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Analysis affirms that giving birth protects against endometrial cancer
Compared with having no children, the risk reduction for endometrial cancer was 21% with having one child, 38% with having two, and 51% with having three, Gunn-Helen Moen, MSc, PhD, a research fellow at the University of Queensland Institute for Molecular Bioscience in St. Lucia, Australia, and the senior author of the study, said in an email.
In the United States, the prevalence of endometrial cancer is 25.7 per 100,000 women per year, with a lifetime risk of 2.8%.
Multiple observational studies have linked giving birth to risk of endometrial cancer. For the new study, Dr. Moen and her team assessed various risk factors related to ovulation and reproductive function using Mendelian randomization, an epidemiological technique that deploys genetic variants to detect cause-and-effect relationships between potentially modifiable risk factors and health outcomes in observational data.
The researcher published their findings in BMC Medicine.
Leverage genetic data
The study used detailed genetic and health data from the UK Biobank, a databank with more than half a million participants. Genetic variants related to some of the risk factors were used to assess whether the variants make people more likely to develop endometrial cancer.
Genomewide significant single-nucleotide polymorphisms (SNPs) related to number of live births, age at menopause and menarche, and body mass index (BMI) had been identified in previous studies, the researchers reported. They conducted genomewide association analyses of the databank to identify SNPs associated with years ovulating, years using the contraceptive pill, and age at last live birth.
The MR analysis showed a potential causal effect for the number of live births (inverse variance–weighted odds ratio, 0.537) and number of years ovulating (IVW OR, 1.051), in addition to known risk factors of BMI, age at menarche, and age at menopause.
A further multivariable MR analysis showed that number of births had a negative causal effect on endometrial cancer risk (OR, 0.783), independent of the causal effect of known risk factors such as BMI, age at menarche and age at menopause.
Reported limitations included being unable to perform MR analyses on some factors, such as oral contraceptive use, because of a lack of valid genetic instruments. The researchers could not perform an age adjustment at diagnosis because of a lack of data.
In addition, the genetic data came exclusively from White women of European ancestry.
‘A personal choice’
Other investigators have hypothesized that the protective effect of childbirth may be caused by shedding of malignant and premalignant endometrial cells during and after childbirth and exposure to high levels of progesterone in late stages of pregnancy, the research team noted.
Dr. Moen said, based on the results, physicians might consider number of childbirths in assessing a patient’s risk of endometrial cancer.
However, Britton Trabert, MSPH, MS, PhD, an epidemiologist and assistant professor of obstetrics and gynecology at the University of Utah, Salt Lake City, said it’s unlikely the findings will affect clinical practice given that they “largely replicate well-characterized endometrial cancer risk associations.”
“Pregnancy and childbirth are a personal choice and is not largely regarded as a modifiable factor for cancer prevention,” said Dr. Trabert, who was not involved in the study.
The study’s investigators reported funding from the governments of Australia, Norway and the United Kingdom and the British Heart Foundation. No financial conflicts of interest were reported. Dr. Trabert reported no relevant financial interests.
Compared with having no children, the risk reduction for endometrial cancer was 21% with having one child, 38% with having two, and 51% with having three, Gunn-Helen Moen, MSc, PhD, a research fellow at the University of Queensland Institute for Molecular Bioscience in St. Lucia, Australia, and the senior author of the study, said in an email.
In the United States, the prevalence of endometrial cancer is 25.7 per 100,000 women per year, with a lifetime risk of 2.8%.
Multiple observational studies have linked giving birth to risk of endometrial cancer. For the new study, Dr. Moen and her team assessed various risk factors related to ovulation and reproductive function using Mendelian randomization, an epidemiological technique that deploys genetic variants to detect cause-and-effect relationships between potentially modifiable risk factors and health outcomes in observational data.
The researcher published their findings in BMC Medicine.
Leverage genetic data
The study used detailed genetic and health data from the UK Biobank, a databank with more than half a million participants. Genetic variants related to some of the risk factors were used to assess whether the variants make people more likely to develop endometrial cancer.
Genomewide significant single-nucleotide polymorphisms (SNPs) related to number of live births, age at menopause and menarche, and body mass index (BMI) had been identified in previous studies, the researchers reported. They conducted genomewide association analyses of the databank to identify SNPs associated with years ovulating, years using the contraceptive pill, and age at last live birth.
The MR analysis showed a potential causal effect for the number of live births (inverse variance–weighted odds ratio, 0.537) and number of years ovulating (IVW OR, 1.051), in addition to known risk factors of BMI, age at menarche, and age at menopause.
A further multivariable MR analysis showed that number of births had a negative causal effect on endometrial cancer risk (OR, 0.783), independent of the causal effect of known risk factors such as BMI, age at menarche and age at menopause.
Reported limitations included being unable to perform MR analyses on some factors, such as oral contraceptive use, because of a lack of valid genetic instruments. The researchers could not perform an age adjustment at diagnosis because of a lack of data.
In addition, the genetic data came exclusively from White women of European ancestry.
‘A personal choice’
Other investigators have hypothesized that the protective effect of childbirth may be caused by shedding of malignant and premalignant endometrial cells during and after childbirth and exposure to high levels of progesterone in late stages of pregnancy, the research team noted.
Dr. Moen said, based on the results, physicians might consider number of childbirths in assessing a patient’s risk of endometrial cancer.
However, Britton Trabert, MSPH, MS, PhD, an epidemiologist and assistant professor of obstetrics and gynecology at the University of Utah, Salt Lake City, said it’s unlikely the findings will affect clinical practice given that they “largely replicate well-characterized endometrial cancer risk associations.”
“Pregnancy and childbirth are a personal choice and is not largely regarded as a modifiable factor for cancer prevention,” said Dr. Trabert, who was not involved in the study.
The study’s investigators reported funding from the governments of Australia, Norway and the United Kingdom and the British Heart Foundation. No financial conflicts of interest were reported. Dr. Trabert reported no relevant financial interests.
Compared with having no children, the risk reduction for endometrial cancer was 21% with having one child, 38% with having two, and 51% with having three, Gunn-Helen Moen, MSc, PhD, a research fellow at the University of Queensland Institute for Molecular Bioscience in St. Lucia, Australia, and the senior author of the study, said in an email.
In the United States, the prevalence of endometrial cancer is 25.7 per 100,000 women per year, with a lifetime risk of 2.8%.
Multiple observational studies have linked giving birth to risk of endometrial cancer. For the new study, Dr. Moen and her team assessed various risk factors related to ovulation and reproductive function using Mendelian randomization, an epidemiological technique that deploys genetic variants to detect cause-and-effect relationships between potentially modifiable risk factors and health outcomes in observational data.
The researcher published their findings in BMC Medicine.
Leverage genetic data
The study used detailed genetic and health data from the UK Biobank, a databank with more than half a million participants. Genetic variants related to some of the risk factors were used to assess whether the variants make people more likely to develop endometrial cancer.
Genomewide significant single-nucleotide polymorphisms (SNPs) related to number of live births, age at menopause and menarche, and body mass index (BMI) had been identified in previous studies, the researchers reported. They conducted genomewide association analyses of the databank to identify SNPs associated with years ovulating, years using the contraceptive pill, and age at last live birth.
The MR analysis showed a potential causal effect for the number of live births (inverse variance–weighted odds ratio, 0.537) and number of years ovulating (IVW OR, 1.051), in addition to known risk factors of BMI, age at menarche, and age at menopause.
A further multivariable MR analysis showed that number of births had a negative causal effect on endometrial cancer risk (OR, 0.783), independent of the causal effect of known risk factors such as BMI, age at menarche and age at menopause.
Reported limitations included being unable to perform MR analyses on some factors, such as oral contraceptive use, because of a lack of valid genetic instruments. The researchers could not perform an age adjustment at diagnosis because of a lack of data.
In addition, the genetic data came exclusively from White women of European ancestry.
‘A personal choice’
Other investigators have hypothesized that the protective effect of childbirth may be caused by shedding of malignant and premalignant endometrial cells during and after childbirth and exposure to high levels of progesterone in late stages of pregnancy, the research team noted.
Dr. Moen said, based on the results, physicians might consider number of childbirths in assessing a patient’s risk of endometrial cancer.
However, Britton Trabert, MSPH, MS, PhD, an epidemiologist and assistant professor of obstetrics and gynecology at the University of Utah, Salt Lake City, said it’s unlikely the findings will affect clinical practice given that they “largely replicate well-characterized endometrial cancer risk associations.”
“Pregnancy and childbirth are a personal choice and is not largely regarded as a modifiable factor for cancer prevention,” said Dr. Trabert, who was not involved in the study.
The study’s investigators reported funding from the governments of Australia, Norway and the United Kingdom and the British Heart Foundation. No financial conflicts of interest were reported. Dr. Trabert reported no relevant financial interests.
FROM BMC MEDICINE
‘Key cause’ of type 2 diabetes identified
Understanding of the key mechanisms underlying the progression of type 2 diabetes has been advanced by new research from Oxford (England) University suggesting potential ways to “slow the seemingly inexorable decline in beta-cell function in T2D”.
The study in mice elucidated a “key cause” of T2D by showing that
Scientists already knew that chronic hyperglycemia leads to a progressive decline in beta-cell function and, conversely, that the failure of pancreatic beta-cells to produce insulin results in chronically elevated blood glucose. However, the exact cause of beta-cell failure in T2D has remained unclear. T2D typically presents in later adult life, and by the time of diagnosis as much as 50% of beta-cell function has been lost.
In the United Kingdom there are nearly 5 million people diagnosed with T2D, which costs the National Health Service some £10 billion annually.
Glucose metabolites, rather than glucose itself, drives failure of cells to release insulin
The new study, published in Nature Communications, used both an animal model of diabetes and in vitro culture of beta-cells in a high glucose medium. In both cases the researchers showed, for the first time, that it is glucose metabolites, rather than glucose itself, that drives the failure of beta-cells to release insulin and is key to the progression of type 2 diabetes.
Senior researcher Frances Ashcroft, PhD, of the department of physiology, anatomy and genetics at the University of Oxford said: “This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.”
Blood glucose concentration is controlled within narrow limits, the team explained. When it is too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. However chronic elevation of blood glucose leads to the serious complications found in poorly controlled diabetes, such as retinopathy, nephropathy, peripheral neuropathy, and cardiac disease. Insulin, released from pancreatic beta-cells when blood glucose levels rise, is the only hormone that can lower the blood glucose concentration, and insufficient secretion results in diabetes. In T2D, the beta-cells are still present (unlike in T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired.
Vicious spiral of hyperglycemia and beta-cell damage
Previous work by the same team had shown that chronic hyperglycemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise. This suggested that “prolonged hyperglycemia sets off a vicious spiral in which an increase in blood glucose leads to beta-cell damage and less insulin secretion - which causes an even greater increase in blood glucose and a further decline in beta-cell function,” the team explained.
Lead researcher Elizabeth Haythorne, PhD, said: “We realized that we next needed to understand how glucose damages beta-cell function, so we can think about how we might stop it and so slow the seemingly inexorable decline in beta-cell function in T2D.”
In the new study, they showed that altered glycolysis in T2D occurs, in part, through marked up-regulation of mammalian target of rapamycin complex 1 (mTORC1), a protein complex involved in control of cell growth, dysregulation of which underlies a variety of human diseases, including diabetes. Up-regulation of mTORC1 led to changes in metabolic gene expression, oxidative phosphorylation and insulin secretion. Furthermore, they demonstrated that reducing the rate at which glucose is metabolized and at which its metabolites build up could prevent the effects of chronic hyperglycemia and the ensuing beta-cell failure.
“High blood glucose levels cause an increased rate of glucose metabolism in the beta-cell, which leads to a metabolic bottleneck and the pooling of upstream metabolites,” the team said. “These metabolites switch off the insulin gene, so less insulin is made, as well as switching off numerous genes involved in metabolism and stimulus-secretion coupling. Consequently, the beta-cells become glucose blind and no longer respond to changes in blood glucose with insulin secretion.”
Blocking metabolic enzyme could maintain insulin secretion
The team attempted to block the first step in glucose metabolism, and therefore prevent the gene changes from taking place, by blocking the enzyme glucokinase, which regulates the process. They found that this could maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycemia.
“Our results support the idea that progressive impairment of beta-cell metabolism, induced by increasing hyperglycemia, speeds T2D development, and suggest that reducing glycolysis at the level of glucokinase may slow this progression,” they said.
Dr. Ashcroft said: “This is potentially a useful way to try to prevent beta-cell decline in diabetes. Because glucose metabolism normally stimulates insulin secretion, it was previously hypothesized that increasing glucose metabolism would enhance insulin secretion in T2D and glucokinase activators were trialled, with varying results.
“Our data suggests that glucokinase activators could have an adverse effect and, somewhat counter-intuitively, that a glucokinase inhibitor might be a better strategy to treat T2D. Of course, it would be important to reduce glucose flux in T2D to that found in people without diabetes – and no further. But there is a very long way to go before we can tell if this approach would be useful for treating beta-cell decline in T2D.
“In the meantime, the key message from our study if you have type 2 diabetes is that it is important to keep your blood glucose well controlled.”
This study was funded by the UK Medical Research Council, the Biotechnology and Biological Sciences Research Council, the John Fell Fund, and the Nuffield Benefaction for Medicine/Wellcome Institutional Strategic Support Fund. The authors declared no competing interests.
A version of this article first appeared on Medscape UK.
Understanding of the key mechanisms underlying the progression of type 2 diabetes has been advanced by new research from Oxford (England) University suggesting potential ways to “slow the seemingly inexorable decline in beta-cell function in T2D”.
The study in mice elucidated a “key cause” of T2D by showing that
Scientists already knew that chronic hyperglycemia leads to a progressive decline in beta-cell function and, conversely, that the failure of pancreatic beta-cells to produce insulin results in chronically elevated blood glucose. However, the exact cause of beta-cell failure in T2D has remained unclear. T2D typically presents in later adult life, and by the time of diagnosis as much as 50% of beta-cell function has been lost.
In the United Kingdom there are nearly 5 million people diagnosed with T2D, which costs the National Health Service some £10 billion annually.
Glucose metabolites, rather than glucose itself, drives failure of cells to release insulin
The new study, published in Nature Communications, used both an animal model of diabetes and in vitro culture of beta-cells in a high glucose medium. In both cases the researchers showed, for the first time, that it is glucose metabolites, rather than glucose itself, that drives the failure of beta-cells to release insulin and is key to the progression of type 2 diabetes.
Senior researcher Frances Ashcroft, PhD, of the department of physiology, anatomy and genetics at the University of Oxford said: “This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.”
Blood glucose concentration is controlled within narrow limits, the team explained. When it is too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. However chronic elevation of blood glucose leads to the serious complications found in poorly controlled diabetes, such as retinopathy, nephropathy, peripheral neuropathy, and cardiac disease. Insulin, released from pancreatic beta-cells when blood glucose levels rise, is the only hormone that can lower the blood glucose concentration, and insufficient secretion results in diabetes. In T2D, the beta-cells are still present (unlike in T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired.
Vicious spiral of hyperglycemia and beta-cell damage
Previous work by the same team had shown that chronic hyperglycemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise. This suggested that “prolonged hyperglycemia sets off a vicious spiral in which an increase in blood glucose leads to beta-cell damage and less insulin secretion - which causes an even greater increase in blood glucose and a further decline in beta-cell function,” the team explained.
Lead researcher Elizabeth Haythorne, PhD, said: “We realized that we next needed to understand how glucose damages beta-cell function, so we can think about how we might stop it and so slow the seemingly inexorable decline in beta-cell function in T2D.”
In the new study, they showed that altered glycolysis in T2D occurs, in part, through marked up-regulation of mammalian target of rapamycin complex 1 (mTORC1), a protein complex involved in control of cell growth, dysregulation of which underlies a variety of human diseases, including diabetes. Up-regulation of mTORC1 led to changes in metabolic gene expression, oxidative phosphorylation and insulin secretion. Furthermore, they demonstrated that reducing the rate at which glucose is metabolized and at which its metabolites build up could prevent the effects of chronic hyperglycemia and the ensuing beta-cell failure.
“High blood glucose levels cause an increased rate of glucose metabolism in the beta-cell, which leads to a metabolic bottleneck and the pooling of upstream metabolites,” the team said. “These metabolites switch off the insulin gene, so less insulin is made, as well as switching off numerous genes involved in metabolism and stimulus-secretion coupling. Consequently, the beta-cells become glucose blind and no longer respond to changes in blood glucose with insulin secretion.”
Blocking metabolic enzyme could maintain insulin secretion
The team attempted to block the first step in glucose metabolism, and therefore prevent the gene changes from taking place, by blocking the enzyme glucokinase, which regulates the process. They found that this could maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycemia.
“Our results support the idea that progressive impairment of beta-cell metabolism, induced by increasing hyperglycemia, speeds T2D development, and suggest that reducing glycolysis at the level of glucokinase may slow this progression,” they said.
Dr. Ashcroft said: “This is potentially a useful way to try to prevent beta-cell decline in diabetes. Because glucose metabolism normally stimulates insulin secretion, it was previously hypothesized that increasing glucose metabolism would enhance insulin secretion in T2D and glucokinase activators were trialled, with varying results.
“Our data suggests that glucokinase activators could have an adverse effect and, somewhat counter-intuitively, that a glucokinase inhibitor might be a better strategy to treat T2D. Of course, it would be important to reduce glucose flux in T2D to that found in people without diabetes – and no further. But there is a very long way to go before we can tell if this approach would be useful for treating beta-cell decline in T2D.
“In the meantime, the key message from our study if you have type 2 diabetes is that it is important to keep your blood glucose well controlled.”
This study was funded by the UK Medical Research Council, the Biotechnology and Biological Sciences Research Council, the John Fell Fund, and the Nuffield Benefaction for Medicine/Wellcome Institutional Strategic Support Fund. The authors declared no competing interests.
A version of this article first appeared on Medscape UK.
Understanding of the key mechanisms underlying the progression of type 2 diabetes has been advanced by new research from Oxford (England) University suggesting potential ways to “slow the seemingly inexorable decline in beta-cell function in T2D”.
The study in mice elucidated a “key cause” of T2D by showing that
Scientists already knew that chronic hyperglycemia leads to a progressive decline in beta-cell function and, conversely, that the failure of pancreatic beta-cells to produce insulin results in chronically elevated blood glucose. However, the exact cause of beta-cell failure in T2D has remained unclear. T2D typically presents in later adult life, and by the time of diagnosis as much as 50% of beta-cell function has been lost.
In the United Kingdom there are nearly 5 million people diagnosed with T2D, which costs the National Health Service some £10 billion annually.
Glucose metabolites, rather than glucose itself, drives failure of cells to release insulin
The new study, published in Nature Communications, used both an animal model of diabetes and in vitro culture of beta-cells in a high glucose medium. In both cases the researchers showed, for the first time, that it is glucose metabolites, rather than glucose itself, that drives the failure of beta-cells to release insulin and is key to the progression of type 2 diabetes.
Senior researcher Frances Ashcroft, PhD, of the department of physiology, anatomy and genetics at the University of Oxford said: “This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.”
Blood glucose concentration is controlled within narrow limits, the team explained. When it is too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. However chronic elevation of blood glucose leads to the serious complications found in poorly controlled diabetes, such as retinopathy, nephropathy, peripheral neuropathy, and cardiac disease. Insulin, released from pancreatic beta-cells when blood glucose levels rise, is the only hormone that can lower the blood glucose concentration, and insufficient secretion results in diabetes. In T2D, the beta-cells are still present (unlike in T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired.
Vicious spiral of hyperglycemia and beta-cell damage
Previous work by the same team had shown that chronic hyperglycemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise. This suggested that “prolonged hyperglycemia sets off a vicious spiral in which an increase in blood glucose leads to beta-cell damage and less insulin secretion - which causes an even greater increase in blood glucose and a further decline in beta-cell function,” the team explained.
Lead researcher Elizabeth Haythorne, PhD, said: “We realized that we next needed to understand how glucose damages beta-cell function, so we can think about how we might stop it and so slow the seemingly inexorable decline in beta-cell function in T2D.”
In the new study, they showed that altered glycolysis in T2D occurs, in part, through marked up-regulation of mammalian target of rapamycin complex 1 (mTORC1), a protein complex involved in control of cell growth, dysregulation of which underlies a variety of human diseases, including diabetes. Up-regulation of mTORC1 led to changes in metabolic gene expression, oxidative phosphorylation and insulin secretion. Furthermore, they demonstrated that reducing the rate at which glucose is metabolized and at which its metabolites build up could prevent the effects of chronic hyperglycemia and the ensuing beta-cell failure.
“High blood glucose levels cause an increased rate of glucose metabolism in the beta-cell, which leads to a metabolic bottleneck and the pooling of upstream metabolites,” the team said. “These metabolites switch off the insulin gene, so less insulin is made, as well as switching off numerous genes involved in metabolism and stimulus-secretion coupling. Consequently, the beta-cells become glucose blind and no longer respond to changes in blood glucose with insulin secretion.”
Blocking metabolic enzyme could maintain insulin secretion
The team attempted to block the first step in glucose metabolism, and therefore prevent the gene changes from taking place, by blocking the enzyme glucokinase, which regulates the process. They found that this could maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycemia.
“Our results support the idea that progressive impairment of beta-cell metabolism, induced by increasing hyperglycemia, speeds T2D development, and suggest that reducing glycolysis at the level of glucokinase may slow this progression,” they said.
Dr. Ashcroft said: “This is potentially a useful way to try to prevent beta-cell decline in diabetes. Because glucose metabolism normally stimulates insulin secretion, it was previously hypothesized that increasing glucose metabolism would enhance insulin secretion in T2D and glucokinase activators were trialled, with varying results.
“Our data suggests that glucokinase activators could have an adverse effect and, somewhat counter-intuitively, that a glucokinase inhibitor might be a better strategy to treat T2D. Of course, it would be important to reduce glucose flux in T2D to that found in people without diabetes – and no further. But there is a very long way to go before we can tell if this approach would be useful for treating beta-cell decline in T2D.
“In the meantime, the key message from our study if you have type 2 diabetes is that it is important to keep your blood glucose well controlled.”
This study was funded by the UK Medical Research Council, the Biotechnology and Biological Sciences Research Council, the John Fell Fund, and the Nuffield Benefaction for Medicine/Wellcome Institutional Strategic Support Fund. The authors declared no competing interests.
A version of this article first appeared on Medscape UK.
FROM NATURE COMMUNICATIONS
Infant anaphylaxis: Study characterizes symptoms, treatment
LOUISVILLE, KY. – , research findings indicate.
Given that early administration of epinephrine can be potentially lifesaving for infants with anaphylaxis, the study highlighted the real-world successes in increased uptake of treatment in this vulnerable patient population.
Most infants in the study who presented to the ED and received epinephrine were able to be discharged home after just a few hours, with only 1 out of 10 requiring hospitalization.
The study also reported that most symptoms were in the skin/mucosal, gastrointestinal, respiratory, and cardiovascular (CV) systems, providing improved characterization of anaphylaxis symptoms in the infant population.
Nearly “all episodes were triggered by food – especially egg, peanut, milk, and cashew,” commented Colleen Shannon, MD, a pediatrician at Children’s Hospital of Philadelphia, who presented the research findings at the annual meeting of the American College of Allergy, Asthma, and Immunology.
Dr. Shannon noted that despite previous research demonstrating age-based differences in the presentation of anaphylaxis, the symptomatology of anaphylaxis in infants has not been robustly characterized. Better characterization of anaphylaxis in infants with allergies may help ensure earlier and more accurate diagnosis and management, she said.
For the study, the researchers performed a retrospective chart review of 169 patients between 0 and 24 months of age (mean age, 1.0 years) who presented to the emergency department of a pediatric tertiary referral center between 2019 and 2022.
All patients in the study met diagnostic criteria for anaphylaxis. The investigators used the medical records of patients to evaluate for demographics, as well as presenting symptoms and treatment.
More than half (56.2%) of infants in the study were 12 months of age or younger, and 64.5% were male.
Nearly all (96.5%) anaphylaxis episodes presenting to the ED were triggered by food. The most common foods triggering these episodes were egg (26.6%), peanut (25.4%), milk (13.6%), and cashew (10.1%).
Most symptoms involved the skin/mucosal (97.6%) and GI (74.6%) systems, followed by respiratory (56.8%) and CV (34.3%) systems. Isolated tachycardia was recorded in 84.5% of patients with CV-related symptoms.
Epinephrine was administered to 86.4% of infants who presented to the ED with anaphylaxis. Nearly a third (30.1%) of these infants received epinephrine before arriving to the ED, and 9.5% required more than 1 dose.
The researchers also found that 10.1% of patients required hospital admission, but none had symptoms severe enough to require intensive care.
Jennifer Hoffmann, MD, an emergency medicine physician at the Lurie Children’s Hospital of Chicago, told this news organization that while characterizing anaphylaxis symptoms is relevant for clinicians, it also remains vitally important “to teach parents of infants how to recognize the signs of anaphylaxis, particularly as they begin to introduce new foods,” to ensure timely treatment.
She added that since most infants in the study improved after a single dose of epinephrine, most infants presenting to the ED with anaphylaxis can therefore be safely discharged home after only a brief period of observation. “That is, age alone should not be a reason for admission,” explained Dr. Hoffmann, who wasn’t involved in the research study.
The study was independently supported. Dr. Shannon and Dr. Hoffmann report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
LOUISVILLE, KY. – , research findings indicate.
Given that early administration of epinephrine can be potentially lifesaving for infants with anaphylaxis, the study highlighted the real-world successes in increased uptake of treatment in this vulnerable patient population.
Most infants in the study who presented to the ED and received epinephrine were able to be discharged home after just a few hours, with only 1 out of 10 requiring hospitalization.
The study also reported that most symptoms were in the skin/mucosal, gastrointestinal, respiratory, and cardiovascular (CV) systems, providing improved characterization of anaphylaxis symptoms in the infant population.
Nearly “all episodes were triggered by food – especially egg, peanut, milk, and cashew,” commented Colleen Shannon, MD, a pediatrician at Children’s Hospital of Philadelphia, who presented the research findings at the annual meeting of the American College of Allergy, Asthma, and Immunology.
Dr. Shannon noted that despite previous research demonstrating age-based differences in the presentation of anaphylaxis, the symptomatology of anaphylaxis in infants has not been robustly characterized. Better characterization of anaphylaxis in infants with allergies may help ensure earlier and more accurate diagnosis and management, she said.
For the study, the researchers performed a retrospective chart review of 169 patients between 0 and 24 months of age (mean age, 1.0 years) who presented to the emergency department of a pediatric tertiary referral center between 2019 and 2022.
All patients in the study met diagnostic criteria for anaphylaxis. The investigators used the medical records of patients to evaluate for demographics, as well as presenting symptoms and treatment.
More than half (56.2%) of infants in the study were 12 months of age or younger, and 64.5% were male.
Nearly all (96.5%) anaphylaxis episodes presenting to the ED were triggered by food. The most common foods triggering these episodes were egg (26.6%), peanut (25.4%), milk (13.6%), and cashew (10.1%).
Most symptoms involved the skin/mucosal (97.6%) and GI (74.6%) systems, followed by respiratory (56.8%) and CV (34.3%) systems. Isolated tachycardia was recorded in 84.5% of patients with CV-related symptoms.
Epinephrine was administered to 86.4% of infants who presented to the ED with anaphylaxis. Nearly a third (30.1%) of these infants received epinephrine before arriving to the ED, and 9.5% required more than 1 dose.
The researchers also found that 10.1% of patients required hospital admission, but none had symptoms severe enough to require intensive care.
Jennifer Hoffmann, MD, an emergency medicine physician at the Lurie Children’s Hospital of Chicago, told this news organization that while characterizing anaphylaxis symptoms is relevant for clinicians, it also remains vitally important “to teach parents of infants how to recognize the signs of anaphylaxis, particularly as they begin to introduce new foods,” to ensure timely treatment.
She added that since most infants in the study improved after a single dose of epinephrine, most infants presenting to the ED with anaphylaxis can therefore be safely discharged home after only a brief period of observation. “That is, age alone should not be a reason for admission,” explained Dr. Hoffmann, who wasn’t involved in the research study.
The study was independently supported. Dr. Shannon and Dr. Hoffmann report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
LOUISVILLE, KY. – , research findings indicate.
Given that early administration of epinephrine can be potentially lifesaving for infants with anaphylaxis, the study highlighted the real-world successes in increased uptake of treatment in this vulnerable patient population.
Most infants in the study who presented to the ED and received epinephrine were able to be discharged home after just a few hours, with only 1 out of 10 requiring hospitalization.
The study also reported that most symptoms were in the skin/mucosal, gastrointestinal, respiratory, and cardiovascular (CV) systems, providing improved characterization of anaphylaxis symptoms in the infant population.
Nearly “all episodes were triggered by food – especially egg, peanut, milk, and cashew,” commented Colleen Shannon, MD, a pediatrician at Children’s Hospital of Philadelphia, who presented the research findings at the annual meeting of the American College of Allergy, Asthma, and Immunology.
Dr. Shannon noted that despite previous research demonstrating age-based differences in the presentation of anaphylaxis, the symptomatology of anaphylaxis in infants has not been robustly characterized. Better characterization of anaphylaxis in infants with allergies may help ensure earlier and more accurate diagnosis and management, she said.
For the study, the researchers performed a retrospective chart review of 169 patients between 0 and 24 months of age (mean age, 1.0 years) who presented to the emergency department of a pediatric tertiary referral center between 2019 and 2022.
All patients in the study met diagnostic criteria for anaphylaxis. The investigators used the medical records of patients to evaluate for demographics, as well as presenting symptoms and treatment.
More than half (56.2%) of infants in the study were 12 months of age or younger, and 64.5% were male.
Nearly all (96.5%) anaphylaxis episodes presenting to the ED were triggered by food. The most common foods triggering these episodes were egg (26.6%), peanut (25.4%), milk (13.6%), and cashew (10.1%).
Most symptoms involved the skin/mucosal (97.6%) and GI (74.6%) systems, followed by respiratory (56.8%) and CV (34.3%) systems. Isolated tachycardia was recorded in 84.5% of patients with CV-related symptoms.
Epinephrine was administered to 86.4% of infants who presented to the ED with anaphylaxis. Nearly a third (30.1%) of these infants received epinephrine before arriving to the ED, and 9.5% required more than 1 dose.
The researchers also found that 10.1% of patients required hospital admission, but none had symptoms severe enough to require intensive care.
Jennifer Hoffmann, MD, an emergency medicine physician at the Lurie Children’s Hospital of Chicago, told this news organization that while characterizing anaphylaxis symptoms is relevant for clinicians, it also remains vitally important “to teach parents of infants how to recognize the signs of anaphylaxis, particularly as they begin to introduce new foods,” to ensure timely treatment.
She added that since most infants in the study improved after a single dose of epinephrine, most infants presenting to the ED with anaphylaxis can therefore be safely discharged home after only a brief period of observation. “That is, age alone should not be a reason for admission,” explained Dr. Hoffmann, who wasn’t involved in the research study.
The study was independently supported. Dr. Shannon and Dr. Hoffmann report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ACAAI
ED visits for kids with suicidal thoughts increasing: Study
A new study sheds light on the escalating youth suicide crisis, revealing that emergency room visits for suicidal thoughts among kids and teens steeply increased even before the start of the COVID-19 pandemic.
Emergency room visits for “suicidal ideation” (or suicidal thoughts) among 5- to 19-year-olds increased 59% from 2016 to 2021, and hospitalizations rose 57% from fall 2019 to the fall of 2020, according to the study published in Pediatrics.
“A lot of people have talked about mental health problems in youth during the pandemic, but it was happening before the pandemic,” said author Audrey Brewer, MD, MPH, in a news release from the Ann and Robert H. Lurie Children’s Hospital of Chicago. “This has been an issue for so long, and it’s getting worse.”
Researchers looked at data for 81,105 emergency room visits across 205 Illinois hospitals from 2016 to 2021 for kids between the ages of 5 and 19.
The researchers found “there was a very sharp spike in fall 2019, followed by a similar spike during the pandemic fall of 2020, with the highest number of monthly visits during October 2020,” the authors said. “Youth aged 14-17 years had the highest frequency of [suicidal ideation emergency room] monthly visits, with visits in this group greater than the other age groups combined.”
Last year, the Centers for Disease Control and Prevention announced that suicide is the second leading cause of death among 10- to 19-year-olds.
The new research is being called a benchmark because it evaluates emergency room data for suicidal thoughts – a critical point of care for serving youths’ mental health needs. The data showed that providers were increasingly likely to list suicidal thoughts as the main diagnosis.
“Suicidal ideation can be thought about as two types: actively thinking about suicide or having thoughts, but not having a plan,” Dr. Brewer said in the news release. “That could be the difference in why someone might get admitted to the hospital.”
The researchers hypothesize that care in 2019 (when the initial spike occurred) was delayed in the early days of the pandemic, and that delay possibly contributed to the increase in providers identifying suicidal ideation as the main diagnosis.
“The early pandemic period coincided with constrained access to pediatric mental health services through schools, pediatric primary care homes, and mental health clinics for many children and their families,” the authors wrote. “The proportion of child mental health visits increased relative to other types as patients avoided ED visits during the early wave of the COVID-19 pandemic. Thus, the increase in hospitalizations during fall 2020 may reflect patients’ deferring care until symptoms became even more severe.”
Other health care scholars agreed the study spurred questions about whether the pandemic was truly the source of the crisis.
“Was it the pandemic that exacerbated the increase or is this a growing trend?” wrote Lisa M. Horowitz, PhD, MPH, and Jeffrey A. Bridge, PhD, in a commentary published along with the study. “These rising rates underscore the worsening mental health crisis for youth, as noted by the 2022 Surgeon General report and several youth mental health organizations.”
A version of this article first appeared on WebMD.com.
A new study sheds light on the escalating youth suicide crisis, revealing that emergency room visits for suicidal thoughts among kids and teens steeply increased even before the start of the COVID-19 pandemic.
Emergency room visits for “suicidal ideation” (or suicidal thoughts) among 5- to 19-year-olds increased 59% from 2016 to 2021, and hospitalizations rose 57% from fall 2019 to the fall of 2020, according to the study published in Pediatrics.
“A lot of people have talked about mental health problems in youth during the pandemic, but it was happening before the pandemic,” said author Audrey Brewer, MD, MPH, in a news release from the Ann and Robert H. Lurie Children’s Hospital of Chicago. “This has been an issue for so long, and it’s getting worse.”
Researchers looked at data for 81,105 emergency room visits across 205 Illinois hospitals from 2016 to 2021 for kids between the ages of 5 and 19.
The researchers found “there was a very sharp spike in fall 2019, followed by a similar spike during the pandemic fall of 2020, with the highest number of monthly visits during October 2020,” the authors said. “Youth aged 14-17 years had the highest frequency of [suicidal ideation emergency room] monthly visits, with visits in this group greater than the other age groups combined.”
Last year, the Centers for Disease Control and Prevention announced that suicide is the second leading cause of death among 10- to 19-year-olds.
The new research is being called a benchmark because it evaluates emergency room data for suicidal thoughts – a critical point of care for serving youths’ mental health needs. The data showed that providers were increasingly likely to list suicidal thoughts as the main diagnosis.
“Suicidal ideation can be thought about as two types: actively thinking about suicide or having thoughts, but not having a plan,” Dr. Brewer said in the news release. “That could be the difference in why someone might get admitted to the hospital.”
The researchers hypothesize that care in 2019 (when the initial spike occurred) was delayed in the early days of the pandemic, and that delay possibly contributed to the increase in providers identifying suicidal ideation as the main diagnosis.
“The early pandemic period coincided with constrained access to pediatric mental health services through schools, pediatric primary care homes, and mental health clinics for many children and their families,” the authors wrote. “The proportion of child mental health visits increased relative to other types as patients avoided ED visits during the early wave of the COVID-19 pandemic. Thus, the increase in hospitalizations during fall 2020 may reflect patients’ deferring care until symptoms became even more severe.”
Other health care scholars agreed the study spurred questions about whether the pandemic was truly the source of the crisis.
“Was it the pandemic that exacerbated the increase or is this a growing trend?” wrote Lisa M. Horowitz, PhD, MPH, and Jeffrey A. Bridge, PhD, in a commentary published along with the study. “These rising rates underscore the worsening mental health crisis for youth, as noted by the 2022 Surgeon General report and several youth mental health organizations.”
A version of this article first appeared on WebMD.com.
A new study sheds light on the escalating youth suicide crisis, revealing that emergency room visits for suicidal thoughts among kids and teens steeply increased even before the start of the COVID-19 pandemic.
Emergency room visits for “suicidal ideation” (or suicidal thoughts) among 5- to 19-year-olds increased 59% from 2016 to 2021, and hospitalizations rose 57% from fall 2019 to the fall of 2020, according to the study published in Pediatrics.
“A lot of people have talked about mental health problems in youth during the pandemic, but it was happening before the pandemic,” said author Audrey Brewer, MD, MPH, in a news release from the Ann and Robert H. Lurie Children’s Hospital of Chicago. “This has been an issue for so long, and it’s getting worse.”
Researchers looked at data for 81,105 emergency room visits across 205 Illinois hospitals from 2016 to 2021 for kids between the ages of 5 and 19.
The researchers found “there was a very sharp spike in fall 2019, followed by a similar spike during the pandemic fall of 2020, with the highest number of monthly visits during October 2020,” the authors said. “Youth aged 14-17 years had the highest frequency of [suicidal ideation emergency room] monthly visits, with visits in this group greater than the other age groups combined.”
Last year, the Centers for Disease Control and Prevention announced that suicide is the second leading cause of death among 10- to 19-year-olds.
The new research is being called a benchmark because it evaluates emergency room data for suicidal thoughts – a critical point of care for serving youths’ mental health needs. The data showed that providers were increasingly likely to list suicidal thoughts as the main diagnosis.
“Suicidal ideation can be thought about as two types: actively thinking about suicide or having thoughts, but not having a plan,” Dr. Brewer said in the news release. “That could be the difference in why someone might get admitted to the hospital.”
The researchers hypothesize that care in 2019 (when the initial spike occurred) was delayed in the early days of the pandemic, and that delay possibly contributed to the increase in providers identifying suicidal ideation as the main diagnosis.
“The early pandemic period coincided with constrained access to pediatric mental health services through schools, pediatric primary care homes, and mental health clinics for many children and their families,” the authors wrote. “The proportion of child mental health visits increased relative to other types as patients avoided ED visits during the early wave of the COVID-19 pandemic. Thus, the increase in hospitalizations during fall 2020 may reflect patients’ deferring care until symptoms became even more severe.”
Other health care scholars agreed the study spurred questions about whether the pandemic was truly the source of the crisis.
“Was it the pandemic that exacerbated the increase or is this a growing trend?” wrote Lisa M. Horowitz, PhD, MPH, and Jeffrey A. Bridge, PhD, in a commentary published along with the study. “These rising rates underscore the worsening mental health crisis for youth, as noted by the 2022 Surgeon General report and several youth mental health organizations.”
A version of this article first appeared on WebMD.com.
FROM PEDIATRICS
Tirzepatide cuts BP during obesity treatment
CHICAGO – compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.
“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.
“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.
The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m2) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.
Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
24-hour ambulatory pressures from 494 people
The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.
Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.
The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”
Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.
Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.
Lowering of blood pressure plateaus
Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.
This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.
“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.
Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
Incretin agonists as antihypertensive drugs
The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.
“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.
Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.
“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
Heart rate increases were usually modest
The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.
SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.
Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.
SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.
CHICAGO – compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.
“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.
“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.
The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m2) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.
Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
24-hour ambulatory pressures from 494 people
The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.
Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.
The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”
Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.
Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.
Lowering of blood pressure plateaus
Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.
This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.
“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.
Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
Incretin agonists as antihypertensive drugs
The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.
“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.
Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.
“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
Heart rate increases were usually modest
The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.
SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.
Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.
SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.
CHICAGO – compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.
“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.
“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.
The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m2) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.
Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
24-hour ambulatory pressures from 494 people
The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.
Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.
The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”
Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.
Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.
Lowering of blood pressure plateaus
Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.
This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.
“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.
Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
Incretin agonists as antihypertensive drugs
The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.
“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.
Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.
“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
Heart rate increases were usually modest
The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.
SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.
Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.
SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.
AT AHA 2022
Teclistamab for MM: Lifesaver or 'cause of death'?
Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live.
This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”
The first cut of the data appeared in the New England Journal of Medicine.
At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.
Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”
Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.
He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.
Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”
However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?
Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.
When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”
He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”
Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”
For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.
In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”
In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.
Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.
A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”
Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.
“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”
Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.
“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”
The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.
Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.
Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.
Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.
Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.
The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.
To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.
Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.
Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.
Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live.
This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”
The first cut of the data appeared in the New England Journal of Medicine.
At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.
Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”
Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.
He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.
Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”
However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?
Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.
When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”
He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”
Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”
For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.
In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”
In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.
Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.
A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”
Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.
“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”
Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.
“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”
The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.
Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.
Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.
Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.
Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.
The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.
To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.
Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.
Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.
Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live.
This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”
The first cut of the data appeared in the New England Journal of Medicine.
At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.
Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”
Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.
He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.
Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”
However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?
Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.
When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”
He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”
Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”
For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.
In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”
In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.
Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”
On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.
A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”
Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.
“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”
Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.
“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”
The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.
Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.
Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.
Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.
Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.
The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.
To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.
Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.
Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE