Article

Actively Recruiting

→Continuous Glucose Monitoring Devices in Hospitalized Veterans With Diabetes

More than 25% of the patients admitted in the general wards have a history of diabetes mellitus. Up to 30% of the hospitalized diabetics develop hypoglycemia (low glucose values); a condition that is associated with seizures, cardiac arrhythmias, and even death. In veterans, the prevalence is disproportionally higher. It is estimated that 40% to 50% of hospitalized veterans are diabetics. In this clinical trial the investigators describe the development of a novel system, the Glucose Telemetry System, with which glucose values can be wirelessly transmitted from the patient’s bedside to a monitor device at the nursing station. The goal of this work is to develop a more effective glucose surveillance system at the general wards, which can decrease hypoglycemia in the hospital and improve clinical outcomes.

ID: NCT03508934

Sponsor; Investigator: VA Office of Research and Development; Ilias Spanakis, MD

Locations: Baltimore VA Medical Center, Maryland

→Optimizing Gait Rehabilitation for Veterans With Non-Traumatic Lower Limb Amputation (GEM)

The population of older veterans with nontraumatic lower limb amputation is growing. Following lower limb amputation, asymmetrical movements persist during walking and likely contribute to disabling sequelae including secondary pain conditions, poor gait efficiency, impaired physical function, and compromised skin integrity of the residual limb. This study seeks to address chronic gait asymmetry by evaluating the efficacy of two error-manipulation gait training programs to improve gait symmetry for veterans with nontraumatic lower limb amputation. Additionally, this study will evaluate the potential of error-manipulation training programs to improve secondary measures of disability and residual limb skin health. Ultimately, this study aims to improve conventional prosthetic rehabilitation for veterans with nontraumatic amputation through gait training programs based in motor learning principles, resulting in improved.

ID: NCT003995238

Sponsor; Investigator: VA Office of Research and Development; Cory L. Christiansen, PhD

Locations: Rocky Mountain Regional VA Medical Center, Aurora, Colorado; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

→Empowering Veterans to Actively Communicate and Engage in Shared Decision Making in Medical Visits, A Randomized Controlled Trial (ACTIVet-2)

Type 2 diabetes is a significant condition in VA affecting 20% of VA patients. Adherence to medication regimens and lifestyle factors is important to achieve care goals for these patients. Patients who use active participatory communication behaviors with their providers have better adherence to treatment and better biomedical outcomes, yet many patients are not prepared to engage in active communication with their providers. Existing coaching interventions have not been adopted in practice because of the cost of trained personnel. The investigators haveshown the efficacy of a low-cost video that did not require trained personnel. This proposal proposes to test implementation strategies to deliver that video in VA primary care clinics and to test the effectiveness of the video to improve outcomes in a hybrid type 2 effectiveness implementation trial using a cluster randomized stepped wedgedesign at eight sites. This proposal will test feasibility of implementing the video and if successful will generate the evidence to justify widespread dissemination of the video.

ID: NCT05169359

Sponsor; Investigator: VA Office of Research and Development; Howard S. Gordon, MD

Location: 8 locations, including Jesse Brown VA Medical Center, Chicago; Edward Hines Jr. VA Hopsital, Hines, Illinois

→The Diabetes Staging System in Patient Aligned Care Teams

The purpose of this study is to examine the feasibility/acceptability of the Diabetes Staging System in patient aligned care teams and its ability to increase sodium-glucosecotransporter-2 inhibitor and glucagon-like-1 peptide use in veteran patients with type 2 diabetes and cardiovascular disease and/or chronic kidney disease. A novel type 2 diabetes staging system patterned after Tumor Node Metastasis cancer staging that uses the number of macrovascular and microvascular complications and most recent hemoglobin A_1c and glomerular filtration rate to determine Diabetes Staging System stage which reflects disease severity.

ID: NCT06142006

Sponsor; Collaborator: Durham VA Medical Center; Moahad Dar, MD

Location: Greenville VA Health Care Center, North Carolina

→Enhancing Mental and Physical Health of Women Veterans (EMPOWER)

Women veterans are the fastest growing segment of VA users. This dramatic growth has created challenges for VA to ensure that appropriate services are available to meet women veterans’ needs, and that they will want and be able to use those services. The EMPOWER QUERI 2.0 Program is a cluster randomized type 3 hybrid implementation effectiveness trial testing 2 strategies designed to support implementation and sustainment of evidence-based practices for women veterans in at least 20 VA facilities from 4 regions.

ID: NCT05050266

Sponsor; Investigator: VA Office of Research and Development; Alison B. Hamilton, PhD, MPH

Location: VA Greater Los Angeles Healthcare System

→Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA INTREPID)

The purpose of this research study is to determine if rifampin, an antibiotic (a medicine that treats infections), is effective in treating osteomyelitis (infection of the bone) of the foot in patients with diabetes. Despite use of powerful antibiotics prescribed over a long period of time, many diabetic patients remain at a high risk for needing an amputation of part of the foot or lower leg because the osteomyelitis is not cured. Some small research studies have shown that addition of rifampin to other antibiotics is effective in treating osteomyelitis. However, because few diabetics with osteomyelitis have been studied, there is no definite proof that it is better than the usual treatments for diabetic patients. If this study finds that adding rifampin to the usual antibiotics prescribed for osteomyelitis reduces the risk for amputations, doctors will be able to more effectively treat many veteran patients with this serious infection. Improving treatment outcomes is an important healthcare goal of the VA.

ID: NCT03012529

Sponsor; Investigator: VA Office of Research and Development; Paul A. Monach, MD, PhD

Location: 30 VA locations, including South Texas Health Care System, San Antonio; Cincinnati VA Medical Center, Ohio; VA Northern California Health Care System, Mather; Washington DC VA Medical Center; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

→Effectiveness of Remote Foot Temperature Monitoring (STOP)

Diabetic foot ulcers are common, debilitating, and costly complications of diabetes, disproportionately impacting Black and rural veterans. Forty percent of individuals have an ulcer recurrence within a year of ulcer healing and 65% within 5 years. Monitoring plantar foot temperatures is one of the few interventions that reduces the risk of ulcer recurrence. Despite the evidence, adoption has been poorbecause the original procedures, including the use of handheld thermometers, were burdensome and time-consuming. Podimetrics, a private company, has developed a temperature monitoring system involving a “smart” mat that can wirelessly transmit data and a remote monitoring team that works with VA providers to assist with triage and monitoring. This care model has incredible promise, but has been untested in VA. The investigators propose to conduct a randomized trial to evaluate effectiveness of remote temperature monitoring as well as costs. Additionally, the investigators will evaluate the implementation process, including barriers and facilitators to use among key stakeholders.

ID: NCT05728411

Sponsor; Investigator: VA Office of Research and Development; Rachel M. Thomas

Location: Edward Hines Jr. VA Hospital, Hines, Illinois; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia; VA Puget Sound Health Care System, Seattle, Washington

→Continuous Glucose Monitoring for Hyperglycemia in Critically Ill Patients

The investigators intend to conduct a single-center, prospective, randomized comparative trial of patients admitted to the intensive care unit who received continuous glucose monitoring vs point of care glucose monitoring. The study will examine relevant outcomes for patients in the intensive care unit with diabetes mellitus and/or hyperglycemia. The primary outcome of the study will be the proportion of time in target range (blood glucose 70-180 mg/dL).

ID: NCT05442853

Sponsor; Investigator: Malcom Randall VA Medical Center; Andrew J. Franck, PharmD

Location: Malcolm Randall VA Medical Center, Gainesville, Florida

→Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT)

CSP #2002 is a multicenter, prospective, randomized, double blind, secondary prevention trial to test the hypothesis that treatment with metformin, compared with placebo, reduces mortality and cardiovascular morbidity in veterans with pre-diabetes and established atherosclerotic cardiovascular disease. Qualifying patients have pre-diabetes defined by HbA _1c , fasting blood glucose, or oral glucose tolerance test criteria; clinically evident coronary, cerebrovascular, or peripheral arterial atherosclerotic cardiovascular disease; and estimated glomerular filtration rate of at least 45 mL/min/1.73 m ² ; and do not fulfill any exclusion criteria.

ID: NCT04838392

Sponsor; Investigator: VA Office of Research and Development; Gregory G. Schwartz, PhD, MD

Locations: 40 locations

Actively Recruiting

→Continuous Glucose Monitoring Devices in Hospitalized Veterans With Diabetes

More than 25% of the patients admitted in the general wards have a history of diabetes mellitus. Up to 30% of the hospitalized diabetics develop hypoglycemia (low glucose values); a condition that is associated with seizures, cardiac arrhythmias, and even death. In veterans, the prevalence is disproportionally higher. It is estimated that 40% to 50% of hospitalized veterans are diabetics. In this clinical trial the investigators describe the development of a novel system, the Glucose Telemetry System, with which glucose values can be wirelessly transmitted from the patient’s bedside to a monitor device at the nursing station. The goal of this work is to develop a more effective glucose surveillance system at the general wards, which can decrease hypoglycemia in the hospital and improve clinical outcomes.

ID: NCT03508934

Sponsor; Investigator: VA Office of Research and Development; Ilias Spanakis, MD

Locations: Baltimore VA Medical Center, Maryland

→Optimizing Gait Rehabilitation for Veterans With Non-Traumatic Lower Limb Amputation (GEM)

The population of older veterans with nontraumatic lower limb amputation is growing. Following lower limb amputation, asymmetrical movements persist during walking and likely contribute to disabling sequelae including secondary pain conditions, poor gait efficiency, impaired physical function, and compromised skin integrity of the residual limb. This study seeks to address chronic gait asymmetry by evaluating the efficacy of two error-manipulation gait training programs to improve gait symmetry for veterans with nontraumatic lower limb amputation. Additionally, this study will evaluate the potential of error-manipulation training programs to improve secondary measures of disability and residual limb skin health. Ultimately, this study aims to improve conventional prosthetic rehabilitation for veterans with nontraumatic amputation through gait training programs based in motor learning principles, resulting in improved.

ID: NCT003995238

Sponsor; Investigator: VA Office of Research and Development; Cory L. Christiansen, PhD

Locations: Rocky Mountain Regional VA Medical Center, Aurora, Colorado; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

→Empowering Veterans to Actively Communicate and Engage in Shared Decision Making in Medical Visits, A Randomized Controlled Trial (ACTIVet-2)

Type 2 diabetes is a significant condition in VA affecting 20% of VA patients. Adherence to medication regimens and lifestyle factors is important to achieve care goals for these patients. Patients who use active participatory communication behaviors with their providers have better adherence to treatment and better biomedical outcomes, yet many patients are not prepared to engage in active communication with their providers. Existing coaching interventions have not been adopted in practice because of the cost of trained personnel. The investigators haveshown the efficacy of a low-cost video that did not require trained personnel. This proposal proposes to test implementation strategies to deliver that video in VA primary care clinics and to test the effectiveness of the video to improve outcomes in a hybrid type 2 effectiveness implementation trial using a cluster randomized stepped wedgedesign at eight sites. This proposal will test feasibility of implementing the video and if successful will generate the evidence to justify widespread dissemination of the video.

ID: NCT05169359

Sponsor; Investigator: VA Office of Research and Development; Howard S. Gordon, MD

Location: 8 locations, including Jesse Brown VA Medical Center, Chicago; Edward Hines Jr. VA Hopsital, Hines, Illinois

→The Diabetes Staging System in Patient Aligned Care Teams

The purpose of this study is to examine the feasibility/acceptability of the Diabetes Staging System in patient aligned care teams and its ability to increase sodium-glucosecotransporter-2 inhibitor and glucagon-like-1 peptide use in veteran patients with type 2 diabetes and cardiovascular disease and/or chronic kidney disease. A novel type 2 diabetes staging system patterned after Tumor Node Metastasis cancer staging that uses the number of macrovascular and microvascular complications and most recent hemoglobin A_1c and glomerular filtration rate to determine Diabetes Staging System stage which reflects disease severity.

ID: NCT06142006

Sponsor; Collaborator: Durham VA Medical Center; Moahad Dar, MD

Location: Greenville VA Health Care Center, North Carolina

→Enhancing Mental and Physical Health of Women Veterans (EMPOWER)

Women veterans are the fastest growing segment of VA users. This dramatic growth has created challenges for VA to ensure that appropriate services are available to meet women veterans’ needs, and that they will want and be able to use those services. The EMPOWER QUERI 2.0 Program is a cluster randomized type 3 hybrid implementation effectiveness trial testing 2 strategies designed to support implementation and sustainment of evidence-based practices for women veterans in at least 20 VA facilities from 4 regions.

ID: NCT05050266

Sponsor; Investigator: VA Office of Research and Development; Alison B. Hamilton, PhD, MPH

Location: VA Greater Los Angeles Healthcare System

→Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA INTREPID)

The purpose of this research study is to determine if rifampin, an antibiotic (a medicine that treats infections), is effective in treating osteomyelitis (infection of the bone) of the foot in patients with diabetes. Despite use of powerful antibiotics prescribed over a long period of time, many diabetic patients remain at a high risk for needing an amputation of part of the foot or lower leg because the osteomyelitis is not cured. Some small research studies have shown that addition of rifampin to other antibiotics is effective in treating osteomyelitis. However, because few diabetics with osteomyelitis have been studied, there is no definite proof that it is better than the usual treatments for diabetic patients. If this study finds that adding rifampin to the usual antibiotics prescribed for osteomyelitis reduces the risk for amputations, doctors will be able to more effectively treat many veteran patients with this serious infection. Improving treatment outcomes is an important healthcare goal of the VA.

ID: NCT03012529

Sponsor; Investigator: VA Office of Research and Development; Paul A. Monach, MD, PhD

Location: 30 VA locations, including South Texas Health Care System, San Antonio; Cincinnati VA Medical Center, Ohio; VA Northern California Health Care System, Mather; Washington DC VA Medical Center; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

→Effectiveness of Remote Foot Temperature Monitoring (STOP)

Diabetic foot ulcers are common, debilitating, and costly complications of diabetes, disproportionately impacting Black and rural veterans. Forty percent of individuals have an ulcer recurrence within a year of ulcer healing and 65% within 5 years. Monitoring plantar foot temperatures is one of the few interventions that reduces the risk of ulcer recurrence. Despite the evidence, adoption has been poorbecause the original procedures, including the use of handheld thermometers, were burdensome and time-consuming. Podimetrics, a private company, has developed a temperature monitoring system involving a “smart” mat that can wirelessly transmit data and a remote monitoring team that works with VA providers to assist with triage and monitoring. This care model has incredible promise, but has been untested in VA. The investigators propose to conduct a randomized trial to evaluate effectiveness of remote temperature monitoring as well as costs. Additionally, the investigators will evaluate the implementation process, including barriers and facilitators to use among key stakeholders.

ID: NCT05728411

Sponsor; Investigator: VA Office of Research and Development; Rachel M. Thomas

Location: Edward Hines Jr. VA Hospital, Hines, Illinois; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia; VA Puget Sound Health Care System, Seattle, Washington

→Continuous Glucose Monitoring for Hyperglycemia in Critically Ill Patients

The investigators intend to conduct a single-center, prospective, randomized comparative trial of patients admitted to the intensive care unit who received continuous glucose monitoring vs point of care glucose monitoring. The study will examine relevant outcomes for patients in the intensive care unit with diabetes mellitus and/or hyperglycemia. The primary outcome of the study will be the proportion of time in target range (blood glucose 70-180 mg/dL).

ID: NCT05442853

Sponsor; Investigator: Malcom Randall VA Medical Center; Andrew J. Franck, PharmD

Location: Malcolm Randall VA Medical Center, Gainesville, Florida

→Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT)

CSP #2002 is a multicenter, prospective, randomized, double blind, secondary prevention trial to test the hypothesis that treatment with metformin, compared with placebo, reduces mortality and cardiovascular morbidity in veterans with pre-diabetes and established atherosclerotic cardiovascular disease. Qualifying patients have pre-diabetes defined by HbA _1c , fasting blood glucose, or oral glucose tolerance test criteria; clinically evident coronary, cerebrovascular, or peripheral arterial atherosclerotic cardiovascular disease; and estimated glomerular filtration rate of at least 45 mL/min/1.73 m ² ; and do not fulfill any exclusion criteria.

ID: NCT04838392

Sponsor; Investigator: VA Office of Research and Development; Gregory G. Schwartz, PhD, MD

Locations: 40 locations

Actively Recruiting

→Continuous Glucose Monitoring Devices in Hospitalized Veterans With Diabetes

More than 25% of the patients admitted in the general wards have a history of diabetes mellitus. Up to 30% of the hospitalized diabetics develop hypoglycemia (low glucose values); a condition that is associated with seizures, cardiac arrhythmias, and even death. In veterans, the prevalence is disproportionally higher. It is estimated that 40% to 50% of hospitalized veterans are diabetics. In this clinical trial the investigators describe the development of a novel system, the Glucose Telemetry System, with which glucose values can be wirelessly transmitted from the patient’s bedside to a monitor device at the nursing station. The goal of this work is to develop a more effective glucose surveillance system at the general wards, which can decrease hypoglycemia in the hospital and improve clinical outcomes.

ID: NCT03508934

Sponsor; Investigator: VA Office of Research and Development; Ilias Spanakis, MD

Locations: Baltimore VA Medical Center, Maryland

→Optimizing Gait Rehabilitation for Veterans With Non-Traumatic Lower Limb Amputation (GEM)

The population of older veterans with nontraumatic lower limb amputation is growing. Following lower limb amputation, asymmetrical movements persist during walking and likely contribute to disabling sequelae including secondary pain conditions, poor gait efficiency, impaired physical function, and compromised skin integrity of the residual limb. This study seeks to address chronic gait asymmetry by evaluating the efficacy of two error-manipulation gait training programs to improve gait symmetry for veterans with nontraumatic lower limb amputation. Additionally, this study will evaluate the potential of error-manipulation training programs to improve secondary measures of disability and residual limb skin health. Ultimately, this study aims to improve conventional prosthetic rehabilitation for veterans with nontraumatic amputation through gait training programs based in motor learning principles, resulting in improved.

ID: NCT003995238

Sponsor; Investigator: VA Office of Research and Development; Cory L. Christiansen, PhD

Locations: Rocky Mountain Regional VA Medical Center, Aurora, Colorado; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

→Empowering Veterans to Actively Communicate and Engage in Shared Decision Making in Medical Visits, A Randomized Controlled Trial (ACTIVet-2)

Type 2 diabetes is a significant condition in VA affecting 20% of VA patients. Adherence to medication regimens and lifestyle factors is important to achieve care goals for these patients. Patients who use active participatory communication behaviors with their providers have better adherence to treatment and better biomedical outcomes, yet many patients are not prepared to engage in active communication with their providers. Existing coaching interventions have not been adopted in practice because of the cost of trained personnel. The investigators haveshown the efficacy of a low-cost video that did not require trained personnel. This proposal proposes to test implementation strategies to deliver that video in VA primary care clinics and to test the effectiveness of the video to improve outcomes in a hybrid type 2 effectiveness implementation trial using a cluster randomized stepped wedgedesign at eight sites. This proposal will test feasibility of implementing the video and if successful will generate the evidence to justify widespread dissemination of the video.

ID: NCT05169359

Sponsor; Investigator: VA Office of Research and Development; Howard S. Gordon, MD

Location: 8 locations, including Jesse Brown VA Medical Center, Chicago; Edward Hines Jr. VA Hopsital, Hines, Illinois

→The Diabetes Staging System in Patient Aligned Care Teams

The purpose of this study is to examine the feasibility/acceptability of the Diabetes Staging System in patient aligned care teams and its ability to increase sodium-glucosecotransporter-2 inhibitor and glucagon-like-1 peptide use in veteran patients with type 2 diabetes and cardiovascular disease and/or chronic kidney disease. A novel type 2 diabetes staging system patterned after Tumor Node Metastasis cancer staging that uses the number of macrovascular and microvascular complications and most recent hemoglobin A_1c and glomerular filtration rate to determine Diabetes Staging System stage which reflects disease severity.

ID: NCT06142006

Sponsor; Collaborator: Durham VA Medical Center; Moahad Dar, MD

Location: Greenville VA Health Care Center, North Carolina

→Enhancing Mental and Physical Health of Women Veterans (EMPOWER)

Women veterans are the fastest growing segment of VA users. This dramatic growth has created challenges for VA to ensure that appropriate services are available to meet women veterans’ needs, and that they will want and be able to use those services. The EMPOWER QUERI 2.0 Program is a cluster randomized type 3 hybrid implementation effectiveness trial testing 2 strategies designed to support implementation and sustainment of evidence-based practices for women veterans in at least 20 VA facilities from 4 regions.

ID: NCT05050266

Sponsor; Investigator: VA Office of Research and Development; Alison B. Hamilton, PhD, MPH

Location: VA Greater Los Angeles Healthcare System

→Investigation of Rifampin to Reduce Pedal Amputations for Osteomyelitis in Diabetics (VA INTREPID)

The purpose of this research study is to determine if rifampin, an antibiotic (a medicine that treats infections), is effective in treating osteomyelitis (infection of the bone) of the foot in patients with diabetes. Despite use of powerful antibiotics prescribed over a long period of time, many diabetic patients remain at a high risk for needing an amputation of part of the foot or lower leg because the osteomyelitis is not cured. Some small research studies have shown that addition of rifampin to other antibiotics is effective in treating osteomyelitis. However, because few diabetics with osteomyelitis have been studied, there is no definite proof that it is better than the usual treatments for diabetic patients. If this study finds that adding rifampin to the usual antibiotics prescribed for osteomyelitis reduces the risk for amputations, doctors will be able to more effectively treat many veteran patients with this serious infection. Improving treatment outcomes is an important healthcare goal of the VA.

ID: NCT03012529

Sponsor; Investigator: VA Office of Research and Development; Paul A. Monach, MD, PhD

Location: 30 VA locations, including South Texas Health Care System, San Antonio; Cincinnati VA Medical Center, Ohio; VA Northern California Health Care System, Mather; Washington DC VA Medical Center; William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

→Effectiveness of Remote Foot Temperature Monitoring (STOP)

Diabetic foot ulcers are common, debilitating, and costly complications of diabetes, disproportionately impacting Black and rural veterans. Forty percent of individuals have an ulcer recurrence within a year of ulcer healing and 65% within 5 years. Monitoring plantar foot temperatures is one of the few interventions that reduces the risk of ulcer recurrence. Despite the evidence, adoption has been poorbecause the original procedures, including the use of handheld thermometers, were burdensome and time-consuming. Podimetrics, a private company, has developed a temperature monitoring system involving a “smart” mat that can wirelessly transmit data and a remote monitoring team that works with VA providers to assist with triage and monitoring. This care model has incredible promise, but has been untested in VA. The investigators propose to conduct a randomized trial to evaluate effectiveness of remote temperature monitoring as well as costs. Additionally, the investigators will evaluate the implementation process, including barriers and facilitators to use among key stakeholders.

ID: NCT05728411

Sponsor; Investigator: VA Office of Research and Development; Rachel M. Thomas

Location: Edward Hines Jr. VA Hospital, Hines, Illinois; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia; VA Puget Sound Health Care System, Seattle, Washington

→Continuous Glucose Monitoring for Hyperglycemia in Critically Ill Patients

The investigators intend to conduct a single-center, prospective, randomized comparative trial of patients admitted to the intensive care unit who received continuous glucose monitoring vs point of care glucose monitoring. The study will examine relevant outcomes for patients in the intensive care unit with diabetes mellitus and/or hyperglycemia. The primary outcome of the study will be the proportion of time in target range (blood glucose 70-180 mg/dL).

ID: NCT05442853

Sponsor; Investigator: Malcom Randall VA Medical Center; Andrew J. Franck, PharmD

Location: Malcolm Randall VA Medical Center, Gainesville, Florida

→Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes (VA-IMPACT)

CSP #2002 is a multicenter, prospective, randomized, double blind, secondary prevention trial to test the hypothesis that treatment with metformin, compared with placebo, reduces mortality and cardiovascular morbidity in veterans with pre-diabetes and established atherosclerotic cardiovascular disease. Qualifying patients have pre-diabetes defined by HbA _1c , fasting blood glucose, or oral glucose tolerance test criteria; clinically evident coronary, cerebrovascular, or peripheral arterial atherosclerotic cardiovascular disease; and estimated glomerular filtration rate of at least 45 mL/min/1.73 m ² ; and do not fulfill any exclusion criteria.

ID: NCT04838392

Sponsor; Investigator: VA Office of Research and Development; Gregory G. Schwartz, PhD, MD

Locations: 40 locations

Click here to read more 

Click here to read more 

Click here to read more 

With increasing options for migraine therapy, the right choice for each patient might not be clear. And many individual patients could experience relief from any of the different choices, meaning that there is often more than one “right” answer when it comes to selecting a migraine treatment approach for each patient. Triptans and nonsteroidal anti-inflammatory drugs (NSAIDs), which have been around for decades, have shown consistent success in treating migraine episodes. Newer therapies could be safer for patients who have contraindications to triptans or NSAIDs, and these newer medications could be more effective for some patients, but we are still trying to fully understand which types of patients. Studies aimed at reaching conclusions regarding comparisons between triptans, calcitonin gene-related peptide inhibitors (CGRPi), and other treatments can help us determine which of the different categories of treatments are most effective for certain migraine populations (age or migraine subtype) or indications (acute vs preventive therapy).

A review published in 2023 in Aging and Disease described several markers of aging that are associated with migraine, including epigenetic aging and oxidative stress.² The review authors noted that markers of cellular senescence (ie, irreversible inhibition of cellular division) were increased in association with migraine. Additionally, endothelial progenitor cells, which reflect an increased ability for cell renewal, were decreased among migraine patients compared with the control group.

Telomeres, composed of nucleotides, are part of chromosome structures, serving to protect the molecular integrity of DNA. It has been established that shortened telomeres, often considered a reflection of aging and a marker of high potential for genetic and cellular damage, are a risk factor for physiologic changes that occur with the aging process. The 2024 Scientific Reports cross-sectional study included data from 6169 participants in the National Health and Nutrition Survey (NHANES) from 1999 to 2002.¹ The researchers used statistical analysis to determine whether there was an age-influenced telomere length in relation to migraine. They found that “telomere length was inversely associated with migraine risk in those aged 20-50 years, while no relationship was observed in those aged > 50 years.” The significance of this association among the younger group, but not among the older group, is not clear.

The limited research regarding the links between migraine and physiologic markers of aging has not untangled cause-and-effect distinctions. And while there is no evidence that preventing or treating migraine could slow down these pro-aging molecular processes, we do know that the distress of migraine episodes contributes to pain, anxiety, stress, depression, and sleep disruption. Given that we can’t change a patient’s hereditary predisposition to migraines, we can make an effort to alleviate the impact of migraine by using the tools that we have.

An article published in September 2024 in the BMJ described the results of a meta-analysis that included “137 randomized controlled trials with 89,445 participants allocated to 1 of 17 active interventions or placebo.”³ Treatments included NSAIDs, paracetamol, triptans, and CGRPi. The authors observed that triptans “had the best profiles and were more efficacious” than other treatment categories, including CGRPi. Interestingly, they observed that eletriptan and ibuprofen performed better for sustained pain freedom. Efficacy and sustained relief are crucial for patients with migraine, and for those who experience relief with simple over-the-counter ibuprofen, it makes sense to avoid making changes. But for those who are not getting the relief they need with established migraine therapies, trying the newer medications, such as CGRPi, could provide a solution. It is also important to keep in mind that triptans are contraindicated for some patients, such as those with a high-risk cardiovascular profile. Additionally, some patients may have contraindications to NSAIDs.

Prevention is another important aspect of migraine care. A September 2024 article in Headache: The Journal of Head and Face Pain used a retrospective cohort analysis of Patient-Reported Outcomes Measurement Information System (PROMIS) data, which included 1245 patients using a variety of migraine preventive therapies: antidepressants, antiseizure medications, beta-blockers, and CGRPi.⁴ The researchers reported that patients taking “CGRPi had a statistically significant reduction in pain T-scores (60.4 [standard deviation (SD) 7.4] to 58.4 [SD 8.2], p = 0.003), especially those who switched from other preventative medications to CGRPi.” This, along with the BMJ meta-analysis,³ helps in assessing relative benefits for treatments of acute migraine episodes and for migraine prevention. However, the efficacy of various types of therapy highlights the value of considering all options for each patient.

Individual patient characteristics, particularly contraindications, also play an important role in guiding therapeutic selection. And trial and error remain part of migraine treatment, given that there are no pretesting determinants that can predict treatment success for individual patients. We need to emphasize to patients that effective migraine therapy is obtainable and important — for comfort, quality of life, and possibly overall healthy aging.

References

1. Geng D, Liu H, Wang H, Wang H. Telomere length exhibits inverse association with migraine among Americans aged 20-50 years, without implications beyond age 50: a cross-sectional study. Sci Rep. 2024;14:22597. Source
2. Fila M, Pawlowska E, Szczepanska J, Blasiak J. Different aspects of aging in migraine. Aging Dis. 2023;14:6. Source
3. Karlsson WK, Ostinelli EG, Zhuang ZA, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: Systematic review and network meta-analysis. BMJ. 2024;386:e080107. Source
4. Peasah SK, Soh YH, Huang Y, Nguyen J, Hanmer J, Good C. Patient reported outcomes and real-world use of calcitonin gene-related peptide medications in migraine. Headache. Published online September 30, 202 Source

With increasing options for migraine therapy, the right choice for each patient might not be clear. And many individual patients could experience relief from any of the different choices, meaning that there is often more than one “right” answer when it comes to selecting a migraine treatment approach for each patient. Triptans and nonsteroidal anti-inflammatory drugs (NSAIDs), which have been around for decades, have shown consistent success in treating migraine episodes. Newer therapies could be safer for patients who have contraindications to triptans or NSAIDs, and these newer medications could be more effective for some patients, but we are still trying to fully understand which types of patients. Studies aimed at reaching conclusions regarding comparisons between triptans, calcitonin gene-related peptide inhibitors (CGRPi), and other treatments can help us determine which of the different categories of treatments are most effective for certain migraine populations (age or migraine subtype) or indications (acute vs preventive therapy).

A review published in 2023 in Aging and Disease described several markers of aging that are associated with migraine, including epigenetic aging and oxidative stress.² The review authors noted that markers of cellular senescence (ie, irreversible inhibition of cellular division) were increased in association with migraine. Additionally, endothelial progenitor cells, which reflect an increased ability for cell renewal, were decreased among migraine patients compared with the control group.

Telomeres, composed of nucleotides, are part of chromosome structures, serving to protect the molecular integrity of DNA. It has been established that shortened telomeres, often considered a reflection of aging and a marker of high potential for genetic and cellular damage, are a risk factor for physiologic changes that occur with the aging process. The 2024 Scientific Reports cross-sectional study included data from 6169 participants in the National Health and Nutrition Survey (NHANES) from 1999 to 2002.¹ The researchers used statistical analysis to determine whether there was an age-influenced telomere length in relation to migraine. They found that “telomere length was inversely associated with migraine risk in those aged 20-50 years, while no relationship was observed in those aged > 50 years.” The significance of this association among the younger group, but not among the older group, is not clear.

The limited research regarding the links between migraine and physiologic markers of aging has not untangled cause-and-effect distinctions. And while there is no evidence that preventing or treating migraine could slow down these pro-aging molecular processes, we do know that the distress of migraine episodes contributes to pain, anxiety, stress, depression, and sleep disruption. Given that we can’t change a patient’s hereditary predisposition to migraines, we can make an effort to alleviate the impact of migraine by using the tools that we have.

An article published in September 2024 in the BMJ described the results of a meta-analysis that included “137 randomized controlled trials with 89,445 participants allocated to 1 of 17 active interventions or placebo.”³ Treatments included NSAIDs, paracetamol, triptans, and CGRPi. The authors observed that triptans “had the best profiles and were more efficacious” than other treatment categories, including CGRPi. Interestingly, they observed that eletriptan and ibuprofen performed better for sustained pain freedom. Efficacy and sustained relief are crucial for patients with migraine, and for those who experience relief with simple over-the-counter ibuprofen, it makes sense to avoid making changes. But for those who are not getting the relief they need with established migraine therapies, trying the newer medications, such as CGRPi, could provide a solution. It is also important to keep in mind that triptans are contraindicated for some patients, such as those with a high-risk cardiovascular profile. Additionally, some patients may have contraindications to NSAIDs.

Prevention is another important aspect of migraine care. A September 2024 article in Headache: The Journal of Head and Face Pain used a retrospective cohort analysis of Patient-Reported Outcomes Measurement Information System (PROMIS) data, which included 1245 patients using a variety of migraine preventive therapies: antidepressants, antiseizure medications, beta-blockers, and CGRPi.⁴ The researchers reported that patients taking “CGRPi had a statistically significant reduction in pain T-scores (60.4 [standard deviation (SD) 7.4] to 58.4 [SD 8.2], p = 0.003), especially those who switched from other preventative medications to CGRPi.” This, along with the BMJ meta-analysis,³ helps in assessing relative benefits for treatments of acute migraine episodes and for migraine prevention. However, the efficacy of various types of therapy highlights the value of considering all options for each patient.

Individual patient characteristics, particularly contraindications, also play an important role in guiding therapeutic selection. And trial and error remain part of migraine treatment, given that there are no pretesting determinants that can predict treatment success for individual patients. We need to emphasize to patients that effective migraine therapy is obtainable and important — for comfort, quality of life, and possibly overall healthy aging.

References

1. Geng D, Liu H, Wang H, Wang H. Telomere length exhibits inverse association with migraine among Americans aged 20-50 years, without implications beyond age 50: a cross-sectional study. Sci Rep. 2024;14:22597. Source
2. Fila M, Pawlowska E, Szczepanska J, Blasiak J. Different aspects of aging in migraine. Aging Dis. 2023;14:6. Source
3. Karlsson WK, Ostinelli EG, Zhuang ZA, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: Systematic review and network meta-analysis. BMJ. 2024;386:e080107. Source
4. Peasah SK, Soh YH, Huang Y, Nguyen J, Hanmer J, Good C. Patient reported outcomes and real-world use of calcitonin gene-related peptide medications in migraine. Headache. Published online September 30, 202 Source

With increasing options for migraine therapy, the right choice for each patient might not be clear. And many individual patients could experience relief from any of the different choices, meaning that there is often more than one “right” answer when it comes to selecting a migraine treatment approach for each patient. Triptans and nonsteroidal anti-inflammatory drugs (NSAIDs), which have been around for decades, have shown consistent success in treating migraine episodes. Newer therapies could be safer for patients who have contraindications to triptans or NSAIDs, and these newer medications could be more effective for some patients, but we are still trying to fully understand which types of patients. Studies aimed at reaching conclusions regarding comparisons between triptans, calcitonin gene-related peptide inhibitors (CGRPi), and other treatments can help us determine which of the different categories of treatments are most effective for certain migraine populations (age or migraine subtype) or indications (acute vs preventive therapy).

A review published in 2023 in Aging and Disease described several markers of aging that are associated with migraine, including epigenetic aging and oxidative stress.² The review authors noted that markers of cellular senescence (ie, irreversible inhibition of cellular division) were increased in association with migraine. Additionally, endothelial progenitor cells, which reflect an increased ability for cell renewal, were decreased among migraine patients compared with the control group.

Telomeres, composed of nucleotides, are part of chromosome structures, serving to protect the molecular integrity of DNA. It has been established that shortened telomeres, often considered a reflection of aging and a marker of high potential for genetic and cellular damage, are a risk factor for physiologic changes that occur with the aging process. The 2024 Scientific Reports cross-sectional study included data from 6169 participants in the National Health and Nutrition Survey (NHANES) from 1999 to 2002.¹ The researchers used statistical analysis to determine whether there was an age-influenced telomere length in relation to migraine. They found that “telomere length was inversely associated with migraine risk in those aged 20-50 years, while no relationship was observed in those aged > 50 years.” The significance of this association among the younger group, but not among the older group, is not clear.

The limited research regarding the links between migraine and physiologic markers of aging has not untangled cause-and-effect distinctions. And while there is no evidence that preventing or treating migraine could slow down these pro-aging molecular processes, we do know that the distress of migraine episodes contributes to pain, anxiety, stress, depression, and sleep disruption. Given that we can’t change a patient’s hereditary predisposition to migraines, we can make an effort to alleviate the impact of migraine by using the tools that we have.

An article published in September 2024 in the BMJ described the results of a meta-analysis that included “137 randomized controlled trials with 89,445 participants allocated to 1 of 17 active interventions or placebo.”³ Treatments included NSAIDs, paracetamol, triptans, and CGRPi. The authors observed that triptans “had the best profiles and were more efficacious” than other treatment categories, including CGRPi. Interestingly, they observed that eletriptan and ibuprofen performed better for sustained pain freedom. Efficacy and sustained relief are crucial for patients with migraine, and for those who experience relief with simple over-the-counter ibuprofen, it makes sense to avoid making changes. But for those who are not getting the relief they need with established migraine therapies, trying the newer medications, such as CGRPi, could provide a solution. It is also important to keep in mind that triptans are contraindicated for some patients, such as those with a high-risk cardiovascular profile. Additionally, some patients may have contraindications to NSAIDs.

Prevention is another important aspect of migraine care. A September 2024 article in Headache: The Journal of Head and Face Pain used a retrospective cohort analysis of Patient-Reported Outcomes Measurement Information System (PROMIS) data, which included 1245 patients using a variety of migraine preventive therapies: antidepressants, antiseizure medications, beta-blockers, and CGRPi.⁴ The researchers reported that patients taking “CGRPi had a statistically significant reduction in pain T-scores (60.4 [standard deviation (SD) 7.4] to 58.4 [SD 8.2], p = 0.003), especially those who switched from other preventative medications to CGRPi.” This, along with the BMJ meta-analysis,³ helps in assessing relative benefits for treatments of acute migraine episodes and for migraine prevention. However, the efficacy of various types of therapy highlights the value of considering all options for each patient.

Individual patient characteristics, particularly contraindications, also play an important role in guiding therapeutic selection. And trial and error remain part of migraine treatment, given that there are no pretesting determinants that can predict treatment success for individual patients. We need to emphasize to patients that effective migraine therapy is obtainable and important — for comfort, quality of life, and possibly overall healthy aging.

References

1. Geng D, Liu H, Wang H, Wang H. Telomere length exhibits inverse association with migraine among Americans aged 20-50 years, without implications beyond age 50: a cross-sectional study. Sci Rep. 2024;14:22597. Source
2. Fila M, Pawlowska E, Szczepanska J, Blasiak J. Different aspects of aging in migraine. Aging Dis. 2023;14:6. Source
3. Karlsson WK, Ostinelli EG, Zhuang ZA, et al. Comparative effects of drug interventions for the acute management of migraine episodes in adults: Systematic review and network meta-analysis. BMJ. 2024;386:e080107. Source
4. Peasah SK, Soh YH, Huang Y, Nguyen J, Hanmer J, Good C. Patient reported outcomes and real-world use of calcitonin gene-related peptide medications in migraine. Headache. Published online September 30, 202 Source

About 1 in 10 Americans have diabetes mellitus (DM), of which about 90% to 95% are diagnosed with type 2 DM (T2DM) and veterans are disproportionately affected.^1,2 About 25% enrolled in the Veterans Health Administration (VHA) have T2DM, which has been attributed to exposure to herbicides (eg, Agent Orange), decreased physical activity resulting from past physical strain, chronic pain, and other physical limitations resulting from military service.^3-5

Pharmacologic management of DM is guided by the effectiveness of lifestyle interventions and comorbid diagnoses. Current DM management guidelines recommend patients with comorbid atherosclerotic cardiovascular disease, chronic kidney disease, or congestive heart failure receive first-line diabetes therapy with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 receptor (GLP-1) agonist.

Metformin remains a first-line pharmacologic option for the treatment of T2DM with the goal of achieving glycemic management when lifestyle interventions are insufficient.^6,7 Newer antihyperglycemic therapies have been studied as adjunct therapy to metformin. However, there is limited literature comparing metformin directly to other medication classes for the treatment of T2DM.^8-13 A systematic review of treatment-naive patients found HbA_1c reductions were similar whether patients received metformin vs an SGLT-2 inhibitor, GLP-1 agonist, sulfonylurea, or thiazolidinedione monotherapy.¹⁰ The analysis found dipeptidyl-peptidase-4 (DPP-4) inhibitors had inferior HbA_1c reduction compared to metformin.¹⁰ A Japanese systematic review compared metformin to thiazolidinediones, sulfonylureas, glinides, DPP-4 inhibitors, α-glucosidase inhibitors, or SGLT-2 inhibitors for ≥ 12 weeks but found no statistically significant differences in HbA_1c reduction.¹¹ The AWARD-3 trial compared once-weekly dulaglutide to metformin in treatment-experienced patients and found greater improvement in HbA_1c and achievement of HbA_1c goal with dulaglutide.¹³ While these studies show some comparisons of metformin to alternative pharmacologic therapy, researchers have not looked at what happens to patients’ HbA_1c levels when an event, such as a recall, prompts a rapid change to a different antihyperglycemic agent.

On May 28, 2020, the US Food and Drug Administration (FDA) asked 5 pharmaceutical companies to voluntarily recall certain formulations of metformin. This action was taken when FDA testing revealed unacceptably high levels of N-Nitrosodimethylamine, a probable carcinogen.¹⁴ This FDA recall of metformin extended-release, referred to as metformin sustained-action (SA) within the VHA electronic medication file but the same type of formulation, prompted clinicians to revisit and revise the pharmacologic regimens of patients taking the drug. Because of the paucity of head-to-head trials comparing metformin with newer alternative antihyperglycemic therapies, the effect of treatment change was unknown. In response, we aimed to establish a data registry within Veterans Integrated Service Network (VISN) 6.

Registry Development

The VISN 6 registry was established to gather long-term, observational, head-to-head data that would allow review of HbA_1c levels before and after the recall, as well as HbA_1c levels broken down by the agent that patients were switched to after the recall. Another goal was to explore prescribing trends following the recall.

Data Access Request Tracker approval was obtained and a US Department of Veterans Affairs (VA) Information and Computing Infrastructure workspace was developed to host the registry data. The research cohort was established from this data, and the registry framework was finalized using Structured Query Language (SQL). The SQL coding allows for recurring data updates for all individuals within the cohort including date of birth, race, sex, ethnicity, VHA facility visited, weight, body mass index, HbA_1c level, creatinine clearance, serum creatinine, antihyperglycemic medication prescriptions, adverse drug reactions, medication adherence (as defined by ≥ 80% refill history), and hospitalizations related to diabetes. For the purposes of this initial analysis, registry data included demographics, diabetes medications, and HbA_1c results.

METHODS

This study was a concurrent, observational, multicenter, registry-based study conducted at the Western North Carolina VA Health Care System (WNCVAHCS). The study was approved by the WNCVAHCS institutional review board and research and development committees.

All patients aged ≥ 18 years with T2DM and receiving health care from VISN 6 facilities who had an active metformin SA prescription on, and 1 year prior to, June 1, 2020 (the initial date VHA began implementing the FDA metformin recall) were entered into the registry. Data from 1 year prior were collected to provide a baseline. Veterans were excluded if they received metformin SA for any indication other than T2DM, there was no pre- or postrecall HbA_1c measurement, or death. We included 15,594 VISN 6 veterans.

Registry data were analyzed to determine whether a significant change in HbA_1c level occurred after the metformin recall and in response to alternative agents being prescribed. Data from veterans who met all inclusion criteria were assessed during the year before and after June 1, 2020. Demographic data were analyzed using frequency and descriptive statistics. The Shapiro Wilkes test was performed, and data were found to be nonparametric; therefore the Wilcoxon signed-rank test was used to evaluate the hypothesis that HbA_1c levels were not impacted by the recall.

Our sample size allowed us to create exact matched pairs of 9130 individuals and utilize rank-biserial correlation to establish effect size. Following this initial population-level test, we constructed 2 models. The first, a linear mixed-effects model, focused solely on the interaction effects between the pre- and postrecall periods and various medication classes on HbA_1c levels. Second, we constructed a random-effects within-between model (REWB) to evaluate the impact ofmedication classes and demographic variables. Statistical significance was measured at P < .05 with conservative power at .90. The effect size was set to 1.0, reflecting a minimum clinically important difference. Literature establishes 0.5 as a modest level of HbA_1c improvement and 1.0 as a clinically significant improvement.

RESULTS

Preliminary results included 15,594 veterans who received a metformin SA prescription as of June 1, 2020 from VISN 6 facilities; 15,392 veterans had a drug exposure end on June 1, 2020, indicating their standard therapy of metformin SA was discontinued following the FDA recall. Two hundred and two veterans were excluded from the registry because they continued to receive metformin SA from existing stock at a VISN6 facility. After identifying veterans with data for 1 year prior (June 1, 2019) to the index date and 1 year after (June 1, 2021) the study population was adjusted to 9130. The population was predominantly males aged> 60 years. Roughly 55% of the registry identified as White and nearly 40% as Black, and 2% indentified as Hispanic (Table 1).

Wilcoxon Signed-Rank Test

We created exact pairs by iterating the data and finding the closest measurements for each patient before and after the recall. This has the advantage over averaging a patient’s pre- and post-HbA_1c levels, as it allows for a rank-biserial correlation. Using the nonparametric Wilcoxon signed-rank test, V was 20,100,707 (P < .001), indicating a significant effect. The –0.29 rank-biserial correlation, which was computed to assess the effect size of the recall, suggests that the median HbA_1c level was lower postrecall vs prerecall. The magnitude of the correlation suggests a moderate effect size, and while the recall had a noticeable impact at a population level, it was not extreme (Table 2).

Linear Mixed-Effects Model

The binary variable for medication class exposure suggests the use of a logit link function for binary outcomes within the multilevel modeling framework.¹⁵ We employed a linear mixed-effects model to investigate the impact that switching from metformin SA to other T2DM medications had on HbA_1c levels. The model was adjusted for patient-specific random effects and included interaction terms between the recall period (before and after) and the usage of different T2DM medications.

Model Fit and Random Effects

The model demonstrated a residual maximum likelihood criterion of 100,219.7, indicating its fit to the data. Notably, the random effects analysis revealed a substantial variability in baseline HbA_1c levels across patients (SD, 0.94), highlighting the importance of individual differences in DM management. Medication classes with zero or near-zero exposure rate were removed. Due to demographic homogeneity, the model did not converge on demographic variables. Veterans were taking a mean of 1.8 T2DM medications and metformin SA was most common (Table 3).

During the postrecall period, metformin SA remained the most frequently prescribed medication class. This may be attributed to the existence of multiple manufacturers of metformin SA, some of which may not have been impacted by the recall. VISN 6 medical centers could have sought metformin SA outside of the usual procurement path following the recall.

Complex Random Effects Model

We employed a complex REWB model that evaluated the impact of medication classes on HbA_1c levels, accounting for both within and between subject effects of these medications, along with demographic variables (sex, race, and ethnicity) (eAppendix). This model accounts for individual-level changes over time (within-patient effects) and between groups of patients (between-patient effects). This is a more comprehensive model aimed at understanding the broader impact of medications on HbA_1c levels across diverse patient groups.

Most demographic categories did not demonstrate significant effects in this model. Black individuals experienced a slight increase in HbA_1c levels compared with other racial categories that was not statistically significant. However, this model confirms the findings from the linear mixed-effects model that GLP-1 agonists showed a substantial decrease in HbA_1c levels within patients (coefficient –0.5; 95% CI, –0.56 to –0.44; P < .001) and a moderate increase between patients (coefficient, 0.21; 95% CI, 0.12-0.31; P < .001). Additionally, SGLT-2 inhibitors had a notable decrease within patients (coefficient, –0.27; 95% CI, –0.32 to –0.22; P < .001).Another notable finding with our REWB model is insulin usage was associated with high HbA_1c levels, but only between subjects. Long-acting insulin (coefficient, 0.96; 95% CI, 0.90-1.01; P <. 001) and mixed insulin (coefficient, 1.09; 95% CI, 0.94-1.24; P < .001) both displayed marked increases between patients, suggesting future analysis may benefit from stratifying across insulin users and nonusers.

Fixed Effect Analysis

The fixed effects analysis yielded several notable findings. The intercept, representing the mean baseline HbA_1c level, was estimated at 7.8% (58 mmol/mol). The coefficient for the period (postrecall) was not statistically significant, indicating no overall change in HbA_1c levels from before to after the recall when specific medication classes were not considered (Table 4). Among medication classes examined, several showed significant associations with HbA_1c levels. DPP-4 inhibitors and GLP-1 agonists were associated with a decrease in HbA_1c levels, with coefficients of −0.08 and −0.24, respectively. Long-acting insulin and metformin immediate-release (IR) were associated with an increase in HbA_1c levels, as indicated by their positive coefficients of 0.38 and 0.16, respectively. Mixed insulin formulations and sulfonylureas showed an association with decreased HbA_1c levels.

Interaction Effects

The interaction terms between the recall period and the medication classes provided insights into the differential impact of the medication switch postrecall. Notably, the interaction term for long-acting insulin (coefficient, −0.10) was significant, suggesting a differential effect on HbA_1c levels postrecall. Other medications, like metformin IR, also exhibited significant interaction effects, indicating changes in the impact on HbA_1c levels in the postrecall period. The binary variable for medication class exposure suggests the use of a logit link function for binary outcomes within the multilevel modeling framework.¹⁵ We did not address the potential for cross cluster heterogeneity due to different medication classes.

DISCUSSION

This study is an ongoing, concurrent, observational, multicenter, registry-based study consisting of VISN 6 veterans who have T2DM and were prescribed metformin SA on June 1, 2020. This initial aim was to evaluate change in HbA_1c levels following the FDA metformin recall. While there was substantial variability in baseline HbA_1c levels across the patients, the mean baseline HbA_1c level at 7.5% (58 mmol/mol). Patients taking GLP-1 agonists showed substantial decrease in HbA_1c levels (coefficient; –0.5; 95% CI, –0.56 to –0.44; P <. 001). Patients taking SGLT-2 inhibitors had a notable decrease in HbA_1c (coefficient, –0.27; 95% CI, –0.32 to –0.22; P < .001). Despite this, the coefficient for the postrecall period was not statistically significant, indicating no overall change in HbA_1c levels from pre- to postrecall when specific medication classes were not considered.

Further analysis included assessment of prescribing trends postrecall. There was an increase in SGLT-2 inhibitor, GLP-1 agonist, and DPP-4 inhibitor prescribing. Considering the growing evidence of the cardiovascular and renal benefits of these medication classes, specifically the GLP-1 agonists and SGLT-2 inhibitors, this trend would be expected.

Limitations

This study cohort did not capture veterans with T2DM who transferred their health care to VISN 6 after June 1, 2020, and continued to receive metformin SA from the prior facility. Inclusion of these veterans would have increased the registry population. Additionally, the cohort did not identify veterans who continued to receive metformin SA through a source other than the VA. Without that information, the registry cohort may include veterans thought to have either transitioned to a different therapy or to no other T2DM therapy after the recall.

Given that DM can progress over time, it is possible the transition to a new medication after the recall was the result of suboptimal management, or in response to an adverse effect from a previous medication, and not solely due to the metformin SA recall. In addition, there are several factors that could impact HbA_1c level over time that were not accounted for in this study, such as medication adherence and lifestyle modifications.

The notable level of metformin SA prescriptions, despite the recall, may be attributed to several factors. First, not all patients stopped metformin completely. Review of the prescription data indicated that some veterans were provided with limited refills at select VA medical centers that had supplies (medication lots not recalled). Access to a safe supply of metformin SA after the recall may have varied among VISN 6 facilities. It is also possible that as new supplies of metformin SA became available, veterans restarted metformin SA. This may have been resumed while continuing a new medication prescribed at the beginning of the recall. As the year progressed after the recall, an increase in metformin SA prescriptions likely occurred as supplies became available and clinicians/veterans chose to resume this medication therapy.

Conclusions

Results of this initial registry study found no difference in HbA_1c levels across the study population after the metformin SA recall. However, there was clinical difference in the HbA_1c within veterans prescribed SGLT-2 inhibitors and GLP-1 agonists. As expected, prescribing trends showed an increase in these agents after the recall. With the known benefits of these medications beyond glucose lowering, it is anticipated the cohort of veterans prescribed these medications will continue to grow.

The VISN 6 research registry allowed this study to gain an important snapshot in time following the metformin SA recall, and will serve as an important resource for future DM research endeavors. It will allow for ongoing evaluation of the impact of the transition to alternative T2DM medications after the metformin SA recall. Future exploration will include evaluation of adverse drug reactions, DM-related hospitalizations, emergency department visits related to T2DM, changes in renal function, and cardiovascular events among all diabetes medication classes.

Acknowledgments

The study team thanks the Veterans Affairs Informatics and Computing Infrastructure for their help and expertise throughout this project. The authors acknowledge the contributions of Philip Nelson, PharmD, and Brian Peek, PharmD.

About 1 in 10 Americans have diabetes mellitus (DM), of which about 90% to 95% are diagnosed with type 2 DM (T2DM) and veterans are disproportionately affected.^1,2 About 25% enrolled in the Veterans Health Administration (VHA) have T2DM, which has been attributed to exposure to herbicides (eg, Agent Orange), decreased physical activity resulting from past physical strain, chronic pain, and other physical limitations resulting from military service.^3-5

Pharmacologic management of DM is guided by the effectiveness of lifestyle interventions and comorbid diagnoses. Current DM management guidelines recommend patients with comorbid atherosclerotic cardiovascular disease, chronic kidney disease, or congestive heart failure receive first-line diabetes therapy with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 receptor (GLP-1) agonist.

Metformin remains a first-line pharmacologic option for the treatment of T2DM with the goal of achieving glycemic management when lifestyle interventions are insufficient.^6,7 Newer antihyperglycemic therapies have been studied as adjunct therapy to metformin. However, there is limited literature comparing metformin directly to other medication classes for the treatment of T2DM.^8-13 A systematic review of treatment-naive patients found HbA_1c reductions were similar whether patients received metformin vs an SGLT-2 inhibitor, GLP-1 agonist, sulfonylurea, or thiazolidinedione monotherapy.¹⁰ The analysis found dipeptidyl-peptidase-4 (DPP-4) inhibitors had inferior HbA_1c reduction compared to metformin.¹⁰ A Japanese systematic review compared metformin to thiazolidinediones, sulfonylureas, glinides, DPP-4 inhibitors, α-glucosidase inhibitors, or SGLT-2 inhibitors for ≥ 12 weeks but found no statistically significant differences in HbA_1c reduction.¹¹ The AWARD-3 trial compared once-weekly dulaglutide to metformin in treatment-experienced patients and found greater improvement in HbA_1c and achievement of HbA_1c goal with dulaglutide.¹³ While these studies show some comparisons of metformin to alternative pharmacologic therapy, researchers have not looked at what happens to patients’ HbA_1c levels when an event, such as a recall, prompts a rapid change to a different antihyperglycemic agent.

On May 28, 2020, the US Food and Drug Administration (FDA) asked 5 pharmaceutical companies to voluntarily recall certain formulations of metformin. This action was taken when FDA testing revealed unacceptably high levels of N-Nitrosodimethylamine, a probable carcinogen.¹⁴ This FDA recall of metformin extended-release, referred to as metformin sustained-action (SA) within the VHA electronic medication file but the same type of formulation, prompted clinicians to revisit and revise the pharmacologic regimens of patients taking the drug. Because of the paucity of head-to-head trials comparing metformin with newer alternative antihyperglycemic therapies, the effect of treatment change was unknown. In response, we aimed to establish a data registry within Veterans Integrated Service Network (VISN) 6.

Registry Development

The VISN 6 registry was established to gather long-term, observational, head-to-head data that would allow review of HbA_1c levels before and after the recall, as well as HbA_1c levels broken down by the agent that patients were switched to after the recall. Another goal was to explore prescribing trends following the recall.

Data Access Request Tracker approval was obtained and a US Department of Veterans Affairs (VA) Information and Computing Infrastructure workspace was developed to host the registry data. The research cohort was established from this data, and the registry framework was finalized using Structured Query Language (SQL). The SQL coding allows for recurring data updates for all individuals within the cohort including date of birth, race, sex, ethnicity, VHA facility visited, weight, body mass index, HbA_1c level, creatinine clearance, serum creatinine, antihyperglycemic medication prescriptions, adverse drug reactions, medication adherence (as defined by ≥ 80% refill history), and hospitalizations related to diabetes. For the purposes of this initial analysis, registry data included demographics, diabetes medications, and HbA_1c results.

METHODS

This study was a concurrent, observational, multicenter, registry-based study conducted at the Western North Carolina VA Health Care System (WNCVAHCS). The study was approved by the WNCVAHCS institutional review board and research and development committees.

All patients aged ≥ 18 years with T2DM and receiving health care from VISN 6 facilities who had an active metformin SA prescription on, and 1 year prior to, June 1, 2020 (the initial date VHA began implementing the FDA metformin recall) were entered into the registry. Data from 1 year prior were collected to provide a baseline. Veterans were excluded if they received metformin SA for any indication other than T2DM, there was no pre- or postrecall HbA_1c measurement, or death. We included 15,594 VISN 6 veterans.

Registry data were analyzed to determine whether a significant change in HbA_1c level occurred after the metformin recall and in response to alternative agents being prescribed. Data from veterans who met all inclusion criteria were assessed during the year before and after June 1, 2020. Demographic data were analyzed using frequency and descriptive statistics. The Shapiro Wilkes test was performed, and data were found to be nonparametric; therefore the Wilcoxon signed-rank test was used to evaluate the hypothesis that HbA_1c levels were not impacted by the recall.

Our sample size allowed us to create exact matched pairs of 9130 individuals and utilize rank-biserial correlation to establish effect size. Following this initial population-level test, we constructed 2 models. The first, a linear mixed-effects model, focused solely on the interaction effects between the pre- and postrecall periods and various medication classes on HbA_1c levels. Second, we constructed a random-effects within-between model (REWB) to evaluate the impact ofmedication classes and demographic variables. Statistical significance was measured at P < .05 with conservative power at .90. The effect size was set to 1.0, reflecting a minimum clinically important difference. Literature establishes 0.5 as a modest level of HbA_1c improvement and 1.0 as a clinically significant improvement.

RESULTS

Preliminary results included 15,594 veterans who received a metformin SA prescription as of June 1, 2020 from VISN 6 facilities; 15,392 veterans had a drug exposure end on June 1, 2020, indicating their standard therapy of metformin SA was discontinued following the FDA recall. Two hundred and two veterans were excluded from the registry because they continued to receive metformin SA from existing stock at a VISN6 facility. After identifying veterans with data for 1 year prior (June 1, 2019) to the index date and 1 year after (June 1, 2021) the study population was adjusted to 9130. The population was predominantly males aged> 60 years. Roughly 55% of the registry identified as White and nearly 40% as Black, and 2% indentified as Hispanic (Table 1).

Wilcoxon Signed-Rank Test

We created exact pairs by iterating the data and finding the closest measurements for each patient before and after the recall. This has the advantage over averaging a patient’s pre- and post-HbA_1c levels, as it allows for a rank-biserial correlation. Using the nonparametric Wilcoxon signed-rank test, V was 20,100,707 (P < .001), indicating a significant effect. The –0.29 rank-biserial correlation, which was computed to assess the effect size of the recall, suggests that the median HbA_1c level was lower postrecall vs prerecall. The magnitude of the correlation suggests a moderate effect size, and while the recall had a noticeable impact at a population level, it was not extreme (Table 2).

Linear Mixed-Effects Model

The binary variable for medication class exposure suggests the use of a logit link function for binary outcomes within the multilevel modeling framework.¹⁵ We employed a linear mixed-effects model to investigate the impact that switching from metformin SA to other T2DM medications had on HbA_1c levels. The model was adjusted for patient-specific random effects and included interaction terms between the recall period (before and after) and the usage of different T2DM medications.

Model Fit and Random Effects

The model demonstrated a residual maximum likelihood criterion of 100,219.7, indicating its fit to the data. Notably, the random effects analysis revealed a substantial variability in baseline HbA_1c levels across patients (SD, 0.94), highlighting the importance of individual differences in DM management. Medication classes with zero or near-zero exposure rate were removed. Due to demographic homogeneity, the model did not converge on demographic variables. Veterans were taking a mean of 1.8 T2DM medications and metformin SA was most common (Table 3).

During the postrecall period, metformin SA remained the most frequently prescribed medication class. This may be attributed to the existence of multiple manufacturers of metformin SA, some of which may not have been impacted by the recall. VISN 6 medical centers could have sought metformin SA outside of the usual procurement path following the recall.

Complex Random Effects Model

We employed a complex REWB model that evaluated the impact of medication classes on HbA_1c levels, accounting for both within and between subject effects of these medications, along with demographic variables (sex, race, and ethnicity) (eAppendix). This model accounts for individual-level changes over time (within-patient effects) and between groups of patients (between-patient effects). This is a more comprehensive model aimed at understanding the broader impact of medications on HbA_1c levels across diverse patient groups.

Most demographic categories did not demonstrate significant effects in this model. Black individuals experienced a slight increase in HbA_1c levels compared with other racial categories that was not statistically significant. However, this model confirms the findings from the linear mixed-effects model that GLP-1 agonists showed a substantial decrease in HbA_1c levels within patients (coefficient –0.5; 95% CI, –0.56 to –0.44; P < .001) and a moderate increase between patients (coefficient, 0.21; 95% CI, 0.12-0.31; P < .001). Additionally, SGLT-2 inhibitors had a notable decrease within patients (coefficient, –0.27; 95% CI, –0.32 to –0.22; P < .001).Another notable finding with our REWB model is insulin usage was associated with high HbA_1c levels, but only between subjects. Long-acting insulin (coefficient, 0.96; 95% CI, 0.90-1.01; P <. 001) and mixed insulin (coefficient, 1.09; 95% CI, 0.94-1.24; P < .001) both displayed marked increases between patients, suggesting future analysis may benefit from stratifying across insulin users and nonusers.

Fixed Effect Analysis

The fixed effects analysis yielded several notable findings. The intercept, representing the mean baseline HbA_1c level, was estimated at 7.8% (58 mmol/mol). The coefficient for the period (postrecall) was not statistically significant, indicating no overall change in HbA_1c levels from before to after the recall when specific medication classes were not considered (Table 4). Among medication classes examined, several showed significant associations with HbA_1c levels. DPP-4 inhibitors and GLP-1 agonists were associated with a decrease in HbA_1c levels, with coefficients of −0.08 and −0.24, respectively. Long-acting insulin and metformin immediate-release (IR) were associated with an increase in HbA_1c levels, as indicated by their positive coefficients of 0.38 and 0.16, respectively. Mixed insulin formulations and sulfonylureas showed an association with decreased HbA_1c levels.

Interaction Effects

The interaction terms between the recall period and the medication classes provided insights into the differential impact of the medication switch postrecall. Notably, the interaction term for long-acting insulin (coefficient, −0.10) was significant, suggesting a differential effect on HbA_1c levels postrecall. Other medications, like metformin IR, also exhibited significant interaction effects, indicating changes in the impact on HbA_1c levels in the postrecall period. The binary variable for medication class exposure suggests the use of a logit link function for binary outcomes within the multilevel modeling framework.¹⁵ We did not address the potential for cross cluster heterogeneity due to different medication classes.

DISCUSSION

This study is an ongoing, concurrent, observational, multicenter, registry-based study consisting of VISN 6 veterans who have T2DM and were prescribed metformin SA on June 1, 2020. This initial aim was to evaluate change in HbA_1c levels following the FDA metformin recall. While there was substantial variability in baseline HbA_1c levels across the patients, the mean baseline HbA_1c level at 7.5% (58 mmol/mol). Patients taking GLP-1 agonists showed substantial decrease in HbA_1c levels (coefficient; –0.5; 95% CI, –0.56 to –0.44; P <. 001). Patients taking SGLT-2 inhibitors had a notable decrease in HbA_1c (coefficient, –0.27; 95% CI, –0.32 to –0.22; P < .001). Despite this, the coefficient for the postrecall period was not statistically significant, indicating no overall change in HbA_1c levels from pre- to postrecall when specific medication classes were not considered.

Further analysis included assessment of prescribing trends postrecall. There was an increase in SGLT-2 inhibitor, GLP-1 agonist, and DPP-4 inhibitor prescribing. Considering the growing evidence of the cardiovascular and renal benefits of these medication classes, specifically the GLP-1 agonists and SGLT-2 inhibitors, this trend would be expected.

Limitations

This study cohort did not capture veterans with T2DM who transferred their health care to VISN 6 after June 1, 2020, and continued to receive metformin SA from the prior facility. Inclusion of these veterans would have increased the registry population. Additionally, the cohort did not identify veterans who continued to receive metformin SA through a source other than the VA. Without that information, the registry cohort may include veterans thought to have either transitioned to a different therapy or to no other T2DM therapy after the recall.

Given that DM can progress over time, it is possible the transition to a new medication after the recall was the result of suboptimal management, or in response to an adverse effect from a previous medication, and not solely due to the metformin SA recall. In addition, there are several factors that could impact HbA_1c level over time that were not accounted for in this study, such as medication adherence and lifestyle modifications.

The notable level of metformin SA prescriptions, despite the recall, may be attributed to several factors. First, not all patients stopped metformin completely. Review of the prescription data indicated that some veterans were provided with limited refills at select VA medical centers that had supplies (medication lots not recalled). Access to a safe supply of metformin SA after the recall may have varied among VISN 6 facilities. It is also possible that as new supplies of metformin SA became available, veterans restarted metformin SA. This may have been resumed while continuing a new medication prescribed at the beginning of the recall. As the year progressed after the recall, an increase in metformin SA prescriptions likely occurred as supplies became available and clinicians/veterans chose to resume this medication therapy.

Conclusions

Results of this initial registry study found no difference in HbA_1c levels across the study population after the metformin SA recall. However, there was clinical difference in the HbA_1c within veterans prescribed SGLT-2 inhibitors and GLP-1 agonists. As expected, prescribing trends showed an increase in these agents after the recall. With the known benefits of these medications beyond glucose lowering, it is anticipated the cohort of veterans prescribed these medications will continue to grow.

The VISN 6 research registry allowed this study to gain an important snapshot in time following the metformin SA recall, and will serve as an important resource for future DM research endeavors. It will allow for ongoing evaluation of the impact of the transition to alternative T2DM medications after the metformin SA recall. Future exploration will include evaluation of adverse drug reactions, DM-related hospitalizations, emergency department visits related to T2DM, changes in renal function, and cardiovascular events among all diabetes medication classes.

Acknowledgments

The study team thanks the Veterans Affairs Informatics and Computing Infrastructure for their help and expertise throughout this project. The authors acknowledge the contributions of Philip Nelson, PharmD, and Brian Peek, PharmD.

About 1 in 10 Americans have diabetes mellitus (DM), of which about 90% to 95% are diagnosed with type 2 DM (T2DM) and veterans are disproportionately affected.^1,2 About 25% enrolled in the Veterans Health Administration (VHA) have T2DM, which has been attributed to exposure to herbicides (eg, Agent Orange), decreased physical activity resulting from past physical strain, chronic pain, and other physical limitations resulting from military service.^3-5

Pharmacologic management of DM is guided by the effectiveness of lifestyle interventions and comorbid diagnoses. Current DM management guidelines recommend patients with comorbid atherosclerotic cardiovascular disease, chronic kidney disease, or congestive heart failure receive first-line diabetes therapy with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor or glucagon-like peptide-1 receptor (GLP-1) agonist.

Metformin remains a first-line pharmacologic option for the treatment of T2DM with the goal of achieving glycemic management when lifestyle interventions are insufficient.^6,7 Newer antihyperglycemic therapies have been studied as adjunct therapy to metformin. However, there is limited literature comparing metformin directly to other medication classes for the treatment of T2DM.^8-13 A systematic review of treatment-naive patients found HbA_1c reductions were similar whether patients received metformin vs an SGLT-2 inhibitor, GLP-1 agonist, sulfonylurea, or thiazolidinedione monotherapy.¹⁰ The analysis found dipeptidyl-peptidase-4 (DPP-4) inhibitors had inferior HbA_1c reduction compared to metformin.¹⁰ A Japanese systematic review compared metformin to thiazolidinediones, sulfonylureas, glinides, DPP-4 inhibitors, α-glucosidase inhibitors, or SGLT-2 inhibitors for ≥ 12 weeks but found no statistically significant differences in HbA_1c reduction.¹¹ The AWARD-3 trial compared once-weekly dulaglutide to metformin in treatment-experienced patients and found greater improvement in HbA_1c and achievement of HbA_1c goal with dulaglutide.¹³ While these studies show some comparisons of metformin to alternative pharmacologic therapy, researchers have not looked at what happens to patients’ HbA_1c levels when an event, such as a recall, prompts a rapid change to a different antihyperglycemic agent.

On May 28, 2020, the US Food and Drug Administration (FDA) asked 5 pharmaceutical companies to voluntarily recall certain formulations of metformin. This action was taken when FDA testing revealed unacceptably high levels of N-Nitrosodimethylamine, a probable carcinogen.¹⁴ This FDA recall of metformin extended-release, referred to as metformin sustained-action (SA) within the VHA electronic medication file but the same type of formulation, prompted clinicians to revisit and revise the pharmacologic regimens of patients taking the drug. Because of the paucity of head-to-head trials comparing metformin with newer alternative antihyperglycemic therapies, the effect of treatment change was unknown. In response, we aimed to establish a data registry within Veterans Integrated Service Network (VISN) 6.

Registry Development

The VISN 6 registry was established to gather long-term, observational, head-to-head data that would allow review of HbA_1c levels before and after the recall, as well as HbA_1c levels broken down by the agent that patients were switched to after the recall. Another goal was to explore prescribing trends following the recall.

Data Access Request Tracker approval was obtained and a US Department of Veterans Affairs (VA) Information and Computing Infrastructure workspace was developed to host the registry data. The research cohort was established from this data, and the registry framework was finalized using Structured Query Language (SQL). The SQL coding allows for recurring data updates for all individuals within the cohort including date of birth, race, sex, ethnicity, VHA facility visited, weight, body mass index, HbA_1c level, creatinine clearance, serum creatinine, antihyperglycemic medication prescriptions, adverse drug reactions, medication adherence (as defined by ≥ 80% refill history), and hospitalizations related to diabetes. For the purposes of this initial analysis, registry data included demographics, diabetes medications, and HbA_1c results.

METHODS

This study was a concurrent, observational, multicenter, registry-based study conducted at the Western North Carolina VA Health Care System (WNCVAHCS). The study was approved by the WNCVAHCS institutional review board and research and development committees.

All patients aged ≥ 18 years with T2DM and receiving health care from VISN 6 facilities who had an active metformin SA prescription on, and 1 year prior to, June 1, 2020 (the initial date VHA began implementing the FDA metformin recall) were entered into the registry. Data from 1 year prior were collected to provide a baseline. Veterans were excluded if they received metformin SA for any indication other than T2DM, there was no pre- or postrecall HbA_1c measurement, or death. We included 15,594 VISN 6 veterans.

Registry data were analyzed to determine whether a significant change in HbA_1c level occurred after the metformin recall and in response to alternative agents being prescribed. Data from veterans who met all inclusion criteria were assessed during the year before and after June 1, 2020. Demographic data were analyzed using frequency and descriptive statistics. The Shapiro Wilkes test was performed, and data were found to be nonparametric; therefore the Wilcoxon signed-rank test was used to evaluate the hypothesis that HbA_1c levels were not impacted by the recall.

Our sample size allowed us to create exact matched pairs of 9130 individuals and utilize rank-biserial correlation to establish effect size. Following this initial population-level test, we constructed 2 models. The first, a linear mixed-effects model, focused solely on the interaction effects between the pre- and postrecall periods and various medication classes on HbA_1c levels. Second, we constructed a random-effects within-between model (REWB) to evaluate the impact ofmedication classes and demographic variables. Statistical significance was measured at P < .05 with conservative power at .90. The effect size was set to 1.0, reflecting a minimum clinically important difference. Literature establishes 0.5 as a modest level of HbA_1c improvement and 1.0 as a clinically significant improvement.

RESULTS

Preliminary results included 15,594 veterans who received a metformin SA prescription as of June 1, 2020 from VISN 6 facilities; 15,392 veterans had a drug exposure end on June 1, 2020, indicating their standard therapy of metformin SA was discontinued following the FDA recall. Two hundred and two veterans were excluded from the registry because they continued to receive metformin SA from existing stock at a VISN6 facility. After identifying veterans with data for 1 year prior (June 1, 2019) to the index date and 1 year after (June 1, 2021) the study population was adjusted to 9130. The population was predominantly males aged> 60 years. Roughly 55% of the registry identified as White and nearly 40% as Black, and 2% indentified as Hispanic (Table 1).

Wilcoxon Signed-Rank Test

We created exact pairs by iterating the data and finding the closest measurements for each patient before and after the recall. This has the advantage over averaging a patient’s pre- and post-HbA_1c levels, as it allows for a rank-biserial correlation. Using the nonparametric Wilcoxon signed-rank test, V was 20,100,707 (P < .001), indicating a significant effect. The –0.29 rank-biserial correlation, which was computed to assess the effect size of the recall, suggests that the median HbA_1c level was lower postrecall vs prerecall. The magnitude of the correlation suggests a moderate effect size, and while the recall had a noticeable impact at a population level, it was not extreme (Table 2).

Linear Mixed-Effects Model

The binary variable for medication class exposure suggests the use of a logit link function for binary outcomes within the multilevel modeling framework.¹⁵ We employed a linear mixed-effects model to investigate the impact that switching from metformin SA to other T2DM medications had on HbA_1c levels. The model was adjusted for patient-specific random effects and included interaction terms between the recall period (before and after) and the usage of different T2DM medications.

Model Fit and Random Effects

The model demonstrated a residual maximum likelihood criterion of 100,219.7, indicating its fit to the data. Notably, the random effects analysis revealed a substantial variability in baseline HbA_1c levels across patients (SD, 0.94), highlighting the importance of individual differences in DM management. Medication classes with zero or near-zero exposure rate were removed. Due to demographic homogeneity, the model did not converge on demographic variables. Veterans were taking a mean of 1.8 T2DM medications and metformin SA was most common (Table 3).

During the postrecall period, metformin SA remained the most frequently prescribed medication class. This may be attributed to the existence of multiple manufacturers of metformin SA, some of which may not have been impacted by the recall. VISN 6 medical centers could have sought metformin SA outside of the usual procurement path following the recall.

Complex Random Effects Model

We employed a complex REWB model that evaluated the impact of medication classes on HbA_1c levels, accounting for both within and between subject effects of these medications, along with demographic variables (sex, race, and ethnicity) (eAppendix). This model accounts for individual-level changes over time (within-patient effects) and between groups of patients (between-patient effects). This is a more comprehensive model aimed at understanding the broader impact of medications on HbA_1c levels across diverse patient groups.

Most demographic categories did not demonstrate significant effects in this model. Black individuals experienced a slight increase in HbA_1c levels compared with other racial categories that was not statistically significant. However, this model confirms the findings from the linear mixed-effects model that GLP-1 agonists showed a substantial decrease in HbA_1c levels within patients (coefficient –0.5; 95% CI, –0.56 to –0.44; P < .001) and a moderate increase between patients (coefficient, 0.21; 95% CI, 0.12-0.31; P < .001). Additionally, SGLT-2 inhibitors had a notable decrease within patients (coefficient, –0.27; 95% CI, –0.32 to –0.22; P < .001).Another notable finding with our REWB model is insulin usage was associated with high HbA_1c levels, but only between subjects. Long-acting insulin (coefficient, 0.96; 95% CI, 0.90-1.01; P <. 001) and mixed insulin (coefficient, 1.09; 95% CI, 0.94-1.24; P < .001) both displayed marked increases between patients, suggesting future analysis may benefit from stratifying across insulin users and nonusers.

Fixed Effect Analysis

The fixed effects analysis yielded several notable findings. The intercept, representing the mean baseline HbA_1c level, was estimated at 7.8% (58 mmol/mol). The coefficient for the period (postrecall) was not statistically significant, indicating no overall change in HbA_1c levels from before to after the recall when specific medication classes were not considered (Table 4). Among medication classes examined, several showed significant associations with HbA_1c levels. DPP-4 inhibitors and GLP-1 agonists were associated with a decrease in HbA_1c levels, with coefficients of −0.08 and −0.24, respectively. Long-acting insulin and metformin immediate-release (IR) were associated with an increase in HbA_1c levels, as indicated by their positive coefficients of 0.38 and 0.16, respectively. Mixed insulin formulations and sulfonylureas showed an association with decreased HbA_1c levels.

Interaction Effects

The interaction terms between the recall period and the medication classes provided insights into the differential impact of the medication switch postrecall. Notably, the interaction term for long-acting insulin (coefficient, −0.10) was significant, suggesting a differential effect on HbA_1c levels postrecall. Other medications, like metformin IR, also exhibited significant interaction effects, indicating changes in the impact on HbA_1c levels in the postrecall period. The binary variable for medication class exposure suggests the use of a logit link function for binary outcomes within the multilevel modeling framework.¹⁵ We did not address the potential for cross cluster heterogeneity due to different medication classes.

DISCUSSION

This study is an ongoing, concurrent, observational, multicenter, registry-based study consisting of VISN 6 veterans who have T2DM and were prescribed metformin SA on June 1, 2020. This initial aim was to evaluate change in HbA_1c levels following the FDA metformin recall. While there was substantial variability in baseline HbA_1c levels across the patients, the mean baseline HbA_1c level at 7.5% (58 mmol/mol). Patients taking GLP-1 agonists showed substantial decrease in HbA_1c levels (coefficient; –0.5; 95% CI, –0.56 to –0.44; P <. 001). Patients taking SGLT-2 inhibitors had a notable decrease in HbA_1c (coefficient, –0.27; 95% CI, –0.32 to –0.22; P < .001). Despite this, the coefficient for the postrecall period was not statistically significant, indicating no overall change in HbA_1c levels from pre- to postrecall when specific medication classes were not considered.

Further analysis included assessment of prescribing trends postrecall. There was an increase in SGLT-2 inhibitor, GLP-1 agonist, and DPP-4 inhibitor prescribing. Considering the growing evidence of the cardiovascular and renal benefits of these medication classes, specifically the GLP-1 agonists and SGLT-2 inhibitors, this trend would be expected.

Limitations

This study cohort did not capture veterans with T2DM who transferred their health care to VISN 6 after June 1, 2020, and continued to receive metformin SA from the prior facility. Inclusion of these veterans would have increased the registry population. Additionally, the cohort did not identify veterans who continued to receive metformin SA through a source other than the VA. Without that information, the registry cohort may include veterans thought to have either transitioned to a different therapy or to no other T2DM therapy after the recall.

Given that DM can progress over time, it is possible the transition to a new medication after the recall was the result of suboptimal management, or in response to an adverse effect from a previous medication, and not solely due to the metformin SA recall. In addition, there are several factors that could impact HbA_1c level over time that were not accounted for in this study, such as medication adherence and lifestyle modifications.

The notable level of metformin SA prescriptions, despite the recall, may be attributed to several factors. First, not all patients stopped metformin completely. Review of the prescription data indicated that some veterans were provided with limited refills at select VA medical centers that had supplies (medication lots not recalled). Access to a safe supply of metformin SA after the recall may have varied among VISN 6 facilities. It is also possible that as new supplies of metformin SA became available, veterans restarted metformin SA. This may have been resumed while continuing a new medication prescribed at the beginning of the recall. As the year progressed after the recall, an increase in metformin SA prescriptions likely occurred as supplies became available and clinicians/veterans chose to resume this medication therapy.

Conclusions

Results of this initial registry study found no difference in HbA_1c levels across the study population after the metformin SA recall. However, there was clinical difference in the HbA_1c within veterans prescribed SGLT-2 inhibitors and GLP-1 agonists. As expected, prescribing trends showed an increase in these agents after the recall. With the known benefits of these medications beyond glucose lowering, it is anticipated the cohort of veterans prescribed these medications will continue to grow.

The VISN 6 research registry allowed this study to gain an important snapshot in time following the metformin SA recall, and will serve as an important resource for future DM research endeavors. It will allow for ongoing evaluation of the impact of the transition to alternative T2DM medications after the metformin SA recall. Future exploration will include evaluation of adverse drug reactions, DM-related hospitalizations, emergency department visits related to T2DM, changes in renal function, and cardiovascular events among all diabetes medication classes.

Acknowledgments

The study team thanks the Veterans Affairs Informatics and Computing Infrastructure for their help and expertise throughout this project. The authors acknowledge the contributions of Philip Nelson, PharmD, and Brian Peek, PharmD.

Smoking is another important modifiable environmental factor. Smoking generally has an adverse impact on treatment. In a post hoc analysis of pooled data from phase 2 and 3 trials and a long-term extension study involving 914 patients with PsA and 372 patients with ankylosing spondylitis who received tofacitinib (a Janus kinase inhibitor) or placebo, Ogdie and coworkers assessed the impact of smoking on treatment efficacy and safety. The efficacy rates were generally similar in current/past smokers and never-smokers. The incidence rates of treatment-emergent adverse events were higher in current/past smokers compared with never-smokers. Thus, in contrast to tumor necrosis factor inhibitors, smoking status may not have an impact on tofacitinib efficacy. However, current/past smokers experienced increased rates of adverse events.

Secukinumab, an anti-interleukin (IL)-17A antibody, is an established treatment for PsA and is approved for use as fixed-dose (150/300 mg) subcutaneous injections. The efficacy and safety of weight-based intravenous (IV) therapy is unknown. Kivitz and colleagues recently reported the results of the phase 3 INVIGORATE-2 trial, in which 381 patients with active PsA and either plaque psoriasis or nail psoriasis were randomly assigned to receive IV secukinumab or placebo with crossover to IV secukinumab at week 16. They demonstrated that at week 16, IV secukinumab significantly improved the American College of Rheumatology 50 response rate (ACR50) compared with placebo (31.4% vs 6.3%; adjusted P < .0001). Improvements were observed as early as week 4 and were sustained through week 52. No new safety signals were reported. Thus, IV secukinumab is a safe and efficacious treatment for PsA. This mode of administration of secukinumab is a welcome addition to the PsA therapeutic armamentarium.

There are many targeted therapies available for PsA. However, data on comparative effectiveness is lacking. Kristensen and associates reported the results of an interim analysis of the PRO-SPIRIT real-world study that included 1192 patients with PsA across six countries who initiated or switched to a new biologic or targeted synthetic disease-modifying antirheumatic drug. They showed that at 3 months, ixekizumab significantly improved clinical disease activity in patients with PsA compared with IL-12/23 inhibitors and IL-23 inhibitors. The improvements in the joints were similar to those with TNF inhibitors and JAK inhibitors, but the improvement in psoriasis was higher. Thus, ixekizumab leads to rapid response to active skin and musculoskeletal disease activity in PsA. Comparative data on treatment persistence as well as adverse events are required.

Smoking is another important modifiable environmental factor. Smoking generally has an adverse impact on treatment. In a post hoc analysis of pooled data from phase 2 and 3 trials and a long-term extension study involving 914 patients with PsA and 372 patients with ankylosing spondylitis who received tofacitinib (a Janus kinase inhibitor) or placebo, Ogdie and coworkers assessed the impact of smoking on treatment efficacy and safety. The efficacy rates were generally similar in current/past smokers and never-smokers. The incidence rates of treatment-emergent adverse events were higher in current/past smokers compared with never-smokers. Thus, in contrast to tumor necrosis factor inhibitors, smoking status may not have an impact on tofacitinib efficacy. However, current/past smokers experienced increased rates of adverse events.

Secukinumab, an anti-interleukin (IL)-17A antibody, is an established treatment for PsA and is approved for use as fixed-dose (150/300 mg) subcutaneous injections. The efficacy and safety of weight-based intravenous (IV) therapy is unknown. Kivitz and colleagues recently reported the results of the phase 3 INVIGORATE-2 trial, in which 381 patients with active PsA and either plaque psoriasis or nail psoriasis were randomly assigned to receive IV secukinumab or placebo with crossover to IV secukinumab at week 16. They demonstrated that at week 16, IV secukinumab significantly improved the American College of Rheumatology 50 response rate (ACR50) compared with placebo (31.4% vs 6.3%; adjusted P < .0001). Improvements were observed as early as week 4 and were sustained through week 52. No new safety signals were reported. Thus, IV secukinumab is a safe and efficacious treatment for PsA. This mode of administration of secukinumab is a welcome addition to the PsA therapeutic armamentarium.

There are many targeted therapies available for PsA. However, data on comparative effectiveness is lacking. Kristensen and associates reported the results of an interim analysis of the PRO-SPIRIT real-world study that included 1192 patients with PsA across six countries who initiated or switched to a new biologic or targeted synthetic disease-modifying antirheumatic drug. They showed that at 3 months, ixekizumab significantly improved clinical disease activity in patients with PsA compared with IL-12/23 inhibitors and IL-23 inhibitors. The improvements in the joints were similar to those with TNF inhibitors and JAK inhibitors, but the improvement in psoriasis was higher. Thus, ixekizumab leads to rapid response to active skin and musculoskeletal disease activity in PsA. Comparative data on treatment persistence as well as adverse events are required.

Smoking is another important modifiable environmental factor. Smoking generally has an adverse impact on treatment. In a post hoc analysis of pooled data from phase 2 and 3 trials and a long-term extension study involving 914 patients with PsA and 372 patients with ankylosing spondylitis who received tofacitinib (a Janus kinase inhibitor) or placebo, Ogdie and coworkers assessed the impact of smoking on treatment efficacy and safety. The efficacy rates were generally similar in current/past smokers and never-smokers. The incidence rates of treatment-emergent adverse events were higher in current/past smokers compared with never-smokers. Thus, in contrast to tumor necrosis factor inhibitors, smoking status may not have an impact on tofacitinib efficacy. However, current/past smokers experienced increased rates of adverse events.

Secukinumab, an anti-interleukin (IL)-17A antibody, is an established treatment for PsA and is approved for use as fixed-dose (150/300 mg) subcutaneous injections. The efficacy and safety of weight-based intravenous (IV) therapy is unknown. Kivitz and colleagues recently reported the results of the phase 3 INVIGORATE-2 trial, in which 381 patients with active PsA and either plaque psoriasis or nail psoriasis were randomly assigned to receive IV secukinumab or placebo with crossover to IV secukinumab at week 16. They demonstrated that at week 16, IV secukinumab significantly improved the American College of Rheumatology 50 response rate (ACR50) compared with placebo (31.4% vs 6.3%; adjusted P < .0001). Improvements were observed as early as week 4 and were sustained through week 52. No new safety signals were reported. Thus, IV secukinumab is a safe and efficacious treatment for PsA. This mode of administration of secukinumab is a welcome addition to the PsA therapeutic armamentarium.

There are many targeted therapies available for PsA. However, data on comparative effectiveness is lacking. Kristensen and associates reported the results of an interim analysis of the PRO-SPIRIT real-world study that included 1192 patients with PsA across six countries who initiated or switched to a new biologic or targeted synthetic disease-modifying antirheumatic drug. They showed that at 3 months, ixekizumab significantly improved clinical disease activity in patients with PsA compared with IL-12/23 inhibitors and IL-23 inhibitors. The improvements in the joints were similar to those with TNF inhibitors and JAK inhibitors, but the improvement in psoriasis was higher. Thus, ixekizumab leads to rapid response to active skin and musculoskeletal disease activity in PsA. Comparative data on treatment persistence as well as adverse events are required.

Over the past two decades, the treatment of active psoriatic arthritis (PsA) has been transformed by targeted biologic therapies. In this ReCAP, Dr Eric Ruderman, from the Feinberg School of Medicine at Northwestern University, reports on the safety and efficacy of several approved therapies.

Dr Ruderman first discusses different treatment options, including TNF inhibitors, which have been the standard first-line therapy for nearly two decades. He also reports that other agents, including Il-12/23 inhibitors abatacept, apremilast, and a number of JAK inhibitors, have shown efficacy for patients who don’t respond well or are intolerant to TNF inhibitors.

In recent years, various specific IL-23 inhibitors have been approved to treat psoriasis and, most recently, psoriatic arthritis in psoriasis. Guselkumab, risankizumab, and tildrakizumab were approved to treat the skin disease.

In psoriatic arthritis, guselkumab and risankizumab have also been approved. These drugs have shown more efficacy than the IL-12/23 inhibitor, according to Ruderman, and show a lower risk for infection compared with some of the other agents.

--

Eric M. Ruderman, MD, Professor, Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine; Associate Division Chief, Clinical Affairs, Department of Rheumatology, Northwestern Medical Group, Chicago, Illinois

Eric M. Ruderman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Amgen; Bristol Myers Squibb; Janssen; Lilly; Merck; Novartis; NS Pharma; UCB

Over the past two decades, the treatment of active psoriatic arthritis (PsA) has been transformed by targeted biologic therapies. In this ReCAP, Dr Eric Ruderman, from the Feinberg School of Medicine at Northwestern University, reports on the safety and efficacy of several approved therapies.

Dr Ruderman first discusses different treatment options, including TNF inhibitors, which have been the standard first-line therapy for nearly two decades. He also reports that other agents, including Il-12/23 inhibitors abatacept, apremilast, and a number of JAK inhibitors, have shown efficacy for patients who don’t respond well or are intolerant to TNF inhibitors.

In recent years, various specific IL-23 inhibitors have been approved to treat psoriasis and, most recently, psoriatic arthritis in psoriasis. Guselkumab, risankizumab, and tildrakizumab were approved to treat the skin disease.

In psoriatic arthritis, guselkumab and risankizumab have also been approved. These drugs have shown more efficacy than the IL-12/23 inhibitor, according to Ruderman, and show a lower risk for infection compared with some of the other agents.

--

Eric M. Ruderman, MD, Professor, Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine; Associate Division Chief, Clinical Affairs, Department of Rheumatology, Northwestern Medical Group, Chicago, Illinois

Eric M. Ruderman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Amgen; Bristol Myers Squibb; Janssen; Lilly; Merck; Novartis; NS Pharma; UCB

Over the past two decades, the treatment of active psoriatic arthritis (PsA) has been transformed by targeted biologic therapies. In this ReCAP, Dr Eric Ruderman, from the Feinberg School of Medicine at Northwestern University, reports on the safety and efficacy of several approved therapies.

Dr Ruderman first discusses different treatment options, including TNF inhibitors, which have been the standard first-line therapy for nearly two decades. He also reports that other agents, including Il-12/23 inhibitors abatacept, apremilast, and a number of JAK inhibitors, have shown efficacy for patients who don’t respond well or are intolerant to TNF inhibitors.

In recent years, various specific IL-23 inhibitors have been approved to treat psoriasis and, most recently, psoriatic arthritis in psoriasis. Guselkumab, risankizumab, and tildrakizumab were approved to treat the skin disease.

In psoriatic arthritis, guselkumab and risankizumab have also been approved. These drugs have shown more efficacy than the IL-12/23 inhibitor, according to Ruderman, and show a lower risk for infection compared with some of the other agents.

--

Eric M. Ruderman, MD, Professor, Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine; Associate Division Chief, Clinical Affairs, Department of Rheumatology, Northwestern Medical Group, Chicago, Illinois

Eric M. Ruderman, MD, has disclosed the following relevant financial relationships:

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; Amgen; Bristol Myers Squibb; Janssen; Lilly; Merck; Novartis; NS Pharma; UCB

Efficacy data on ensifentrine, recently FDA-approved for moderate to severe COPD, as well as dupilumab use for symptom control, are key updates in COPD from the CHEST Annual Meeting. Dharani Narendra, MD, FCCP, CHEST Physician Editorial Board Member, from Baylor College of Medicine in Houston, Texas, reports on the findings.

Dr. Narendra begins with a trial examining the role of muscle relaxants in COPD exacerbation. The results showed that patients with COPD who were taking muscle relaxants experienced a rising risk for exacerbations over 1, 3, and 5 years, with a 20% relative risk increase by year 5.

Next, Dr. Narendra reports on ensifentrine efficacy in a subgroup analysis of the ENHANCE phase 3 trial, which provided the basis for FDA approval. Ensifentrine significantly improved peak and average FEV₁ at week 12, compared with placebo.

Dr. Narendra discusses a second presentation on ensifentrine — a meta-analysis of six randomized controlled trials of ensifentrine vs placebo in 2,365 patients. Significant improvements were seen in peak FEV₁ and average FEV₁, confirming ensifentrine efficacy in symptomatic patients with COPD with moderate to severe obstruction.

She also reviews subgroup analyses from the BOREAS and NOTUS trials, which led to the approval of dupilumab. One analysis demonstrated that dupilumab improved respiratory symptoms in patients with COPD with type 2 inflammation. Another showed significant reduction in annual exacerbation rates in patients with and without emphysema.

--

Dharani K. Narendra, MD, FCCP, Assistant Professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas

Dharani K. Narendra, MD, FCCP, has disclosed no relevant financial relationships.

Efficacy data on ensifentrine, recently FDA-approved for moderate to severe COPD, as well as dupilumab use for symptom control, are key updates in COPD from the CHEST Annual Meeting. Dharani Narendra, MD, FCCP, CHEST Physician Editorial Board Member, from Baylor College of Medicine in Houston, Texas, reports on the findings.

Dr. Narendra begins with a trial examining the role of muscle relaxants in COPD exacerbation. The results showed that patients with COPD who were taking muscle relaxants experienced a rising risk for exacerbations over 1, 3, and 5 years, with a 20% relative risk increase by year 5.

Next, Dr. Narendra reports on ensifentrine efficacy in a subgroup analysis of the ENHANCE phase 3 trial, which provided the basis for FDA approval. Ensifentrine significantly improved peak and average FEV₁ at week 12, compared with placebo.

Dr. Narendra discusses a second presentation on ensifentrine — a meta-analysis of six randomized controlled trials of ensifentrine vs placebo in 2,365 patients. Significant improvements were seen in peak FEV₁ and average FEV₁, confirming ensifentrine efficacy in symptomatic patients with COPD with moderate to severe obstruction.

She also reviews subgroup analyses from the BOREAS and NOTUS trials, which led to the approval of dupilumab. One analysis demonstrated that dupilumab improved respiratory symptoms in patients with COPD with type 2 inflammation. Another showed significant reduction in annual exacerbation rates in patients with and without emphysema.

--

Dharani K. Narendra, MD, FCCP, Assistant Professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas

Dharani K. Narendra, MD, FCCP, has disclosed no relevant financial relationships.

Efficacy data on ensifentrine, recently FDA-approved for moderate to severe COPD, as well as dupilumab use for symptom control, are key updates in COPD from the CHEST Annual Meeting. Dharani Narendra, MD, FCCP, CHEST Physician Editorial Board Member, from Baylor College of Medicine in Houston, Texas, reports on the findings.

Dr. Narendra begins with a trial examining the role of muscle relaxants in COPD exacerbation. The results showed that patients with COPD who were taking muscle relaxants experienced a rising risk for exacerbations over 1, 3, and 5 years, with a 20% relative risk increase by year 5.

Next, Dr. Narendra reports on ensifentrine efficacy in a subgroup analysis of the ENHANCE phase 3 trial, which provided the basis for FDA approval. Ensifentrine significantly improved peak and average FEV₁ at week 12, compared with placebo.

Dr. Narendra discusses a second presentation on ensifentrine — a meta-analysis of six randomized controlled trials of ensifentrine vs placebo in 2,365 patients. Significant improvements were seen in peak FEV₁ and average FEV₁, confirming ensifentrine efficacy in symptomatic patients with COPD with moderate to severe obstruction.

She also reviews subgroup analyses from the BOREAS and NOTUS trials, which led to the approval of dupilumab. One analysis demonstrated that dupilumab improved respiratory symptoms in patients with COPD with type 2 inflammation. Another showed significant reduction in annual exacerbation rates in patients with and without emphysema.

--

Dharani K. Narendra, MD, FCCP, Assistant Professor, Department of Pulmonary, Critical Care, and Sleep Medicine, Baylor College of Medicine, Houston, Texas

Dharani K. Narendra, MD, FCCP, has disclosed no relevant financial relationships.

The sun often is rising in the rearview mirror as I travel with the University of New Mexico dermatology team from Albuquerque to our satellite clinic in Gallup, New Mexico. This twice-monthly trip—with a group usually comprising an attending physician, residents, and medical students—provides an invaluable opportunity for me to take part in delivering care to a majority Native American population and connects our institution and its trainees to the state’s rural and indigenous cultures and communities.

Community outreach is an important initiative for many dermatology residency training programs. Engaging with the community outside the clinic setting allows residents to hone their clinical skills, interact with and meet new people, and help to improve access to health care, especially for members of underserved populations.

Limited access to health care remains a pressing issue in the United States, especially for underserved and rural communities. There currently is no standardized way to measure access to care, but multiple contributing factors have been identified, including but not limited to patient wait times and throughput, provider turnover, ratio of dermatologists to patient population, insurance type, and patient outcomes.¹ Fortunately, there are many ways for dermatology residents to get involved and improve access to dermatologic services in their communities, including skin cancer screenings, free clinics, and teledermatology.

Skin Cancer Screenings

More than 40% of community outreach initiatives offered by dermatology residency programs are related to skin cancer screening and prevention.² The American Academy of Dermatology’s free skin cancer check program (https://www.aad.org/member/career/volunteer/spot) offers a way to participate in or even host a skin cancer screening in your community. Since 1985, this program has identified nearly 300,000 suspicious lesions and more than 30,000 suspected melanomas. Resources for setting up a skin cancer screening in your community are available on the program’s website. Residents may take this opportunity to teach medical students how to perform full-body skin examinations and/or practice making independent decisions as the supervisor for medical trainees. Skin cancer screening events not only expand access to care in underserved communities but also help residents feel more connected to the local community, especially if they have moved to a new location for their residency training.

Free Clinics

Engaging in educational opportunities offered through residency programs is another way to participate in community outreach. In particular, many programs are affiliated with a School of Medicine within their institution that allows residents to spearhead volunteer opportunities such as working at a free clinic. In fact, more than 30% of initiatives offered at dermatology residency programs are free general dermatology clinics.² Residents are in the unique position of being both learners themselves as well as educators to trainees.³ As part of our role, we can provide crucial specialty care to the community by working in concert with medical students and while also familiarizing ourselves with treating populations that we may not reach in our daily clinical work. For example, by participating in free clinics, we can provide care to vulnerable populations who typically may have financial or time barriers that prevent them from seeking care at the institution-associated clinic, including individuals experiencing homelessness, patients who are uninsured, and individuals who cannot take time off work to pursue medical care. Our presence in the community helps to reduce barriers to specialty care, particularly in the field of dermatology where the access shortage in the context of rising skin cancer rates prompts public health concerns.⁴

Teledermatology

Teledermatology became a way to extend our reach in the community more than ever before during the COVID-19 pandemic. Advances in audio, visual, and data telecommunication have been particularly helpful in dermatology, a specialty that relies heavily on visual cues for diagnosis. Synchronous, asynchronous, and hybrid teledermatology services implemented during the pandemic have gained favor among patients and dermatologists and are still applied in current practice.^5,6

For example, in the state of New Mexico (where there is a severe shortage of board-certified dermatologists to care for the state’s population), teledermatology has allowed rural providers of all specialties to consult University of New Mexico dermatologists by sending clinical photographs along with patient information and history via secure messaging. Instead of having the patient travel hundreds of miles to see the nearest dermatologist for their skin condition or endure long wait times to get in to see a specialist, primary providers now can initiate treatment or work-up for their patient’s skin issue in a timely manner with the use of teledermatology to consult specialists.

Teledermatology has demonstrated cost-effectiveness, accuracy, and efficiency in conveniently expanding access to care. It offers patients and dermatologists flexibility in receiving and delivering health care, respectively.⁷ As residents, learning how to navigate this technologic frontier in health care delivery is imperative, as it will remain a prevalent tool in the future care of our communities, particularly in underserved areas.

Final Thoughts

Through community outreach initiatives, dermatology residents have an opportunity not only to enrich our education but also to connect with and become closer to our patients. Skin cancer screenings, free clinics, and teledermatology have provided ways to reach more communities and remain important aspects of dermatology residency.

The sun often is rising in the rearview mirror as I travel with the University of New Mexico dermatology team from Albuquerque to our satellite clinic in Gallup, New Mexico. This twice-monthly trip—with a group usually comprising an attending physician, residents, and medical students—provides an invaluable opportunity for me to take part in delivering care to a majority Native American population and connects our institution and its trainees to the state’s rural and indigenous cultures and communities.

Community outreach is an important initiative for many dermatology residency training programs. Engaging with the community outside the clinic setting allows residents to hone their clinical skills, interact with and meet new people, and help to improve access to health care, especially for members of underserved populations.

Limited access to health care remains a pressing issue in the United States, especially for underserved and rural communities. There currently is no standardized way to measure access to care, but multiple contributing factors have been identified, including but not limited to patient wait times and throughput, provider turnover, ratio of dermatologists to patient population, insurance type, and patient outcomes.¹ Fortunately, there are many ways for dermatology residents to get involved and improve access to dermatologic services in their communities, including skin cancer screenings, free clinics, and teledermatology.

Skin Cancer Screenings

More than 40% of community outreach initiatives offered by dermatology residency programs are related to skin cancer screening and prevention.² The American Academy of Dermatology’s free skin cancer check program (https://www.aad.org/member/career/volunteer/spot) offers a way to participate in or even host a skin cancer screening in your community. Since 1985, this program has identified nearly 300,000 suspicious lesions and more than 30,000 suspected melanomas. Resources for setting up a skin cancer screening in your community are available on the program’s website. Residents may take this opportunity to teach medical students how to perform full-body skin examinations and/or practice making independent decisions as the supervisor for medical trainees. Skin cancer screening events not only expand access to care in underserved communities but also help residents feel more connected to the local community, especially if they have moved to a new location for their residency training.

Free Clinics

Engaging in educational opportunities offered through residency programs is another way to participate in community outreach. In particular, many programs are affiliated with a School of Medicine within their institution that allows residents to spearhead volunteer opportunities such as working at a free clinic. In fact, more than 30% of initiatives offered at dermatology residency programs are free general dermatology clinics.² Residents are in the unique position of being both learners themselves as well as educators to trainees.³ As part of our role, we can provide crucial specialty care to the community by working in concert with medical students and while also familiarizing ourselves with treating populations that we may not reach in our daily clinical work. For example, by participating in free clinics, we can provide care to vulnerable populations who typically may have financial or time barriers that prevent them from seeking care at the institution-associated clinic, including individuals experiencing homelessness, patients who are uninsured, and individuals who cannot take time off work to pursue medical care. Our presence in the community helps to reduce barriers to specialty care, particularly in the field of dermatology where the access shortage in the context of rising skin cancer rates prompts public health concerns.⁴

Teledermatology

Teledermatology became a way to extend our reach in the community more than ever before during the COVID-19 pandemic. Advances in audio, visual, and data telecommunication have been particularly helpful in dermatology, a specialty that relies heavily on visual cues for diagnosis. Synchronous, asynchronous, and hybrid teledermatology services implemented during the pandemic have gained favor among patients and dermatologists and are still applied in current practice.^5,6

For example, in the state of New Mexico (where there is a severe shortage of board-certified dermatologists to care for the state’s population), teledermatology has allowed rural providers of all specialties to consult University of New Mexico dermatologists by sending clinical photographs along with patient information and history via secure messaging. Instead of having the patient travel hundreds of miles to see the nearest dermatologist for their skin condition or endure long wait times to get in to see a specialist, primary providers now can initiate treatment or work-up for their patient’s skin issue in a timely manner with the use of teledermatology to consult specialists.

Teledermatology has demonstrated cost-effectiveness, accuracy, and efficiency in conveniently expanding access to care. It offers patients and dermatologists flexibility in receiving and delivering health care, respectively.⁷ As residents, learning how to navigate this technologic frontier in health care delivery is imperative, as it will remain a prevalent tool in the future care of our communities, particularly in underserved areas.

Final Thoughts

Through community outreach initiatives, dermatology residents have an opportunity not only to enrich our education but also to connect with and become closer to our patients. Skin cancer screenings, free clinics, and teledermatology have provided ways to reach more communities and remain important aspects of dermatology residency.

The sun often is rising in the rearview mirror as I travel with the University of New Mexico dermatology team from Albuquerque to our satellite clinic in Gallup, New Mexico. This twice-monthly trip—with a group usually comprising an attending physician, residents, and medical students—provides an invaluable opportunity for me to take part in delivering care to a majority Native American population and connects our institution and its trainees to the state’s rural and indigenous cultures and communities.

Community outreach is an important initiative for many dermatology residency training programs. Engaging with the community outside the clinic setting allows residents to hone their clinical skills, interact with and meet new people, and help to improve access to health care, especially for members of underserved populations.

Limited access to health care remains a pressing issue in the United States, especially for underserved and rural communities. There currently is no standardized way to measure access to care, but multiple contributing factors have been identified, including but not limited to patient wait times and throughput, provider turnover, ratio of dermatologists to patient population, insurance type, and patient outcomes.¹ Fortunately, there are many ways for dermatology residents to get involved and improve access to dermatologic services in their communities, including skin cancer screenings, free clinics, and teledermatology.

Skin Cancer Screenings

More than 40% of community outreach initiatives offered by dermatology residency programs are related to skin cancer screening and prevention.² The American Academy of Dermatology’s free skin cancer check program (https://www.aad.org/member/career/volunteer/spot) offers a way to participate in or even host a skin cancer screening in your community. Since 1985, this program has identified nearly 300,000 suspicious lesions and more than 30,000 suspected melanomas. Resources for setting up a skin cancer screening in your community are available on the program’s website. Residents may take this opportunity to teach medical students how to perform full-body skin examinations and/or practice making independent decisions as the supervisor for medical trainees. Skin cancer screening events not only expand access to care in underserved communities but also help residents feel more connected to the local community, especially if they have moved to a new location for their residency training.

Free Clinics

Engaging in educational opportunities offered through residency programs is another way to participate in community outreach. In particular, many programs are affiliated with a School of Medicine within their institution that allows residents to spearhead volunteer opportunities such as working at a free clinic. In fact, more than 30% of initiatives offered at dermatology residency programs are free general dermatology clinics.² Residents are in the unique position of being both learners themselves as well as educators to trainees.³ As part of our role, we can provide crucial specialty care to the community by working in concert with medical students and while also familiarizing ourselves with treating populations that we may not reach in our daily clinical work. For example, by participating in free clinics, we can provide care to vulnerable populations who typically may have financial or time barriers that prevent them from seeking care at the institution-associated clinic, including individuals experiencing homelessness, patients who are uninsured, and individuals who cannot take time off work to pursue medical care. Our presence in the community helps to reduce barriers to specialty care, particularly in the field of dermatology where the access shortage in the context of rising skin cancer rates prompts public health concerns.⁴

Teledermatology

Teledermatology became a way to extend our reach in the community more than ever before during the COVID-19 pandemic. Advances in audio, visual, and data telecommunication have been particularly helpful in dermatology, a specialty that relies heavily on visual cues for diagnosis. Synchronous, asynchronous, and hybrid teledermatology services implemented during the pandemic have gained favor among patients and dermatologists and are still applied in current practice.^5,6

For example, in the state of New Mexico (where there is a severe shortage of board-certified dermatologists to care for the state’s population), teledermatology has allowed rural providers of all specialties to consult University of New Mexico dermatologists by sending clinical photographs along with patient information and history via secure messaging. Instead of having the patient travel hundreds of miles to see the nearest dermatologist for their skin condition or endure long wait times to get in to see a specialist, primary providers now can initiate treatment or work-up for their patient’s skin issue in a timely manner with the use of teledermatology to consult specialists.

Teledermatology has demonstrated cost-effectiveness, accuracy, and efficiency in conveniently expanding access to care. It offers patients and dermatologists flexibility in receiving and delivering health care, respectively.⁷ As residents, learning how to navigate this technologic frontier in health care delivery is imperative, as it will remain a prevalent tool in the future care of our communities, particularly in underserved areas.

Final Thoughts

Through community outreach initiatives, dermatology residents have an opportunity not only to enrich our education but also to connect with and become closer to our patients. Skin cancer screenings, free clinics, and teledermatology have provided ways to reach more communities and remain important aspects of dermatology residency.

THE DIAGNOSIS: Chemotherapy-Induced Flagellate Dermatitis

Based on the clinical presentation and temporal relation with chemotherapy, a diagnosis of bleomycininduced flagellate dermatitis (FD) was made, as bleomycin is the only chemotherapeutic agent from this regimen that has been linked with FD.^1,2 Laboratory findings revealed eosinophilia, further supporting a druginduced dermatitis. The patient was treated with oral steroids and diphenhydramine to alleviate itching and discomfort. The chemotherapy was temporarily discontinued until symptomatic improvement was observed within 2 to 3 days.

Flagellate dermatitis is characterized by unique erythematous, linear, intermingled streaks of adjoining firm papules—often preceded by a prodrome of global pruritus—that eventually become hyperpigmented as the erythema subsides. The clinical manifestation of FD can be idiopathic; true/mechanical (dermatitis artefacta, abuse, sadomasochism); chemotherapy induced (peplomycin, trastuzumab, cisplatin, docetaxel, bendamustine); toxin induced (shiitake mushroom, cnidarian stings, Paederus insects); related to rheumatologic diseases (dermatomyositis, adult-onset Still disease), dermatographism, phytophotodermatitis, or poison ivy dermatitis; or induced by chikungunya fever.¹

The term flagellate originates from the Latin word flagellum, which pertains to the distinctive whiplike pattern. It was first described by Moulin et al³ in 1970 in reference to bleomycin-induced linear hyperpigmentation. Bleomycin, a glycopeptide antibiotic derived from Streptomyces verticillus, is used to treat Hodgkin lymphoma, squamous cell carcinoma, and germ cell tumors. The worldwide incidence of bleomycin-induced FD is 8% to 22% and commonly is associated with a cumulative dose greater than 100 U.² Clinical presentation is variable in terms of onset, distribution, and morphology of the eruption and could be independent of dose, route of administration, or type of malignancy being treated. The flagellate rash commonly involves the trunk, arms, and legs; can develop within hours to 6 months of starting bleomycin therapy; often is preceded by generalized itching; and eventually heals with hyperpigmentation.

Possible mechanisms of bleomycin-induced FD include localized melanogenesis, inflammatory pigmentary incontinence, alterations to normal pigmentation patterns, cytotoxic effects of the drug itself, minor trauma/ scratching leading to increased blood flow and causing local accumulation of bleomycin, heat recall, and reduced epidermal turnover leading to extended interaction between keratinocytes and melanocytes.² Heat exposure can act as a trigger for bleomycin-induced skin rash recall even months after the treatment is stopped.

Apart from discontinuing the drug, there is no specific treatment available for bleomycin-induced FD. The primary objective of treatment is to alleviate pruritus, which often involves the use of topical or systemic corticosteroids and oral antihistamines. The duration of treatment depends on the patient’s clinical response. Once treatment is discontinued, FD typically resolves within 6 to 8 months. However, there can be a permanent postinflammatory hyperpigmentation in the affected area.⁴ Although there is a concern for increased mortality after postponement of chemotherapy,⁵ the decision to proceed with or discontinue the chemotherapy regimen necessitates a comprehensive interdisciplinary discussion and a meticulous assessment of the risks and benefits that is customized to each individual patient. Flagellate dermatitis can reoccur with bleomycin re-exposure; a combined approach of proactive topical and systemic steroid treatment seems to diminish the likelihood of FD recurrence.⁵

Our case underscores the importance of recognizing, detecting, and managing FD promptly in individuals undergoing bleomycin-based chemotherapy. Medical professionals should familiarize themselves with this distinct adverse effect linked to bleomycin, enabling prompt discontinuation if necessary, and educate patients about the condition’s typically temporary nature, thereby alleviating their concerns.

THE DIAGNOSIS: Chemotherapy-Induced Flagellate Dermatitis

Based on the clinical presentation and temporal relation with chemotherapy, a diagnosis of bleomycininduced flagellate dermatitis (FD) was made, as bleomycin is the only chemotherapeutic agent from this regimen that has been linked with FD.^1,2 Laboratory findings revealed eosinophilia, further supporting a druginduced dermatitis. The patient was treated with oral steroids and diphenhydramine to alleviate itching and discomfort. The chemotherapy was temporarily discontinued until symptomatic improvement was observed within 2 to 3 days.

Flagellate dermatitis is characterized by unique erythematous, linear, intermingled streaks of adjoining firm papules—often preceded by a prodrome of global pruritus—that eventually become hyperpigmented as the erythema subsides. The clinical manifestation of FD can be idiopathic; true/mechanical (dermatitis artefacta, abuse, sadomasochism); chemotherapy induced (peplomycin, trastuzumab, cisplatin, docetaxel, bendamustine); toxin induced (shiitake mushroom, cnidarian stings, Paederus insects); related to rheumatologic diseases (dermatomyositis, adult-onset Still disease), dermatographism, phytophotodermatitis, or poison ivy dermatitis; or induced by chikungunya fever.¹

The term flagellate originates from the Latin word flagellum, which pertains to the distinctive whiplike pattern. It was first described by Moulin et al³ in 1970 in reference to bleomycin-induced linear hyperpigmentation. Bleomycin, a glycopeptide antibiotic derived from Streptomyces verticillus, is used to treat Hodgkin lymphoma, squamous cell carcinoma, and germ cell tumors. The worldwide incidence of bleomycin-induced FD is 8% to 22% and commonly is associated with a cumulative dose greater than 100 U.² Clinical presentation is variable in terms of onset, distribution, and morphology of the eruption and could be independent of dose, route of administration, or type of malignancy being treated. The flagellate rash commonly involves the trunk, arms, and legs; can develop within hours to 6 months of starting bleomycin therapy; often is preceded by generalized itching; and eventually heals with hyperpigmentation.

Possible mechanisms of bleomycin-induced FD include localized melanogenesis, inflammatory pigmentary incontinence, alterations to normal pigmentation patterns, cytotoxic effects of the drug itself, minor trauma/ scratching leading to increased blood flow and causing local accumulation of bleomycin, heat recall, and reduced epidermal turnover leading to extended interaction between keratinocytes and melanocytes.² Heat exposure can act as a trigger for bleomycin-induced skin rash recall even months after the treatment is stopped.

Apart from discontinuing the drug, there is no specific treatment available for bleomycin-induced FD. The primary objective of treatment is to alleviate pruritus, which often involves the use of topical or systemic corticosteroids and oral antihistamines. The duration of treatment depends on the patient’s clinical response. Once treatment is discontinued, FD typically resolves within 6 to 8 months. However, there can be a permanent postinflammatory hyperpigmentation in the affected area.⁴ Although there is a concern for increased mortality after postponement of chemotherapy,⁵ the decision to proceed with or discontinue the chemotherapy regimen necessitates a comprehensive interdisciplinary discussion and a meticulous assessment of the risks and benefits that is customized to each individual patient. Flagellate dermatitis can reoccur with bleomycin re-exposure; a combined approach of proactive topical and systemic steroid treatment seems to diminish the likelihood of FD recurrence.⁵

Our case underscores the importance of recognizing, detecting, and managing FD promptly in individuals undergoing bleomycin-based chemotherapy. Medical professionals should familiarize themselves with this distinct adverse effect linked to bleomycin, enabling prompt discontinuation if necessary, and educate patients about the condition’s typically temporary nature, thereby alleviating their concerns.

THE DIAGNOSIS: Chemotherapy-Induced Flagellate Dermatitis

Based on the clinical presentation and temporal relation with chemotherapy, a diagnosis of bleomycininduced flagellate dermatitis (FD) was made, as bleomycin is the only chemotherapeutic agent from this regimen that has been linked with FD.^1,2 Laboratory findings revealed eosinophilia, further supporting a druginduced dermatitis. The patient was treated with oral steroids and diphenhydramine to alleviate itching and discomfort. The chemotherapy was temporarily discontinued until symptomatic improvement was observed within 2 to 3 days.

Flagellate dermatitis is characterized by unique erythematous, linear, intermingled streaks of adjoining firm papules—often preceded by a prodrome of global pruritus—that eventually become hyperpigmented as the erythema subsides. The clinical manifestation of FD can be idiopathic; true/mechanical (dermatitis artefacta, abuse, sadomasochism); chemotherapy induced (peplomycin, trastuzumab, cisplatin, docetaxel, bendamustine); toxin induced (shiitake mushroom, cnidarian stings, Paederus insects); related to rheumatologic diseases (dermatomyositis, adult-onset Still disease), dermatographism, phytophotodermatitis, or poison ivy dermatitis; or induced by chikungunya fever.¹

The term flagellate originates from the Latin word flagellum, which pertains to the distinctive whiplike pattern. It was first described by Moulin et al³ in 1970 in reference to bleomycin-induced linear hyperpigmentation. Bleomycin, a glycopeptide antibiotic derived from Streptomyces verticillus, is used to treat Hodgkin lymphoma, squamous cell carcinoma, and germ cell tumors. The worldwide incidence of bleomycin-induced FD is 8% to 22% and commonly is associated with a cumulative dose greater than 100 U.² Clinical presentation is variable in terms of onset, distribution, and morphology of the eruption and could be independent of dose, route of administration, or type of malignancy being treated. The flagellate rash commonly involves the trunk, arms, and legs; can develop within hours to 6 months of starting bleomycin therapy; often is preceded by generalized itching; and eventually heals with hyperpigmentation.

Possible mechanisms of bleomycin-induced FD include localized melanogenesis, inflammatory pigmentary incontinence, alterations to normal pigmentation patterns, cytotoxic effects of the drug itself, minor trauma/ scratching leading to increased blood flow and causing local accumulation of bleomycin, heat recall, and reduced epidermal turnover leading to extended interaction between keratinocytes and melanocytes.² Heat exposure can act as a trigger for bleomycin-induced skin rash recall even months after the treatment is stopped.

Apart from discontinuing the drug, there is no specific treatment available for bleomycin-induced FD. The primary objective of treatment is to alleviate pruritus, which often involves the use of topical or systemic corticosteroids and oral antihistamines. The duration of treatment depends on the patient’s clinical response. Once treatment is discontinued, FD typically resolves within 6 to 8 months. However, there can be a permanent postinflammatory hyperpigmentation in the affected area.⁴ Although there is a concern for increased mortality after postponement of chemotherapy,⁵ the decision to proceed with or discontinue the chemotherapy regimen necessitates a comprehensive interdisciplinary discussion and a meticulous assessment of the risks and benefits that is customized to each individual patient. Flagellate dermatitis can reoccur with bleomycin re-exposure; a combined approach of proactive topical and systemic steroid treatment seems to diminish the likelihood of FD recurrence.⁵

Our case underscores the importance of recognizing, detecting, and managing FD promptly in individuals undergoing bleomycin-based chemotherapy. Medical professionals should familiarize themselves with this distinct adverse effect linked to bleomycin, enabling prompt discontinuation if necessary, and educate patients about the condition’s typically temporary nature, thereby alleviating their concerns.

The Asteraceae (formerly Compositae) family of plants is derived from the ancient Greek word aster, meaning “star,” referring to the starlike arrangement of flower petals around a central disc known as a capitulum. What initially appears as a single flower is actually a composite of several smaller flowers, hence the former name Compositae.¹ Well-known members of the Asteraceae family include ornamental annuals (eg, sunflowers, marigolds, cosmos), herbaceous ­perennials (eg, chrysanthemums, dandelions), vegetables (eg, lettuce, chicory, artichokes), herbs (eg, chamomile, tarragon), and weeds (eg, ragweed, horseweed, capeweed)(Figure 1).²

There are more than 25,000 species of Asteraceae plants that thrive in a wide range of climates worldwide. Cases of Asteraceae-induced skin reactions have been reported in North America, Europe, Asia, and Australia.³ Members of the Asteraceae family are ubiquitous in gardens, along roadsides, and in the wilderness. Occupational exposure commonly affects gardeners, florists, farmers, and forestry workers through either direct contact with plants or via airborne pollen. Furthermore, plants of the Asteraceae family are used in various products, including pediculicides (eg, insect repellents), cosmetics (eg, eye creams, body washes), and food products (eg, cooking oils, sweetening agents, coffee substitutes, herbal teas).^4-6 These plants have substantial allergic potential, resulting in numerous cutaneous reactions.

Allergic Potential

Asteraceae plants can elicit both immediate and delayed hypersensitivity reactions (HSRs); for instance, exposure to ragweed pollen may cause an IgE-mediated type 1 HSR manifesting as allergic rhinitis or a type IV HSR manifesting as airborne allergic contact dermatitis.^7,8 The main contact allergens present in Asteraceae plants are sesquiterpene lactones, which are found in the leaves, stems, flowers, and pollen.^9-11 Sesquiterpene lactones consist of an α-methyl group attached to a lactone ring combined with a sesquiterpene.¹² Patch testing can be used to diagnose Asteraceae allergy; however, the results are not consistently reliable because there is no perfect screening allergen. Patch test preparations commonly used to detect Asteraceae allergy include Compositae mix (consisting of Anthemis nobilis extract, Chamomilla recutita extract, Achillea millefolium extract, Tanacetum vulgare extract, Arnica montana extract, and parthenolide) and sesquiterpene lactone mix (consisting of alantolactone, dehydrocostus lactone, and costunolide). In North America, the prevalence of positive patch tests to Compositae mix and sesquiterpene lactone mix is approximately 2% and 0.5%, respectively.¹³ When patch testing is performed, both Compositae mix and sesquiterpene lactone mix should be utilized to minimize the risk of missing Asteraceae allergy, as sesquiterpene lactone mix alone does not detect all Compositae-sensitized patients. Additionally, it may be necessary to test supplemental Asteraceae allergens, including preparations from specific plants to which the patient has been exposed. Exposure to Asteraceae-containing cosmetic products may lead to dermatitis, though this is highly dependent on the particular plant species involved. For instance, the prevalence of sensitization is high in arnica (tincture) and elecampane but low with more commonly used species such as German chamomile.¹⁴

Cutaneous Manifestations

Asteraceae dermatitis, which also is known as Australian bush dermatitis, weed dermatitis, and chrysanthemum dermatitis,² can manifest on any area of the body that directly contacts the plant or is exposed to the pollen. Asteraceae dermatitis historically was reported in older adults with a recent history of plant exposure.^6,15 However, recent data have shown a female preponderance and a younger mean age of onset (46–49 years).¹⁶

There are multiple distinct clinical manifestations of Asteraceae dermatitis. The most common cutaneous finding is localized vesicular or eczematous patches on the hands or wrists. Other variations include eczematous rashes on the exposed skin of the hands, arms, face, and neck; generalized eczema; and isolated facial eczema.^16,17 These variations can be attributed to contact dermatitis caused by airborne pollen, which may mimic photodermatitis. However, airborne Asteraceae dermatitis can be distinguished clinically from photodermatitis by the involvement of sun-protected areas such as the skinfolds of the eyelids, retroauricular sulci, and nasolabial folds (Figure 2).^2,9 In rare cases, systemic allergic contact dermatitis can occur if the Asteraceae allergen is ingested.^2,18

Management

While complete avoidance of Asteraceae plants is ideal, it often is unrealistic due to their abundance in nature. Therefore, minimizing exposure to the causative plants is recommended. Primary preventive measures such as wearing protective gloves and clothing and applying bentonite clay prior to exposure should be taken when working outdoors. Promptly showering after contact with plants also can reduce the risk for Asteraceae dermatitis.

Symptomatic treatment is appropriate for mild cases and includes topical corticosteroids and calcineurin inhibitors. For severe cases, systemic corticosteroids may be needed for acute flares, with azathioprine, mycophenolate, cyclosporine, or methotrexate available for recalcitrant disease. Verma et al²⁵ found that treatment with azathioprine for 6 months resulted in greater than 60% clearance in all 12 patients, with a majority achieving 80% to 100% clearance. Methotrexate has been used at doses of 15 mg once weekly.²⁶ Narrowband UVB and psoralen plus UVA have been effective in extensive cases; however, care should be exercised in patients with photosensitive dermatitis, who instead should practice strict photoprotection.^27-29 Lakshmi et al³⁰ reported the use of cyclosporine during the acute phase of Asteraceae dermatitis at a dose of 2.5 mg/kg daily for 4 to 8 weeks. There have been several case reports of dupilumab treating allergic contact dermatitis; however, there have been 3 cases of patients with atopic dermatitis developing Asteraceae dermatitis while taking dupilumab.^31,32 Recently, oral Janus kinase inhibitors have shown success in treating refractory cases of airborne Asteraceae dermatitis.^33,34 Further research is needed to determine the safety and efficacy of dupilumab and Janus kinase inhibitors for treatment of Asteraceae dermatitis.

Final Thoughts

The Asteraceae plant family is vast and diverse, with more than 200 species reported to cause allergic contact dermatitis.¹² Common modes of contact include gardening, occupational exposure, airborne pollen, and use of pediculicides and cosmetics that contain components of Asteraceae plants. Educating patients on how to minimize contact with Asteraceae plants is the most effective management strategy; topical agents and oral immunosuppressives can be used for symptomatic treatment.

The Asteraceae (formerly Compositae) family of plants is derived from the ancient Greek word aster, meaning “star,” referring to the starlike arrangement of flower petals around a central disc known as a capitulum. What initially appears as a single flower is actually a composite of several smaller flowers, hence the former name Compositae.¹ Well-known members of the Asteraceae family include ornamental annuals (eg, sunflowers, marigolds, cosmos), herbaceous ­perennials (eg, chrysanthemums, dandelions), vegetables (eg, lettuce, chicory, artichokes), herbs (eg, chamomile, tarragon), and weeds (eg, ragweed, horseweed, capeweed)(Figure 1).²

There are more than 25,000 species of Asteraceae plants that thrive in a wide range of climates worldwide. Cases of Asteraceae-induced skin reactions have been reported in North America, Europe, Asia, and Australia.³ Members of the Asteraceae family are ubiquitous in gardens, along roadsides, and in the wilderness. Occupational exposure commonly affects gardeners, florists, farmers, and forestry workers through either direct contact with plants or via airborne pollen. Furthermore, plants of the Asteraceae family are used in various products, including pediculicides (eg, insect repellents), cosmetics (eg, eye creams, body washes), and food products (eg, cooking oils, sweetening agents, coffee substitutes, herbal teas).^4-6 These plants have substantial allergic potential, resulting in numerous cutaneous reactions.

Allergic Potential

Asteraceae plants can elicit both immediate and delayed hypersensitivity reactions (HSRs); for instance, exposure to ragweed pollen may cause an IgE-mediated type 1 HSR manifesting as allergic rhinitis or a type IV HSR manifesting as airborne allergic contact dermatitis.^7,8 The main contact allergens present in Asteraceae plants are sesquiterpene lactones, which are found in the leaves, stems, flowers, and pollen.^9-11 Sesquiterpene lactones consist of an α-methyl group attached to a lactone ring combined with a sesquiterpene.¹² Patch testing can be used to diagnose Asteraceae allergy; however, the results are not consistently reliable because there is no perfect screening allergen. Patch test preparations commonly used to detect Asteraceae allergy include Compositae mix (consisting of Anthemis nobilis extract, Chamomilla recutita extract, Achillea millefolium extract, Tanacetum vulgare extract, Arnica montana extract, and parthenolide) and sesquiterpene lactone mix (consisting of alantolactone, dehydrocostus lactone, and costunolide). In North America, the prevalence of positive patch tests to Compositae mix and sesquiterpene lactone mix is approximately 2% and 0.5%, respectively.¹³ When patch testing is performed, both Compositae mix and sesquiterpene lactone mix should be utilized to minimize the risk of missing Asteraceae allergy, as sesquiterpene lactone mix alone does not detect all Compositae-sensitized patients. Additionally, it may be necessary to test supplemental Asteraceae allergens, including preparations from specific plants to which the patient has been exposed. Exposure to Asteraceae-containing cosmetic products may lead to dermatitis, though this is highly dependent on the particular plant species involved. For instance, the prevalence of sensitization is high in arnica (tincture) and elecampane but low with more commonly used species such as German chamomile.¹⁴

Cutaneous Manifestations

Asteraceae dermatitis, which also is known as Australian bush dermatitis, weed dermatitis, and chrysanthemum dermatitis,² can manifest on any area of the body that directly contacts the plant or is exposed to the pollen. Asteraceae dermatitis historically was reported in older adults with a recent history of plant exposure.^6,15 However, recent data have shown a female preponderance and a younger mean age of onset (46–49 years).¹⁶

There are multiple distinct clinical manifestations of Asteraceae dermatitis. The most common cutaneous finding is localized vesicular or eczematous patches on the hands or wrists. Other variations include eczematous rashes on the exposed skin of the hands, arms, face, and neck; generalized eczema; and isolated facial eczema.^16,17 These variations can be attributed to contact dermatitis caused by airborne pollen, which may mimic photodermatitis. However, airborne Asteraceae dermatitis can be distinguished clinically from photodermatitis by the involvement of sun-protected areas such as the skinfolds of the eyelids, retroauricular sulci, and nasolabial folds (Figure 2).^2,9 In rare cases, systemic allergic contact dermatitis can occur if the Asteraceae allergen is ingested.^2,18

Management

While complete avoidance of Asteraceae plants is ideal, it often is unrealistic due to their abundance in nature. Therefore, minimizing exposure to the causative plants is recommended. Primary preventive measures such as wearing protective gloves and clothing and applying bentonite clay prior to exposure should be taken when working outdoors. Promptly showering after contact with plants also can reduce the risk for Asteraceae dermatitis.

Symptomatic treatment is appropriate for mild cases and includes topical corticosteroids and calcineurin inhibitors. For severe cases, systemic corticosteroids may be needed for acute flares, with azathioprine, mycophenolate, cyclosporine, or methotrexate available for recalcitrant disease. Verma et al²⁵ found that treatment with azathioprine for 6 months resulted in greater than 60% clearance in all 12 patients, with a majority achieving 80% to 100% clearance. Methotrexate has been used at doses of 15 mg once weekly.²⁶ Narrowband UVB and psoralen plus UVA have been effective in extensive cases; however, care should be exercised in patients with photosensitive dermatitis, who instead should practice strict photoprotection.^27-29 Lakshmi et al³⁰ reported the use of cyclosporine during the acute phase of Asteraceae dermatitis at a dose of 2.5 mg/kg daily for 4 to 8 weeks. There have been several case reports of dupilumab treating allergic contact dermatitis; however, there have been 3 cases of patients with atopic dermatitis developing Asteraceae dermatitis while taking dupilumab.^31,32 Recently, oral Janus kinase inhibitors have shown success in treating refractory cases of airborne Asteraceae dermatitis.^33,34 Further research is needed to determine the safety and efficacy of dupilumab and Janus kinase inhibitors for treatment of Asteraceae dermatitis.

Final Thoughts

The Asteraceae plant family is vast and diverse, with more than 200 species reported to cause allergic contact dermatitis.¹² Common modes of contact include gardening, occupational exposure, airborne pollen, and use of pediculicides and cosmetics that contain components of Asteraceae plants. Educating patients on how to minimize contact with Asteraceae plants is the most effective management strategy; topical agents and oral immunosuppressives can be used for symptomatic treatment.

The Asteraceae (formerly Compositae) family of plants is derived from the ancient Greek word aster, meaning “star,” referring to the starlike arrangement of flower petals around a central disc known as a capitulum. What initially appears as a single flower is actually a composite of several smaller flowers, hence the former name Compositae.¹ Well-known members of the Asteraceae family include ornamental annuals (eg, sunflowers, marigolds, cosmos), herbaceous ­perennials (eg, chrysanthemums, dandelions), vegetables (eg, lettuce, chicory, artichokes), herbs (eg, chamomile, tarragon), and weeds (eg, ragweed, horseweed, capeweed)(Figure 1).²

There are more than 25,000 species of Asteraceae plants that thrive in a wide range of climates worldwide. Cases of Asteraceae-induced skin reactions have been reported in North America, Europe, Asia, and Australia.³ Members of the Asteraceae family are ubiquitous in gardens, along roadsides, and in the wilderness. Occupational exposure commonly affects gardeners, florists, farmers, and forestry workers through either direct contact with plants or via airborne pollen. Furthermore, plants of the Asteraceae family are used in various products, including pediculicides (eg, insect repellents), cosmetics (eg, eye creams, body washes), and food products (eg, cooking oils, sweetening agents, coffee substitutes, herbal teas).^4-6 These plants have substantial allergic potential, resulting in numerous cutaneous reactions.

Allergic Potential

Asteraceae plants can elicit both immediate and delayed hypersensitivity reactions (HSRs); for instance, exposure to ragweed pollen may cause an IgE-mediated type 1 HSR manifesting as allergic rhinitis or a type IV HSR manifesting as airborne allergic contact dermatitis.^7,8 The main contact allergens present in Asteraceae plants are sesquiterpene lactones, which are found in the leaves, stems, flowers, and pollen.^9-11 Sesquiterpene lactones consist of an α-methyl group attached to a lactone ring combined with a sesquiterpene.¹² Patch testing can be used to diagnose Asteraceae allergy; however, the results are not consistently reliable because there is no perfect screening allergen. Patch test preparations commonly used to detect Asteraceae allergy include Compositae mix (consisting of Anthemis nobilis extract, Chamomilla recutita extract, Achillea millefolium extract, Tanacetum vulgare extract, Arnica montana extract, and parthenolide) and sesquiterpene lactone mix (consisting of alantolactone, dehydrocostus lactone, and costunolide). In North America, the prevalence of positive patch tests to Compositae mix and sesquiterpene lactone mix is approximately 2% and 0.5%, respectively.¹³ When patch testing is performed, both Compositae mix and sesquiterpene lactone mix should be utilized to minimize the risk of missing Asteraceae allergy, as sesquiterpene lactone mix alone does not detect all Compositae-sensitized patients. Additionally, it may be necessary to test supplemental Asteraceae allergens, including preparations from specific plants to which the patient has been exposed. Exposure to Asteraceae-containing cosmetic products may lead to dermatitis, though this is highly dependent on the particular plant species involved. For instance, the prevalence of sensitization is high in arnica (tincture) and elecampane but low with more commonly used species such as German chamomile.¹⁴

Cutaneous Manifestations

Asteraceae dermatitis, which also is known as Australian bush dermatitis, weed dermatitis, and chrysanthemum dermatitis,² can manifest on any area of the body that directly contacts the plant or is exposed to the pollen. Asteraceae dermatitis historically was reported in older adults with a recent history of plant exposure.^6,15 However, recent data have shown a female preponderance and a younger mean age of onset (46–49 years).¹⁶

There are multiple distinct clinical manifestations of Asteraceae dermatitis. The most common cutaneous finding is localized vesicular or eczematous patches on the hands or wrists. Other variations include eczematous rashes on the exposed skin of the hands, arms, face, and neck; generalized eczema; and isolated facial eczema.^16,17 These variations can be attributed to contact dermatitis caused by airborne pollen, which may mimic photodermatitis. However, airborne Asteraceae dermatitis can be distinguished clinically from photodermatitis by the involvement of sun-protected areas such as the skinfolds of the eyelids, retroauricular sulci, and nasolabial folds (Figure 2).^2,9 In rare cases, systemic allergic contact dermatitis can occur if the Asteraceae allergen is ingested.^2,18

Management

While complete avoidance of Asteraceae plants is ideal, it often is unrealistic due to their abundance in nature. Therefore, minimizing exposure to the causative plants is recommended. Primary preventive measures such as wearing protective gloves and clothing and applying bentonite clay prior to exposure should be taken when working outdoors. Promptly showering after contact with plants also can reduce the risk for Asteraceae dermatitis.

Symptomatic treatment is appropriate for mild cases and includes topical corticosteroids and calcineurin inhibitors. For severe cases, systemic corticosteroids may be needed for acute flares, with azathioprine, mycophenolate, cyclosporine, or methotrexate available for recalcitrant disease. Verma et al²⁵ found that treatment with azathioprine for 6 months resulted in greater than 60% clearance in all 12 patients, with a majority achieving 80% to 100% clearance. Methotrexate has been used at doses of 15 mg once weekly.²⁶ Narrowband UVB and psoralen plus UVA have been effective in extensive cases; however, care should be exercised in patients with photosensitive dermatitis, who instead should practice strict photoprotection.^27-29 Lakshmi et al³⁰ reported the use of cyclosporine during the acute phase of Asteraceae dermatitis at a dose of 2.5 mg/kg daily for 4 to 8 weeks. There have been several case reports of dupilumab treating allergic contact dermatitis; however, there have been 3 cases of patients with atopic dermatitis developing Asteraceae dermatitis while taking dupilumab.^31,32 Recently, oral Janus kinase inhibitors have shown success in treating refractory cases of airborne Asteraceae dermatitis.^33,34 Further research is needed to determine the safety and efficacy of dupilumab and Janus kinase inhibitors for treatment of Asteraceae dermatitis.

Final Thoughts

The Asteraceae plant family is vast and diverse, with more than 200 species reported to cause allergic contact dermatitis.¹² Common modes of contact include gardening, occupational exposure, airborne pollen, and use of pediculicides and cosmetics that contain components of Asteraceae plants. Educating patients on how to minimize contact with Asteraceae plants is the most effective management strategy; topical agents and oral immunosuppressives can be used for symptomatic treatment.