline medications. All patients were followed through the registries for a maximum of 3 years, the duration of beta-blocker therapy post MI recommended in American Heart Association/American College of Cardiology guidelines. (The Danish Society of Cardiology recommends 2 years.)

At 3 years post MI, there was no between-group difference in a composite outcome comprising cardiovascular death, recurrent MI, heart failure, stroke, angina, or a cardiac procedure, with a rate of 22.9% in the beta-blocker group and 21.6% in patients not on long-term beta-blocker therapy. The rate of recurrent MI was identical at 6.7% in both groups. Cardiovascular death occurred during 3 years of follow-up in 1.4% of patients on beta-blocker therapy and 1.7% who weren’t, a nonsignificant difference.

“We saw no evidence of any cardioprotective effect, but no increased risk of adverse events resulting in hospitalization, either,” Dr. Holt observed. “I would like to acknowledge that no evidence of effect does not necessarily equal evidence of no effect, but even if there was an effect we can with fair certainty say that it’s probably quite minimal.”

He noted that the Danish registry data indicates that each year since 2012 has shown a growing trend for Danish patients to dispense with long-term beta-blocker therapy after an acute MI.

“This might indicate we are nudging toward a change in practice, where more physicians are thinking that long-term beta-blocker therapy might not be indicated for all MI patients in the reperfusion era,” according to Dr. Holt.

Asked by the four-judge award panel about the possibility of unmeasured confounding in this observational study, Dr Holt responded: “I would be very cautious about asking patients to stop beta-blocker therapy after 3 months just based on this observational data. We can’t speak to causality in an observational study.” But he added that “well-designed observational studies provide valuable data regarding this topic and should not be ignored. They should possibly influence the guidelines and the designs for upcoming randomized trials.”

He conducted several supplementary analyses designed to address the possibility of unevenly distributed unmeasured confounding in the registry study. These analyses proved reassuring. A positive exposure control analysis compared 3-year outcomes in patients who remained on long-term statin therapy and those who didn’t. As expected, outcomes were significantly better in those who did: a 3-year composite outcome rate of 22.1%, compared with 32.1% in patients not on a statin; a cardiovascular death rate of 1.3% with and 2.1% without statin therapy; a recurrent MI rate of 6.6%, compared with 10.1% without a statin; and a 2.8% all-cause mortality with and 5.4% without statin therapy.

In contrast, all-cause mortality was unaffected by whether or not patients were on long-term beta-blocker therapy. And in a negative exposure outcome analysis, no association was found between beta-blocker therapy and the risk of hospitalization for pneumonia, as to be expected if the beta-blocker and no-beta-blocker groups were comparable in key respects.

Dr. Holt reported having no financial conflicts regarding his study.

bjancin@mdedge.com

Current American and European guidelines recommending long-term beta-blocker therapy following an acute MI appear to be obsolete in the modern reperfusion era, suggests an analysis of Danish registry data.

Those guidelines are based on old randomized trials of beta-blocker therapy conducted prior to introduction of routine percutaneous coronary intervention and modern multidrug optimal medical therapy for acute MI. There have been no prospective controlled studies in the reperfusion era. And a new Danish national observational study strongly suggests it’s time to reexamine the beta-blocker recommendation, Anders Holt, MD, said at the virtual annual congress of the European Society of Cardiology.

“Stable, optimally treated MI patients do not seem to benefit from beta-blocker treatment exceeding 3 months post hospitalization – bearing in mind this doesn’t apply to patients with other indications for beta-blockers, like heart failure or atrial fibrillation,” said Dr. Holt of Copenhagen University Hospital.

His analysis of Danish national registry data on more than 30,000 patients hospitalized for acute MI during 2003-2018 earned him the annual ESC Young Investigator Award in Population Science.

Frontline Medical News

“This was a crisp and clear presentation of a very creative use of observational epidemiology to try to understand the length of therapy that may or may not be appropriate,” commented award session cochair Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

Dr. Holt reported on 30,177 patients optimally treated for a first MI in Danish hospitals during 2003-2018, none of whom had a prior indication or contraindication for beta-blocker therapy. “Optimally treated” meant they underwent percutaneous coronary revascularization and were discharged on a statin and aspirin. As a study requirement, all had to be stable 90 days post hospitalization, at which point 24,770 of the patients were on long-term beta-blocker therapy, and 5,407 (18%) were not. The two groups were comparable in terms of age, sex, comorbidities, and baseline medications. All patients were followed through the registries for a maximum of 3 years, the duration of beta-blocker therapy post MI recommended in American Heart Association/American College of Cardiology guidelines. (The Danish Society of Cardiology recommends 2 years.)

At 3 years post MI, there was no between-group difference in a composite outcome comprising cardiovascular death, recurrent MI, heart failure, stroke, angina, or a cardiac procedure, with a rate of 22.9% in the beta-blocker group and 21.6% in patients not on long-term beta-blocker therapy. The rate of recurrent MI was identical at 6.7% in both groups. Cardiovascular death occurred during 3 years of follow-up in 1.4% of patients on beta-blocker therapy and 1.7% who weren’t, a nonsignificant difference.

“We saw no evidence of any cardioprotective effect, but no increased risk of adverse events resulting in hospitalization, either,” Dr. Holt observed. “I would like to acknowledge that no evidence of effect does not necessarily equal evidence of no effect, but even if there was an effect we can with fair certainty say that it’s probably quite minimal.”

He noted that the Danish registry data indicates that each year since 2012 has shown a growing trend for Danish patients to dispense with long-term beta-blocker therapy after an acute MI.

“This might indicate we are nudging toward a change in practice, where more physicians are thinking that long-term beta-blocker therapy might not be indicated for all MI patients in the reperfusion era,” according to Dr. Holt.

Asked by the four-judge award panel about the possibility of unmeasured confounding in this observational study, Dr Holt responded: “I would be very cautious about asking patients to stop beta-blocker therapy after 3 months just based on this observational data. We can’t speak to causality in an observational study.” But he added that “well-designed observational studies provide valuable data regarding this topic and should not be ignored. They should possibly influence the guidelines and the designs for upcoming randomized trials.”

He conducted several supplementary analyses designed to address the possibility of unevenly distributed unmeasured confounding in the registry study. These analyses proved reassuring. A positive exposure control analysis compared 3-year outcomes in patients who remained on long-term statin therapy and those who didn’t. As expected, outcomes were significantly better in those who did: a 3-year composite outcome rate of 22.1%, compared with 32.1% in patients not on a statin; a cardiovascular death rate of 1.3% with and 2.1% without statin therapy; a recurrent MI rate of 6.6%, compared with 10.1% without a statin; and a 2.8% all-cause mortality with and 5.4% without statin therapy.

In contrast, all-cause mortality was unaffected by whether or not patients were on long-term beta-blocker therapy. And in a negative exposure outcome analysis, no association was found between beta-blocker therapy and the risk of hospitalization for pneumonia, as to be expected if the beta-blocker and no-beta-blocker groups were comparable in key respects.

Dr. Holt reported having no financial conflicts regarding his study.

bjancin@mdedge.com

Current American and European guidelines recommending long-term beta-blocker therapy following an acute MI appear to be obsolete in the modern reperfusion era, suggests an analysis of Danish registry data.

Those guidelines are based on old randomized trials of beta-blocker therapy conducted prior to introduction of routine percutaneous coronary intervention and modern multidrug optimal medical therapy for acute MI. There have been no prospective controlled studies in the reperfusion era. And a new Danish national observational study strongly suggests it’s time to reexamine the beta-blocker recommendation, Anders Holt, MD, said at the virtual annual congress of the European Society of Cardiology.

“Stable, optimally treated MI patients do not seem to benefit from beta-blocker treatment exceeding 3 months post hospitalization – bearing in mind this doesn’t apply to patients with other indications for beta-blockers, like heart failure or atrial fibrillation,” said Dr. Holt of Copenhagen University Hospital.

His analysis of Danish national registry data on more than 30,000 patients hospitalized for acute MI during 2003-2018 earned him the annual ESC Young Investigator Award in Population Science.

Frontline Medical News

“This was a crisp and clear presentation of a very creative use of observational epidemiology to try to understand the length of therapy that may or may not be appropriate,” commented award session cochair Paul M. Ridker, MD, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, both in Boston.

Dr. Holt reported on 30,177 patients optimally treated for a first MI in Danish hospitals during 2003-2018, none of whom had a prior indication or contraindication for beta-blocker therapy. “Optimally treated” meant they underwent percutaneous coronary revascularization and were discharged on a statin and aspirin. As a study requirement, all had to be stable 90 days post hospitalization, at which point 24,770 of the patients were on long-term beta-blocker therapy, and 5,407 (18%) were not. The two groups were comparable in terms of age, sex, comorbidities, and baseline medications. All patients were followed through the registries for a maximum of 3 years, the duration of beta-blocker therapy post MI recommended in American Heart Association/American College of Cardiology guidelines. (The Danish Society of Cardiology recommends 2 years.)

At 3 years post MI, there was no between-group difference in a composite outcome comprising cardiovascular death, recurrent MI, heart failure, stroke, angina, or a cardiac procedure, with a rate of 22.9% in the beta-blocker group and 21.6% in patients not on long-term beta-blocker therapy. The rate of recurrent MI was identical at 6.7% in both groups. Cardiovascular death occurred during 3 years of follow-up in 1.4% of patients on beta-blocker therapy and 1.7% who weren’t, a nonsignificant difference.

“We saw no evidence of any cardioprotective effect, but no increased risk of adverse events resulting in hospitalization, either,” Dr. Holt observed. “I would like to acknowledge that no evidence of effect does not necessarily equal evidence of no effect, but even if there was an effect we can with fair certainty say that it’s probably quite minimal.”

He noted that the Danish registry data indicates that each year since 2012 has shown a growing trend for Danish patients to dispense with long-term beta-blocker therapy after an acute MI.

“This might indicate we are nudging toward a change in practice, where more physicians are thinking that long-term beta-blocker therapy might not be indicated for all MI patients in the reperfusion era,” according to Dr. Holt.

Asked by the four-judge award panel about the possibility of unmeasured confounding in this observational study, Dr Holt responded: “I would be very cautious about asking patients to stop beta-blocker therapy after 3 months just based on this observational data. We can’t speak to causality in an observational study.” But he added that “well-designed observational studies provide valuable data regarding this topic and should not be ignored. They should possibly influence the guidelines and the designs for upcoming randomized trials.”

He conducted several supplementary analyses designed to address the possibility of unevenly distributed unmeasured confounding in the registry study. These analyses proved reassuring. A positive exposure control analysis compared 3-year outcomes in patients who remained on long-term statin therapy and those who didn’t. As expected, outcomes were significantly better in those who did: a 3-year composite outcome rate of 22.1%, compared with 32.1% in patients not on a statin; a cardiovascular death rate of 1.3% with and 2.1% without statin therapy; a recurrent MI rate of 6.6%, compared with 10.1% without a statin; and a 2.8% all-cause mortality with and 5.4% without statin therapy.

In contrast, all-cause mortality was unaffected by whether or not patients were on long-term beta-blocker therapy. And in a negative exposure outcome analysis, no association was found between beta-blocker therapy and the risk of hospitalization for pneumonia, as to be expected if the beta-blocker and no-beta-blocker groups were comparable in key respects.

Dr. Holt reported having no financial conflicts regarding his study.

bjancin@mdedge.com

For patients with hypothyroidism who underwent treatment with desiccated thyroid, there were no significant differences in the time spent in normal ranges of thyroid stimulating hormone (TSH) over 3 years, compared with patients who received the standard therapy of synthetic levothyroxine (T4), new research shows.

The findings are “unanticipated ... given concerns for variability between batches of desiccated thyroid cited by national guidelines,” wrote the authors of the study, which was published this month in the Annals of Family Medicine.

In the trial, patients who had been treated for hypothyroidism at Kaiser Permanente Colorado were matched retrospectively into groups of 450 patients each according to whether they were treated with desiccated thyroid or synthetic levothyroxine.

After a follow-up of 3 years, TSH values within normal ranges (0.320-5.500 uIU/mL) were seen at approximately the same rate among those treated with desiccated thyroid and those who received levothyroxine (79.1% vs. 79.3%; P = .905).

“This study showed that after 3 years TSH values in both groups remained within reference ranges approximately 80% of the time,” said Rolake Kuye, PharmD, and colleagues with Kaiser Permanente, in Denver, Colorado.

In an accompanying editorial, Jill Schneiderhan, MD, and Suzanna Zick, ND, MPH, of the University of Michigan, Ann Arbor, say the overall results indicate that the continued use of desiccated thyroid is warranted in some cases.

“Keeping desiccated thyroid medications as an option in our tool kit will allow for improved shared decision-making, while allowing for patient preference, and offer an option for those patients who remain symptomatic on levothyroxine monotherapy,” they advised.
 

Some variability still seen with desiccated thyroid

Desiccated thyroid (dehydrated porcine thyroid), which was long the standard of care, is still commonly used in the treatment of hypothyroidism, despite having been replaced beginning in the 1970s by synthetic levothyroxine in light of evidence that the former was associated with more variability in thyroid hormone levels.

Desiccated thyroid is still sold legally by prescription in the United States under the names Nature Thyroid, Thyroid USP, and Armour Thyroid and is currently used by up to 30% of patients with hypothyroidism, according to recent estimates.

Consistent with concerns about variability in thyroid hormone levels, the new study did show greater variability in TSH levels with desiccated thyroid when assessed on a visit-to-visit basis.

Dr. Kuye and coauthors therefore recommended that, “[f]or providers targeting a tighter TSH goal in certain patients, the decreased TSH variability with levothyroxine could be clinically meaningful.”
 

This long-term investigation is “much needed”

This new study adds important new insight to the ongoing debate over hypothyroidism treatment, said Dr. Schneiderhan and Dr. Zick in their editorial.

“[The study authors] begin a much-needed investigation into whether patients prescribed synthetic levothyroxine compared with desiccated thyroid had differences in TSH stability over the course of 3 years.

“Further prospective studies are needed to confirm these results and to explore differences in more diverse patient populations, such as Hashimoto’s thyroiditis, as well as on quality of life and other important patient-reported outcomes such as fatigue and weight gain,” the editorialists added.

“This study does, however, provide helpful information that desiccated thyroid products are a reasonable choice for treating some hypothyroid patients.”
 

For 60% of patients in both groups, TSH levels were within reference range for whole study

In the study, Dr. Kuye and colleagues matched patients (average age, 63 years; 90% women) in terms of characteristics such as race, comorbidities, and cholesterol levels.

Patients were excluded if they had been prescribed more than one agent for the treatment of hypothyroidism or if they had comorbid conditions, including a history of thyroid cancer or other related comorbidities, as well as pregnancy.

With respect to visit-to-visit TSH level variability, the lower rate among patients prescribed levothyroxine in comparison with patients prescribed desiccated thyroid was statistically significant (1.25 vs. 1.44; P = .015). Among 60% of patients in both groups, all TSH values measured during the study period were within reference ranges, however (P = .951).

The median number of TSH laboratory studies obtained during the study was four in the synthetic levothyroxine group and three for patients prescribed desiccated thyroid (P = .578).

There were some notable differences between the groups. Patients in the desiccated thyroid group had lower body mass index (P = .032), hemoglobin A1c levels (P = .041), and lower baseline TSH values (2.4 vs. 3.4 uIU/mL; P = .001). compared with those prescribed levothyroxine.

Limitations include the fact that the authors could not account for potentially important variables such as rates of adherence, differences in prescriber practice between agents, or the concurrent use of other medications.
 

Subjective outcomes not assessed: “One-size-fits-all approach doesn’t work”

The authors note they were not able to assess subjective outcomes, which, as noted by the editorialists, are particularly important in hypothyroidism.

“Emerging evidence shows that for many patients, symptoms persist despite normal TSH values,” Dr. Schneiderhan and Dr. Zick write.

They cite as an example a large study that found significant impairment in psychological well-being among patients treated with thyroxine replacement, despite their achieving normal TSH levels.

In addition, synthetic levothyroxine is associated with other uncertainties, such as complexities in the conversion of T4 to triiodothyronine (T3) that may disrupt thyroid metabolism in some patients.

In addition, there are differences in the amounts of thyroid replacement needed by certain groups, such as patients who have undergone thyroidectomies.

“The one-size-fits-all approach for treating hypothyroidism does not work ... for all patients,” they concluded.

The study authors and editorialists have disclosed no relevant financial relationships.
 

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

For patients with hypothyroidism who underwent treatment with desiccated thyroid, there were no significant differences in the time spent in normal ranges of thyroid stimulating hormone (TSH) over 3 years, compared with patients who received the standard therapy of synthetic levothyroxine (T4), new research shows.

The findings are “unanticipated ... given concerns for variability between batches of desiccated thyroid cited by national guidelines,” wrote the authors of the study, which was published this month in the Annals of Family Medicine.

In the trial, patients who had been treated for hypothyroidism at Kaiser Permanente Colorado were matched retrospectively into groups of 450 patients each according to whether they were treated with desiccated thyroid or synthetic levothyroxine.

After a follow-up of 3 years, TSH values within normal ranges (0.320-5.500 uIU/mL) were seen at approximately the same rate among those treated with desiccated thyroid and those who received levothyroxine (79.1% vs. 79.3%; P = .905).

“This study showed that after 3 years TSH values in both groups remained within reference ranges approximately 80% of the time,” said Rolake Kuye, PharmD, and colleagues with Kaiser Permanente, in Denver, Colorado.

In an accompanying editorial, Jill Schneiderhan, MD, and Suzanna Zick, ND, MPH, of the University of Michigan, Ann Arbor, say the overall results indicate that the continued use of desiccated thyroid is warranted in some cases.

“Keeping desiccated thyroid medications as an option in our tool kit will allow for improved shared decision-making, while allowing for patient preference, and offer an option for those patients who remain symptomatic on levothyroxine monotherapy,” they advised.
 

Some variability still seen with desiccated thyroid

Desiccated thyroid (dehydrated porcine thyroid), which was long the standard of care, is still commonly used in the treatment of hypothyroidism, despite having been replaced beginning in the 1970s by synthetic levothyroxine in light of evidence that the former was associated with more variability in thyroid hormone levels.

Desiccated thyroid is still sold legally by prescription in the United States under the names Nature Thyroid, Thyroid USP, and Armour Thyroid and is currently used by up to 30% of patients with hypothyroidism, according to recent estimates.

Consistent with concerns about variability in thyroid hormone levels, the new study did show greater variability in TSH levels with desiccated thyroid when assessed on a visit-to-visit basis.

Dr. Kuye and coauthors therefore recommended that, “[f]or providers targeting a tighter TSH goal in certain patients, the decreased TSH variability with levothyroxine could be clinically meaningful.”
 

This long-term investigation is “much needed”

This new study adds important new insight to the ongoing debate over hypothyroidism treatment, said Dr. Schneiderhan and Dr. Zick in their editorial.

“[The study authors] begin a much-needed investigation into whether patients prescribed synthetic levothyroxine compared with desiccated thyroid had differences in TSH stability over the course of 3 years.

“Further prospective studies are needed to confirm these results and to explore differences in more diverse patient populations, such as Hashimoto’s thyroiditis, as well as on quality of life and other important patient-reported outcomes such as fatigue and weight gain,” the editorialists added.

“This study does, however, provide helpful information that desiccated thyroid products are a reasonable choice for treating some hypothyroid patients.”
 

For 60% of patients in both groups, TSH levels were within reference range for whole study

In the study, Dr. Kuye and colleagues matched patients (average age, 63 years; 90% women) in terms of characteristics such as race, comorbidities, and cholesterol levels.

Patients were excluded if they had been prescribed more than one agent for the treatment of hypothyroidism or if they had comorbid conditions, including a history of thyroid cancer or other related comorbidities, as well as pregnancy.

With respect to visit-to-visit TSH level variability, the lower rate among patients prescribed levothyroxine in comparison with patients prescribed desiccated thyroid was statistically significant (1.25 vs. 1.44; P = .015). Among 60% of patients in both groups, all TSH values measured during the study period were within reference ranges, however (P = .951).

The median number of TSH laboratory studies obtained during the study was four in the synthetic levothyroxine group and three for patients prescribed desiccated thyroid (P = .578).

There were some notable differences between the groups. Patients in the desiccated thyroid group had lower body mass index (P = .032), hemoglobin A1c levels (P = .041), and lower baseline TSH values (2.4 vs. 3.4 uIU/mL; P = .001). compared with those prescribed levothyroxine.

Limitations include the fact that the authors could not account for potentially important variables such as rates of adherence, differences in prescriber practice between agents, or the concurrent use of other medications.
 

Subjective outcomes not assessed: “One-size-fits-all approach doesn’t work”

The authors note they were not able to assess subjective outcomes, which, as noted by the editorialists, are particularly important in hypothyroidism.

“Emerging evidence shows that for many patients, symptoms persist despite normal TSH values,” Dr. Schneiderhan and Dr. Zick write.

They cite as an example a large study that found significant impairment in psychological well-being among patients treated with thyroxine replacement, despite their achieving normal TSH levels.

In addition, synthetic levothyroxine is associated with other uncertainties, such as complexities in the conversion of T4 to triiodothyronine (T3) that may disrupt thyroid metabolism in some patients.

In addition, there are differences in the amounts of thyroid replacement needed by certain groups, such as patients who have undergone thyroidectomies.

“The one-size-fits-all approach for treating hypothyroidism does not work ... for all patients,” they concluded.

The study authors and editorialists have disclosed no relevant financial relationships.
 

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

For patients with hypothyroidism who underwent treatment with desiccated thyroid, there were no significant differences in the time spent in normal ranges of thyroid stimulating hormone (TSH) over 3 years, compared with patients who received the standard therapy of synthetic levothyroxine (T4), new research shows.

The findings are “unanticipated ... given concerns for variability between batches of desiccated thyroid cited by national guidelines,” wrote the authors of the study, which was published this month in the Annals of Family Medicine.

In the trial, patients who had been treated for hypothyroidism at Kaiser Permanente Colorado were matched retrospectively into groups of 450 patients each according to whether they were treated with desiccated thyroid or synthetic levothyroxine.

After a follow-up of 3 years, TSH values within normal ranges (0.320-5.500 uIU/mL) were seen at approximately the same rate among those treated with desiccated thyroid and those who received levothyroxine (79.1% vs. 79.3%; P = .905).

“This study showed that after 3 years TSH values in both groups remained within reference ranges approximately 80% of the time,” said Rolake Kuye, PharmD, and colleagues with Kaiser Permanente, in Denver, Colorado.

In an accompanying editorial, Jill Schneiderhan, MD, and Suzanna Zick, ND, MPH, of the University of Michigan, Ann Arbor, say the overall results indicate that the continued use of desiccated thyroid is warranted in some cases.

“Keeping desiccated thyroid medications as an option in our tool kit will allow for improved shared decision-making, while allowing for patient preference, and offer an option for those patients who remain symptomatic on levothyroxine monotherapy,” they advised.
 

Some variability still seen with desiccated thyroid

Desiccated thyroid (dehydrated porcine thyroid), which was long the standard of care, is still commonly used in the treatment of hypothyroidism, despite having been replaced beginning in the 1970s by synthetic levothyroxine in light of evidence that the former was associated with more variability in thyroid hormone levels.

Desiccated thyroid is still sold legally by prescription in the United States under the names Nature Thyroid, Thyroid USP, and Armour Thyroid and is currently used by up to 30% of patients with hypothyroidism, according to recent estimates.

Consistent with concerns about variability in thyroid hormone levels, the new study did show greater variability in TSH levels with desiccated thyroid when assessed on a visit-to-visit basis.

Dr. Kuye and coauthors therefore recommended that, “[f]or providers targeting a tighter TSH goal in certain patients, the decreased TSH variability with levothyroxine could be clinically meaningful.”
 

This long-term investigation is “much needed”

This new study adds important new insight to the ongoing debate over hypothyroidism treatment, said Dr. Schneiderhan and Dr. Zick in their editorial.

“[The study authors] begin a much-needed investigation into whether patients prescribed synthetic levothyroxine compared with desiccated thyroid had differences in TSH stability over the course of 3 years.

“Further prospective studies are needed to confirm these results and to explore differences in more diverse patient populations, such as Hashimoto’s thyroiditis, as well as on quality of life and other important patient-reported outcomes such as fatigue and weight gain,” the editorialists added.

“This study does, however, provide helpful information that desiccated thyroid products are a reasonable choice for treating some hypothyroid patients.”
 

For 60% of patients in both groups, TSH levels were within reference range for whole study

In the study, Dr. Kuye and colleagues matched patients (average age, 63 years; 90% women) in terms of characteristics such as race, comorbidities, and cholesterol levels.

Patients were excluded if they had been prescribed more than one agent for the treatment of hypothyroidism or if they had comorbid conditions, including a history of thyroid cancer or other related comorbidities, as well as pregnancy.

With respect to visit-to-visit TSH level variability, the lower rate among patients prescribed levothyroxine in comparison with patients prescribed desiccated thyroid was statistically significant (1.25 vs. 1.44; P = .015). Among 60% of patients in both groups, all TSH values measured during the study period were within reference ranges, however (P = .951).

The median number of TSH laboratory studies obtained during the study was four in the synthetic levothyroxine group and three for patients prescribed desiccated thyroid (P = .578).

There were some notable differences between the groups. Patients in the desiccated thyroid group had lower body mass index (P = .032), hemoglobin A1c levels (P = .041), and lower baseline TSH values (2.4 vs. 3.4 uIU/mL; P = .001). compared with those prescribed levothyroxine.

Limitations include the fact that the authors could not account for potentially important variables such as rates of adherence, differences in prescriber practice between agents, or the concurrent use of other medications.
 

Subjective outcomes not assessed: “One-size-fits-all approach doesn’t work”

The authors note they were not able to assess subjective outcomes, which, as noted by the editorialists, are particularly important in hypothyroidism.

“Emerging evidence shows that for many patients, symptoms persist despite normal TSH values,” Dr. Schneiderhan and Dr. Zick write.

They cite as an example a large study that found significant impairment in psychological well-being among patients treated with thyroxine replacement, despite their achieving normal TSH levels.

In addition, synthetic levothyroxine is associated with other uncertainties, such as complexities in the conversion of T4 to triiodothyronine (T3) that may disrupt thyroid metabolism in some patients.

In addition, there are differences in the amounts of thyroid replacement needed by certain groups, such as patients who have undergone thyroidectomies.

“The one-size-fits-all approach for treating hypothyroidism does not work ... for all patients,” they concluded.

The study authors and editorialists have disclosed no relevant financial relationships.
 

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

Phase 2 data for the investigational, once-weekly basal insulin analog icodec (Novo Nordisk) showing comparable efficacy and safety to once-daily insulin glargine U100 have been published in the New England Journal of Medicine.

“Insulin icodec could potentially improve acceptance and likely would facilitate management in type 2 diabetes patients needing basal insulin, and I think it will be transformational in the way we manage people with type 2 diabetes requiring insulin,” said lead author Julio Rosenstock, MD, University of Texas Southwestern Medical Center, Dallas, who also presented the data at the virtual annual meeting of the European Association for the Study of Diabetes.

Insulin icodec binds to albumin to create a circulating depot with a 196-hour (8.1 days) half-life, so the once-weekly injection is designed to cover an individual’s basal insulin requirements for a full week, with steady insulin release. Because of its concentrated formulation, its injection volume is equivalent to that of daily glargine U100.

In the 26-week, randomized, phase 2 trial involving 247 insulin-naive patients with type 2 diabetes, once-weekly icodec’s glucose-lowering and safety profiles were similar to those of once-daily insulin glargine U100. These results were previously presented by Dr. Rosenstock in June at the virtual American Diabetes Association conference, as reported by Medscape Medical News.

In addition, new data in a poster at EASD 2020 showed that switching to icodec from other basal insulins is efficacious without causing significant hypoglycemia, as reported by Harpreet Bajaj, MD, MPH, director of the Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto.

Charles M. Alexander, MD, an endocrinologist and managing director of Alexander Associates, Gwynedd Valley, Pa., said in an interview that “some patients will find once-weekly basal insulin an attractive option, while other patients will be indifferent to its availability.”

Dr. Alexander also pointed out that “payers are not going to be very interested in paying for a once-weekly basal insulin when daily basal insulins have been available for many years, unless the cost is the same or less. Resource-constrained health plans will wait until the price is [similar].”
 

The phase 2 study: Once weekly is just as good as daily

In the phase 2, randomized, double-blind, double-dummy, parallel-group, treat-to-target trial, the patients had baseline hemoglobin A1c levels of 7.0%-9.5% despite taking metformin, with or without a dipeptidyl peptidase–4 inhibitor.

They were randomized to weekly insulin icodec plus daily placebo (n = 125) or daily insulin glargine U100 plus weekly placebo (n = 122). The primary endpoint, change in A1c from baseline to week 26, dropped 1.33 percentage points with icodec and 1.15 percentage points with glargine, down to 6.7% and 6.9%, respectively. The difference wasn’t significant (P = .08). Fasting plasma glucose levels dropped by 58 mg/dL with icodec and 54 mg/dL with glargine (P = .34).

Time in range (70-140 mg/dL or 3.9-7.8 mmol/L) as assessed by flash glucose monitoring (FreeStyle Libre Pro) was greater with Icodec, by 5.4 percentage points, corresponding to an extra 78 minutes per day in range.

Mild hypoglycemia was more common with icodec than glargine (509 vs. 211 events per 100 patient-years, but rates of moderate/clinically significant hypoglycemia (52.5 vs. 46 per 100 patient-years, respectively) and severe hypoglycemia (1.4 vs. 0 per 100 patient-years) did not differ significantly (P = .85).

And the duration of hypoglycemia wasn’t longer with icodec, compared with glargine, despite its longer duration of action, Dr. Rosenstock emphasized.

Rates of other adverse events were similar between the groups.

Use of a once-weekly basal insulin could reduce the number of annual insulin injections from 365 to just 52, the authors noted in their paper.
 

New data: Switching to icodec is effective, safe

The new data on switching came from a 16-week, open-label, phase 2 trial of 154 patients with type 2 diabetes with insufficient glycemic control (mean A1c 7.9%) while taking oral medication and basal insulin. They were randomized to once-weekly icodec with or without an initial loading dose, or once-daily glargine U100.

Insulin doses were titrated weekly based on blood glucose levels as measured by continuous glucose monitoring (Dexcom G6).

The primary endpoint, time in range (70-180 mg/dL or 3.9-10.0 mmol/L) during weeks 15-16 was significantly better for icodec plus loading dose, compared with glargine U100 (72.9% vs 65.0%, P = .01) and similar between icodec and glargine U100 (66.0% vs 65.0%, P = .75).

Estimated mean percentage point reductions in A1c were 0.77 for icodec plus loading dose, 0.47 for icodec without the loading dose, and 0.54 for glargine U100.

Rates of moderate to severe hypoglycemia were similar between icodec plus loading dose and glargine U100 (78.0 and 79.4 events per 100 patient-years, respectively), and lower for icodec without the loading dose (14.8/100 patient-years).

There were no unexpected safety findings.

Novo Nordisk’s phase 3 trial for icodec is set to begin in late November.

The company is also developing a coformulation of icodec with its glucagonlike peptide–1 receptor agonist semaglutide, currently in phase 1 testing. Meanwhile, Eli Lilly is also developing a once-weekly basal analog, LY3209590, currently in phase 2 trials.

Dr. Rosenstock reported receiving research support from, being on advisory boards for, and/or receiving consulting honoraria from Merck, Pfizer, Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Oramed, Boehringer Ingelheim, Applied Therapeutics, and Intarcia. Dr. Alexander reported no relevant financial relationships.

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

Phase 2 data for the investigational, once-weekly basal insulin analog icodec (Novo Nordisk) showing comparable efficacy and safety to once-daily insulin glargine U100 have been published in the New England Journal of Medicine.

“Insulin icodec could potentially improve acceptance and likely would facilitate management in type 2 diabetes patients needing basal insulin, and I think it will be transformational in the way we manage people with type 2 diabetes requiring insulin,” said lead author Julio Rosenstock, MD, University of Texas Southwestern Medical Center, Dallas, who also presented the data at the virtual annual meeting of the European Association for the Study of Diabetes.

Insulin icodec binds to albumin to create a circulating depot with a 196-hour (8.1 days) half-life, so the once-weekly injection is designed to cover an individual’s basal insulin requirements for a full week, with steady insulin release. Because of its concentrated formulation, its injection volume is equivalent to that of daily glargine U100.

In the 26-week, randomized, phase 2 trial involving 247 insulin-naive patients with type 2 diabetes, once-weekly icodec’s glucose-lowering and safety profiles were similar to those of once-daily insulin glargine U100. These results were previously presented by Dr. Rosenstock in June at the virtual American Diabetes Association conference, as reported by Medscape Medical News.

In addition, new data in a poster at EASD 2020 showed that switching to icodec from other basal insulins is efficacious without causing significant hypoglycemia, as reported by Harpreet Bajaj, MD, MPH, director of the Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto.

Charles M. Alexander, MD, an endocrinologist and managing director of Alexander Associates, Gwynedd Valley, Pa., said in an interview that “some patients will find once-weekly basal insulin an attractive option, while other patients will be indifferent to its availability.”

Dr. Alexander also pointed out that “payers are not going to be very interested in paying for a once-weekly basal insulin when daily basal insulins have been available for many years, unless the cost is the same or less. Resource-constrained health plans will wait until the price is [similar].”
 

The phase 2 study: Once weekly is just as good as daily

In the phase 2, randomized, double-blind, double-dummy, parallel-group, treat-to-target trial, the patients had baseline hemoglobin A1c levels of 7.0%-9.5% despite taking metformin, with or without a dipeptidyl peptidase–4 inhibitor.

They were randomized to weekly insulin icodec plus daily placebo (n = 125) or daily insulin glargine U100 plus weekly placebo (n = 122). The primary endpoint, change in A1c from baseline to week 26, dropped 1.33 percentage points with icodec and 1.15 percentage points with glargine, down to 6.7% and 6.9%, respectively. The difference wasn’t significant (P = .08). Fasting plasma glucose levels dropped by 58 mg/dL with icodec and 54 mg/dL with glargine (P = .34).

Time in range (70-140 mg/dL or 3.9-7.8 mmol/L) as assessed by flash glucose monitoring (FreeStyle Libre Pro) was greater with Icodec, by 5.4 percentage points, corresponding to an extra 78 minutes per day in range.

Mild hypoglycemia was more common with icodec than glargine (509 vs. 211 events per 100 patient-years, but rates of moderate/clinically significant hypoglycemia (52.5 vs. 46 per 100 patient-years, respectively) and severe hypoglycemia (1.4 vs. 0 per 100 patient-years) did not differ significantly (P = .85).

And the duration of hypoglycemia wasn’t longer with icodec, compared with glargine, despite its longer duration of action, Dr. Rosenstock emphasized.

Rates of other adverse events were similar between the groups.

Use of a once-weekly basal insulin could reduce the number of annual insulin injections from 365 to just 52, the authors noted in their paper.
 

New data: Switching to icodec is effective, safe

The new data on switching came from a 16-week, open-label, phase 2 trial of 154 patients with type 2 diabetes with insufficient glycemic control (mean A1c 7.9%) while taking oral medication and basal insulin. They were randomized to once-weekly icodec with or without an initial loading dose, or once-daily glargine U100.

Insulin doses were titrated weekly based on blood glucose levels as measured by continuous glucose monitoring (Dexcom G6).

The primary endpoint, time in range (70-180 mg/dL or 3.9-10.0 mmol/L) during weeks 15-16 was significantly better for icodec plus loading dose, compared with glargine U100 (72.9% vs 65.0%, P = .01) and similar between icodec and glargine U100 (66.0% vs 65.0%, P = .75).

Estimated mean percentage point reductions in A1c were 0.77 for icodec plus loading dose, 0.47 for icodec without the loading dose, and 0.54 for glargine U100.

Rates of moderate to severe hypoglycemia were similar between icodec plus loading dose and glargine U100 (78.0 and 79.4 events per 100 patient-years, respectively), and lower for icodec without the loading dose (14.8/100 patient-years).

There were no unexpected safety findings.

Novo Nordisk’s phase 3 trial for icodec is set to begin in late November.

The company is also developing a coformulation of icodec with its glucagonlike peptide–1 receptor agonist semaglutide, currently in phase 1 testing. Meanwhile, Eli Lilly is also developing a once-weekly basal analog, LY3209590, currently in phase 2 trials.

Dr. Rosenstock reported receiving research support from, being on advisory boards for, and/or receiving consulting honoraria from Merck, Pfizer, Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Oramed, Boehringer Ingelheim, Applied Therapeutics, and Intarcia. Dr. Alexander reported no relevant financial relationships.

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

Phase 2 data for the investigational, once-weekly basal insulin analog icodec (Novo Nordisk) showing comparable efficacy and safety to once-daily insulin glargine U100 have been published in the New England Journal of Medicine.

“Insulin icodec could potentially improve acceptance and likely would facilitate management in type 2 diabetes patients needing basal insulin, and I think it will be transformational in the way we manage people with type 2 diabetes requiring insulin,” said lead author Julio Rosenstock, MD, University of Texas Southwestern Medical Center, Dallas, who also presented the data at the virtual annual meeting of the European Association for the Study of Diabetes.

Insulin icodec binds to albumin to create a circulating depot with a 196-hour (8.1 days) half-life, so the once-weekly injection is designed to cover an individual’s basal insulin requirements for a full week, with steady insulin release. Because of its concentrated formulation, its injection volume is equivalent to that of daily glargine U100.

In the 26-week, randomized, phase 2 trial involving 247 insulin-naive patients with type 2 diabetes, once-weekly icodec’s glucose-lowering and safety profiles were similar to those of once-daily insulin glargine U100. These results were previously presented by Dr. Rosenstock in June at the virtual American Diabetes Association conference, as reported by Medscape Medical News.

In addition, new data in a poster at EASD 2020 showed that switching to icodec from other basal insulins is efficacious without causing significant hypoglycemia, as reported by Harpreet Bajaj, MD, MPH, director of the Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto.

Charles M. Alexander, MD, an endocrinologist and managing director of Alexander Associates, Gwynedd Valley, Pa., said in an interview that “some patients will find once-weekly basal insulin an attractive option, while other patients will be indifferent to its availability.”

Dr. Alexander also pointed out that “payers are not going to be very interested in paying for a once-weekly basal insulin when daily basal insulins have been available for many years, unless the cost is the same or less. Resource-constrained health plans will wait until the price is [similar].”
 

The phase 2 study: Once weekly is just as good as daily

In the phase 2, randomized, double-blind, double-dummy, parallel-group, treat-to-target trial, the patients had baseline hemoglobin A1c levels of 7.0%-9.5% despite taking metformin, with or without a dipeptidyl peptidase–4 inhibitor.

They were randomized to weekly insulin icodec plus daily placebo (n = 125) or daily insulin glargine U100 plus weekly placebo (n = 122). The primary endpoint, change in A1c from baseline to week 26, dropped 1.33 percentage points with icodec and 1.15 percentage points with glargine, down to 6.7% and 6.9%, respectively. The difference wasn’t significant (P = .08). Fasting plasma glucose levels dropped by 58 mg/dL with icodec and 54 mg/dL with glargine (P = .34).

Time in range (70-140 mg/dL or 3.9-7.8 mmol/L) as assessed by flash glucose monitoring (FreeStyle Libre Pro) was greater with Icodec, by 5.4 percentage points, corresponding to an extra 78 minutes per day in range.

Mild hypoglycemia was more common with icodec than glargine (509 vs. 211 events per 100 patient-years, but rates of moderate/clinically significant hypoglycemia (52.5 vs. 46 per 100 patient-years, respectively) and severe hypoglycemia (1.4 vs. 0 per 100 patient-years) did not differ significantly (P = .85).

And the duration of hypoglycemia wasn’t longer with icodec, compared with glargine, despite its longer duration of action, Dr. Rosenstock emphasized.

Rates of other adverse events were similar between the groups.

Use of a once-weekly basal insulin could reduce the number of annual insulin injections from 365 to just 52, the authors noted in their paper.
 

New data: Switching to icodec is effective, safe

The new data on switching came from a 16-week, open-label, phase 2 trial of 154 patients with type 2 diabetes with insufficient glycemic control (mean A1c 7.9%) while taking oral medication and basal insulin. They were randomized to once-weekly icodec with or without an initial loading dose, or once-daily glargine U100.

Insulin doses were titrated weekly based on blood glucose levels as measured by continuous glucose monitoring (Dexcom G6).

The primary endpoint, time in range (70-180 mg/dL or 3.9-10.0 mmol/L) during weeks 15-16 was significantly better for icodec plus loading dose, compared with glargine U100 (72.9% vs 65.0%, P = .01) and similar between icodec and glargine U100 (66.0% vs 65.0%, P = .75).

Estimated mean percentage point reductions in A1c were 0.77 for icodec plus loading dose, 0.47 for icodec without the loading dose, and 0.54 for glargine U100.

Rates of moderate to severe hypoglycemia were similar between icodec plus loading dose and glargine U100 (78.0 and 79.4 events per 100 patient-years, respectively), and lower for icodec without the loading dose (14.8/100 patient-years).

There were no unexpected safety findings.

Novo Nordisk’s phase 3 trial for icodec is set to begin in late November.

The company is also developing a coformulation of icodec with its glucagonlike peptide–1 receptor agonist semaglutide, currently in phase 1 testing. Meanwhile, Eli Lilly is also developing a once-weekly basal analog, LY3209590, currently in phase 2 trials.

Dr. Rosenstock reported receiving research support from, being on advisory boards for, and/or receiving consulting honoraria from Merck, Pfizer, Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Oramed, Boehringer Ingelheim, Applied Therapeutics, and Intarcia. Dr. Alexander reported no relevant financial relationships.

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

Chronic obstructive pulmonary disease (COPD) is caused by airway and alveolar abnormalities and is the third most common cause of death worldwide. COPD results in airflow obstruction that is not fully reversible. The diagnosis of COPD should be considered in patients over 40 years who have chronic cough and/or dyspnea, particularly if they have a history of tobacco use. The diagnosis is confirmed by a diminished forced expiratory volume in 1 second (FEV₁) that is not fully reversible with the use of a bronchodilator and an FEV₁/forced vital capacity ratio of less than or equal to 0.7.¹The American Thoracic Society released a guideline on the pharmacologic management of COPD after formulating specific questions to be answered using rigorous GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.²

Recommendation 1

Patients with COPD who report dyspnea or exercise intolerance should be treated with both a long-acting muscarinic antagonist (LAMA) and a long-acting beta agonist (LABA) (dual LAMA/LABA therapy) instead of monotherapy, the guideline says.

This recommendation represents a critical change in care and is based on strong evidence. For years practitioners have been using single bronchodilator therapy, often a LAMA as the entrance to treatment for patients with symptomatic COPD. The recommendation to begin treatment with dual bronchodilator therapy is an important one. This is the only recommendation that received a “strong” grade.

The evidence comes from the compilation of 24 randomized controlled trials that altogether included 45,441 patients. Dual therapy versus monotherapy was evaluated by examining differences in dyspnea, health-related quality of life, exacerbations (which were defined as requiring antibiotics, oral steroids, or hospitalizations), and hospitalizations independently. Marked improvements were observed for exacerbations and hospitalizations in the dual LAMA/LABA group, compared with treatment with use of a single bronchodilator. In 22,733 patients across 15 RCTs, there were 88 fewer exacerbations per 1,000 patients with a rate ratio (RR) of 0.80 (P < .002), the guideline states.

The decrease in exacerbations is a critical factor in treating patients with COPD because each exacerbation can lead to a sustained decrease in airflow and increases the risk of future exacerbations.
 

Recommendation 2

In COPD patients who report dyspnea or exercise intolerance, with an exacerbation in the last year, the guideline recommends triple therapy with an inhaled corticosteroid (ICS) instead of just dual LAMA/LABA therapy.

In the past many clinicians have relegated triple therapy to a “last ditch resort.” This recommendation makes it clear that triple therapy is appropriate for a broad range of patients with moderate to severe COPD.
 

Recommendation 3

In patients with COPD who are on triple therapy, the inhaled corticosteroid component can be withdrawn if patients have not had an exacerbation within the last year, according to the guideline.

It should be noted that the committee said that the ICS can be withdrawn, not that it necessarily needs to be withdrawn. The data showed that it would be safe to withdraw the ICS, but the data is limited in time to 1 year’s follow-up.
 

Recommendation 4

ATS was not able to make a recommendation for or against ICS as an additive therapy to LAMA/LABA in those without an exacerbation and elevated blood eosinophilia (defined as ≥2% blood eosinophils or >149 cell/mcL). In those with at least one exacerbation and increased blood eosinophilia, the society does recommend addition of ICS to dual LAMA/LABA therapy.

An area of ongoing discussion is at what point in disease severity, before exacerbations occur, might ICS be useful in preventing a first exacerbation. This awaits further studies and evidence.
 

Recommendation 5

In COPD patients with frequent and severe exacerbations who are otherwise medically optimized, the ATS advises against the use of maintenance oral corticosteroid therapy.

It has been known and accepted for years that oral steroids should be avoided if at all possible because they have little benefit and can cause significant harm. The guideline reinforces this.
 

The Bottom Line

Dual LAMA/LABA therapy in symptomatic patients is the standard of care. If a patient has had an exacerbation within the last year, add an ICS to the LAMA/LABA, most conveniently given in the form of triple therapy in one inhaler. Finally, even in refractory COPD, maintenance oral corticosteroids bring more harm than benefit.

Dr. Skolnik is professor of family and community medicine at the Thomas Jefferson University, Philadelphia, and associate director of the Family Medicine Residency Program at Abington (Pa.) Jefferson Health. Dr. Matthews is a second-year resident in the family medicine residency program at Abington Jefferson Health.

References

1. Wells C, Joo MJ. COPD and asthma: Diagnostic accuracy requires spirometry. J Fam Pract. 2019;68(2):76-81.

2. Nici L, Mammen MJ, Charbek E, et al. Pharmacologic management of chronic obstructive pulmonary disease. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201(9):e56-69.

Chronic obstructive pulmonary disease (COPD) is caused by airway and alveolar abnormalities and is the third most common cause of death worldwide. COPD results in airflow obstruction that is not fully reversible. The diagnosis of COPD should be considered in patients over 40 years who have chronic cough and/or dyspnea, particularly if they have a history of tobacco use. The diagnosis is confirmed by a diminished forced expiratory volume in 1 second (FEV₁) that is not fully reversible with the use of a bronchodilator and an FEV₁/forced vital capacity ratio of less than or equal to 0.7.¹The American Thoracic Society released a guideline on the pharmacologic management of COPD after formulating specific questions to be answered using rigorous GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.²

Recommendation 1

Patients with COPD who report dyspnea or exercise intolerance should be treated with both a long-acting muscarinic antagonist (LAMA) and a long-acting beta agonist (LABA) (dual LAMA/LABA therapy) instead of monotherapy, the guideline says.

This recommendation represents a critical change in care and is based on strong evidence. For years practitioners have been using single bronchodilator therapy, often a LAMA as the entrance to treatment for patients with symptomatic COPD. The recommendation to begin treatment with dual bronchodilator therapy is an important one. This is the only recommendation that received a “strong” grade.

The evidence comes from the compilation of 24 randomized controlled trials that altogether included 45,441 patients. Dual therapy versus monotherapy was evaluated by examining differences in dyspnea, health-related quality of life, exacerbations (which were defined as requiring antibiotics, oral steroids, or hospitalizations), and hospitalizations independently. Marked improvements were observed for exacerbations and hospitalizations in the dual LAMA/LABA group, compared with treatment with use of a single bronchodilator. In 22,733 patients across 15 RCTs, there were 88 fewer exacerbations per 1,000 patients with a rate ratio (RR) of 0.80 (P < .002), the guideline states.

The decrease in exacerbations is a critical factor in treating patients with COPD because each exacerbation can lead to a sustained decrease in airflow and increases the risk of future exacerbations.
 

Recommendation 2

In COPD patients who report dyspnea or exercise intolerance, with an exacerbation in the last year, the guideline recommends triple therapy with an inhaled corticosteroid (ICS) instead of just dual LAMA/LABA therapy.

In the past many clinicians have relegated triple therapy to a “last ditch resort.” This recommendation makes it clear that triple therapy is appropriate for a broad range of patients with moderate to severe COPD.
 

Recommendation 3

In patients with COPD who are on triple therapy, the inhaled corticosteroid component can be withdrawn if patients have not had an exacerbation within the last year, according to the guideline.

It should be noted that the committee said that the ICS can be withdrawn, not that it necessarily needs to be withdrawn. The data showed that it would be safe to withdraw the ICS, but the data is limited in time to 1 year’s follow-up.
 

Recommendation 4

ATS was not able to make a recommendation for or against ICS as an additive therapy to LAMA/LABA in those without an exacerbation and elevated blood eosinophilia (defined as ≥2% blood eosinophils or >149 cell/mcL). In those with at least one exacerbation and increased blood eosinophilia, the society does recommend addition of ICS to dual LAMA/LABA therapy.

An area of ongoing discussion is at what point in disease severity, before exacerbations occur, might ICS be useful in preventing a first exacerbation. This awaits further studies and evidence.
 

Recommendation 5

In COPD patients with frequent and severe exacerbations who are otherwise medically optimized, the ATS advises against the use of maintenance oral corticosteroid therapy.

It has been known and accepted for years that oral steroids should be avoided if at all possible because they have little benefit and can cause significant harm. The guideline reinforces this.
 

The Bottom Line

Dual LAMA/LABA therapy in symptomatic patients is the standard of care. If a patient has had an exacerbation within the last year, add an ICS to the LAMA/LABA, most conveniently given in the form of triple therapy in one inhaler. Finally, even in refractory COPD, maintenance oral corticosteroids bring more harm than benefit.

Dr. Skolnik is professor of family and community medicine at the Thomas Jefferson University, Philadelphia, and associate director of the Family Medicine Residency Program at Abington (Pa.) Jefferson Health. Dr. Matthews is a second-year resident in the family medicine residency program at Abington Jefferson Health.

References

1. Wells C, Joo MJ. COPD and asthma: Diagnostic accuracy requires spirometry. J Fam Pract. 2019;68(2):76-81.

2. Nici L, Mammen MJ, Charbek E, et al. Pharmacologic management of chronic obstructive pulmonary disease. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201(9):e56-69.

Chronic obstructive pulmonary disease (COPD) is caused by airway and alveolar abnormalities and is the third most common cause of death worldwide. COPD results in airflow obstruction that is not fully reversible. The diagnosis of COPD should be considered in patients over 40 years who have chronic cough and/or dyspnea, particularly if they have a history of tobacco use. The diagnosis is confirmed by a diminished forced expiratory volume in 1 second (FEV₁) that is not fully reversible with the use of a bronchodilator and an FEV₁/forced vital capacity ratio of less than or equal to 0.7.¹The American Thoracic Society released a guideline on the pharmacologic management of COPD after formulating specific questions to be answered using rigorous GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.²

Recommendation 1

Patients with COPD who report dyspnea or exercise intolerance should be treated with both a long-acting muscarinic antagonist (LAMA) and a long-acting beta agonist (LABA) (dual LAMA/LABA therapy) instead of monotherapy, the guideline says.

This recommendation represents a critical change in care and is based on strong evidence. For years practitioners have been using single bronchodilator therapy, often a LAMA as the entrance to treatment for patients with symptomatic COPD. The recommendation to begin treatment with dual bronchodilator therapy is an important one. This is the only recommendation that received a “strong” grade.

The evidence comes from the compilation of 24 randomized controlled trials that altogether included 45,441 patients. Dual therapy versus monotherapy was evaluated by examining differences in dyspnea, health-related quality of life, exacerbations (which were defined as requiring antibiotics, oral steroids, or hospitalizations), and hospitalizations independently. Marked improvements were observed for exacerbations and hospitalizations in the dual LAMA/LABA group, compared with treatment with use of a single bronchodilator. In 22,733 patients across 15 RCTs, there were 88 fewer exacerbations per 1,000 patients with a rate ratio (RR) of 0.80 (P < .002), the guideline states.

The decrease in exacerbations is a critical factor in treating patients with COPD because each exacerbation can lead to a sustained decrease in airflow and increases the risk of future exacerbations.
 

Recommendation 2

In COPD patients who report dyspnea or exercise intolerance, with an exacerbation in the last year, the guideline recommends triple therapy with an inhaled corticosteroid (ICS) instead of just dual LAMA/LABA therapy.

In the past many clinicians have relegated triple therapy to a “last ditch resort.” This recommendation makes it clear that triple therapy is appropriate for a broad range of patients with moderate to severe COPD.
 

Recommendation 3

In patients with COPD who are on triple therapy, the inhaled corticosteroid component can be withdrawn if patients have not had an exacerbation within the last year, according to the guideline.

It should be noted that the committee said that the ICS can be withdrawn, not that it necessarily needs to be withdrawn. The data showed that it would be safe to withdraw the ICS, but the data is limited in time to 1 year’s follow-up.
 

Recommendation 4

ATS was not able to make a recommendation for or against ICS as an additive therapy to LAMA/LABA in those without an exacerbation and elevated blood eosinophilia (defined as ≥2% blood eosinophils or >149 cell/mcL). In those with at least one exacerbation and increased blood eosinophilia, the society does recommend addition of ICS to dual LAMA/LABA therapy.

An area of ongoing discussion is at what point in disease severity, before exacerbations occur, might ICS be useful in preventing a first exacerbation. This awaits further studies and evidence.
 

Recommendation 5

In COPD patients with frequent and severe exacerbations who are otherwise medically optimized, the ATS advises against the use of maintenance oral corticosteroid therapy.

It has been known and accepted for years that oral steroids should be avoided if at all possible because they have little benefit and can cause significant harm. The guideline reinforces this.
 

The Bottom Line

Dual LAMA/LABA therapy in symptomatic patients is the standard of care. If a patient has had an exacerbation within the last year, add an ICS to the LAMA/LABA, most conveniently given in the form of triple therapy in one inhaler. Finally, even in refractory COPD, maintenance oral corticosteroids bring more harm than benefit.

Dr. Skolnik is professor of family and community medicine at the Thomas Jefferson University, Philadelphia, and associate director of the Family Medicine Residency Program at Abington (Pa.) Jefferson Health. Dr. Matthews is a second-year resident in the family medicine residency program at Abington Jefferson Health.

References

1. Wells C, Joo MJ. COPD and asthma: Diagnostic accuracy requires spirometry. J Fam Pract. 2019;68(2):76-81.

2. Nici L, Mammen MJ, Charbek E, et al. Pharmacologic management of chronic obstructive pulmonary disease. An official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med. 2020;201(9):e56-69.

Proton pump inhibitors may short-circuit the benefits of atezolizumab (Tecentriq) in patients with advanced/metastatic urothelial cancer, according to a post hoc analysis of 1,360 subjects from two atezolizumab trials.

Proton pump inhibitor (PPI) use was associated with worse overall and progression-free survival among patients on atezolizumab, but there was no such association in a matched cohort receiving chemotherapy alone. In short, concomitant “PPI users had no atezolizumab benefit,” wrote the investigators led by Ashley Hopkins, PhD, a research fellow at Flinders University in Adelaide, Australia.

This is the first time that PPI use has been shown to be an independent prognostic factor for worse survival in this setting with atezolizumab use – but not with chemotherapy, wrote the authors of the study, published online in Clinical Cancer Research.

“PPIs are overused, or inappropriately used, in patients with cancer by up to 50%, seemingly from a perspective that they will cause no harm. The findings from this study suggest that noncritical PPI use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer,” Hopkins said in a press release.

Although about one third of cancer patients use PPIs, there has been growing evidence that the changes they induce in the gut microbiome impact immune checkpoint inhibitor (ICI) effectiveness. A similar study of pooled trial data recently found that PPIs, as well as antibiotics, were associated with worse survival in advanced non–small cell lung cancer treated with atezolizumab, while no such tie was found with chemotherapy (Ann Oncol. 2020;31:525-31. doi: 10.1016/j.annonc.2020.01.006).

The mechanism is uncertain. PPIs have been associated with T-cell tolerance, pharmacokinetic changes, and decreased gut microbiota diversity. High diversity, the investigators noted, has been associated with stronger ICI responses in melanoma. Antibiotics have been associated with similar gut dysbiosis.

“It is increasingly evident that altered gut microbiota impacts homeostasis, immune response, cancer prognosis, and ICI efficacy. The hypothetical basis of [our] research is that PPIs are associated with marked changes to the gut microbiota, driven by both altered stomach acidity and direct compound effects, and these changes may impact immunotherapy,” Hopkins said in an email to Medscape.

The associations with urothelial cancer hadn’t been investigated before, so Hopkins and his team pooled patient-level data from the single-arm IMvigor210 trial of atezolizumab for urothelial cancer and the randomized IMvigor211 trial, which pitted atezolizumab against chemotherapy for the indication.

The investigators compared the outcomes of the 471 subjects who were on a PPI from 30 days before to 30 days after starting atezolizumab with the outcomes of 889 subjects who were not on a PPI. Findings were adjusted for tumor histology and the number of prior treatments and metastases sites, as well as age, body mass index, performance status, and other potential confounders.

PPI use was associated with markedly worse overall survival (hazard ratio, 1.52; 95% confidence interval, 1.27-1.83; P < .001) and progression-free survival (HR, 1.38; 95% CI, 1.18-1.62; P < .001) in patients on atezolizumab but not chemotherapy. PPI use was also associated with worse objective response to the ICI (HR, 0.51; 95% CI, 0.32-0.82; P = .006).

In the randomized trial, atezolizumab seemed to offer no overall survival benefit versus chemotherapy when PPIs were onboard (HR, 1.04; 95% CI, 0.81-1.34), but atezolizumab offered a substantial benefit when PPIs were not in use (HR, 0.69; 95% CI, 0.56-0.84). Findings were consistent when limited to the PD-L1 IC2/3 population.

It seems that PPIs negate “the magnitude of atezolizumab efficacy,” the investigators wrote.

Concomitant antibiotics made the effect of PPIs on overall survival with atezolizumab even worse (antibiotics plus PPI: HR 2.51; 95% CI, 1.12-5.59; versus no antibiotics with PPI: HR, 1.44; 95% CI, 1.19-1.74).

The investigators cautioned that, although “the conducted analyses have been adjusted, there is the potential that PPI use constitutes a surrogate marker for an unfit or immunodeficient patient.” They called for further investigation with other ICIs, cancer types, and chemotherapy regimens.

The dose and compliance with PPI therapy were unknown, but the team noted that over 90% of the PPI subjects were on PPIs for long-term reasons, most commonly gastric protection and gastroesophageal reflux disease (GERD). Omeprazole, pantoprazole, and esomeprazole were the most frequently used. 

There were no significant associations between PPI use and the first occurrence of atezolizumab-induced adverse events.

The study was funded by the National Breast Cancer Foundation (Australia) and the Cancer Council South Australia. Hopkins has disclosed no relevant financial relationships. Multiple study authors have financial ties to industry, including makers of ICIs. The full list can be found with the original article.

This article first appeared on Medscape.com.

Proton pump inhibitors may short-circuit the benefits of atezolizumab (Tecentriq) in patients with advanced/metastatic urothelial cancer, according to a post hoc analysis of 1,360 subjects from two atezolizumab trials.

Proton pump inhibitor (PPI) use was associated with worse overall and progression-free survival among patients on atezolizumab, but there was no such association in a matched cohort receiving chemotherapy alone. In short, concomitant “PPI users had no atezolizumab benefit,” wrote the investigators led by Ashley Hopkins, PhD, a research fellow at Flinders University in Adelaide, Australia.

This is the first time that PPI use has been shown to be an independent prognostic factor for worse survival in this setting with atezolizumab use – but not with chemotherapy, wrote the authors of the study, published online in Clinical Cancer Research.

“PPIs are overused, or inappropriately used, in patients with cancer by up to 50%, seemingly from a perspective that they will cause no harm. The findings from this study suggest that noncritical PPI use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer,” Hopkins said in a press release.

Although about one third of cancer patients use PPIs, there has been growing evidence that the changes they induce in the gut microbiome impact immune checkpoint inhibitor (ICI) effectiveness. A similar study of pooled trial data recently found that PPIs, as well as antibiotics, were associated with worse survival in advanced non–small cell lung cancer treated with atezolizumab, while no such tie was found with chemotherapy (Ann Oncol. 2020;31:525-31. doi: 10.1016/j.annonc.2020.01.006).

The mechanism is uncertain. PPIs have been associated with T-cell tolerance, pharmacokinetic changes, and decreased gut microbiota diversity. High diversity, the investigators noted, has been associated with stronger ICI responses in melanoma. Antibiotics have been associated with similar gut dysbiosis.

“It is increasingly evident that altered gut microbiota impacts homeostasis, immune response, cancer prognosis, and ICI efficacy. The hypothetical basis of [our] research is that PPIs are associated with marked changes to the gut microbiota, driven by both altered stomach acidity and direct compound effects, and these changes may impact immunotherapy,” Hopkins said in an email to Medscape.

The associations with urothelial cancer hadn’t been investigated before, so Hopkins and his team pooled patient-level data from the single-arm IMvigor210 trial of atezolizumab for urothelial cancer and the randomized IMvigor211 trial, which pitted atezolizumab against chemotherapy for the indication.

The investigators compared the outcomes of the 471 subjects who were on a PPI from 30 days before to 30 days after starting atezolizumab with the outcomes of 889 subjects who were not on a PPI. Findings were adjusted for tumor histology and the number of prior treatments and metastases sites, as well as age, body mass index, performance status, and other potential confounders.

PPI use was associated with markedly worse overall survival (hazard ratio, 1.52; 95% confidence interval, 1.27-1.83; P < .001) and progression-free survival (HR, 1.38; 95% CI, 1.18-1.62; P < .001) in patients on atezolizumab but not chemotherapy. PPI use was also associated with worse objective response to the ICI (HR, 0.51; 95% CI, 0.32-0.82; P = .006).

In the randomized trial, atezolizumab seemed to offer no overall survival benefit versus chemotherapy when PPIs were onboard (HR, 1.04; 95% CI, 0.81-1.34), but atezolizumab offered a substantial benefit when PPIs were not in use (HR, 0.69; 95% CI, 0.56-0.84). Findings were consistent when limited to the PD-L1 IC2/3 population.

It seems that PPIs negate “the magnitude of atezolizumab efficacy,” the investigators wrote.

Concomitant antibiotics made the effect of PPIs on overall survival with atezolizumab even worse (antibiotics plus PPI: HR 2.51; 95% CI, 1.12-5.59; versus no antibiotics with PPI: HR, 1.44; 95% CI, 1.19-1.74).

The investigators cautioned that, although “the conducted analyses have been adjusted, there is the potential that PPI use constitutes a surrogate marker for an unfit or immunodeficient patient.” They called for further investigation with other ICIs, cancer types, and chemotherapy regimens.

The dose and compliance with PPI therapy were unknown, but the team noted that over 90% of the PPI subjects were on PPIs for long-term reasons, most commonly gastric protection and gastroesophageal reflux disease (GERD). Omeprazole, pantoprazole, and esomeprazole were the most frequently used. 

There were no significant associations between PPI use and the first occurrence of atezolizumab-induced adverse events.

The study was funded by the National Breast Cancer Foundation (Australia) and the Cancer Council South Australia. Hopkins has disclosed no relevant financial relationships. Multiple study authors have financial ties to industry, including makers of ICIs. The full list can be found with the original article.

This article first appeared on Medscape.com.

Proton pump inhibitors may short-circuit the benefits of atezolizumab (Tecentriq) in patients with advanced/metastatic urothelial cancer, according to a post hoc analysis of 1,360 subjects from two atezolizumab trials.

Proton pump inhibitor (PPI) use was associated with worse overall and progression-free survival among patients on atezolizumab, but there was no such association in a matched cohort receiving chemotherapy alone. In short, concomitant “PPI users had no atezolizumab benefit,” wrote the investigators led by Ashley Hopkins, PhD, a research fellow at Flinders University in Adelaide, Australia.

This is the first time that PPI use has been shown to be an independent prognostic factor for worse survival in this setting with atezolizumab use – but not with chemotherapy, wrote the authors of the study, published online in Clinical Cancer Research.

“PPIs are overused, or inappropriately used, in patients with cancer by up to 50%, seemingly from a perspective that they will cause no harm. The findings from this study suggest that noncritical PPI use needs to be approached very cautiously, particularly when an immune checkpoint inhibitor is being used to treat urothelial cancer,” Hopkins said in a press release.

Although about one third of cancer patients use PPIs, there has been growing evidence that the changes they induce in the gut microbiome impact immune checkpoint inhibitor (ICI) effectiveness. A similar study of pooled trial data recently found that PPIs, as well as antibiotics, were associated with worse survival in advanced non–small cell lung cancer treated with atezolizumab, while no such tie was found with chemotherapy (Ann Oncol. 2020;31:525-31. doi: 10.1016/j.annonc.2020.01.006).

The mechanism is uncertain. PPIs have been associated with T-cell tolerance, pharmacokinetic changes, and decreased gut microbiota diversity. High diversity, the investigators noted, has been associated with stronger ICI responses in melanoma. Antibiotics have been associated with similar gut dysbiosis.

“It is increasingly evident that altered gut microbiota impacts homeostasis, immune response, cancer prognosis, and ICI efficacy. The hypothetical basis of [our] research is that PPIs are associated with marked changes to the gut microbiota, driven by both altered stomach acidity and direct compound effects, and these changes may impact immunotherapy,” Hopkins said in an email to Medscape.

The associations with urothelial cancer hadn’t been investigated before, so Hopkins and his team pooled patient-level data from the single-arm IMvigor210 trial of atezolizumab for urothelial cancer and the randomized IMvigor211 trial, which pitted atezolizumab against chemotherapy for the indication.

The investigators compared the outcomes of the 471 subjects who were on a PPI from 30 days before to 30 days after starting atezolizumab with the outcomes of 889 subjects who were not on a PPI. Findings were adjusted for tumor histology and the number of prior treatments and metastases sites, as well as age, body mass index, performance status, and other potential confounders.

PPI use was associated with markedly worse overall survival (hazard ratio, 1.52; 95% confidence interval, 1.27-1.83; P < .001) and progression-free survival (HR, 1.38; 95% CI, 1.18-1.62; P < .001) in patients on atezolizumab but not chemotherapy. PPI use was also associated with worse objective response to the ICI (HR, 0.51; 95% CI, 0.32-0.82; P = .006).

In the randomized trial, atezolizumab seemed to offer no overall survival benefit versus chemotherapy when PPIs were onboard (HR, 1.04; 95% CI, 0.81-1.34), but atezolizumab offered a substantial benefit when PPIs were not in use (HR, 0.69; 95% CI, 0.56-0.84). Findings were consistent when limited to the PD-L1 IC2/3 population.

It seems that PPIs negate “the magnitude of atezolizumab efficacy,” the investigators wrote.

Concomitant antibiotics made the effect of PPIs on overall survival with atezolizumab even worse (antibiotics plus PPI: HR 2.51; 95% CI, 1.12-5.59; versus no antibiotics with PPI: HR, 1.44; 95% CI, 1.19-1.74).

The investigators cautioned that, although “the conducted analyses have been adjusted, there is the potential that PPI use constitutes a surrogate marker for an unfit or immunodeficient patient.” They called for further investigation with other ICIs, cancer types, and chemotherapy regimens.

The dose and compliance with PPI therapy were unknown, but the team noted that over 90% of the PPI subjects were on PPIs for long-term reasons, most commonly gastric protection and gastroesophageal reflux disease (GERD). Omeprazole, pantoprazole, and esomeprazole were the most frequently used. 

There were no significant associations between PPI use and the first occurrence of atezolizumab-induced adverse events.

The study was funded by the National Breast Cancer Foundation (Australia) and the Cancer Council South Australia. Hopkins has disclosed no relevant financial relationships. Multiple study authors have financial ties to industry, including makers of ICIs. The full list can be found with the original article.

This article first appeared on Medscape.com.