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Neutrophils may offer therapeutic target for Wilson’s disease
Inhibiting neutrophil function via transforming growth factor (TGF-beta 1) inhibition or methylation inhibition reduced parenchymal liver fibrosis and injury while improving liver function in a mouse model of Wilson’s disease, shows new research published in Cellular and Molecular Gastroenterology and Hepatology.
Also called progressive hepatolenticular degeneration, Wilson’s disease is an inherited nervous system disorder that can occur as a result of severe liver disease. It is caused by variants in the ATP7B gene which can lead to abnormalities in copper metabolism that lead to accumulation of the heavy metal in the liver and brain, resulting in damage to both organs. Approximately 60% of patients with Wilson’s disease present with hepatic syndromes, and of those 50%-60% go on to develop liver cirrhosis.
Current treatments aim to address metal deposition, but this approach is poorly tolerated by many patients, wrote investigators who were led by Junping Shi, MD, PhD, of the Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, China.
“Drug interventions (such as copper chelators and zinc salts) reduce pathologic copper deposition, but side effects can be observed in up to 40% of patients during treatment and even after years of treatment, particularly nephropathy, autoimmune conditions, and skin changes,” the investigators wrote. “Liver transplantation is an effective treatment for Wilson’s disease, particularly for patients with end-stage liver disease, but donor shortages and lifelong immunosuppression limit its use. Therefore, alternative treatments with higher specificity in Wilson’s disease patients are urgently needed.”
The present study explored the underlying metabolic abnormalities in Wilson’s disease that result in liver injury and fibrosis, and related therapeutic approaches. Based on previous studies that have shown a relationship between persistent neutrophil infiltration and chronic tissue inflammation and damage, the investigators sought to explore the role of neutrophils in Wilson’s disease, with a focus on the N2 subtype.
First, they analyzed neutrophil populations in the livers of Atp7b–/– mice and atp7b–/– zebrafish, both of which are established animal models of Wilson’s disease. Compared with the wild-type comparison animals, the livers of disease model animals showed increased neutrophil infiltration, in terms of both count and density.
In one of several related experiments, administering a neutrophil agonist in the presence of copper led to significantly greater neutrophil infiltration in mutant versus wild-type fish, as well as greater increases in lipid droplets and disorganized tissue structure, which serve as markers of disease activity.
“Collectively, these data suggested that neutrophils infiltrated the liver and accelerated liver defects in Wilson’s disease,” the investigators wrote.
Additional experiments with the mouse model showed that pharmacologic ablation of N2 neutrophils via two approaches led to reduced liver fibrosis, offering a glimpse at therapeutic potential.
These findings were further supported by experiments involving a cellular model of Wilson’s disease with isolated bone marrow neutrophils. These analyses revealed the role of the TGF1–DNMT3A/STAT3 signaling axis in neutrophil polarization, and resultant liver disease progression, in Wilson’s disease.
“Neutrophil heterogeneity shows therapeutic potential, and pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease,” the investigators concluded, noting that TGF-beta 1, DNMT3A, or STAT3 could all serve as rational therapeutic targets.
Beyond Wilson’s disease, the findings may offer broader value for understanding the mechanisms driving other neutrophil-related diseases, as well as possible therapeutic approaches for those conditions, the authors added.
The authors disclosed no conflicts of interest.
The treatment of Wilson disease relies on use of chelators (D-pencilliamine; trientine) that promote urinary copper excretion and zinc, which blocks intestinal absorption.
These drugs, which must be taken continuously, are effective but are associated with significant side effects. Another chelator, bis-choline-tetrathiomolybdate (TTM), promotes biliary, rather than urinary copper excretion.
TTM improved neurological function in clinical trials; however, dose-dependent transaminase elevations were noted.
Thus, there is a need to identify new therapeutic approaches to reduce impact of copper toxicity in hepatocytes.
In the current issue of CMGH, Mi and colleagues utilize zebrafish and mouse models of Wilson disease to generate novel insights into the pathogenesis and molecular basis of liver injury and fibrosis caused by ATP7B mutations. In the zebrafish model, they first showed that fluorescently-labeled neutrophils accumulate in the livers of live, mutant animals, which are transparent, and thus, uniquely suited to these studies. Gene expression analyses showed that the liver neutrophils are metabolically active and sensitize hepatocytes to copper-induced injury, thus providing a therapeutic rational for neutrophil inhibition. Next, the authors confirmed these findings in the mouse model, showing specifically that the N2-neutrophil subtype predominated and correlated with the degree of liver injury. Subsequent gene expression studies in the mouse, combined with in vitro analysis of bone marrow-derived neutrophils, identified a molecular signaling pathway originating in hepatocytes that triggered N2 differentiation. This pathway, which was previously shown to drive N2 differentiation in cancer models, involves TGF-beta induced methylation (and hence repression) of a gene (SOCS3) that itself, blocks expression of STAT3, a gene that drives N2 differentiation. Importantly, liver injury and fibrosis were reduced in the mouse model by drugs that inhibit TGF-beta or DNA methylation, and hence N2 differentiation, or by directly blocking the activity of N2 neutrophils.
In summary, this new study provides novel insights into not only into the pathogenesis and potential treatment of Wilson disease, but also demonstrates how signaling pathways, such as the one involving TGFbeta-SOCS3-STAT3, are reiteratively used in a variety of pathologic contexts. Going forward, it will be important to determine whether this pharmacologically modifiable signaling pathway is activated in Wilson disease patients, and whether it impacts the pathogenesis of more common liver disorders.
Michael Pack, M.D., is professor of medicine at Perelman School of Medicine, University of Pennsylvania. He has no conflicts.
The treatment of Wilson disease relies on use of chelators (D-pencilliamine; trientine) that promote urinary copper excretion and zinc, which blocks intestinal absorption.
These drugs, which must be taken continuously, are effective but are associated with significant side effects. Another chelator, bis-choline-tetrathiomolybdate (TTM), promotes biliary, rather than urinary copper excretion.
TTM improved neurological function in clinical trials; however, dose-dependent transaminase elevations were noted.
Thus, there is a need to identify new therapeutic approaches to reduce impact of copper toxicity in hepatocytes.
In the current issue of CMGH, Mi and colleagues utilize zebrafish and mouse models of Wilson disease to generate novel insights into the pathogenesis and molecular basis of liver injury and fibrosis caused by ATP7B mutations. In the zebrafish model, they first showed that fluorescently-labeled neutrophils accumulate in the livers of live, mutant animals, which are transparent, and thus, uniquely suited to these studies. Gene expression analyses showed that the liver neutrophils are metabolically active and sensitize hepatocytes to copper-induced injury, thus providing a therapeutic rational for neutrophil inhibition. Next, the authors confirmed these findings in the mouse model, showing specifically that the N2-neutrophil subtype predominated and correlated with the degree of liver injury. Subsequent gene expression studies in the mouse, combined with in vitro analysis of bone marrow-derived neutrophils, identified a molecular signaling pathway originating in hepatocytes that triggered N2 differentiation. This pathway, which was previously shown to drive N2 differentiation in cancer models, involves TGF-beta induced methylation (and hence repression) of a gene (SOCS3) that itself, blocks expression of STAT3, a gene that drives N2 differentiation. Importantly, liver injury and fibrosis were reduced in the mouse model by drugs that inhibit TGF-beta or DNA methylation, and hence N2 differentiation, or by directly blocking the activity of N2 neutrophils.
In summary, this new study provides novel insights into not only into the pathogenesis and potential treatment of Wilson disease, but also demonstrates how signaling pathways, such as the one involving TGFbeta-SOCS3-STAT3, are reiteratively used in a variety of pathologic contexts. Going forward, it will be important to determine whether this pharmacologically modifiable signaling pathway is activated in Wilson disease patients, and whether it impacts the pathogenesis of more common liver disorders.
Michael Pack, M.D., is professor of medicine at Perelman School of Medicine, University of Pennsylvania. He has no conflicts.
The treatment of Wilson disease relies on use of chelators (D-pencilliamine; trientine) that promote urinary copper excretion and zinc, which blocks intestinal absorption.
These drugs, which must be taken continuously, are effective but are associated with significant side effects. Another chelator, bis-choline-tetrathiomolybdate (TTM), promotes biliary, rather than urinary copper excretion.
TTM improved neurological function in clinical trials; however, dose-dependent transaminase elevations were noted.
Thus, there is a need to identify new therapeutic approaches to reduce impact of copper toxicity in hepatocytes.
In the current issue of CMGH, Mi and colleagues utilize zebrafish and mouse models of Wilson disease to generate novel insights into the pathogenesis and molecular basis of liver injury and fibrosis caused by ATP7B mutations. In the zebrafish model, they first showed that fluorescently-labeled neutrophils accumulate in the livers of live, mutant animals, which are transparent, and thus, uniquely suited to these studies. Gene expression analyses showed that the liver neutrophils are metabolically active and sensitize hepatocytes to copper-induced injury, thus providing a therapeutic rational for neutrophil inhibition. Next, the authors confirmed these findings in the mouse model, showing specifically that the N2-neutrophil subtype predominated and correlated with the degree of liver injury. Subsequent gene expression studies in the mouse, combined with in vitro analysis of bone marrow-derived neutrophils, identified a molecular signaling pathway originating in hepatocytes that triggered N2 differentiation. This pathway, which was previously shown to drive N2 differentiation in cancer models, involves TGF-beta induced methylation (and hence repression) of a gene (SOCS3) that itself, blocks expression of STAT3, a gene that drives N2 differentiation. Importantly, liver injury and fibrosis were reduced in the mouse model by drugs that inhibit TGF-beta or DNA methylation, and hence N2 differentiation, or by directly blocking the activity of N2 neutrophils.
In summary, this new study provides novel insights into not only into the pathogenesis and potential treatment of Wilson disease, but also demonstrates how signaling pathways, such as the one involving TGFbeta-SOCS3-STAT3, are reiteratively used in a variety of pathologic contexts. Going forward, it will be important to determine whether this pharmacologically modifiable signaling pathway is activated in Wilson disease patients, and whether it impacts the pathogenesis of more common liver disorders.
Michael Pack, M.D., is professor of medicine at Perelman School of Medicine, University of Pennsylvania. He has no conflicts.
Inhibiting neutrophil function via transforming growth factor (TGF-beta 1) inhibition or methylation inhibition reduced parenchymal liver fibrosis and injury while improving liver function in a mouse model of Wilson’s disease, shows new research published in Cellular and Molecular Gastroenterology and Hepatology.
Also called progressive hepatolenticular degeneration, Wilson’s disease is an inherited nervous system disorder that can occur as a result of severe liver disease. It is caused by variants in the ATP7B gene which can lead to abnormalities in copper metabolism that lead to accumulation of the heavy metal in the liver and brain, resulting in damage to both organs. Approximately 60% of patients with Wilson’s disease present with hepatic syndromes, and of those 50%-60% go on to develop liver cirrhosis.
Current treatments aim to address metal deposition, but this approach is poorly tolerated by many patients, wrote investigators who were led by Junping Shi, MD, PhD, of the Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, China.
“Drug interventions (such as copper chelators and zinc salts) reduce pathologic copper deposition, but side effects can be observed in up to 40% of patients during treatment and even after years of treatment, particularly nephropathy, autoimmune conditions, and skin changes,” the investigators wrote. “Liver transplantation is an effective treatment for Wilson’s disease, particularly for patients with end-stage liver disease, but donor shortages and lifelong immunosuppression limit its use. Therefore, alternative treatments with higher specificity in Wilson’s disease patients are urgently needed.”
The present study explored the underlying metabolic abnormalities in Wilson’s disease that result in liver injury and fibrosis, and related therapeutic approaches. Based on previous studies that have shown a relationship between persistent neutrophil infiltration and chronic tissue inflammation and damage, the investigators sought to explore the role of neutrophils in Wilson’s disease, with a focus on the N2 subtype.
First, they analyzed neutrophil populations in the livers of Atp7b–/– mice and atp7b–/– zebrafish, both of which are established animal models of Wilson’s disease. Compared with the wild-type comparison animals, the livers of disease model animals showed increased neutrophil infiltration, in terms of both count and density.
In one of several related experiments, administering a neutrophil agonist in the presence of copper led to significantly greater neutrophil infiltration in mutant versus wild-type fish, as well as greater increases in lipid droplets and disorganized tissue structure, which serve as markers of disease activity.
“Collectively, these data suggested that neutrophils infiltrated the liver and accelerated liver defects in Wilson’s disease,” the investigators wrote.
Additional experiments with the mouse model showed that pharmacologic ablation of N2 neutrophils via two approaches led to reduced liver fibrosis, offering a glimpse at therapeutic potential.
These findings were further supported by experiments involving a cellular model of Wilson’s disease with isolated bone marrow neutrophils. These analyses revealed the role of the TGF1–DNMT3A/STAT3 signaling axis in neutrophil polarization, and resultant liver disease progression, in Wilson’s disease.
“Neutrophil heterogeneity shows therapeutic potential, and pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease,” the investigators concluded, noting that TGF-beta 1, DNMT3A, or STAT3 could all serve as rational therapeutic targets.
Beyond Wilson’s disease, the findings may offer broader value for understanding the mechanisms driving other neutrophil-related diseases, as well as possible therapeutic approaches for those conditions, the authors added.
The authors disclosed no conflicts of interest.
Inhibiting neutrophil function via transforming growth factor (TGF-beta 1) inhibition or methylation inhibition reduced parenchymal liver fibrosis and injury while improving liver function in a mouse model of Wilson’s disease, shows new research published in Cellular and Molecular Gastroenterology and Hepatology.
Also called progressive hepatolenticular degeneration, Wilson’s disease is an inherited nervous system disorder that can occur as a result of severe liver disease. It is caused by variants in the ATP7B gene which can lead to abnormalities in copper metabolism that lead to accumulation of the heavy metal in the liver and brain, resulting in damage to both organs. Approximately 60% of patients with Wilson’s disease present with hepatic syndromes, and of those 50%-60% go on to develop liver cirrhosis.
Current treatments aim to address metal deposition, but this approach is poorly tolerated by many patients, wrote investigators who were led by Junping Shi, MD, PhD, of the Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, China.
“Drug interventions (such as copper chelators and zinc salts) reduce pathologic copper deposition, but side effects can be observed in up to 40% of patients during treatment and even after years of treatment, particularly nephropathy, autoimmune conditions, and skin changes,” the investigators wrote. “Liver transplantation is an effective treatment for Wilson’s disease, particularly for patients with end-stage liver disease, but donor shortages and lifelong immunosuppression limit its use. Therefore, alternative treatments with higher specificity in Wilson’s disease patients are urgently needed.”
The present study explored the underlying metabolic abnormalities in Wilson’s disease that result in liver injury and fibrosis, and related therapeutic approaches. Based on previous studies that have shown a relationship between persistent neutrophil infiltration and chronic tissue inflammation and damage, the investigators sought to explore the role of neutrophils in Wilson’s disease, with a focus on the N2 subtype.
First, they analyzed neutrophil populations in the livers of Atp7b–/– mice and atp7b–/– zebrafish, both of which are established animal models of Wilson’s disease. Compared with the wild-type comparison animals, the livers of disease model animals showed increased neutrophil infiltration, in terms of both count and density.
In one of several related experiments, administering a neutrophil agonist in the presence of copper led to significantly greater neutrophil infiltration in mutant versus wild-type fish, as well as greater increases in lipid droplets and disorganized tissue structure, which serve as markers of disease activity.
“Collectively, these data suggested that neutrophils infiltrated the liver and accelerated liver defects in Wilson’s disease,” the investigators wrote.
Additional experiments with the mouse model showed that pharmacologic ablation of N2 neutrophils via two approaches led to reduced liver fibrosis, offering a glimpse at therapeutic potential.
These findings were further supported by experiments involving a cellular model of Wilson’s disease with isolated bone marrow neutrophils. These analyses revealed the role of the TGF1–DNMT3A/STAT3 signaling axis in neutrophil polarization, and resultant liver disease progression, in Wilson’s disease.
“Neutrophil heterogeneity shows therapeutic potential, and pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease,” the investigators concluded, noting that TGF-beta 1, DNMT3A, or STAT3 could all serve as rational therapeutic targets.
Beyond Wilson’s disease, the findings may offer broader value for understanding the mechanisms driving other neutrophil-related diseases, as well as possible therapeutic approaches for those conditions, the authors added.
The authors disclosed no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Two-thirds with microscopic colitis respond to bile acid sequestrants
, based on a recent retrospective study from the Mayo Clinic.
The findings support use of BAS in patients with microscopic colitis who fail first-line therapy, or have intolerance to those agents, wrote researchers who were led by Darrell S. Pardi, MD, AGAF, a gastroenterologist with Mayo Clinic, Rochester, Minn. To date, the American Gastroenterological Association (AGA) has refrained from issuing any recommendations for BAS monotherapy in microscopic colitis (MC), the study authors wrote, citing a lack of relevant data.
The AGA recommends budesonide as first-line therapy for patients with moderate to severe symptoms of microscopic colitis. However, the treatment is associated with a high rate of relapse (40%-81%) once the patient stops taking the drug. Its long-term use is associated with a risk of side effects.
“At present, there are no randomized controlled trials that have evaluated the efficacy of BAS monotherapy for MC,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Studies investigating the role of BAM [bile acid malabsorption] in MC are comprised of small cohorts and have shown inconsistent results. Patients without BAM may also respond to BAS therapy. Therefore, the role of BAM and treatment with BAS in MC merits further investigation.”
The study analyzed data from 282 patients (88.3% women) with microscopic colitis treated between 2010 to 2020. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing. After a median follow-up of 4.5 years, cholestyramine was the most prescribed BAS (64.9%), followed by colesevelam (21.6%) and colestipol (13.5%). Approximately half of the patients achieved a complete response (49.3%), while 16.3% had a partial response. Nonresponders accounted for 24.8% of the population, and 9.6% of patients did not tolerate BAS therapy. These outcomes were not significantly impacted by BAS dose or combination with other agents. Additional logistic regression analysis revealed no predictors of response.
After discontinuing BAS, 41.6% of patients had recurrence in a median of 21 weeks, ranging from 1 to 172 weeks.
“Consistent with prior studies evaluating the clinical course of MC and similar to the high rate of recurrence after discontinuation of budesonide, relapse was common after cessation of BAS therapy,” the investigators noted.
Still, the findings suggest that BAS is a valid second-line option with a favorable risk-benefit profile, and an elevated dose appears unnecessary to achieve clinical response.
“These results suggest that BAS may be considered as a treatment option in those that do not respond to first-line options or have intolerance to these agents,” the researchers wrote.
They suggested that BAS may be particularly useful as long-term maintenance therapy for patients wishing to avoid prolonged corticosteroid exposure.
“However, BAS have the potential to interfere with the administration and absorption of other medications, particularly in older populations with polypharmacy,” the researchers wrote. “Patients should thus be closely monitored for drug interactions, especially those taking concurrent medications. BAS should be administered separately from other medications to avoid the potential for drug interactions.”
Ideally, prospective studies will be conducted to confirm these findings, and to identify the subset of patients who are most likely to respond to BAS, the investigators concluded.
Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda; and has consulted for Vedanta, Seres, Phantom Pharmaceuticals, Abbvie, Immunic, and Otsuka.
Despite being increasingly recognized and diagnosed, there remains a scantiness of studies addressing therapeutic options in microscopic colitis (MC). Oral budesonide is recommended as first-line option; however, there is a high relapse rate after budesonide discontinuation, some patients are intolerant, and there is concern for steroid toxicity associated with long-term exposure.
While the cause of MC remains elusive, there is a rationale to suggest that bile acids may play a role in disease pathogenesis. Not only are BA important signaling molecules, acting in inflammation and metabolism, but also prior small studies reported on BA malabsorption co-existing in MC, with variable response rates to BA sequestrants.
This retrospective large study of 282 patients with MC showed that almost two-thirds of patients will present a complete or partial response to BA sequestrant therapy (cholestyramine, colesevelam, and colestipol). For those that relapsed following BA therapy discontinuation, re-treatment was successful in the majority of cases.
Therapy was well tolerated, however caution is needed, as it can interfere with absorption of other medications, and in the long-term also with fat-soluble vitamins. It remains to be determined which patients could benefit the most from BA therapy, since no predictors of response were identified, nor was response associated with BA malabsorption. Nonetheless, this study shows that BA therapy could be an attractive option for steroid-dependent, steroid refractory or intolerant MC patients potentially worth trying before embarking on immunosuppressive or biological therapy. It also highlights the need for carefully conducted clinical trials exploring other options beyond budesonide for this chronic and debilitating condition.
Joana Torres, MD, PhD, is a consultant gastroenterologist at Hospital Beatriz Angelo and Hospital da Luz in Portugal and assistant professor in Uniersidade de Lisboa, Portugal. She has no conflicts.
Despite being increasingly recognized and diagnosed, there remains a scantiness of studies addressing therapeutic options in microscopic colitis (MC). Oral budesonide is recommended as first-line option; however, there is a high relapse rate after budesonide discontinuation, some patients are intolerant, and there is concern for steroid toxicity associated with long-term exposure.
While the cause of MC remains elusive, there is a rationale to suggest that bile acids may play a role in disease pathogenesis. Not only are BA important signaling molecules, acting in inflammation and metabolism, but also prior small studies reported on BA malabsorption co-existing in MC, with variable response rates to BA sequestrants.
This retrospective large study of 282 patients with MC showed that almost two-thirds of patients will present a complete or partial response to BA sequestrant therapy (cholestyramine, colesevelam, and colestipol). For those that relapsed following BA therapy discontinuation, re-treatment was successful in the majority of cases.
Therapy was well tolerated, however caution is needed, as it can interfere with absorption of other medications, and in the long-term also with fat-soluble vitamins. It remains to be determined which patients could benefit the most from BA therapy, since no predictors of response were identified, nor was response associated with BA malabsorption. Nonetheless, this study shows that BA therapy could be an attractive option for steroid-dependent, steroid refractory or intolerant MC patients potentially worth trying before embarking on immunosuppressive or biological therapy. It also highlights the need for carefully conducted clinical trials exploring other options beyond budesonide for this chronic and debilitating condition.
Joana Torres, MD, PhD, is a consultant gastroenterologist at Hospital Beatriz Angelo and Hospital da Luz in Portugal and assistant professor in Uniersidade de Lisboa, Portugal. She has no conflicts.
Despite being increasingly recognized and diagnosed, there remains a scantiness of studies addressing therapeutic options in microscopic colitis (MC). Oral budesonide is recommended as first-line option; however, there is a high relapse rate after budesonide discontinuation, some patients are intolerant, and there is concern for steroid toxicity associated with long-term exposure.
While the cause of MC remains elusive, there is a rationale to suggest that bile acids may play a role in disease pathogenesis. Not only are BA important signaling molecules, acting in inflammation and metabolism, but also prior small studies reported on BA malabsorption co-existing in MC, with variable response rates to BA sequestrants.
This retrospective large study of 282 patients with MC showed that almost two-thirds of patients will present a complete or partial response to BA sequestrant therapy (cholestyramine, colesevelam, and colestipol). For those that relapsed following BA therapy discontinuation, re-treatment was successful in the majority of cases.
Therapy was well tolerated, however caution is needed, as it can interfere with absorption of other medications, and in the long-term also with fat-soluble vitamins. It remains to be determined which patients could benefit the most from BA therapy, since no predictors of response were identified, nor was response associated with BA malabsorption. Nonetheless, this study shows that BA therapy could be an attractive option for steroid-dependent, steroid refractory or intolerant MC patients potentially worth trying before embarking on immunosuppressive or biological therapy. It also highlights the need for carefully conducted clinical trials exploring other options beyond budesonide for this chronic and debilitating condition.
Joana Torres, MD, PhD, is a consultant gastroenterologist at Hospital Beatriz Angelo and Hospital da Luz in Portugal and assistant professor in Uniersidade de Lisboa, Portugal. She has no conflicts.
, based on a recent retrospective study from the Mayo Clinic.
The findings support use of BAS in patients with microscopic colitis who fail first-line therapy, or have intolerance to those agents, wrote researchers who were led by Darrell S. Pardi, MD, AGAF, a gastroenterologist with Mayo Clinic, Rochester, Minn. To date, the American Gastroenterological Association (AGA) has refrained from issuing any recommendations for BAS monotherapy in microscopic colitis (MC), the study authors wrote, citing a lack of relevant data.
The AGA recommends budesonide as first-line therapy for patients with moderate to severe symptoms of microscopic colitis. However, the treatment is associated with a high rate of relapse (40%-81%) once the patient stops taking the drug. Its long-term use is associated with a risk of side effects.
“At present, there are no randomized controlled trials that have evaluated the efficacy of BAS monotherapy for MC,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Studies investigating the role of BAM [bile acid malabsorption] in MC are comprised of small cohorts and have shown inconsistent results. Patients without BAM may also respond to BAS therapy. Therefore, the role of BAM and treatment with BAS in MC merits further investigation.”
The study analyzed data from 282 patients (88.3% women) with microscopic colitis treated between 2010 to 2020. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing. After a median follow-up of 4.5 years, cholestyramine was the most prescribed BAS (64.9%), followed by colesevelam (21.6%) and colestipol (13.5%). Approximately half of the patients achieved a complete response (49.3%), while 16.3% had a partial response. Nonresponders accounted for 24.8% of the population, and 9.6% of patients did not tolerate BAS therapy. These outcomes were not significantly impacted by BAS dose or combination with other agents. Additional logistic regression analysis revealed no predictors of response.
After discontinuing BAS, 41.6% of patients had recurrence in a median of 21 weeks, ranging from 1 to 172 weeks.
“Consistent with prior studies evaluating the clinical course of MC and similar to the high rate of recurrence after discontinuation of budesonide, relapse was common after cessation of BAS therapy,” the investigators noted.
Still, the findings suggest that BAS is a valid second-line option with a favorable risk-benefit profile, and an elevated dose appears unnecessary to achieve clinical response.
“These results suggest that BAS may be considered as a treatment option in those that do not respond to first-line options or have intolerance to these agents,” the researchers wrote.
They suggested that BAS may be particularly useful as long-term maintenance therapy for patients wishing to avoid prolonged corticosteroid exposure.
“However, BAS have the potential to interfere with the administration and absorption of other medications, particularly in older populations with polypharmacy,” the researchers wrote. “Patients should thus be closely monitored for drug interactions, especially those taking concurrent medications. BAS should be administered separately from other medications to avoid the potential for drug interactions.”
Ideally, prospective studies will be conducted to confirm these findings, and to identify the subset of patients who are most likely to respond to BAS, the investigators concluded.
Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda; and has consulted for Vedanta, Seres, Phantom Pharmaceuticals, Abbvie, Immunic, and Otsuka.
, based on a recent retrospective study from the Mayo Clinic.
The findings support use of BAS in patients with microscopic colitis who fail first-line therapy, or have intolerance to those agents, wrote researchers who were led by Darrell S. Pardi, MD, AGAF, a gastroenterologist with Mayo Clinic, Rochester, Minn. To date, the American Gastroenterological Association (AGA) has refrained from issuing any recommendations for BAS monotherapy in microscopic colitis (MC), the study authors wrote, citing a lack of relevant data.
The AGA recommends budesonide as first-line therapy for patients with moderate to severe symptoms of microscopic colitis. However, the treatment is associated with a high rate of relapse (40%-81%) once the patient stops taking the drug. Its long-term use is associated with a risk of side effects.
“At present, there are no randomized controlled trials that have evaluated the efficacy of BAS monotherapy for MC,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Studies investigating the role of BAM [bile acid malabsorption] in MC are comprised of small cohorts and have shown inconsistent results. Patients without BAM may also respond to BAS therapy. Therefore, the role of BAM and treatment with BAS in MC merits further investigation.”
The study analyzed data from 282 patients (88.3% women) with microscopic colitis treated between 2010 to 2020. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing. After a median follow-up of 4.5 years, cholestyramine was the most prescribed BAS (64.9%), followed by colesevelam (21.6%) and colestipol (13.5%). Approximately half of the patients achieved a complete response (49.3%), while 16.3% had a partial response. Nonresponders accounted for 24.8% of the population, and 9.6% of patients did not tolerate BAS therapy. These outcomes were not significantly impacted by BAS dose or combination with other agents. Additional logistic regression analysis revealed no predictors of response.
After discontinuing BAS, 41.6% of patients had recurrence in a median of 21 weeks, ranging from 1 to 172 weeks.
“Consistent with prior studies evaluating the clinical course of MC and similar to the high rate of recurrence after discontinuation of budesonide, relapse was common after cessation of BAS therapy,” the investigators noted.
Still, the findings suggest that BAS is a valid second-line option with a favorable risk-benefit profile, and an elevated dose appears unnecessary to achieve clinical response.
“These results suggest that BAS may be considered as a treatment option in those that do not respond to first-line options or have intolerance to these agents,” the researchers wrote.
They suggested that BAS may be particularly useful as long-term maintenance therapy for patients wishing to avoid prolonged corticosteroid exposure.
“However, BAS have the potential to interfere with the administration and absorption of other medications, particularly in older populations with polypharmacy,” the researchers wrote. “Patients should thus be closely monitored for drug interactions, especially those taking concurrent medications. BAS should be administered separately from other medications to avoid the potential for drug interactions.”
Ideally, prospective studies will be conducted to confirm these findings, and to identify the subset of patients who are most likely to respond to BAS, the investigators concluded.
Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda; and has consulted for Vedanta, Seres, Phantom Pharmaceuticals, Abbvie, Immunic, and Otsuka.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Survival on the upswing in myeloma
Back then, the treatments for MM were chemotherapy and steroids. Stem-cell transplants were on the horizon, as was a most unexpected therapy: the infamous drug thalidomide.
But in the wake of the rib facture, the health of Stanley Katz, MD, worsened and he died after 25 weeks, Dr. Berenson recalled in an interview. At that time, Dr. Katz’s horrifically shortened lifespan following diagnosis was not unusual.
About 4 decades later, hematologists like Dr. Berenson are heralding a new era in MM, a sharp reversal of the previous eras of grim prognoses.
In a new study, Dr. Berenson tracked 161 patients with MM treated at his West Hollywood, Calif., private clinic from 2006 to 2023 and found that their median survival was 136.2 months – more than 11 years. “The OS reported in this study ... is the longest reported to date in an unselected, newly diagnosed MM population,” the study authors write.
Dr. Berenson’s patients are unique: They’re largely White, and they didn’t undergo stem-cell transplants. But other recent studies also suggest that lifespans of more than 10 years are increasingly possible after MM diagnosis. Former TV news anchor Tom Brokaw, for one, has reached that point.
In fact, a pair of other hematologists say the overall survival in Dr. Berenson’s report is hardly out of the question. And, they say, patients diagnosed today could potentially live even longer, because treatments continue to improve.
“With data that’s 10 years old, we expect the median overall survival to be 10 years,” hematologist Sagar Lonial, MD, who’s been tracking survival data in MM, said in an interview. “When patients ask about my outlook, I say it’s a constantly evolving field. Things are changing fast enough that I use 10 years as a floor.”
Dr. Lonial is chair of the department of hematology and medical oncology and chief medical officer at Emory University, Atlanta, Winship Cancer Institute.
Hematologist Rafael Fonseca, MD, chief innovation officer at Mayo Clinic–Arizona, put it this way in an interview: Dr. Berenson’s results “are probably in sync with what we would anticipate with similar cohorts of patients. The reality is that we’ve seen a huge improvement in the life expectancy of patients who were diagnosed with multiple myeloma. It’s not unusual to see patients in the clinic now that are 15 or 20 years out from their diagnosis.”
According to Yale Medicine, MM accounts for 10% of blood cancers and 1%-2% of all cancers and is more common in men vs. women and Blacks vs. Whites. It’s most frequently diagnosed between the ages of 65 and 74, according to the National Cancer Institute, and the median age at diagnosis is 69.
Among the most famous American people currently battling MM are newsman Mr. Brokaw, the former NBC News anchor, and Republican Congressman Steve Scalise, majority leader of the U.S. House of Representatives and a candidate for House speaker.
Mr. Brokaw was diagnosed in 2013 while in his early 70s and has talked about his intense struggle with the disease: the infections, operations, infusions, and daily regimens of 24 pills.
“I didn’t want to be Tom Brokaw, cancer victim,” he said in 2018 at the annual meeting of the American Society of Hematology. But he opened up about his illness, and became “the multiple myeloma poster boy.”
Rep. Scalise, who’s in his late 50s, is undergoing chemotherapy. He survived being gravely wounded in an assassination attempt in 2017.
Dr. Berenson’s new study, published in Targeted Oncology, tracked 161 patients (89 women, 72 men; median age, 65.4; 125 White, 3 Black, 10 Hispanic, 15 Asian, and 8 multi-ethnic).
All started frontline treatment at Dr. Berenson’s clinic and were included if they could read consent forms and gave permission for blood draws. None underwent stem-cell transplants as part of initial therapy. Another 1,036 patients had been treated elsewhere and were not included in the study.
Over a median of 42.7 months (range, 1.9-195.1), the 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively.
The study claims “these results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries.”
In the interview, Dr. Berenson said the study is unique because it’s not limited like many studies to younger, healthier patients. Nor does it include those treated at other facilities, he said.
The study is unusual in other ways. Dr. Berenson said his drug regimens aren’t necessarily standard, and he doesn’t treat patients with stem-cell transplants. “I stopped transplanting in about 2000 because clearly it was not improving the length of life,” he said.
Dr. Berenson said colleagues can learn from his insistence on sensitively treating the quality of life of patients, his embrace of clinical trials with novel combinations, and his close monitoring of myeloma proteins to gauge whether patients need to rapidly switch therapies.
He noted that his drug regimens are typically off-label and vary by patient. “We’re not using as high doses of drugs like Velcade [bortezomib] or Revlimid [lenalidomide] as my colleagues. We’re not necessarily giving as many doses. Also, we’re not adding as many drugs in many cases as they are. We’re taking it slower.”
The National Comprehensive Cancer Network recommends bortezomib and lenalidomide as standard induction treatments in patients with MM who are candidates for stem-cell transplantation, a procedure it considers the “preferred approach in transplant-eligible patients.”
There are limitations to Dr. Berenson’s new study. The patients aren’t representative of people with MM as a whole: His cohort is overwhelmingly White (78%) and just 2% Black, while an estimated one-fifth of patients with MM in the United States are Black and have poorer outcomes.
Dr. Berenson also acknowledged that his patients are most likely a wealthier group, although he said it’s not feasible to ask them about income. The study provides no information about socioeconomics.
Dr. Lonial said survival of 10-11 years is fairly typical in MM, with standard-risk patients reaching 14 years.
He highlighted a 2021 Canadian study that tracked 3,030 patients with newly diagnosed MM from 2007 to 2018 (average age, 64; 58.6% men). Those who received an upfront autologous stem-cell transplant had a median overall survival of 122.0 months (95% confidence interval, 115.0-135.0 months) vs. 54.3 months (95% CI, 50.8-58.8 months) for those who didn’t get the transplants. Not surprisingly, survival dipped with each subsequent treatment regimen.
Dr. Lonial is coauthor of a 2020 study that tracked 1,000 consecutive patients (mean age, 61; 35.2% Black) with newly diagnosed myeloma who were treated with RVD (lenalidomide, bortezomib, and dexamethasone) induction therapy from 2007 to 2016. The median overall survival was 126.6 months (95% CI, 113.3-139.8 months).
Dr. Fonseca noted that the news about MM survival rates is not entirely positive. Patients with high-risk disease often die early on in their disease course, he said.
Research suggests even the youngest patients with MM may die within years of diagnosis. A 2021 French study tracked 214 patients in the 18-40 age group for 15 years (2000-2015). At 5 years, “relative survival compared with same age- and sex-matched individuals was 83.5%,” and estimated overall survival was 14.5 years.
Still, a “very, very fertile environment for the development of drugs” has made a huge difference, Dr. Fonseca said. “We’ve had about 19 FDA approvals in the last 15 or 20 years.”
He urged colleagues to keep in mind that survival drops as patients decline in a line of therapy and need to switch to another one. “It might make intuitive sense to say ‘I’m gonna save something for later. I want to keep my powder dry.’ But put your best foot forward. Always go with your best treatments first.”
This approach can play out in a decision, say, to start with a four-drug initial regimen instead of a weaker two-drug regimen, he said. “Be mindful of managing toxicities, but hit harder.”
As he noted, side effects were worse with older generations of drugs. In regard to cost, multidrug treatments can cost hundreds of thousands of dollars. Dr. Fonseca said insurance tends to cover drugs that are approved by guidelines.
Dr. Fonseca discloses relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, Bayer, Binding Site, BMS (Celgene), Millennium Takeda, Janssen, Juno, Kite, Merck, Pfizer, Pharmacyclics, Regeneron, Sanofi, Adaptive Biotechnologies, Caris Life Sciences, Oncotracker, Antegene, and AZBio, and a patent in MM. Dr. Berenson discloses ties with Janssen, Amgen, Sanofi, BMS, Karyopharm, and Incyte. Dr. Lonial reports ties with TG Therapeutics, Celgene, BMS, Janssen, Novartis, GlaxoSmithKline, AbbVie, Takeda, Merck, Sanofi, Pfizer, Regeneron, and Novartis.
Back then, the treatments for MM were chemotherapy and steroids. Stem-cell transplants were on the horizon, as was a most unexpected therapy: the infamous drug thalidomide.
But in the wake of the rib facture, the health of Stanley Katz, MD, worsened and he died after 25 weeks, Dr. Berenson recalled in an interview. At that time, Dr. Katz’s horrifically shortened lifespan following diagnosis was not unusual.
About 4 decades later, hematologists like Dr. Berenson are heralding a new era in MM, a sharp reversal of the previous eras of grim prognoses.
In a new study, Dr. Berenson tracked 161 patients with MM treated at his West Hollywood, Calif., private clinic from 2006 to 2023 and found that their median survival was 136.2 months – more than 11 years. “The OS reported in this study ... is the longest reported to date in an unselected, newly diagnosed MM population,” the study authors write.
Dr. Berenson’s patients are unique: They’re largely White, and they didn’t undergo stem-cell transplants. But other recent studies also suggest that lifespans of more than 10 years are increasingly possible after MM diagnosis. Former TV news anchor Tom Brokaw, for one, has reached that point.
In fact, a pair of other hematologists say the overall survival in Dr. Berenson’s report is hardly out of the question. And, they say, patients diagnosed today could potentially live even longer, because treatments continue to improve.
“With data that’s 10 years old, we expect the median overall survival to be 10 years,” hematologist Sagar Lonial, MD, who’s been tracking survival data in MM, said in an interview. “When patients ask about my outlook, I say it’s a constantly evolving field. Things are changing fast enough that I use 10 years as a floor.”
Dr. Lonial is chair of the department of hematology and medical oncology and chief medical officer at Emory University, Atlanta, Winship Cancer Institute.
Hematologist Rafael Fonseca, MD, chief innovation officer at Mayo Clinic–Arizona, put it this way in an interview: Dr. Berenson’s results “are probably in sync with what we would anticipate with similar cohorts of patients. The reality is that we’ve seen a huge improvement in the life expectancy of patients who were diagnosed with multiple myeloma. It’s not unusual to see patients in the clinic now that are 15 or 20 years out from their diagnosis.”
According to Yale Medicine, MM accounts for 10% of blood cancers and 1%-2% of all cancers and is more common in men vs. women and Blacks vs. Whites. It’s most frequently diagnosed between the ages of 65 and 74, according to the National Cancer Institute, and the median age at diagnosis is 69.
Among the most famous American people currently battling MM are newsman Mr. Brokaw, the former NBC News anchor, and Republican Congressman Steve Scalise, majority leader of the U.S. House of Representatives and a candidate for House speaker.
Mr. Brokaw was diagnosed in 2013 while in his early 70s and has talked about his intense struggle with the disease: the infections, operations, infusions, and daily regimens of 24 pills.
“I didn’t want to be Tom Brokaw, cancer victim,” he said in 2018 at the annual meeting of the American Society of Hematology. But he opened up about his illness, and became “the multiple myeloma poster boy.”
Rep. Scalise, who’s in his late 50s, is undergoing chemotherapy. He survived being gravely wounded in an assassination attempt in 2017.
Dr. Berenson’s new study, published in Targeted Oncology, tracked 161 patients (89 women, 72 men; median age, 65.4; 125 White, 3 Black, 10 Hispanic, 15 Asian, and 8 multi-ethnic).
All started frontline treatment at Dr. Berenson’s clinic and were included if they could read consent forms and gave permission for blood draws. None underwent stem-cell transplants as part of initial therapy. Another 1,036 patients had been treated elsewhere and were not included in the study.
Over a median of 42.7 months (range, 1.9-195.1), the 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively.
The study claims “these results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries.”
In the interview, Dr. Berenson said the study is unique because it’s not limited like many studies to younger, healthier patients. Nor does it include those treated at other facilities, he said.
The study is unusual in other ways. Dr. Berenson said his drug regimens aren’t necessarily standard, and he doesn’t treat patients with stem-cell transplants. “I stopped transplanting in about 2000 because clearly it was not improving the length of life,” he said.
Dr. Berenson said colleagues can learn from his insistence on sensitively treating the quality of life of patients, his embrace of clinical trials with novel combinations, and his close monitoring of myeloma proteins to gauge whether patients need to rapidly switch therapies.
He noted that his drug regimens are typically off-label and vary by patient. “We’re not using as high doses of drugs like Velcade [bortezomib] or Revlimid [lenalidomide] as my colleagues. We’re not necessarily giving as many doses. Also, we’re not adding as many drugs in many cases as they are. We’re taking it slower.”
The National Comprehensive Cancer Network recommends bortezomib and lenalidomide as standard induction treatments in patients with MM who are candidates for stem-cell transplantation, a procedure it considers the “preferred approach in transplant-eligible patients.”
There are limitations to Dr. Berenson’s new study. The patients aren’t representative of people with MM as a whole: His cohort is overwhelmingly White (78%) and just 2% Black, while an estimated one-fifth of patients with MM in the United States are Black and have poorer outcomes.
Dr. Berenson also acknowledged that his patients are most likely a wealthier group, although he said it’s not feasible to ask them about income. The study provides no information about socioeconomics.
Dr. Lonial said survival of 10-11 years is fairly typical in MM, with standard-risk patients reaching 14 years.
He highlighted a 2021 Canadian study that tracked 3,030 patients with newly diagnosed MM from 2007 to 2018 (average age, 64; 58.6% men). Those who received an upfront autologous stem-cell transplant had a median overall survival of 122.0 months (95% confidence interval, 115.0-135.0 months) vs. 54.3 months (95% CI, 50.8-58.8 months) for those who didn’t get the transplants. Not surprisingly, survival dipped with each subsequent treatment regimen.
Dr. Lonial is coauthor of a 2020 study that tracked 1,000 consecutive patients (mean age, 61; 35.2% Black) with newly diagnosed myeloma who were treated with RVD (lenalidomide, bortezomib, and dexamethasone) induction therapy from 2007 to 2016. The median overall survival was 126.6 months (95% CI, 113.3-139.8 months).
Dr. Fonseca noted that the news about MM survival rates is not entirely positive. Patients with high-risk disease often die early on in their disease course, he said.
Research suggests even the youngest patients with MM may die within years of diagnosis. A 2021 French study tracked 214 patients in the 18-40 age group for 15 years (2000-2015). At 5 years, “relative survival compared with same age- and sex-matched individuals was 83.5%,” and estimated overall survival was 14.5 years.
Still, a “very, very fertile environment for the development of drugs” has made a huge difference, Dr. Fonseca said. “We’ve had about 19 FDA approvals in the last 15 or 20 years.”
He urged colleagues to keep in mind that survival drops as patients decline in a line of therapy and need to switch to another one. “It might make intuitive sense to say ‘I’m gonna save something for later. I want to keep my powder dry.’ But put your best foot forward. Always go with your best treatments first.”
This approach can play out in a decision, say, to start with a four-drug initial regimen instead of a weaker two-drug regimen, he said. “Be mindful of managing toxicities, but hit harder.”
As he noted, side effects were worse with older generations of drugs. In regard to cost, multidrug treatments can cost hundreds of thousands of dollars. Dr. Fonseca said insurance tends to cover drugs that are approved by guidelines.
Dr. Fonseca discloses relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, Bayer, Binding Site, BMS (Celgene), Millennium Takeda, Janssen, Juno, Kite, Merck, Pfizer, Pharmacyclics, Regeneron, Sanofi, Adaptive Biotechnologies, Caris Life Sciences, Oncotracker, Antegene, and AZBio, and a patent in MM. Dr. Berenson discloses ties with Janssen, Amgen, Sanofi, BMS, Karyopharm, and Incyte. Dr. Lonial reports ties with TG Therapeutics, Celgene, BMS, Janssen, Novartis, GlaxoSmithKline, AbbVie, Takeda, Merck, Sanofi, Pfizer, Regeneron, and Novartis.
Back then, the treatments for MM were chemotherapy and steroids. Stem-cell transplants were on the horizon, as was a most unexpected therapy: the infamous drug thalidomide.
But in the wake of the rib facture, the health of Stanley Katz, MD, worsened and he died after 25 weeks, Dr. Berenson recalled in an interview. At that time, Dr. Katz’s horrifically shortened lifespan following diagnosis was not unusual.
About 4 decades later, hematologists like Dr. Berenson are heralding a new era in MM, a sharp reversal of the previous eras of grim prognoses.
In a new study, Dr. Berenson tracked 161 patients with MM treated at his West Hollywood, Calif., private clinic from 2006 to 2023 and found that their median survival was 136.2 months – more than 11 years. “The OS reported in this study ... is the longest reported to date in an unselected, newly diagnosed MM population,” the study authors write.
Dr. Berenson’s patients are unique: They’re largely White, and they didn’t undergo stem-cell transplants. But other recent studies also suggest that lifespans of more than 10 years are increasingly possible after MM diagnosis. Former TV news anchor Tom Brokaw, for one, has reached that point.
In fact, a pair of other hematologists say the overall survival in Dr. Berenson’s report is hardly out of the question. And, they say, patients diagnosed today could potentially live even longer, because treatments continue to improve.
“With data that’s 10 years old, we expect the median overall survival to be 10 years,” hematologist Sagar Lonial, MD, who’s been tracking survival data in MM, said in an interview. “When patients ask about my outlook, I say it’s a constantly evolving field. Things are changing fast enough that I use 10 years as a floor.”
Dr. Lonial is chair of the department of hematology and medical oncology and chief medical officer at Emory University, Atlanta, Winship Cancer Institute.
Hematologist Rafael Fonseca, MD, chief innovation officer at Mayo Clinic–Arizona, put it this way in an interview: Dr. Berenson’s results “are probably in sync with what we would anticipate with similar cohorts of patients. The reality is that we’ve seen a huge improvement in the life expectancy of patients who were diagnosed with multiple myeloma. It’s not unusual to see patients in the clinic now that are 15 or 20 years out from their diagnosis.”
According to Yale Medicine, MM accounts for 10% of blood cancers and 1%-2% of all cancers and is more common in men vs. women and Blacks vs. Whites. It’s most frequently diagnosed between the ages of 65 and 74, according to the National Cancer Institute, and the median age at diagnosis is 69.
Among the most famous American people currently battling MM are newsman Mr. Brokaw, the former NBC News anchor, and Republican Congressman Steve Scalise, majority leader of the U.S. House of Representatives and a candidate for House speaker.
Mr. Brokaw was diagnosed in 2013 while in his early 70s and has talked about his intense struggle with the disease: the infections, operations, infusions, and daily regimens of 24 pills.
“I didn’t want to be Tom Brokaw, cancer victim,” he said in 2018 at the annual meeting of the American Society of Hematology. But he opened up about his illness, and became “the multiple myeloma poster boy.”
Rep. Scalise, who’s in his late 50s, is undergoing chemotherapy. He survived being gravely wounded in an assassination attempt in 2017.
Dr. Berenson’s new study, published in Targeted Oncology, tracked 161 patients (89 women, 72 men; median age, 65.4; 125 White, 3 Black, 10 Hispanic, 15 Asian, and 8 multi-ethnic).
All started frontline treatment at Dr. Berenson’s clinic and were included if they could read consent forms and gave permission for blood draws. None underwent stem-cell transplants as part of initial therapy. Another 1,036 patients had been treated elsewhere and were not included in the study.
Over a median of 42.7 months (range, 1.9-195.1), the 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively.
The study claims “these results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries.”
In the interview, Dr. Berenson said the study is unique because it’s not limited like many studies to younger, healthier patients. Nor does it include those treated at other facilities, he said.
The study is unusual in other ways. Dr. Berenson said his drug regimens aren’t necessarily standard, and he doesn’t treat patients with stem-cell transplants. “I stopped transplanting in about 2000 because clearly it was not improving the length of life,” he said.
Dr. Berenson said colleagues can learn from his insistence on sensitively treating the quality of life of patients, his embrace of clinical trials with novel combinations, and his close monitoring of myeloma proteins to gauge whether patients need to rapidly switch therapies.
He noted that his drug regimens are typically off-label and vary by patient. “We’re not using as high doses of drugs like Velcade [bortezomib] or Revlimid [lenalidomide] as my colleagues. We’re not necessarily giving as many doses. Also, we’re not adding as many drugs in many cases as they are. We’re taking it slower.”
The National Comprehensive Cancer Network recommends bortezomib and lenalidomide as standard induction treatments in patients with MM who are candidates for stem-cell transplantation, a procedure it considers the “preferred approach in transplant-eligible patients.”
There are limitations to Dr. Berenson’s new study. The patients aren’t representative of people with MM as a whole: His cohort is overwhelmingly White (78%) and just 2% Black, while an estimated one-fifth of patients with MM in the United States are Black and have poorer outcomes.
Dr. Berenson also acknowledged that his patients are most likely a wealthier group, although he said it’s not feasible to ask them about income. The study provides no information about socioeconomics.
Dr. Lonial said survival of 10-11 years is fairly typical in MM, with standard-risk patients reaching 14 years.
He highlighted a 2021 Canadian study that tracked 3,030 patients with newly diagnosed MM from 2007 to 2018 (average age, 64; 58.6% men). Those who received an upfront autologous stem-cell transplant had a median overall survival of 122.0 months (95% confidence interval, 115.0-135.0 months) vs. 54.3 months (95% CI, 50.8-58.8 months) for those who didn’t get the transplants. Not surprisingly, survival dipped with each subsequent treatment regimen.
Dr. Lonial is coauthor of a 2020 study that tracked 1,000 consecutive patients (mean age, 61; 35.2% Black) with newly diagnosed myeloma who were treated with RVD (lenalidomide, bortezomib, and dexamethasone) induction therapy from 2007 to 2016. The median overall survival was 126.6 months (95% CI, 113.3-139.8 months).
Dr. Fonseca noted that the news about MM survival rates is not entirely positive. Patients with high-risk disease often die early on in their disease course, he said.
Research suggests even the youngest patients with MM may die within years of diagnosis. A 2021 French study tracked 214 patients in the 18-40 age group for 15 years (2000-2015). At 5 years, “relative survival compared with same age- and sex-matched individuals was 83.5%,” and estimated overall survival was 14.5 years.
Still, a “very, very fertile environment for the development of drugs” has made a huge difference, Dr. Fonseca said. “We’ve had about 19 FDA approvals in the last 15 or 20 years.”
He urged colleagues to keep in mind that survival drops as patients decline in a line of therapy and need to switch to another one. “It might make intuitive sense to say ‘I’m gonna save something for later. I want to keep my powder dry.’ But put your best foot forward. Always go with your best treatments first.”
This approach can play out in a decision, say, to start with a four-drug initial regimen instead of a weaker two-drug regimen, he said. “Be mindful of managing toxicities, but hit harder.”
As he noted, side effects were worse with older generations of drugs. In regard to cost, multidrug treatments can cost hundreds of thousands of dollars. Dr. Fonseca said insurance tends to cover drugs that are approved by guidelines.
Dr. Fonseca discloses relationships with AbbVie, Adaptive Biotechnologies, Amgen, AstraZeneca, Bayer, Binding Site, BMS (Celgene), Millennium Takeda, Janssen, Juno, Kite, Merck, Pfizer, Pharmacyclics, Regeneron, Sanofi, Adaptive Biotechnologies, Caris Life Sciences, Oncotracker, Antegene, and AZBio, and a patent in MM. Dr. Berenson discloses ties with Janssen, Amgen, Sanofi, BMS, Karyopharm, and Incyte. Dr. Lonial reports ties with TG Therapeutics, Celgene, BMS, Janssen, Novartis, GlaxoSmithKline, AbbVie, Takeda, Merck, Sanofi, Pfizer, Regeneron, and Novartis.
Nonsurgical option for more large thyroid nodule patients?
WASHINGTON – , compared with only those that were.
While more research is needed, “the risk of false negative FNA results for large nodules may not be as high as reported in previous studies if you include patients who do not have indication for surgery, such as compressive symptoms, suspicious ultrasound features, etc.,” senior author Tracy Tylee, MD, an associate professor of endocrinology at the University of Washington, Seattle, said in an interview.
The implication is that nonsurgical options such as radiofrequency ablation may be appropriate for more patients than realized, she added.
“Clinicians should consider following these patients more conservatively, either with a second FNA to confirm [the] nodule is benign or with ultrasound follow-up for 5 years with intervention only if [there are] significant changes on imaging,” she said.
The findings were presented at the annual meeting of the American Thyroid Association.
Concerns about nodules over 4 cm having high false negative rates
Management of large thyroid nodules over 4 cm that are classified as Bethesda II, indicative of being benign, is complicated by concerns of false negatives in such cases. While the false negative rate for thyroid nodules in general is approximately 3%, the rate for large nodules over 4 cm has been reported as high as 35%.
Importantly, however, most studies evaluating the issue only involve patients who have received thyroid surgery, whereas most benign nodules are not referred for surgery.
“This may overestimate the false negative FNA biopsy risk for this group,” first author Melbin Thomas, MD, also of the University of Washington, said in her talk.
To better assess the false negative rate in the broader context of large nodules that did and did not undergo surgery, Dr. Thomas and her colleagues conducted a retrospective chart review of all patients undergoing FNA biopsy at her center between 2008 and 2014 for thyroid nodules larger than 4 cm and initially classified as Bethesda II, or benign.
With a follow-up of up to 10 years, nodules were considered accurately benign if they showed benign pathology on surgical resection, if they remained benign based on repeat FNA biopsy with Bethesda II results, or if there were no changes on imaging characteristics on ultrasound after at least 2 years.
Overall, 47 nodules over 4 cm and Bethesda II cytology were included, with an average follow-up of 5 years (range 2.2-9.7 years).
Of the nodules, 23 were treated with surgery, two of which were determined to have been malignant (8.7%) and, hence, false negatives. Nine of the nodules had repeat FNA, with none found to be malignant, and 15 received repeat ultrasound, also with no malignancies.
Overall, the false negative rate including all patients was 4.3%.
“False negative FNA biopsy results were not markedly elevated if nodules greater than 4 cm are evaluated, but rates were considerably higher if limited to surgical patients,” Dr. Thomas said.
Clinicians may be compelled to perform more aggressive surgery on large but benign thyroid nodules for a number of reasons, Dr. Tylee noted.
“A concern is that we may discontinue follow-up on these larger nodules and fail to diagnose a cancer early on, before there has been extrathyroidal extension or lymph node metastases,” she said.
In such cases, patients could wind up presenting at a higher stage of disease and require more intensive therapy.
However, with a low false negative rate overall, “all of this can increase the long-term health care costs and anxiety for patients, so having a better understanding of the true benign rate for large nodules is important,” she concluded.
Commenting on the research, Rodis D. Paparodis, MD, chief of Endocrinology, Diabetes, and Metabolism Clinics, in Patras, Greece, said the findings underscore that, as a surgical procedure, “thyroidectomy should be used cautiously, only when the benefit outweighs the risk.”
In his own previous multicenter study, Dr. Paparodis conducted a review of nearly 2,500 thyroidectomies that were performed based on size or longterm slow growth despite preoperative benign FNA findings. The results showed that only 1.9% of patients had any form of thyroid cancer in the nodule that had led to surgery; however, multiple other significant cancers were often present in other locations in the gland.
“Therefore, we suggest that careful sonographic evaluation of all thyroid nodules is warranted prior to deciding and planning the extent of surgical management for multinodular goiter,” he told this news organization.
“In addition, FNA of all suspicious nodules is required as well, to avoid unnecessary surprises in surgical pathology.”
Dr. Tylee, Dr. Thomas, and Dr. Paparodis report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WASHINGTON – , compared with only those that were.
While more research is needed, “the risk of false negative FNA results for large nodules may not be as high as reported in previous studies if you include patients who do not have indication for surgery, such as compressive symptoms, suspicious ultrasound features, etc.,” senior author Tracy Tylee, MD, an associate professor of endocrinology at the University of Washington, Seattle, said in an interview.
The implication is that nonsurgical options such as radiofrequency ablation may be appropriate for more patients than realized, she added.
“Clinicians should consider following these patients more conservatively, either with a second FNA to confirm [the] nodule is benign or with ultrasound follow-up for 5 years with intervention only if [there are] significant changes on imaging,” she said.
The findings were presented at the annual meeting of the American Thyroid Association.
Concerns about nodules over 4 cm having high false negative rates
Management of large thyroid nodules over 4 cm that are classified as Bethesda II, indicative of being benign, is complicated by concerns of false negatives in such cases. While the false negative rate for thyroid nodules in general is approximately 3%, the rate for large nodules over 4 cm has been reported as high as 35%.
Importantly, however, most studies evaluating the issue only involve patients who have received thyroid surgery, whereas most benign nodules are not referred for surgery.
“This may overestimate the false negative FNA biopsy risk for this group,” first author Melbin Thomas, MD, also of the University of Washington, said in her talk.
To better assess the false negative rate in the broader context of large nodules that did and did not undergo surgery, Dr. Thomas and her colleagues conducted a retrospective chart review of all patients undergoing FNA biopsy at her center between 2008 and 2014 for thyroid nodules larger than 4 cm and initially classified as Bethesda II, or benign.
With a follow-up of up to 10 years, nodules were considered accurately benign if they showed benign pathology on surgical resection, if they remained benign based on repeat FNA biopsy with Bethesda II results, or if there were no changes on imaging characteristics on ultrasound after at least 2 years.
Overall, 47 nodules over 4 cm and Bethesda II cytology were included, with an average follow-up of 5 years (range 2.2-9.7 years).
Of the nodules, 23 were treated with surgery, two of which were determined to have been malignant (8.7%) and, hence, false negatives. Nine of the nodules had repeat FNA, with none found to be malignant, and 15 received repeat ultrasound, also with no malignancies.
Overall, the false negative rate including all patients was 4.3%.
“False negative FNA biopsy results were not markedly elevated if nodules greater than 4 cm are evaluated, but rates were considerably higher if limited to surgical patients,” Dr. Thomas said.
Clinicians may be compelled to perform more aggressive surgery on large but benign thyroid nodules for a number of reasons, Dr. Tylee noted.
“A concern is that we may discontinue follow-up on these larger nodules and fail to diagnose a cancer early on, before there has been extrathyroidal extension or lymph node metastases,” she said.
In such cases, patients could wind up presenting at a higher stage of disease and require more intensive therapy.
However, with a low false negative rate overall, “all of this can increase the long-term health care costs and anxiety for patients, so having a better understanding of the true benign rate for large nodules is important,” she concluded.
Commenting on the research, Rodis D. Paparodis, MD, chief of Endocrinology, Diabetes, and Metabolism Clinics, in Patras, Greece, said the findings underscore that, as a surgical procedure, “thyroidectomy should be used cautiously, only when the benefit outweighs the risk.”
In his own previous multicenter study, Dr. Paparodis conducted a review of nearly 2,500 thyroidectomies that were performed based on size or longterm slow growth despite preoperative benign FNA findings. The results showed that only 1.9% of patients had any form of thyroid cancer in the nodule that had led to surgery; however, multiple other significant cancers were often present in other locations in the gland.
“Therefore, we suggest that careful sonographic evaluation of all thyroid nodules is warranted prior to deciding and planning the extent of surgical management for multinodular goiter,” he told this news organization.
“In addition, FNA of all suspicious nodules is required as well, to avoid unnecessary surprises in surgical pathology.”
Dr. Tylee, Dr. Thomas, and Dr. Paparodis report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
WASHINGTON – , compared with only those that were.
While more research is needed, “the risk of false negative FNA results for large nodules may not be as high as reported in previous studies if you include patients who do not have indication for surgery, such as compressive symptoms, suspicious ultrasound features, etc.,” senior author Tracy Tylee, MD, an associate professor of endocrinology at the University of Washington, Seattle, said in an interview.
The implication is that nonsurgical options such as radiofrequency ablation may be appropriate for more patients than realized, she added.
“Clinicians should consider following these patients more conservatively, either with a second FNA to confirm [the] nodule is benign or with ultrasound follow-up for 5 years with intervention only if [there are] significant changes on imaging,” she said.
The findings were presented at the annual meeting of the American Thyroid Association.
Concerns about nodules over 4 cm having high false negative rates
Management of large thyroid nodules over 4 cm that are classified as Bethesda II, indicative of being benign, is complicated by concerns of false negatives in such cases. While the false negative rate for thyroid nodules in general is approximately 3%, the rate for large nodules over 4 cm has been reported as high as 35%.
Importantly, however, most studies evaluating the issue only involve patients who have received thyroid surgery, whereas most benign nodules are not referred for surgery.
“This may overestimate the false negative FNA biopsy risk for this group,” first author Melbin Thomas, MD, also of the University of Washington, said in her talk.
To better assess the false negative rate in the broader context of large nodules that did and did not undergo surgery, Dr. Thomas and her colleagues conducted a retrospective chart review of all patients undergoing FNA biopsy at her center between 2008 and 2014 for thyroid nodules larger than 4 cm and initially classified as Bethesda II, or benign.
With a follow-up of up to 10 years, nodules were considered accurately benign if they showed benign pathology on surgical resection, if they remained benign based on repeat FNA biopsy with Bethesda II results, or if there were no changes on imaging characteristics on ultrasound after at least 2 years.
Overall, 47 nodules over 4 cm and Bethesda II cytology were included, with an average follow-up of 5 years (range 2.2-9.7 years).
Of the nodules, 23 were treated with surgery, two of which were determined to have been malignant (8.7%) and, hence, false negatives. Nine of the nodules had repeat FNA, with none found to be malignant, and 15 received repeat ultrasound, also with no malignancies.
Overall, the false negative rate including all patients was 4.3%.
“False negative FNA biopsy results were not markedly elevated if nodules greater than 4 cm are evaluated, but rates were considerably higher if limited to surgical patients,” Dr. Thomas said.
Clinicians may be compelled to perform more aggressive surgery on large but benign thyroid nodules for a number of reasons, Dr. Tylee noted.
“A concern is that we may discontinue follow-up on these larger nodules and fail to diagnose a cancer early on, before there has been extrathyroidal extension or lymph node metastases,” she said.
In such cases, patients could wind up presenting at a higher stage of disease and require more intensive therapy.
However, with a low false negative rate overall, “all of this can increase the long-term health care costs and anxiety for patients, so having a better understanding of the true benign rate for large nodules is important,” she concluded.
Commenting on the research, Rodis D. Paparodis, MD, chief of Endocrinology, Diabetes, and Metabolism Clinics, in Patras, Greece, said the findings underscore that, as a surgical procedure, “thyroidectomy should be used cautiously, only when the benefit outweighs the risk.”
In his own previous multicenter study, Dr. Paparodis conducted a review of nearly 2,500 thyroidectomies that were performed based on size or longterm slow growth despite preoperative benign FNA findings. The results showed that only 1.9% of patients had any form of thyroid cancer in the nodule that had led to surgery; however, multiple other significant cancers were often present in other locations in the gland.
“Therefore, we suggest that careful sonographic evaluation of all thyroid nodules is warranted prior to deciding and planning the extent of surgical management for multinodular goiter,” he told this news organization.
“In addition, FNA of all suspicious nodules is required as well, to avoid unnecessary surprises in surgical pathology.”
Dr. Tylee, Dr. Thomas, and Dr. Paparodis report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ATA 2023
Treatment of the neck and lower face with botulinum toxin
.
The neck and the lower face are covered by thin layers of a vertical muscle, the anterior and posterior platysma muscle that is innervated by the cervical branch of the facial nerve. This muscle superficially blends with the muscles of the lower face, including the depressor anguli oris, depressor labii inferioris, mentalis, risorius, and orbicularis oris muscles. The inferior portion blends with the pectoralis and anterior deltoid muscles and lifts the skin of the neck.
Treatment of the platysma muscle and bands with botulinum toxin is an effective treatment for aging and sagging of the lower face and neck. Although treatment techniques differ and there are currently no standardized guidelines, the treatment starts by having the patient contract the neck muscles (I have them sit upright, with their head completely straight and say “E” with force). After evaluating the tension of the muscle, the muscle should be grasped and pulled away from the neck. Botulinum toxin is injected perpendicular to the muscle, with a dose of approximately 2 units, 2 cm apart along the vertical muscle. Approximately 20-40 units are used for the anterior and lateral bands.
To balance the opposing forces of the depressors of the lower face and improve jowling and downturning of the mouth, 10-20 units are also injected subdermally 1 cm above and 1 cm below the mandibular border.
Understanding the anatomy of the face and neck is crucial to proper injection. Side effects from improper injection include dysphagia, dysphonia, asymmetric smile, and weakness of the neck muscles. It is also important to set realistic expectations and address other components of neck aging, including actinic damage, as well as submental and jowl fat. The manufacturer of onabotulinumtoxinA (Botox Cosmetic) recently announced positive results of a second phase 3 clinical trial evaluating onabotulinumtoxinA for the treatment of moderate to severe platysma prominence. Results of the multicenter, randomized, double blind, placebo-controlled study evaluated the safety and efficacy of one treatment versus placebo in 426 adults with moderate to severe platysmal prominence. The results showed statistically significant improvement of platysma prominence from baseline, based on investigator and patient assessments, with no new safety signals, according to the company. The company expects to submit phase 3 data to the Food and Drug Administration by the end of this year and if approved, it will be the first neurotoxin approved for the treatment of platysmal bands.
Dr. Talakoub is in private practice in McLean, Va. Write to her at [email protected]. She had no relevant disclosures.
References
Brandt FS, Bellman B. Dermatol Surg. 1998 Nov;24(11):1232-4.
Matarasso A et al. Plast Reconstr Surg. 1999 Feb;103(2):645-52.
Rohrich RJ et al. Plast Reconstr Surg Glob Open. 2020 Jun 23;8(6):e2812.
.
The neck and the lower face are covered by thin layers of a vertical muscle, the anterior and posterior platysma muscle that is innervated by the cervical branch of the facial nerve. This muscle superficially blends with the muscles of the lower face, including the depressor anguli oris, depressor labii inferioris, mentalis, risorius, and orbicularis oris muscles. The inferior portion blends with the pectoralis and anterior deltoid muscles and lifts the skin of the neck.
Treatment of the platysma muscle and bands with botulinum toxin is an effective treatment for aging and sagging of the lower face and neck. Although treatment techniques differ and there are currently no standardized guidelines, the treatment starts by having the patient contract the neck muscles (I have them sit upright, with their head completely straight and say “E” with force). After evaluating the tension of the muscle, the muscle should be grasped and pulled away from the neck. Botulinum toxin is injected perpendicular to the muscle, with a dose of approximately 2 units, 2 cm apart along the vertical muscle. Approximately 20-40 units are used for the anterior and lateral bands.
To balance the opposing forces of the depressors of the lower face and improve jowling and downturning of the mouth, 10-20 units are also injected subdermally 1 cm above and 1 cm below the mandibular border.
Understanding the anatomy of the face and neck is crucial to proper injection. Side effects from improper injection include dysphagia, dysphonia, asymmetric smile, and weakness of the neck muscles. It is also important to set realistic expectations and address other components of neck aging, including actinic damage, as well as submental and jowl fat. The manufacturer of onabotulinumtoxinA (Botox Cosmetic) recently announced positive results of a second phase 3 clinical trial evaluating onabotulinumtoxinA for the treatment of moderate to severe platysma prominence. Results of the multicenter, randomized, double blind, placebo-controlled study evaluated the safety and efficacy of one treatment versus placebo in 426 adults with moderate to severe platysmal prominence. The results showed statistically significant improvement of platysma prominence from baseline, based on investigator and patient assessments, with no new safety signals, according to the company. The company expects to submit phase 3 data to the Food and Drug Administration by the end of this year and if approved, it will be the first neurotoxin approved for the treatment of platysmal bands.
Dr. Talakoub is in private practice in McLean, Va. Write to her at [email protected]. She had no relevant disclosures.
References
Brandt FS, Bellman B. Dermatol Surg. 1998 Nov;24(11):1232-4.
Matarasso A et al. Plast Reconstr Surg. 1999 Feb;103(2):645-52.
Rohrich RJ et al. Plast Reconstr Surg Glob Open. 2020 Jun 23;8(6):e2812.
.
The neck and the lower face are covered by thin layers of a vertical muscle, the anterior and posterior platysma muscle that is innervated by the cervical branch of the facial nerve. This muscle superficially blends with the muscles of the lower face, including the depressor anguli oris, depressor labii inferioris, mentalis, risorius, and orbicularis oris muscles. The inferior portion blends with the pectoralis and anterior deltoid muscles and lifts the skin of the neck.
Treatment of the platysma muscle and bands with botulinum toxin is an effective treatment for aging and sagging of the lower face and neck. Although treatment techniques differ and there are currently no standardized guidelines, the treatment starts by having the patient contract the neck muscles (I have them sit upright, with their head completely straight and say “E” with force). After evaluating the tension of the muscle, the muscle should be grasped and pulled away from the neck. Botulinum toxin is injected perpendicular to the muscle, with a dose of approximately 2 units, 2 cm apart along the vertical muscle. Approximately 20-40 units are used for the anterior and lateral bands.
To balance the opposing forces of the depressors of the lower face and improve jowling and downturning of the mouth, 10-20 units are also injected subdermally 1 cm above and 1 cm below the mandibular border.
Understanding the anatomy of the face and neck is crucial to proper injection. Side effects from improper injection include dysphagia, dysphonia, asymmetric smile, and weakness of the neck muscles. It is also important to set realistic expectations and address other components of neck aging, including actinic damage, as well as submental and jowl fat. The manufacturer of onabotulinumtoxinA (Botox Cosmetic) recently announced positive results of a second phase 3 clinical trial evaluating onabotulinumtoxinA for the treatment of moderate to severe platysma prominence. Results of the multicenter, randomized, double blind, placebo-controlled study evaluated the safety and efficacy of one treatment versus placebo in 426 adults with moderate to severe platysmal prominence. The results showed statistically significant improvement of platysma prominence from baseline, based on investigator and patient assessments, with no new safety signals, according to the company. The company expects to submit phase 3 data to the Food and Drug Administration by the end of this year and if approved, it will be the first neurotoxin approved for the treatment of platysmal bands.
Dr. Talakoub is in private practice in McLean, Va. Write to her at [email protected]. She had no relevant disclosures.
References
Brandt FS, Bellman B. Dermatol Surg. 1998 Nov;24(11):1232-4.
Matarasso A et al. Plast Reconstr Surg. 1999 Feb;103(2):645-52.
Rohrich RJ et al. Plast Reconstr Surg Glob Open. 2020 Jun 23;8(6):e2812.
Many young adults with type 2 diabetes skip medications
Young adults who developed type 2 diabetes as children often do not take medications to control blood pressure or cholesterol, according to a new study in JAMA Network Open. Researchers expressed alarm that young people who forgo these medications increase their chances of developing kidney disease or having a stroke.
“We’re learning more and more that those with youth onset [type 2 diabetes] really differ from those with adult onset: It looks like a more virulent form of the disease because kids are getting complications and comorbidities at much earlier ages and more severe levels,” said study author Paula Trief, PhD, a professor of psychiatry and behavioral science at State University of New York, Syracuse.
Participants in the new study were on average aged 26 years. They also had previously been part of the Treating Options for Type 2 Diabetes in Adolescents and Youth study, known as TODAY, which took place from 2004 to 2011. TODAY enrolled children between ages 10 and 17 years with type 2 diabetes who received either metformin, metformin plus rosiglitazone, or metformin plus a lifestyle intervention.
The study included extensive education and contact from medical professionals to the participants about managing diabetes.
“This cohort was followed a long time and they had a lot of support. It may be better than the real world where people haven’t had the history of this much attention,” said Lorraine Katz, MD, who specializes in endocrinology and diabetes at the Children’s Hospital of Philadelphia. Dr. Katz has enrolled participants in TODAY and published about medication adherence rates but was not part of the recent analysis.
Unannounced pill counts, addressing concerns about medication
The analysis, known as iCount, included 243 participants from the original TODAY study (159 girls) who had hypertension, neuropathy, or dyslipidemia that required ongoing medication. As the TODAY study was concluding between 2017 and 2019, researchers made unannounced phone calls to participants to request the numbers of pills they had prescribed, number of refills, and the refill date. Participants also counted aloud every pill in their possession twice.
Those phone calls continued for 3 consecutive months after iCount began and again at the same intervals 1 year later.
If the number of pills counted at a later time was at least 80% of the starting total, researchers considered this rate as low adherence. Anything less than 80% was considered high adherence.
“That’s kind of an arbitrary cutoff, but it’s one that’s used consistently in the literature” to measure medication adherence for many conditions including cancer and heart disease, Dr. Trief said. Unannounced calls to initiate pill counts were first used to understand how often people took medications for HIV, and this method was found to be a more reliable method than are self-reports.
Of 196 participants with hypertension or neuropathy, 157 (80.1%) had low adherence. And of the 146 people with high cholesterol, 137 (93.8%) had low adherence. Ninety-nine people with high cholesterol also had neuropathy or diabetes.
“This is new to the literature: We don’t really know as much about this age group,” because medication adherence studies of people who have had diabetes for more than a decade and are still in their 20s are rare, Dr. Katz said.
During the core TODAY study period, all medications were provided for free. In contrast, in the current study, participants had to obtain their prescriptions on their own. The researchers found that many participants who showed low adherence to blood pressure medications reported sometimes having trouble obtaining food (n = 62), struggling with securing stable housing (n = 47), or lacking reliable health care insurance (n = 28), all factors linked to medication adherence success, according to the analysis authors.
Researchers also assessed the impact of concerns that taking blood pressure medications may be harmful and found that people with these concerns were 37% less likely to maintain high adherence than others were by the 1-year follow-up point (odds ratio, 0.63; 95% confidence interval, 0.40-0.96; P = .01).
To some extent, the reasons people avoid medications are understandable, according to pediatric endocrinologist Tamara Hannon, MD, of Indiana University, Indianapolis.
“Rather than taking a medicine to feel better, you’re taking one not to have a problem in the future: You might not feel blood pressure, you certainly don’t feel cholesterol,” Dr. Hannon, who was not involved in the analysis, said. “Scolding them or telling them you’re going to be sorry one day doesn’t generally work.”
Dr. Hannon added that education alone about the benefits of medications does not generally drive people to adherence but that adding reminders to their phone calendar when refills are due could help. Or, the clinician could reach out to a trusted person in the patient’s life and enlist their support in taking medications consistently.
Dr. Trief advised that clinicians should carve out time for people to express their concerns about medications rather than simply writing a prescription and sending them on their way and to ask patients open-ended questions.
“If you just say to people do you have any questions, they usually say, ‘no.’ ”
No disclosures were reported.
A version of this article first appeared on Medscape.com.
Young adults who developed type 2 diabetes as children often do not take medications to control blood pressure or cholesterol, according to a new study in JAMA Network Open. Researchers expressed alarm that young people who forgo these medications increase their chances of developing kidney disease or having a stroke.
“We’re learning more and more that those with youth onset [type 2 diabetes] really differ from those with adult onset: It looks like a more virulent form of the disease because kids are getting complications and comorbidities at much earlier ages and more severe levels,” said study author Paula Trief, PhD, a professor of psychiatry and behavioral science at State University of New York, Syracuse.
Participants in the new study were on average aged 26 years. They also had previously been part of the Treating Options for Type 2 Diabetes in Adolescents and Youth study, known as TODAY, which took place from 2004 to 2011. TODAY enrolled children between ages 10 and 17 years with type 2 diabetes who received either metformin, metformin plus rosiglitazone, or metformin plus a lifestyle intervention.
The study included extensive education and contact from medical professionals to the participants about managing diabetes.
“This cohort was followed a long time and they had a lot of support. It may be better than the real world where people haven’t had the history of this much attention,” said Lorraine Katz, MD, who specializes in endocrinology and diabetes at the Children’s Hospital of Philadelphia. Dr. Katz has enrolled participants in TODAY and published about medication adherence rates but was not part of the recent analysis.
Unannounced pill counts, addressing concerns about medication
The analysis, known as iCount, included 243 participants from the original TODAY study (159 girls) who had hypertension, neuropathy, or dyslipidemia that required ongoing medication. As the TODAY study was concluding between 2017 and 2019, researchers made unannounced phone calls to participants to request the numbers of pills they had prescribed, number of refills, and the refill date. Participants also counted aloud every pill in their possession twice.
Those phone calls continued for 3 consecutive months after iCount began and again at the same intervals 1 year later.
If the number of pills counted at a later time was at least 80% of the starting total, researchers considered this rate as low adherence. Anything less than 80% was considered high adherence.
“That’s kind of an arbitrary cutoff, but it’s one that’s used consistently in the literature” to measure medication adherence for many conditions including cancer and heart disease, Dr. Trief said. Unannounced calls to initiate pill counts were first used to understand how often people took medications for HIV, and this method was found to be a more reliable method than are self-reports.
Of 196 participants with hypertension or neuropathy, 157 (80.1%) had low adherence. And of the 146 people with high cholesterol, 137 (93.8%) had low adherence. Ninety-nine people with high cholesterol also had neuropathy or diabetes.
“This is new to the literature: We don’t really know as much about this age group,” because medication adherence studies of people who have had diabetes for more than a decade and are still in their 20s are rare, Dr. Katz said.
During the core TODAY study period, all medications were provided for free. In contrast, in the current study, participants had to obtain their prescriptions on their own. The researchers found that many participants who showed low adherence to blood pressure medications reported sometimes having trouble obtaining food (n = 62), struggling with securing stable housing (n = 47), or lacking reliable health care insurance (n = 28), all factors linked to medication adherence success, according to the analysis authors.
Researchers also assessed the impact of concerns that taking blood pressure medications may be harmful and found that people with these concerns were 37% less likely to maintain high adherence than others were by the 1-year follow-up point (odds ratio, 0.63; 95% confidence interval, 0.40-0.96; P = .01).
To some extent, the reasons people avoid medications are understandable, according to pediatric endocrinologist Tamara Hannon, MD, of Indiana University, Indianapolis.
“Rather than taking a medicine to feel better, you’re taking one not to have a problem in the future: You might not feel blood pressure, you certainly don’t feel cholesterol,” Dr. Hannon, who was not involved in the analysis, said. “Scolding them or telling them you’re going to be sorry one day doesn’t generally work.”
Dr. Hannon added that education alone about the benefits of medications does not generally drive people to adherence but that adding reminders to their phone calendar when refills are due could help. Or, the clinician could reach out to a trusted person in the patient’s life and enlist their support in taking medications consistently.
Dr. Trief advised that clinicians should carve out time for people to express their concerns about medications rather than simply writing a prescription and sending them on their way and to ask patients open-ended questions.
“If you just say to people do you have any questions, they usually say, ‘no.’ ”
No disclosures were reported.
A version of this article first appeared on Medscape.com.
Young adults who developed type 2 diabetes as children often do not take medications to control blood pressure or cholesterol, according to a new study in JAMA Network Open. Researchers expressed alarm that young people who forgo these medications increase their chances of developing kidney disease or having a stroke.
“We’re learning more and more that those with youth onset [type 2 diabetes] really differ from those with adult onset: It looks like a more virulent form of the disease because kids are getting complications and comorbidities at much earlier ages and more severe levels,” said study author Paula Trief, PhD, a professor of psychiatry and behavioral science at State University of New York, Syracuse.
Participants in the new study were on average aged 26 years. They also had previously been part of the Treating Options for Type 2 Diabetes in Adolescents and Youth study, known as TODAY, which took place from 2004 to 2011. TODAY enrolled children between ages 10 and 17 years with type 2 diabetes who received either metformin, metformin plus rosiglitazone, or metformin plus a lifestyle intervention.
The study included extensive education and contact from medical professionals to the participants about managing diabetes.
“This cohort was followed a long time and they had a lot of support. It may be better than the real world where people haven’t had the history of this much attention,” said Lorraine Katz, MD, who specializes in endocrinology and diabetes at the Children’s Hospital of Philadelphia. Dr. Katz has enrolled participants in TODAY and published about medication adherence rates but was not part of the recent analysis.
Unannounced pill counts, addressing concerns about medication
The analysis, known as iCount, included 243 participants from the original TODAY study (159 girls) who had hypertension, neuropathy, or dyslipidemia that required ongoing medication. As the TODAY study was concluding between 2017 and 2019, researchers made unannounced phone calls to participants to request the numbers of pills they had prescribed, number of refills, and the refill date. Participants also counted aloud every pill in their possession twice.
Those phone calls continued for 3 consecutive months after iCount began and again at the same intervals 1 year later.
If the number of pills counted at a later time was at least 80% of the starting total, researchers considered this rate as low adherence. Anything less than 80% was considered high adherence.
“That’s kind of an arbitrary cutoff, but it’s one that’s used consistently in the literature” to measure medication adherence for many conditions including cancer and heart disease, Dr. Trief said. Unannounced calls to initiate pill counts were first used to understand how often people took medications for HIV, and this method was found to be a more reliable method than are self-reports.
Of 196 participants with hypertension or neuropathy, 157 (80.1%) had low adherence. And of the 146 people with high cholesterol, 137 (93.8%) had low adherence. Ninety-nine people with high cholesterol also had neuropathy or diabetes.
“This is new to the literature: We don’t really know as much about this age group,” because medication adherence studies of people who have had diabetes for more than a decade and are still in their 20s are rare, Dr. Katz said.
During the core TODAY study period, all medications were provided for free. In contrast, in the current study, participants had to obtain their prescriptions on their own. The researchers found that many participants who showed low adherence to blood pressure medications reported sometimes having trouble obtaining food (n = 62), struggling with securing stable housing (n = 47), or lacking reliable health care insurance (n = 28), all factors linked to medication adherence success, according to the analysis authors.
Researchers also assessed the impact of concerns that taking blood pressure medications may be harmful and found that people with these concerns were 37% less likely to maintain high adherence than others were by the 1-year follow-up point (odds ratio, 0.63; 95% confidence interval, 0.40-0.96; P = .01).
To some extent, the reasons people avoid medications are understandable, according to pediatric endocrinologist Tamara Hannon, MD, of Indiana University, Indianapolis.
“Rather than taking a medicine to feel better, you’re taking one not to have a problem in the future: You might not feel blood pressure, you certainly don’t feel cholesterol,” Dr. Hannon, who was not involved in the analysis, said. “Scolding them or telling them you’re going to be sorry one day doesn’t generally work.”
Dr. Hannon added that education alone about the benefits of medications does not generally drive people to adherence but that adding reminders to their phone calendar when refills are due could help. Or, the clinician could reach out to a trusted person in the patient’s life and enlist their support in taking medications consistently.
Dr. Trief advised that clinicians should carve out time for people to express their concerns about medications rather than simply writing a prescription and sending them on their way and to ask patients open-ended questions.
“If you just say to people do you have any questions, they usually say, ‘no.’ ”
No disclosures were reported.
A version of this article first appeared on Medscape.com.
Patch testing finds higher prevalence of ACD among children with AD
, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.
ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.
Dr. Yu and his colleagues utilized a database in which dermatologists and some allergists, all of whom had substantive experience in patch testing and in diagnosing and managing ACD in children, entered information about children who were referred to them for testing.
Of 912 children referred for patch testing between 2018 and 2022 from 14 geographically diverse centers in the United States (615 with AD and 297 without AD), those with AD were more likely to have more than one positive reaction (odds radio, 1.57; 95% confidence interval, 1.14-2.14; P = .005) and had a greater number of positive results overall (2.3 vs. 1.9; P = .012).
AD and ACD both present with red, itchy, eczema-like patches and plaques and can be “really hard to differentiate,” Dr. Yu said in an interview.
“Not everybody with AD needs patch testing,” he said, “but I do think some [patients] who have rashes in unusual locations or rashes that don’t seem to improve within an appropriate amount of time to topical medications ... are the children who probably should have patch testing.”
Candidates for patch testing include children with AD who present with isolated head or neck, hand or foot, or anal or genital dermatitis, Dr. Yu and his colleagues write in the study. In addition, Dr. Yu said in the interview, “if you have a child who has AD that involves the elbow and back of the knees but then they get new-onset facial dermatitis, say, or new-onset eyelid dermatitis ... there’s [significant] value in patch testing.”
Children with AD in the study had a more generalized distribution of dermatitis and were significantly less likely to have dermatitis affecting the anal or genital region, the authors note in the study.
Asked to comment on the results, Jennifer Perryman, MD, a dermatologist at UCHealth, Greeley, Colo., who performs patch testing in children and adults, said that ACD is indeed “often underdiagnosed” in children with AD, and the study “solidifies” the importance of considering ACD in this population.
“Clinicians should think about testing children when AD is [not well controlled or] is getting worse, is in an atypical distribution, or if they are considering systemic treatment,” she said in an e-mail.
“I tell my patients, ‘I know you have AD, but you could also have comorbid ACD, and if we can find and control that, we can make you better without adding more to your routine, medications, etc.’ ” said Dr. Perryman, who was not involved in the research.
Top allergens
The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.
MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.
Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.
Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).
Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.
The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.
Patch testing availability
Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.
Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”
The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.
Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”
Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.
Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.
The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.
The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.
A version of this article first appeared on Medscape.com.
, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.
ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.
Dr. Yu and his colleagues utilized a database in which dermatologists and some allergists, all of whom had substantive experience in patch testing and in diagnosing and managing ACD in children, entered information about children who were referred to them for testing.
Of 912 children referred for patch testing between 2018 and 2022 from 14 geographically diverse centers in the United States (615 with AD and 297 without AD), those with AD were more likely to have more than one positive reaction (odds radio, 1.57; 95% confidence interval, 1.14-2.14; P = .005) and had a greater number of positive results overall (2.3 vs. 1.9; P = .012).
AD and ACD both present with red, itchy, eczema-like patches and plaques and can be “really hard to differentiate,” Dr. Yu said in an interview.
“Not everybody with AD needs patch testing,” he said, “but I do think some [patients] who have rashes in unusual locations or rashes that don’t seem to improve within an appropriate amount of time to topical medications ... are the children who probably should have patch testing.”
Candidates for patch testing include children with AD who present with isolated head or neck, hand or foot, or anal or genital dermatitis, Dr. Yu and his colleagues write in the study. In addition, Dr. Yu said in the interview, “if you have a child who has AD that involves the elbow and back of the knees but then they get new-onset facial dermatitis, say, or new-onset eyelid dermatitis ... there’s [significant] value in patch testing.”
Children with AD in the study had a more generalized distribution of dermatitis and were significantly less likely to have dermatitis affecting the anal or genital region, the authors note in the study.
Asked to comment on the results, Jennifer Perryman, MD, a dermatologist at UCHealth, Greeley, Colo., who performs patch testing in children and adults, said that ACD is indeed “often underdiagnosed” in children with AD, and the study “solidifies” the importance of considering ACD in this population.
“Clinicians should think about testing children when AD is [not well controlled or] is getting worse, is in an atypical distribution, or if they are considering systemic treatment,” she said in an e-mail.
“I tell my patients, ‘I know you have AD, but you could also have comorbid ACD, and if we can find and control that, we can make you better without adding more to your routine, medications, etc.’ ” said Dr. Perryman, who was not involved in the research.
Top allergens
The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.
MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.
Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.
Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).
Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.
The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.
Patch testing availability
Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.
Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”
The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.
Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”
Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.
Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.
The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.
The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.
A version of this article first appeared on Medscape.com.
, a finding that investigators say underscores the value of considering ACD in patients with AD and referring more children for testing.
ACD is underdetected in children with AD. In some cases, it may be misconstrued to be AD, and patch testing, the gold standard for diagnosing ACD, is often not performed, said senior author JiaDe Yu, MD, MS, a pediatric dermatologist and director of contact and occupational dermatology at Massachusetts General Hospital, Boston, and his co-authors, in the study published in the Journal of the American Academy of Dermatology.
Dr. Yu and his colleagues utilized a database in which dermatologists and some allergists, all of whom had substantive experience in patch testing and in diagnosing and managing ACD in children, entered information about children who were referred to them for testing.
Of 912 children referred for patch testing between 2018 and 2022 from 14 geographically diverse centers in the United States (615 with AD and 297 without AD), those with AD were more likely to have more than one positive reaction (odds radio, 1.57; 95% confidence interval, 1.14-2.14; P = .005) and had a greater number of positive results overall (2.3 vs. 1.9; P = .012).
AD and ACD both present with red, itchy, eczema-like patches and plaques and can be “really hard to differentiate,” Dr. Yu said in an interview.
“Not everybody with AD needs patch testing,” he said, “but I do think some [patients] who have rashes in unusual locations or rashes that don’t seem to improve within an appropriate amount of time to topical medications ... are the children who probably should have patch testing.”
Candidates for patch testing include children with AD who present with isolated head or neck, hand or foot, or anal or genital dermatitis, Dr. Yu and his colleagues write in the study. In addition, Dr. Yu said in the interview, “if you have a child who has AD that involves the elbow and back of the knees but then they get new-onset facial dermatitis, say, or new-onset eyelid dermatitis ... there’s [significant] value in patch testing.”
Children with AD in the study had a more generalized distribution of dermatitis and were significantly less likely to have dermatitis affecting the anal or genital region, the authors note in the study.
Asked to comment on the results, Jennifer Perryman, MD, a dermatologist at UCHealth, Greeley, Colo., who performs patch testing in children and adults, said that ACD is indeed “often underdiagnosed” in children with AD, and the study “solidifies” the importance of considering ACD in this population.
“Clinicians should think about testing children when AD is [not well controlled or] is getting worse, is in an atypical distribution, or if they are considering systemic treatment,” she said in an e-mail.
“I tell my patients, ‘I know you have AD, but you could also have comorbid ACD, and if we can find and control that, we can make you better without adding more to your routine, medications, etc.’ ” said Dr. Perryman, who was not involved in the research.
Top allergens
The top 10 allergens between children with and without AD were largely similar, the authors of the study report. Nickel was the most common allergen identified in both groups, and cobalt was in the top five for both groups. Fragrances (including hydroperoxides of linalool), preservatives (including methylisothiazolinone [MI]), and neomycin ranked in the top 10 in both groups, though prevalence differed.
MI, a preservative frequently used in personal care products and in other products like school glue and paint, was the second most common allergen identified in children with AD. Allergy to MI has “recently become an epidemic in the United States, with rapidly increasing prevalence and importance as a source of ACD among both children and adults,” the authors note.
Children with AD were significantly more likely, however, to have ACD to bacitracin (OR, 3.23; P = .030) and to cocamidopropyl betaine (OR, 3.69; P = .0007), the latter of which is a popular surfactant used in “baby” and “gentle” skincare products. This is unsurprising, given that children with AD are “more often exposed to a myriad of topical treatments,” Dr. Yu and his colleagues write.
Although not a top 10 allergen for either group, ACD to “carba mix,” a combination of three chemicals used to make medical adhesives and other rubber products (such as pacifiers, toys, school supplies, and rubber gloves) was significantly more common in children with AD than in those without (OR, 3.36; P = .025).
Among other findings from the study: Children with AD were more likely to have a longer history of dermatitis (4.1 vs. 1.6 years, P < .0001) prior to patch testing. Testing occurred at a mean age of 11 and 12.3 years for children with and without AD, respectively.
The number of allergens tested and the patch testing series chosen per patient were “not statistically different” between the children with and without AD, the researchers report.
Patch testing availability
Clinicians may be hesitant to subject a child to patch testing, but the process is well tolerated in most children, Dr. Perryman said. She uses a modified panel for children that omits less relevant allergens and usually limits patch testing to age 2 years or older due to a young child’s smaller surface area.
Dr. Yu, who developed an interest in patch testing during his residency at the Medical College of Wisconsin, Milwaukee, where he worked with a patch-testing expert, will test children as young as 3-4 months with a “small selection of patches.”
The challenge with a call for more patch testing is a shortage of trained physicians. “In all of Boston, where we have hundreds of dermatologists, there are only about four of us who really do patch testing. My wait time is about 6 months,” said Dr. Yu, who is also an assistant professor at Harvard Medical School, Boston.
Allergists at Massachusetts General Hospital do “some patch testing ... but they refer a lot of the most complicated cases to me,” he said, noting that patch testing and management of ACD involves detailed counseling for patients about avoidance of allergens. “Overall dermatologists represent the largest group of doctors who have proficiency in patch testing, and there just aren’t many of us.”
Dr. Perryman also said that patch testing is often performed by dermatologists who specialize in treating ACD and AD, though there seems to be “regional variance” in the level of involvement of dermatologists and allergists in patch testing.
Not all residency programs have hands-on patch testing opportunities, Dr. Yu said. A study published in Dermatitis, which he co-authored, showed that in 2020, 47.5% of dermatology residency programs had formal patch testing rotations. This represented improvement but is still not enough, he said.
The American Contact Dermatitis Society offers patch-testing mentorship programs, and the American Academy of Dermatology has recently begun offered a patch testing workshop at its annual meetings, said Dr. Yu, who received 4 weeks of training in the Society’s mentorship program and is now involved in the American Academy of Dermatology’s workshops and as a trainer/lecturer at the Contact Dermatitis Institute.
The study was supported by the Dermatology Foundation. Dr. Yu and his co-investigators reported no conflicts of interest. Dr. Perryman had no disclosures.
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
Zuranolone: FAQs for clinicians and patients
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
The Food and Drug Administration approval of zuranolone for postpartum depression in August 2023 has raised many important questions (and opinions) about its future use in clinical practice.
At the UNC-Chapel Hill Center for Women’s Mood Disorders, we treat women and pregnant people throughout hormonal transitions, including pregnancy and the postpartum, and have been part of development, research, and now delivery of both brexanolone and zuranolone. While we are excited about new tools in the arsenal for alleviating maternal mental health, we also want to be clear that our work is far from complete and continued efforts to care for pregnant people and their families are imperative.
What is zuranolone?
Zuranolone (brand name Zurzuvae) is an oral medication developed by Sage Therapeutics and Biogen. It is a positive allosteric modulator of the GABAA receptor, the brain’s major inhibitory system. As a positive allosteric modulator, it increases the sensitivity of the GABAA receptor to GABA.
Zuranolone is very similar to brexanolone, a synthetic form of allopregnanolone, a neurosteroid byproduct of progesterone (see below). However, zuranolone is not an oral form of brexanolone – it was slightly modified to ensure good oral stability and bioavailability. It is metabolized by the hepatic enzyme CYP3A4 and has a half-life of 16-23 hours. Zurzuvae is currently produced in capsule form.
What does zuranolone treat?
Zuranolone is the first FDA-approved oral drug for postpartum depression (PPD). It follows brexanolone, an intravenous drug, which was the first FDA-approved medication for PPD. Though these are the first medications with specific approval for PDD, many other treatment options are currently available including therapy, SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), and other treatments used in major depression.
How does zuranolone work?
Zuranolone is a neuroactive steroid, which means that it is a steroid that goes into and acts on the brain. Zuranolone binds to different GABA receptor subunits from those bound by other positive modulators, such as benzodiazepines (for example, lorazepam). As a synthetic form of allopregnanolone, a metabolite of progesterone which rises dramatically in pregnancy then drops during labor and delivery, zuranolone was originally thought to mitigate the response to this drop in patients that are vulnerable to it during the postpartum. An alternative proposed mechanism is that the increased GABAergic, inhibitory signaling with zuranolone may act directly to decrease depression irrespective of the exact mechanism by which the depression occurred.
How was it studied?
Zuranolone was studied in women with severe postpartum depression and had to meet criteria for major depressive disorder (MDD) no earlier than the third trimester of pregnancy (about 28 weeks’ gestation) and no later than 4 weeks post partum. Patients were excluded from these studies if they had a history of bipolar disorder, psychotic disorders, attempted suicide, or if they were at risk for suicide.
The two phase 3 clinical trials that led to FDA approval are ROBIN and SKYLARK. These studies measured the efficacy and safety of zuranolone at 30 mg and 50 mg, respectively, and met their end points of rapid improvement in depressive and anxiety symptoms in postpartum depression.
When will we be able to start using it?
It is anticipated that zuranolone will become commercially available in early 2024.
Who can prescribe it?
Those with medical licenses. Most people will likely receive treatment from their obstetric, family medicine, or psychiatric clinicians.
How much will it cost?
The manufacturers have not released this information as of August 2023.
What sort of doses and duration is recommended?
The current FDA recommended dose is 50 mg for 14 days, taken once per evening with a fatty meal. The dose can be reduced to 40 mg if there are central nervous system (CNS) depressant effects, and to 30 mg if the patient has severe hepatic or moderate-severe renal impairment. There are currently no studies on longer courses of treatment.
What happens if the patient relapses after a 14-day trial?
While there is no clear guidance, an open-label trial (The SHORELINE Study) demonstrated that a repeated 14-day administration can restore clinical response.
What are the side effects?
Common side effects include drowsiness, dizziness, lower energy, diarrhea, and symptoms similar to the common cold. Zuranolone can act like a CNS depressant and can lead to sedation and somnolence.
Are there any boxed warnings?
Because of the CNS depressant effects, zuranolone was given a boxed warning that patients should not drive or operate heavy machinery within 12 hours of taking the medication as it may lead to impairment. Similar to other antidepressants, there is also a warning that zuranolone may increase risk for suicidal thoughts in patients under 24 years old.
Can it be used with other medications?
Yes. In the original trials, women were allowed to remain on medications treating their depressive symptoms (such as SSRIs and SNRIs). According to the FDA, zuranolone can be used alone or with other antidepressants.
Are there any medicines to avoid?
We recommend caution with other medications which may increase sedation, such as benzodiazepines.
Can it be used with birth control?
Yes. In fact, because the outcomes on a fetus are not yet studied, it is recommended that patients be on concurrent birth control during treatment and for a week after cessation. This does not mean that zuranolone is known to cause issues with fetal development, but rather that we do not know at this time.
Can it be used in pregnancy?
As above, the outcomes on fetal development are not known at this time, nor are the effects of zuranolone on labor and delivery. More research will need to be done to understand if there is risk with taking zuranolone during pregnancy. It should be noted that allopregnanolone levels ordinarily reach quite high levels during pregnancy.
Long-term side effects?
Long-term side effects are unknown. The study duration of ROBIN and SKYLARK was 45 days.
Breastfeeding?
Use in lactation has not yet been studied. Continued research is needed.
Can it be used in mood changes related to other reproductive changes or diagnoses like premenstrual dysphoric disorder and perimenopause?
The mechanism by which zuranolone is thought to work – that is, during changes in reproductive hormones – is implicated in other reproductive transitions such as premenstrual dysphoric disorder and perimenopause when reproductive hormones are fluctuating, though at lower levels than in pregnancy. Research will be required to assess efficacy and safety; however, the mechanistic reasons is worth pursuing. Additionally, zuranolone has not been studied in postpartum psychosis.
Can zuranolone be used to treat other affective conditions besides postpartum depression? Bipolar disorder?
Whether it may be beneficial for patients with a depressive episode that is part of an underlying bipolar disorder or other psychiatric illness is not yet known.
Anxiety?
Along with depressive symptoms, women who received zuranolone in the clinical trials also had improvements in anxiety symptoms. These findings provide some hope that zuranolone may eventually be beneficial in patients with anxiety.
However, to date zuranolone has not been directly studied as a treatment for anxiety disorders (such as generalized anxiety disorder, panic disorder, etc.), so its efficacy for these illnesses is currently unknown.
Insomnia?
In a study of 153 postpartum women, randomized to placebo or zuranolone, scale questions for insomnia were improved in the group receiving zuranolone. This provides some hope that, if zuranolone is appropriate, concurrent polypharmacy with a sleep aid can be avoided. Additionally, future evaluation of use in insomnia outside of PPD may be warranted.
How is it different from brexanolone?
The two are slightly different molecules. Brexanolone is synthetically identical to allopregnanolone and zuranolone has been altered to be active and orally bioavailable.
Brexanolone is a 60-hour infusion that requires hospital admission at an approved health care site. Zuranolone is an oral at-home once-daily dosing treatment for 14 days. Zuranolone does not require enrollment in a risk evaluation and mitigation strategy for risk of excessive sedation and sudden loss of consciousness.
When would you consider zuranolone vs. brexanolone vs. other antidepressants?
Zuranolone and brexanolone are rapid-acting antidepressants with a response within 14 days or 60 hours, respectively. Antidepressants such as SSRIs/SNRIs are still available, well studied, and work, although take longer to reach clinical efficacy and are accompanied by potentially troubling side effects (for example, weight gain, sexual dysfunction).
Time to treatment effect should be considered when assessing severity of symptoms and functional impairment of the mother and the overall family unit. Brexanolone requires continuous monitoring which may be beneficial for women who are severely impaired and may benefit from frequent clinical monitoring. Brexanolone does not require a dose reduction with hepatic impairment, however, should be avoided in end-stage renal disease because of the potential accumulation of the solubilizing agent.
Where can I find more information?
Many states have maternal mental health consultation lines (examples include NCMATTERS here in North Carolina and MCPAP for Moms in Massachusetts) for clinicians (mental health, primary care, and obstetricians) that can be utilized for questions about prescribing. Postpartum Support International also has a clinician line for those without state services.
We plan to update this entry upon market release and access to new information.
Dr. Riddle and Dr. Nathan are assistant professors in the department of psychiatry at the University of North Carolina at Chapel Hill. Dr. Richardson is a perinatal psychiatry fellow, department of psychiatry, UNC-Chapel Hill. Dr. Rubinow is Distinguished Professor in the department of psychiatry, UNC-Chapel Hill. Dr. Meltzer-Brody is Assad Meymandi Distinguished Professor and Chair, department of psychiatry, UNC-Chapel Hill.
References
Deligiannidis KM et al. J Clin Psychiatry. 2023 Jan 30;84(1):22m14475. doi: 10.4088/JCP.22m14475.
Deligiannidis KM et al. . Obstetrics & Gynecology. 2023 May;141(5S):64S-65S. doi: 10.1097/01.AOG.0000930588.16136.3f.
Deligiannidis KM et al. Am J Psychiatry. 2023 Sep 1;180(9):668-75. doi: 10.1176/appi.ajp.20220785.
Deligiannidis KM et al. JAMA Psychiatry. 2021 Sep 1;78(9):951-59. doi: 10.1001/jamapsychiatry.2021.1559.
FDA Approves First Oral Treatment for Postpartum Depression. 2023 Aug 4. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-treatment-postpartum-depression
ZURZUVAE – HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217369s000lbl.pdf
Low-certainty evidence supports probiotics for IBS
or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.
These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.
“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.
They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.
“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.
To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.
“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.
The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.
For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.
For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.
Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.
In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.
“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”
A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.
“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”
The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.
These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.
“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.
They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.
“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.
To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.
“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.
The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.
For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.
For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.
Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.
In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.
“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”
A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.
“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”
The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.
or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.
These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.
“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.
They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.
“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.
To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.
“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.
The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.
For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.
For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.
Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.
In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.
“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”
A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.
“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”
The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.
FROM GASTROENTEROLOGY
Can these salt substitutes prevent complications of hypertension?
ILLUSTRATIVE CASE
A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.
The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?
Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.2 The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).3
Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, 4 the Eighth Joint National Committee (JNC 8), 5 the International Society of Hypertension, 6 and the European Society of Cardiology 7 use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. 8
When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the
Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. 10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. 13 Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of patient-oriented evidence that demonstrates improvement in CV disease and mortality.
The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. 14 Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. 13
Continue to: In this 2022 systematic review...
In this 2022 systematic review and meta-analysis, 1 Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.
STUDY SUMMARY
Salt substitutes reduced BP across diverse populations
This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.
The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.
The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I 2 > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.
Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.
Continue to: Only 2 of the studes...
Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.
WHAT’S NEW
High-quality data demonstrate beneficial outcomes
Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.
CAVEATS
Some patient populations, comorbidities excluded from study
The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.
Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.
Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.
CHALLENGES TO IMPLEMENTATION
For appropriate patients, no challenges anticipated
There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.
1. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398:957-980. doi: 10.1016/S0140-6736(21)01330-1
3. USPSTF. Hypertension in adults: screening. Final recommendation statement. Published April 27, 2021. Accessed September 18, 2023. www.uspreventiveservicestaskforce.org/uspstf/recommendation/hypertension-in-adults-screening
4. Coles S, Fisher L, Lin KW, et al. Blood pressure targets in adults with hypertension: a clinical practice guideline from the AAFP. Published November 4, 2022. Accessed September 18, 2023. www.aafp.org/dam/AAFP/documents/journals/afp/AAFPHypertensionGuideline.pdf
5. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. doi: 10.1001/jama. 2013.284427
6. Unger T, Borgi C, Charchar F, et al. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334-1357. doi: 10.1161/HYPERTENSIONAHA.120.15026
7. Mancia G, Kreutz R, Brunstrom M, et al; the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension. 2023 ESH Guidelines for the management of arterial hypertension. Endorsed by the European Renal Association (ERA) and the International Society of Hypertension (ISH). J Hypertens. 2023; Jun 21. doi: 10.1097/HJH.0000000000003480
8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-e115. 10.1161/HYP.0000000000000065
9. National Center for Health Statistics. National Ambulatory Medical Care Survey: 2014 state and national summary tables. Accessed June 27, 2023. www.cdc.gov/nchs/data/ahcd/namcs_summary/2014_namcs_web_tables.pdf
10. Huang L, Trieu K, Yoshimura S, et al. Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials. BMJ. 2020;368:m315. doi: 10.1136/bmj.m315
11. Filippini T, Violi F, D’Amico R, et al. The effect of potassium supplementation on blood pressure in hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol. 2017;230:127-135. doi: 10.1016/j.ijcard.2016.12.048
12. Brand A, Visser ME, Schoonees A, et al. Replacing salt with low-sodium salt substitutes (LSSS) for cardiovascular health in adults, children and pregnant women. Cochrane Database Syst Rev. 2022;8:CD015207. doi: 10.1002/14651858.CD015207
13. He FJ, Tan M, Ma Y, et al. Salt reduction to prevent hypertension and cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:632-647. doi: 10.1016/j.jacc.2019.11.055
14. Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. 2021;385:1067-1077. doi: 10.1056/NEJMoa2105675
ILLUSTRATIVE CASE
A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.
The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?
Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.2 The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).3
Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, 4 the Eighth Joint National Committee (JNC 8), 5 the International Society of Hypertension, 6 and the European Society of Cardiology 7 use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. 8
When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the
Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. 10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. 13 Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of patient-oriented evidence that demonstrates improvement in CV disease and mortality.
The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. 14 Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. 13
Continue to: In this 2022 systematic review...
In this 2022 systematic review and meta-analysis, 1 Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.
STUDY SUMMARY
Salt substitutes reduced BP across diverse populations
This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.
The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.
The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I 2 > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.
Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.
Continue to: Only 2 of the studes...
Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.
WHAT’S NEW
High-quality data demonstrate beneficial outcomes
Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.
CAVEATS
Some patient populations, comorbidities excluded from study
The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.
Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.
Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.
CHALLENGES TO IMPLEMENTATION
For appropriate patients, no challenges anticipated
There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.
ILLUSTRATIVE CASE
A 47-year-old man in generally good health presents to a family medicine clinic for a well visit. He does not use tobacco products and had a benign colonoscopy last year. He reports walking for 30 minutes 3 to 4 times per week for exercise, althoug h he has gained 3 lbs over the past 2 years. He has no family history of early coronary artery disease, but his father and older brother have hypertension. His mother has a history of diabetes and hyperlipidemia.
The patient’s physical exam is unremarkable except for an elevated BP reading of 151/82 mm Hg. A review of his chart indicates he has had multiple elevated readings in the past that have ranged from 132/72 mm Hg to 139/89 mm Hg. The patient is interested in antihypertensive treatment but wants to know if modifying his diet and replacing his regular table salt with a salt substitute will lower his high BP. What can you recommend?
Hypertension is a leading cause of CV morbidity and mortality worldwide and is linked to increased dietary sodium intake. An estimated 1.28 billion people worldwide have hypertension; however, more than half of cases are undiagnosed.2 The US Preventive Services Task Force recommends screening for hypertension in adults older than 18 years and confirming elevated measurements conducted in a nonclinical setting before starting medication (grade “A”).3
Cut-points for the diagnosis of hypertension vary. The American Academy of Family Physicians, 4 the Eighth Joint National Committee (JNC 8), 5 the International Society of Hypertension, 6 and the European Society of Cardiology 7 use ≥ 140 mm Hg systolic BP (SBP) or ≥ 90 mm Hg diastolic BP (DBP) to define hypertension. The American College of Cardiology/American Heart Association guidelines use ≥ 130/80 mm Hg. 8
When treating patients with hypertension, primary care physicians often recommend lifestyle modifications such as the
Systematic reviews have shown a measurable improvement in BP with sodium reduction and potassium substitution. 10-12 More importantly, high-quality evidence demonstrates a decreased risk for CV disease, kidney disease, and all-cause mortality with lower dietary sodium intake. 13 Previous studies have shown that potassium-enriched salt substitutes lower BP, but their impact on CV morbidity and mortality is not well defined. Although lowering BP is associated with improved clinical impact, there is a lack of patient-oriented evidence that demonstrates improvement in CV disease and mortality.
The Salt Substitute and Stroke Study (SSaSS), published in 2021, demonstrated the protective effect of salt substitution against stroke, other CV events, and death. 14 Furthermore, this 5-year, cluster-randomized controlled trial of 20,995 participants across 600 villages in China demonstrated reduced CV mortality and BP reduction similar to standard pharmacologic treatment. Prior to SSaSS, 17 randomized controlled trials demonstrated a BP-lowering effect of salt substitutes but did not directly study the impact on clinical outcomes. 13
Continue to: In this 2022 systematic review...
In this 2022 systematic review and meta-analysis, 1 Yin et al evaluated 21 trials, including SSaSS, for the effect of salt substitutes on BP and other clinical outcomes, and the generalizability of the study results to diverse populations. The systematic review included parallel-group, step-wedge, and cluster-randomized controlled trials reporting the effect of salt substitutes on BP or clinical outcomes.
STUDY SUMMARY
Salt substitutes reduced BP across diverse populations
This systematic review and meta-analysis reviewed existing literature for randomized controlled trials investigating the effects of potassium-enriched salt substitutes on clinical outcomes for patients without kidney disease. The most commonly used salt substitute was potassium chloride, at 25% to 65% potassium.
The systematic review identified 21 trials comprising 31,949 study participants from 15 different countries with 1 to 60 months’ duration. Meta-analyses were performed using 19 trials for BP outcomes and 5 trials for vascular outcomes. Eleven trials were rated as having low risk for bias, 8 were deemed to have some concern, and 2 were rated as high risk for bias. Comparisons of data excluding studies with high risk for bias yielded results similar to comparisons of all studies.
The meta-analysis of 19 trials demonstrated reduced SBP (–4.6 mm Hg; 95% CI, –6.1 to –3.1) and DBP (–1.6 mm Hg; 95% CI, –2.4 to –0.8) in participants using potassium-enriched salt substitutes. However, the authors noted substantial heterogeneity among the studies (I 2 > 70%) for both SBP and DBP outcomes. Although there were no subgroup differences for age, sex, hypertension history, or other biomarkers, outcome differences were associated with trial duration, baseline potassium intake, and composition of the salt substitute.
Potassium-enriched salt substitutes were associated with reduced total mortality (risk ratio [RR] = 0.89; 95% CI, 0.85-0.94), CV mortality (RR = 0.87; 95% CI, 0.81-0.94), and CV events (RR = 0.89; 95% CI, 0.85-0.94). In a meta-regression, each 10% reduction in the sodium content of the salt substitute was associated with a 1.5–mm Hg greater reduction in SBP (95% CI, –3.0 to –0.03) and a 1.0–mm Hg greater reduction in DBP (95% CI, –1.8 to –0.1). However, the authors suggest interpreting meta-regression results with caution.
Continue to: Only 2 of the studes...
Only 2 of the studies in the systematic review explicitly reported the adverse effect of hyperkalemia, and there was no statistical difference in events between randomized groups. Eight other studies reported no serious adverse events related to hyperkalemia , and 11 studies did not report on the risk for hyperkalemia.
WHAT’S NEW
High-quality data demonstrate beneficial outcomes
Previous observational and interventional studies demonstrated a BP-lowering effect of salt substitutes, but limited data with poor-quality evidence existed for the impact of salt substitutes on clinical outcomes such as mortality and CV events. This systematic review and meta-analysis suggests that potassium-supplemented salt may reduce BP and secondarily reduce the risk for CV events, CV mortality, and total mortality, without clear harmful effects reported.
CAVEATS
Some patient populations, comorbidities excluded from study
The study did not include patients with kidney disease or those taking potassium-sparing diuretics. Furthermore, the available data do not include primary prevention participants.
Subgroup analyses should be interpreted with caution due to the small number of trials available for individual subgroups. In addition, funnel plot asymmetry for studies reporting DBP suggests at least some effect of publication bias for that outcome.
Although BP reduction due to salt substitutes may be small at an individual level, these levels of reduction may be important at a population level.
CHALLENGES TO IMPLEMENTATION
For appropriate patients, no challenges anticipated
There are no significant challenges to implementing conclusions from this study in the primary care setting. Family physicians should be able to recommend potassium-enriched salt substitutes to patients with hypertension who are not at risk for hyperkalemia, including those with kidney disease, on potassium-sparing diuretics, or with a history of hyperkalemia/hyperkalemic conditions. Salt substitutes, including potassium-enriched salts, are readily available in stores.
1. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398:957-980. doi: 10.1016/S0140-6736(21)01330-1
3. USPSTF. Hypertension in adults: screening. Final recommendation statement. Published April 27, 2021. Accessed September 18, 2023. www.uspreventiveservicestaskforce.org/uspstf/recommendation/hypertension-in-adults-screening
4. Coles S, Fisher L, Lin KW, et al. Blood pressure targets in adults with hypertension: a clinical practice guideline from the AAFP. Published November 4, 2022. Accessed September 18, 2023. www.aafp.org/dam/AAFP/documents/journals/afp/AAFPHypertensionGuideline.pdf
5. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. doi: 10.1001/jama. 2013.284427
6. Unger T, Borgi C, Charchar F, et al. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334-1357. doi: 10.1161/HYPERTENSIONAHA.120.15026
7. Mancia G, Kreutz R, Brunstrom M, et al; the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension. 2023 ESH Guidelines for the management of arterial hypertension. Endorsed by the European Renal Association (ERA) and the International Society of Hypertension (ISH). J Hypertens. 2023; Jun 21. doi: 10.1097/HJH.0000000000003480
8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-e115. 10.1161/HYP.0000000000000065
9. National Center for Health Statistics. National Ambulatory Medical Care Survey: 2014 state and national summary tables. Accessed June 27, 2023. www.cdc.gov/nchs/data/ahcd/namcs_summary/2014_namcs_web_tables.pdf
10. Huang L, Trieu K, Yoshimura S, et al. Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials. BMJ. 2020;368:m315. doi: 10.1136/bmj.m315
11. Filippini T, Violi F, D’Amico R, et al. The effect of potassium supplementation on blood pressure in hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol. 2017;230:127-135. doi: 10.1016/j.ijcard.2016.12.048
12. Brand A, Visser ME, Schoonees A, et al. Replacing salt with low-sodium salt substitutes (LSSS) for cardiovascular health in adults, children and pregnant women. Cochrane Database Syst Rev. 2022;8:CD015207. doi: 10.1002/14651858.CD015207
13. He FJ, Tan M, Ma Y, et al. Salt reduction to prevent hypertension and cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:632-647. doi: 10.1016/j.jacc.2019.11.055
14. Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. 2021;385:1067-1077. doi: 10.1056/NEJMoa2105675
1. Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart. 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
2. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants. Lancet. 2021;398:957-980. doi: 10.1016/S0140-6736(21)01330-1
3. USPSTF. Hypertension in adults: screening. Final recommendation statement. Published April 27, 2021. Accessed September 18, 2023. www.uspreventiveservicestaskforce.org/uspstf/recommendation/hypertension-in-adults-screening
4. Coles S, Fisher L, Lin KW, et al. Blood pressure targets in adults with hypertension: a clinical practice guideline from the AAFP. Published November 4, 2022. Accessed September 18, 2023. www.aafp.org/dam/AAFP/documents/journals/afp/AAFPHypertensionGuideline.pdf
5. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. doi: 10.1001/jama. 2013.284427
6. Unger T, Borgi C, Charchar F, et al. 2020 International Society of Hypertension global hypertension practice guidelines. Hypertension. 2020;75:1334-1357. doi: 10.1161/HYPERTENSIONAHA.120.15026
7. Mancia G, Kreutz R, Brunstrom M, et al; the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension. 2023 ESH Guidelines for the management of arterial hypertension. Endorsed by the European Renal Association (ERA) and the International Society of Hypertension (ISH). J Hypertens. 2023; Jun 21. doi: 10.1097/HJH.0000000000003480
8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-e115. 10.1161/HYP.0000000000000065
9. National Center for Health Statistics. National Ambulatory Medical Care Survey: 2014 state and national summary tables. Accessed June 27, 2023. www.cdc.gov/nchs/data/ahcd/namcs_summary/2014_namcs_web_tables.pdf
10. Huang L, Trieu K, Yoshimura S, et al. Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials. BMJ. 2020;368:m315. doi: 10.1136/bmj.m315
11. Filippini T, Violi F, D’Amico R, et al. The effect of potassium supplementation on blood pressure in hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol. 2017;230:127-135. doi: 10.1016/j.ijcard.2016.12.048
12. Brand A, Visser ME, Schoonees A, et al. Replacing salt with low-sodium salt substitutes (LSSS) for cardiovascular health in adults, children and pregnant women. Cochrane Database Syst Rev. 2022;8:CD015207. doi: 10.1002/14651858.CD015207
13. He FJ, Tan M, Ma Y, et al. Salt reduction to prevent hypertension and cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. 2020;75:632-647. doi: 10.1016/j.jacc.2019.11.055
14. Neal B, Wu Y, Feng X, et al. Effect of salt substitution on cardiovascular events and death. N Engl J Med. 2021;385:1067-1077. doi: 10.1056/NEJMoa2105675
PRACTICE CHANGER
Consider recommending potassium-enriched salt substitutes for appropriate patients with hypertension to reduce blood pressure (BP) and risk for related cardiovascular (CV) events or mortality.
STRENGTH OF RECOMMENDATION
A: Based on a systematic review and meta-analysis of controlled trials. 1
Yin X, Rodgers A, Perkovic A, et al. Effects of salt substitutes on clinical outcomes: a systematic review and meta-analysis. Heart . 2022;108:1608-1615. doi: 10.1136/heartjnl-2022-321332
