Dermoscopy showed polylobular, whitish yellow, amorphous structures at the center of the lesion surrounded by a crown of vessels (Figure 1). Histopathology revealed hyperplastic crateriform lesions containing large eosinophilic intracytoplasmic inclusion bodies within keratinocytes (Figure 2). At follow-up 2 weeks after the biopsy, the patient presented with approximately 20 more reddish papules of varying sizes on the abdomen and back that presented as dome-shaped papules and had a typical umbilicated center. The clinical manifestations, dermoscopy, and pathology findings were consistent with molluscum contagiosum (MC).

Molluscum contagiosum was first described in 1814. It is a benign cutaneous infectious disease caused by a double-stranded DNA virus of the poxvirus family. Molluscum contagiosum lesions usually manifest clinically as dome-shaped, flesh-colored or translucent, umbilicated papules measuring 1 to 5 mm in diameter that are commonly distributed over the face, trunk, and extremities and usually are self-limiting.¹

Giant MC is rare and can be seen either in patients on immunosuppressive therapy or in those with diseases that can cause immunosuppression, such as human immunodeficiency virus, leukemia, atopic dermatitis, Wiskott-Aldrich syndrome, and sarcoidosis. In these instances, MC often is greater than 1 cm in diameter. Atypical variants may have an eczematous presentation or a lesion with secondary abscess formation and also can be spread widely over the body.² Due to these atypical appearances and large dimensions in immunocompromised patients, other dermatologic diseases should be considered in the differential diagnosis, such as basal cell carcinoma, keratoacanthoma, squamous cell carcinoma, cutaneous horn, cutaneous cryptococcosis, histoplasmosis, and xanthomatosis.³

In our patient, the differential diagnosis included keratoacanthoma, which may present as a solitary, discrete, round to oval, flesh-colored, umbilicated nodule with a central keratin-filled crater and has a rapid clinical evolution, usually regressing within 4 to 6 months.

Squamous cell carcinoma may appear as scaly red patches, open sores, warts, or elevated growths with a central depression and may crust or bleed. Basal cell carcinoma typically may appear as a dome-shaped skin nodule with visible blood vessels or sometimes presents as a red patch similar to eczema. Xanthomatosis often appears as yellow to orange, mostly asymptomatic, supple patches or plaques, usually with sharp and distinctive edges.

Ancillary diagnostic modalities such as dermoscopy may be used to improve diagnostic accuracy. The best known capillaroscopic feature of MC is the peripheral crown of vessels in a radial distribution. A study of 258 MC lesions highlighted that crown and crown plus radial arrangements are the most common vascular structure patterns under dermoscopy. In addition, polylobular amorphous white structures in the center of the lesions tend to be a feature of larger MC papules.⁴ Histologically, MC shows lobulated crateriform lesions, thickening of the epidermis into the dermis, and the typical appearance of large eosinophilic intracytoplasmic inclusion bodies within keratinocytes.⁵

There are several treatment options available for MC. Common modalities include liquid nitrogen cryospray, curettage, and electrocauterization. In immunocompromised patients, MC lesions usually are resistant to ordinary therapy. The efficacy of topical agents such as imiquimod, which can induce high levels of IFN-α and other cytokines, has been demonstrated in these patients.⁶ Cidofovir, a nucleoside analog that has potent antiviral properties, also can be included as a therapeutic option.³ Our patient’s largest MC lesion was treated with surgical excision, the 2 large lesions on the left side of the chest with cryotherapy, and the other small lesions with curettage.

Dermoscopy showed polylobular, whitish yellow, amorphous structures at the center of the lesion surrounded by a crown of vessels (Figure 1). Histopathology revealed hyperplastic crateriform lesions containing large eosinophilic intracytoplasmic inclusion bodies within keratinocytes (Figure 2). At follow-up 2 weeks after the biopsy, the patient presented with approximately 20 more reddish papules of varying sizes on the abdomen and back that presented as dome-shaped papules and had a typical umbilicated center. The clinical manifestations, dermoscopy, and pathology findings were consistent with molluscum contagiosum (MC).

Molluscum contagiosum was first described in 1814. It is a benign cutaneous infectious disease caused by a double-stranded DNA virus of the poxvirus family. Molluscum contagiosum lesions usually manifest clinically as dome-shaped, flesh-colored or translucent, umbilicated papules measuring 1 to 5 mm in diameter that are commonly distributed over the face, trunk, and extremities and usually are self-limiting.¹

Giant MC is rare and can be seen either in patients on immunosuppressive therapy or in those with diseases that can cause immunosuppression, such as human immunodeficiency virus, leukemia, atopic dermatitis, Wiskott-Aldrich syndrome, and sarcoidosis. In these instances, MC often is greater than 1 cm in diameter. Atypical variants may have an eczematous presentation or a lesion with secondary abscess formation and also can be spread widely over the body.² Due to these atypical appearances and large dimensions in immunocompromised patients, other dermatologic diseases should be considered in the differential diagnosis, such as basal cell carcinoma, keratoacanthoma, squamous cell carcinoma, cutaneous horn, cutaneous cryptococcosis, histoplasmosis, and xanthomatosis.³

In our patient, the differential diagnosis included keratoacanthoma, which may present as a solitary, discrete, round to oval, flesh-colored, umbilicated nodule with a central keratin-filled crater and has a rapid clinical evolution, usually regressing within 4 to 6 months.

Squamous cell carcinoma may appear as scaly red patches, open sores, warts, or elevated growths with a central depression and may crust or bleed. Basal cell carcinoma typically may appear as a dome-shaped skin nodule with visible blood vessels or sometimes presents as a red patch similar to eczema. Xanthomatosis often appears as yellow to orange, mostly asymptomatic, supple patches or plaques, usually with sharp and distinctive edges.

Ancillary diagnostic modalities such as dermoscopy may be used to improve diagnostic accuracy. The best known capillaroscopic feature of MC is the peripheral crown of vessels in a radial distribution. A study of 258 MC lesions highlighted that crown and crown plus radial arrangements are the most common vascular structure patterns under dermoscopy. In addition, polylobular amorphous white structures in the center of the lesions tend to be a feature of larger MC papules.⁴ Histologically, MC shows lobulated crateriform lesions, thickening of the epidermis into the dermis, and the typical appearance of large eosinophilic intracytoplasmic inclusion bodies within keratinocytes.⁵

There are several treatment options available for MC. Common modalities include liquid nitrogen cryospray, curettage, and electrocauterization. In immunocompromised patients, MC lesions usually are resistant to ordinary therapy. The efficacy of topical agents such as imiquimod, which can induce high levels of IFN-α and other cytokines, has been demonstrated in these patients.⁶ Cidofovir, a nucleoside analog that has potent antiviral properties, also can be included as a therapeutic option.³ Our patient’s largest MC lesion was treated with surgical excision, the 2 large lesions on the left side of the chest with cryotherapy, and the other small lesions with curettage.

Dermoscopy showed polylobular, whitish yellow, amorphous structures at the center of the lesion surrounded by a crown of vessels (Figure 1). Histopathology revealed hyperplastic crateriform lesions containing large eosinophilic intracytoplasmic inclusion bodies within keratinocytes (Figure 2). At follow-up 2 weeks after the biopsy, the patient presented with approximately 20 more reddish papules of varying sizes on the abdomen and back that presented as dome-shaped papules and had a typical umbilicated center. The clinical manifestations, dermoscopy, and pathology findings were consistent with molluscum contagiosum (MC).

Molluscum contagiosum was first described in 1814. It is a benign cutaneous infectious disease caused by a double-stranded DNA virus of the poxvirus family. Molluscum contagiosum lesions usually manifest clinically as dome-shaped, flesh-colored or translucent, umbilicated papules measuring 1 to 5 mm in diameter that are commonly distributed over the face, trunk, and extremities and usually are self-limiting.¹

Giant MC is rare and can be seen either in patients on immunosuppressive therapy or in those with diseases that can cause immunosuppression, such as human immunodeficiency virus, leukemia, atopic dermatitis, Wiskott-Aldrich syndrome, and sarcoidosis. In these instances, MC often is greater than 1 cm in diameter. Atypical variants may have an eczematous presentation or a lesion with secondary abscess formation and also can be spread widely over the body.² Due to these atypical appearances and large dimensions in immunocompromised patients, other dermatologic diseases should be considered in the differential diagnosis, such as basal cell carcinoma, keratoacanthoma, squamous cell carcinoma, cutaneous horn, cutaneous cryptococcosis, histoplasmosis, and xanthomatosis.³

In our patient, the differential diagnosis included keratoacanthoma, which may present as a solitary, discrete, round to oval, flesh-colored, umbilicated nodule with a central keratin-filled crater and has a rapid clinical evolution, usually regressing within 4 to 6 months.

Squamous cell carcinoma may appear as scaly red patches, open sores, warts, or elevated growths with a central depression and may crust or bleed. Basal cell carcinoma typically may appear as a dome-shaped skin nodule with visible blood vessels or sometimes presents as a red patch similar to eczema. Xanthomatosis often appears as yellow to orange, mostly asymptomatic, supple patches or plaques, usually with sharp and distinctive edges.

Ancillary diagnostic modalities such as dermoscopy may be used to improve diagnostic accuracy. The best known capillaroscopic feature of MC is the peripheral crown of vessels in a radial distribution. A study of 258 MC lesions highlighted that crown and crown plus radial arrangements are the most common vascular structure patterns under dermoscopy. In addition, polylobular amorphous white structures in the center of the lesions tend to be a feature of larger MC papules.⁴ Histologically, MC shows lobulated crateriform lesions, thickening of the epidermis into the dermis, and the typical appearance of large eosinophilic intracytoplasmic inclusion bodies within keratinocytes.⁵

There are several treatment options available for MC. Common modalities include liquid nitrogen cryospray, curettage, and electrocauterization. In immunocompromised patients, MC lesions usually are resistant to ordinary therapy. The efficacy of topical agents such as imiquimod, which can induce high levels of IFN-α and other cytokines, has been demonstrated in these patients.⁶ Cidofovir, a nucleoside analog that has potent antiviral properties, also can be included as a therapeutic option.³ Our patient’s largest MC lesion was treated with surgical excision, the 2 large lesions on the left side of the chest with cryotherapy, and the other small lesions with curettage.

Since 2012, when the Centers for Medicare & Medicaid Services (CMS) began linking financial penalties to hospitals with excessive readmissions for adult patients, researchers have questioned the extent to which pediatric readmissions can be used as a reliable quality measure. Compared with readmissions among adult patients, readmissions among pediatric patients are relatively uncommon. Furthermore, few (approximately 2%) qualify as potentially preventable, and pediatric readmission rates remain largely unchanged despite targeted attempts to prevent reutilization.^1,2 Nonetheless, state Medicaid agencies have continued to reduce reimbursement for hospitals based on available readmissions metrics, most commonly the Potentially Preventable Readmissions (PPR) algorithm.¹

In this issue of the Journal of Hospital Medicine, Auger et al³ performed a retrospective study to explore four existing metrics of pediatric hospital readmissions for their ability to identify preventable and unplanned readmissions. Investigators examined 30-day readmissions (n = 1,125) from 2014-2016 across multiple subspecialties, and classified readmissions by their preventability and unplanned status with use of a validated chart abstraction tool. Using the results of chart abstraction as the gold standard, investigators calculated the sensitivity and specificity, as well as estimated the positive and negative predictive values, of each readmissions metric. Auger and colleagues found that none of the four readmissions metrics could reliably assess preventability, and that only one metric reliably predicted unplanned hospital readmissions. Specifically, the commonly used PPR algorithm was estimated to have a positive predictive value of 13.0%-35.5% across a prevalence range of 10%-30%. This means that in a hospital where 10% of readmissions are truly preventable, the PPR will be wrong approximately 87% of the time. Tying payments to this metric is difficult to justify.

The authors highlighted the policy implications of the PPR falling short in its ability to identify preventable and unplanned pediatric readmissions. A good quality measure should be consistently reliable, and neither the PPR nor other measures studied meets this benchmark. Yet the findings lead to a broader conclusion: if most pediatric readmissions are not preventable, if there is no reliable way of measuring preventability, and if we have not demonstrated the ability to change patient trajectories away from reutilization, then perhaps the sun has set on using readmissions as a comprehensive quality measure for hospital-based care.

So how, then, should the hospital-to-home transition be evaluated? The paradigm of pediatric value of care is shifting to incorporate family-centered perspectives into consideration of quality measures.² There has to be a balance between healthcare costs and outcomes that affect families; measures should take into account issues such as patient and caregiver anxiety and time away from work.² Moreover, because social determinants of health and medical complexity strongly influence readmission rates,^4,5 focus should be placed on redirecting resources toward patients and families with significant medical, social, and financial needs as they transition home from the hospital. While measures of healthcare equity are currently lacking, the overall quality and equity of pediatric care transitions could be enhanced by looking beyond the narrow lens of readmission rates to incorporate actual needs assessments of families.

In summary, Auger and colleagues identified deficits in existing readmission metrics—but creating a solution that is meaningful to all stakeholders will be more complex than simply identifying a better metric. Family-centered quality metrics show promise in creating value in pediatric care within an equitable health system, but long-term evaluation of these metrics is necessary.

The authors have nothing to disclose.

Since 2012, when the Centers for Medicare & Medicaid Services (CMS) began linking financial penalties to hospitals with excessive readmissions for adult patients, researchers have questioned the extent to which pediatric readmissions can be used as a reliable quality measure. Compared with readmissions among adult patients, readmissions among pediatric patients are relatively uncommon. Furthermore, few (approximately 2%) qualify as potentially preventable, and pediatric readmission rates remain largely unchanged despite targeted attempts to prevent reutilization.^1,2 Nonetheless, state Medicaid agencies have continued to reduce reimbursement for hospitals based on available readmissions metrics, most commonly the Potentially Preventable Readmissions (PPR) algorithm.¹

In this issue of the Journal of Hospital Medicine, Auger et al³ performed a retrospective study to explore four existing metrics of pediatric hospital readmissions for their ability to identify preventable and unplanned readmissions. Investigators examined 30-day readmissions (n = 1,125) from 2014-2016 across multiple subspecialties, and classified readmissions by their preventability and unplanned status with use of a validated chart abstraction tool. Using the results of chart abstraction as the gold standard, investigators calculated the sensitivity and specificity, as well as estimated the positive and negative predictive values, of each readmissions metric. Auger and colleagues found that none of the four readmissions metrics could reliably assess preventability, and that only one metric reliably predicted unplanned hospital readmissions. Specifically, the commonly used PPR algorithm was estimated to have a positive predictive value of 13.0%-35.5% across a prevalence range of 10%-30%. This means that in a hospital where 10% of readmissions are truly preventable, the PPR will be wrong approximately 87% of the time. Tying payments to this metric is difficult to justify.

The authors highlighted the policy implications of the PPR falling short in its ability to identify preventable and unplanned pediatric readmissions. A good quality measure should be consistently reliable, and neither the PPR nor other measures studied meets this benchmark. Yet the findings lead to a broader conclusion: if most pediatric readmissions are not preventable, if there is no reliable way of measuring preventability, and if we have not demonstrated the ability to change patient trajectories away from reutilization, then perhaps the sun has set on using readmissions as a comprehensive quality measure for hospital-based care.

So how, then, should the hospital-to-home transition be evaluated? The paradigm of pediatric value of care is shifting to incorporate family-centered perspectives into consideration of quality measures.² There has to be a balance between healthcare costs and outcomes that affect families; measures should take into account issues such as patient and caregiver anxiety and time away from work.² Moreover, because social determinants of health and medical complexity strongly influence readmission rates,^4,5 focus should be placed on redirecting resources toward patients and families with significant medical, social, and financial needs as they transition home from the hospital. While measures of healthcare equity are currently lacking, the overall quality and equity of pediatric care transitions could be enhanced by looking beyond the narrow lens of readmission rates to incorporate actual needs assessments of families.

In summary, Auger and colleagues identified deficits in existing readmission metrics—but creating a solution that is meaningful to all stakeholders will be more complex than simply identifying a better metric. Family-centered quality metrics show promise in creating value in pediatric care within an equitable health system, but long-term evaluation of these metrics is necessary.

The authors have nothing to disclose.

Since 2012, when the Centers for Medicare & Medicaid Services (CMS) began linking financial penalties to hospitals with excessive readmissions for adult patients, researchers have questioned the extent to which pediatric readmissions can be used as a reliable quality measure. Compared with readmissions among adult patients, readmissions among pediatric patients are relatively uncommon. Furthermore, few (approximately 2%) qualify as potentially preventable, and pediatric readmission rates remain largely unchanged despite targeted attempts to prevent reutilization.^1,2 Nonetheless, state Medicaid agencies have continued to reduce reimbursement for hospitals based on available readmissions metrics, most commonly the Potentially Preventable Readmissions (PPR) algorithm.¹

In this issue of the Journal of Hospital Medicine, Auger et al³ performed a retrospective study to explore four existing metrics of pediatric hospital readmissions for their ability to identify preventable and unplanned readmissions. Investigators examined 30-day readmissions (n = 1,125) from 2014-2016 across multiple subspecialties, and classified readmissions by their preventability and unplanned status with use of a validated chart abstraction tool. Using the results of chart abstraction as the gold standard, investigators calculated the sensitivity and specificity, as well as estimated the positive and negative predictive values, of each readmissions metric. Auger and colleagues found that none of the four readmissions metrics could reliably assess preventability, and that only one metric reliably predicted unplanned hospital readmissions. Specifically, the commonly used PPR algorithm was estimated to have a positive predictive value of 13.0%-35.5% across a prevalence range of 10%-30%. This means that in a hospital where 10% of readmissions are truly preventable, the PPR will be wrong approximately 87% of the time. Tying payments to this metric is difficult to justify.

The authors highlighted the policy implications of the PPR falling short in its ability to identify preventable and unplanned pediatric readmissions. A good quality measure should be consistently reliable, and neither the PPR nor other measures studied meets this benchmark. Yet the findings lead to a broader conclusion: if most pediatric readmissions are not preventable, if there is no reliable way of measuring preventability, and if we have not demonstrated the ability to change patient trajectories away from reutilization, then perhaps the sun has set on using readmissions as a comprehensive quality measure for hospital-based care.

So how, then, should the hospital-to-home transition be evaluated? The paradigm of pediatric value of care is shifting to incorporate family-centered perspectives into consideration of quality measures.² There has to be a balance between healthcare costs and outcomes that affect families; measures should take into account issues such as patient and caregiver anxiety and time away from work.² Moreover, because social determinants of health and medical complexity strongly influence readmission rates,^4,5 focus should be placed on redirecting resources toward patients and families with significant medical, social, and financial needs as they transition home from the hospital. While measures of healthcare equity are currently lacking, the overall quality and equity of pediatric care transitions could be enhanced by looking beyond the narrow lens of readmission rates to incorporate actual needs assessments of families.

In summary, Auger and colleagues identified deficits in existing readmission metrics—but creating a solution that is meaningful to all stakeholders will be more complex than simply identifying a better metric. Family-centered quality metrics show promise in creating value in pediatric care within an equitable health system, but long-term evaluation of these metrics is necessary.

The authors have nothing to disclose.

In this edition of the Journal of Hospital Medicine, Fenster and colleagues evaluate the trend of postdischarge intravenous (IV) antibiotic therapy for children with osteomyelitis, complicated pneumonia, and complicated appendicitis.¹ Children requiring prolonged antibiotic therapy were historically discharged home with a peripherally inserted central catheter (PICC) for IV antibiotics. Recent studies suggest that treatment failure occurs uncommonly, and that oral antibiotics are as effective as those administered intravenously.^2-4 Oral antibiotics also avoid the additional risk of PICC-related complications, such as line malfunction, infections, and thrombi, which all lead to increased re-visits to hospital.

New research seldom leads to rapid change in clinical practice.⁵ This is particularly the case when new evidence favors the abandonment of accepted medical practices or supports the deimplementation of low-value care. The mounting body of evidence suggests that postdischarge IV antibiotic therapy is low-value care for children with osteomyelitis, complicated pneumonia, and complicated appendicitis, and that overuse is associated with unnecessary harm. Fenster and colleagues sought to evaluate the extent to which the management of these conditions has changed over time in the United States. They conducted a retrospective cohort study of children discharged from hospitals contributing data to the Pediatric Health Information System (PHIS) database. Validated algorithms using discharge diagnosis and procedure codes were used to identify children with the three conditions who were discharged home with IV antibiotic therapy.

Between January 2000 and December 2018 and across 52 hospitals, there were 24,753 hospitalizations for osteomyelitis, 13,700 for complicated pneumonia, and 60,575 for complicated appendicitis. Rates of postdischarge IV antibiotic therapy decreased over time for all conditions, from 61% to 22% for osteomyelitis, from 29% to 19% for complicated pneumonia, and from 13% to 2% for complicated appendicitis. Rather than a gradual reduction over time, the authors used piecewise linear regression to identify an inflection point when the decrease started: the inflection points for all three occurred around 2009 or 2010. Despite the observed decrease over time, there was significant variation in practice patterns among hospitals in 2018. For example, while the median rate of postdischarge IV antibiotic therapy for osteomyelitis was 18%, the interquartile ranged from 9% to 40%.

The authors conducted several sensitivity analyses, with the exclusion of hospitals that provided data only for certain years, which supported the robustness of the findings. Yet there are important limitations, most notably the lack of data on outcomes related to overuse and efficiency: type of antibiotics used (narrow vs broad spectrum) and total duration of antibiotics or variation in length of stay. The validated algorithms were also based on older ICD-9 codes and may perform less well with ICD-10 or from 2015 onwards. Lastly, the findings are limited to children’s hospitals and may not apply to general hospitals that care for many children.

The authors suggest that the deimplementation of postdischarge IV antibiotic therapy for the three conditions occurred spontaneously. Yet it is worth considering the different levels of agents of change that may have influenced these observations, such as research evidence, national condition guidelines, national efforts at reducing overuse and improving safety, local hospital efforts, and shared decision-making.

Postdischarge antibiotic therapy options for osteomyelitis, complicated pneumonia, and complicated appendicitis are supported by weak research evidence. Oral and parenteral therapy are equally effective but based on observational data; a randomized controlled trial is unlikely to ever be conducted because of uncommon outcomes, such as treatment failures. For these scenarios, greater emphasis should be placed on factors other than effectiveness, such as harms, availability of alternative options, and cost.⁶ For postdischarge IV antibiotic therapy, one potential explanation for the observed deimplementation is the greater awareness of harm, with up to 20% of cases with IV antibiotics requiring PICC removal.⁷ There is also a readily available alternative (oral antibiotics) with a favorable cost and effectiveness profile.

National condition guidelines advocating early transition to oral antibiotic therapy began to appear before and during the observed inflection point of 2009 and 2010. The 2002 British Thoracic Society guidelines for community-acquired pneumonia suggested considering oral agents after clear evidence of improvement,⁸ and the 2010 Infectious Diseases Society of America guidelines recommended oral antibiotic options for children discharged home with intra-abdominal infections.⁹ A systematic review published in 2002 also questioned the need for prolonged IV antibiotic therapy compared with early transition to oral agents in osteomyelitis.¹⁰ While no targeted national interventions to drive practice change existed, widespread national efforts at reducing overuse (eg, Choosing Wisely^®) and improving safety (eg, reducing central line complications) have increased in the past decade.¹¹

An important agent of change that Fenster and colleagues were not able to tease out was the impact of local hospital level efforts. In parallel to national efforts, there has likely been targeted hospital-level interventions that are disease specific (eg, order sets, pathways/guidelines, shared–decision-making tools) or focused on reducing adverse events (eg, reducing inappropriate PICC use). For example, between 2010 and 2012, one US children’s hospital increased the number of children with osteomyelitis discharged on oral antibiotics from a median of 0% to 100% with a bundle of quality improvement interventions, including standardized treatment protocols and shared decision-making.¹²

Despite the encouraging results, up to 22% of children were discharged from hospitals with postdischarge IV antibiotic therapy, and significant variation persists in 2018. Evidence of harm or even strong recommendations to change practice are themselves inadequate for behavior change.¹³ While it is clear that some element of deimplementation may have occurred organically over the past two decades, it is time for concerted deimplementation strategies that focus on practitioners or hospitals with “entrenched practices.”⁶

Dr Gill has received grant funding from the Canadian Paediatric Society, the Hospital for Sick Children, and the Canadian Institutes of Health Research (CIHR) in the past 5 years. He is on editorial board of BMJ Evidence-Based Medicine (EBM) and on the Institute Advisory Board for the CIHR Institute of Human Development and Child and Youth Health (IHDCYH), for which he has expenses reimbursed to attend meetings. He is a member of the EBMLive steering committee, and he has expenses reimbursed to attend the conference. Dr Mahant has received grant funding from CIHR in the past 5 years and is a Senior Deputy Editor of Journal of Hospital Medicine. The authors reported no conflicts of interest or financial relationships relevant to this manuscript.

In this edition of the Journal of Hospital Medicine, Fenster and colleagues evaluate the trend of postdischarge intravenous (IV) antibiotic therapy for children with osteomyelitis, complicated pneumonia, and complicated appendicitis.¹ Children requiring prolonged antibiotic therapy were historically discharged home with a peripherally inserted central catheter (PICC) for IV antibiotics. Recent studies suggest that treatment failure occurs uncommonly, and that oral antibiotics are as effective as those administered intravenously.^2-4 Oral antibiotics also avoid the additional risk of PICC-related complications, such as line malfunction, infections, and thrombi, which all lead to increased re-visits to hospital.

New research seldom leads to rapid change in clinical practice.⁵ This is particularly the case when new evidence favors the abandonment of accepted medical practices or supports the deimplementation of low-value care. The mounting body of evidence suggests that postdischarge IV antibiotic therapy is low-value care for children with osteomyelitis, complicated pneumonia, and complicated appendicitis, and that overuse is associated with unnecessary harm. Fenster and colleagues sought to evaluate the extent to which the management of these conditions has changed over time in the United States. They conducted a retrospective cohort study of children discharged from hospitals contributing data to the Pediatric Health Information System (PHIS) database. Validated algorithms using discharge diagnosis and procedure codes were used to identify children with the three conditions who were discharged home with IV antibiotic therapy.

Between January 2000 and December 2018 and across 52 hospitals, there were 24,753 hospitalizations for osteomyelitis, 13,700 for complicated pneumonia, and 60,575 for complicated appendicitis. Rates of postdischarge IV antibiotic therapy decreased over time for all conditions, from 61% to 22% for osteomyelitis, from 29% to 19% for complicated pneumonia, and from 13% to 2% for complicated appendicitis. Rather than a gradual reduction over time, the authors used piecewise linear regression to identify an inflection point when the decrease started: the inflection points for all three occurred around 2009 or 2010. Despite the observed decrease over time, there was significant variation in practice patterns among hospitals in 2018. For example, while the median rate of postdischarge IV antibiotic therapy for osteomyelitis was 18%, the interquartile ranged from 9% to 40%.

The authors conducted several sensitivity analyses, with the exclusion of hospitals that provided data only for certain years, which supported the robustness of the findings. Yet there are important limitations, most notably the lack of data on outcomes related to overuse and efficiency: type of antibiotics used (narrow vs broad spectrum) and total duration of antibiotics or variation in length of stay. The validated algorithms were also based on older ICD-9 codes and may perform less well with ICD-10 or from 2015 onwards. Lastly, the findings are limited to children’s hospitals and may not apply to general hospitals that care for many children.

The authors suggest that the deimplementation of postdischarge IV antibiotic therapy for the three conditions occurred spontaneously. Yet it is worth considering the different levels of agents of change that may have influenced these observations, such as research evidence, national condition guidelines, national efforts at reducing overuse and improving safety, local hospital efforts, and shared decision-making.

Postdischarge antibiotic therapy options for osteomyelitis, complicated pneumonia, and complicated appendicitis are supported by weak research evidence. Oral and parenteral therapy are equally effective but based on observational data; a randomized controlled trial is unlikely to ever be conducted because of uncommon outcomes, such as treatment failures. For these scenarios, greater emphasis should be placed on factors other than effectiveness, such as harms, availability of alternative options, and cost.⁶ For postdischarge IV antibiotic therapy, one potential explanation for the observed deimplementation is the greater awareness of harm, with up to 20% of cases with IV antibiotics requiring PICC removal.⁷ There is also a readily available alternative (oral antibiotics) with a favorable cost and effectiveness profile.

National condition guidelines advocating early transition to oral antibiotic therapy began to appear before and during the observed inflection point of 2009 and 2010. The 2002 British Thoracic Society guidelines for community-acquired pneumonia suggested considering oral agents after clear evidence of improvement,⁸ and the 2010 Infectious Diseases Society of America guidelines recommended oral antibiotic options for children discharged home with intra-abdominal infections.⁹ A systematic review published in 2002 also questioned the need for prolonged IV antibiotic therapy compared with early transition to oral agents in osteomyelitis.¹⁰ While no targeted national interventions to drive practice change existed, widespread national efforts at reducing overuse (eg, Choosing Wisely^®) and improving safety (eg, reducing central line complications) have increased in the past decade.¹¹

An important agent of change that Fenster and colleagues were not able to tease out was the impact of local hospital level efforts. In parallel to national efforts, there has likely been targeted hospital-level interventions that are disease specific (eg, order sets, pathways/guidelines, shared–decision-making tools) or focused on reducing adverse events (eg, reducing inappropriate PICC use). For example, between 2010 and 2012, one US children’s hospital increased the number of children with osteomyelitis discharged on oral antibiotics from a median of 0% to 100% with a bundle of quality improvement interventions, including standardized treatment protocols and shared decision-making.¹²

Despite the encouraging results, up to 22% of children were discharged from hospitals with postdischarge IV antibiotic therapy, and significant variation persists in 2018. Evidence of harm or even strong recommendations to change practice are themselves inadequate for behavior change.¹³ While it is clear that some element of deimplementation may have occurred organically over the past two decades, it is time for concerted deimplementation strategies that focus on practitioners or hospitals with “entrenched practices.”⁶

Dr Gill has received grant funding from the Canadian Paediatric Society, the Hospital for Sick Children, and the Canadian Institutes of Health Research (CIHR) in the past 5 years. He is on editorial board of BMJ Evidence-Based Medicine (EBM) and on the Institute Advisory Board for the CIHR Institute of Human Development and Child and Youth Health (IHDCYH), for which he has expenses reimbursed to attend meetings. He is a member of the EBMLive steering committee, and he has expenses reimbursed to attend the conference. Dr Mahant has received grant funding from CIHR in the past 5 years and is a Senior Deputy Editor of Journal of Hospital Medicine. The authors reported no conflicts of interest or financial relationships relevant to this manuscript.

In this edition of the Journal of Hospital Medicine, Fenster and colleagues evaluate the trend of postdischarge intravenous (IV) antibiotic therapy for children with osteomyelitis, complicated pneumonia, and complicated appendicitis.¹ Children requiring prolonged antibiotic therapy were historically discharged home with a peripherally inserted central catheter (PICC) for IV antibiotics. Recent studies suggest that treatment failure occurs uncommonly, and that oral antibiotics are as effective as those administered intravenously.^2-4 Oral antibiotics also avoid the additional risk of PICC-related complications, such as line malfunction, infections, and thrombi, which all lead to increased re-visits to hospital.

New research seldom leads to rapid change in clinical practice.⁵ This is particularly the case when new evidence favors the abandonment of accepted medical practices or supports the deimplementation of low-value care. The mounting body of evidence suggests that postdischarge IV antibiotic therapy is low-value care for children with osteomyelitis, complicated pneumonia, and complicated appendicitis, and that overuse is associated with unnecessary harm. Fenster and colleagues sought to evaluate the extent to which the management of these conditions has changed over time in the United States. They conducted a retrospective cohort study of children discharged from hospitals contributing data to the Pediatric Health Information System (PHIS) database. Validated algorithms using discharge diagnosis and procedure codes were used to identify children with the three conditions who were discharged home with IV antibiotic therapy.

Between January 2000 and December 2018 and across 52 hospitals, there were 24,753 hospitalizations for osteomyelitis, 13,700 for complicated pneumonia, and 60,575 for complicated appendicitis. Rates of postdischarge IV antibiotic therapy decreased over time for all conditions, from 61% to 22% for osteomyelitis, from 29% to 19% for complicated pneumonia, and from 13% to 2% for complicated appendicitis. Rather than a gradual reduction over time, the authors used piecewise linear regression to identify an inflection point when the decrease started: the inflection points for all three occurred around 2009 or 2010. Despite the observed decrease over time, there was significant variation in practice patterns among hospitals in 2018. For example, while the median rate of postdischarge IV antibiotic therapy for osteomyelitis was 18%, the interquartile ranged from 9% to 40%.

The authors conducted several sensitivity analyses, with the exclusion of hospitals that provided data only for certain years, which supported the robustness of the findings. Yet there are important limitations, most notably the lack of data on outcomes related to overuse and efficiency: type of antibiotics used (narrow vs broad spectrum) and total duration of antibiotics or variation in length of stay. The validated algorithms were also based on older ICD-9 codes and may perform less well with ICD-10 or from 2015 onwards. Lastly, the findings are limited to children’s hospitals and may not apply to general hospitals that care for many children.

The authors suggest that the deimplementation of postdischarge IV antibiotic therapy for the three conditions occurred spontaneously. Yet it is worth considering the different levels of agents of change that may have influenced these observations, such as research evidence, national condition guidelines, national efforts at reducing overuse and improving safety, local hospital efforts, and shared decision-making.

Postdischarge antibiotic therapy options for osteomyelitis, complicated pneumonia, and complicated appendicitis are supported by weak research evidence. Oral and parenteral therapy are equally effective but based on observational data; a randomized controlled trial is unlikely to ever be conducted because of uncommon outcomes, such as treatment failures. For these scenarios, greater emphasis should be placed on factors other than effectiveness, such as harms, availability of alternative options, and cost.⁶ For postdischarge IV antibiotic therapy, one potential explanation for the observed deimplementation is the greater awareness of harm, with up to 20% of cases with IV antibiotics requiring PICC removal.⁷ There is also a readily available alternative (oral antibiotics) with a favorable cost and effectiveness profile.

National condition guidelines advocating early transition to oral antibiotic therapy began to appear before and during the observed inflection point of 2009 and 2010. The 2002 British Thoracic Society guidelines for community-acquired pneumonia suggested considering oral agents after clear evidence of improvement,⁸ and the 2010 Infectious Diseases Society of America guidelines recommended oral antibiotic options for children discharged home with intra-abdominal infections.⁹ A systematic review published in 2002 also questioned the need for prolonged IV antibiotic therapy compared with early transition to oral agents in osteomyelitis.¹⁰ While no targeted national interventions to drive practice change existed, widespread national efforts at reducing overuse (eg, Choosing Wisely^®) and improving safety (eg, reducing central line complications) have increased in the past decade.¹¹

An important agent of change that Fenster and colleagues were not able to tease out was the impact of local hospital level efforts. In parallel to national efforts, there has likely been targeted hospital-level interventions that are disease specific (eg, order sets, pathways/guidelines, shared–decision-making tools) or focused on reducing adverse events (eg, reducing inappropriate PICC use). For example, between 2010 and 2012, one US children’s hospital increased the number of children with osteomyelitis discharged on oral antibiotics from a median of 0% to 100% with a bundle of quality improvement interventions, including standardized treatment protocols and shared decision-making.¹²

Despite the encouraging results, up to 22% of children were discharged from hospitals with postdischarge IV antibiotic therapy, and significant variation persists in 2018. Evidence of harm or even strong recommendations to change practice are themselves inadequate for behavior change.¹³ While it is clear that some element of deimplementation may have occurred organically over the past two decades, it is time for concerted deimplementation strategies that focus on practitioners or hospitals with “entrenched practices.”⁶

Dr Gill has received grant funding from the Canadian Paediatric Society, the Hospital for Sick Children, and the Canadian Institutes of Health Research (CIHR) in the past 5 years. He is on editorial board of BMJ Evidence-Based Medicine (EBM) and on the Institute Advisory Board for the CIHR Institute of Human Development and Child and Youth Health (IHDCYH), for which he has expenses reimbursed to attend meetings. He is a member of the EBMLive steering committee, and he has expenses reimbursed to attend the conference. Dr Mahant has received grant funding from CIHR in the past 5 years and is a Senior Deputy Editor of Journal of Hospital Medicine. The authors reported no conflicts of interest or financial relationships relevant to this manuscript.

Key clinical point: Nearly one third of patients with multiple sclerosis (MS) experience migraine.

Major finding: The pooled prevalence rate of migraine was 31% (P less than .001), which significantly varied across the continents (P less than .001).

Study details: A systematic review and meta-analysis of 11 articles and 12 conference abstracts including a total of 11,372 MS cases.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: Mirmosayyeb O et al. J Clin Neuroscience. 2020 Aug 4. doi: 10.1016/j.jocn.2020.06.021.

Key clinical point: Nearly one third of patients with multiple sclerosis (MS) experience migraine.

Major finding: The pooled prevalence rate of migraine was 31% (P less than .001), which significantly varied across the continents (P less than .001).

Study details: A systematic review and meta-analysis of 11 articles and 12 conference abstracts including a total of 11,372 MS cases.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: Mirmosayyeb O et al. J Clin Neuroscience. 2020 Aug 4. doi: 10.1016/j.jocn.2020.06.021.

Key clinical point: Nearly one third of patients with multiple sclerosis (MS) experience migraine.

Major finding: The pooled prevalence rate of migraine was 31% (P less than .001), which significantly varied across the continents (P less than .001).

Study details: A systematic review and meta-analysis of 11 articles and 12 conference abstracts including a total of 11,372 MS cases.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: Mirmosayyeb O et al. J Clin Neuroscience. 2020 Aug 4. doi: 10.1016/j.jocn.2020.06.021.

“Time is the coin of your life. It is the only coin you have, and only you can determine how it will be spent. Be careful lest you let other people spend it for you.”

—Carl Sandburg

No one went into the practice of medicine to check off boxes. Clinicians find joy and purpose by connecting with patients and interacting with colleagues. Unfortunately, our goal of practicing in an environment that allows these experiences is threatened by extreme levels of regulatory and administrative oversight.^1,2 Decreased enjoyment and meaning in work may follow and lead to burnout, poor performance, and for some, premature departure from medicine.³ The negative effects on individuals can erode the morale and productivity of the group.

Many administrative requirements add value to clinical care. For example, interdisciplinary rounds may include a mandatory review of urinary catheters that reduces catheter-associated infections. The usefulness of some requirements, however, may promote implementation of other requirements of lesser value that interfere with the positive impact of meaningful interventions. Best Practice Alerts (BPAs) that are “clicked through” sap enthusiasm. Perfunctory monthly meetings that are informational rather than productive and exhaustive e-learning modules on institutional requirements such as “Corporate Compliance” take time away from patient care. Despite being a prominent driver of burnout, the most common approach to nuisances is nihilism. It is unrealistic for anyone with a full clinical slate to tackle pervasive irritations. Similarly, leaders may not see decreasing administrative burdens as a priority; the excitement for decreasing hassles pales relative to the excitement for developing a new vision or strategic plan.

Rather than acceptance, leaders should take proactive steps to decrease wasteful tasks. Begin by explicitly assessing the burden of tasks through dialogue with administrators, such as the chief medical officer. Administrators may not realize the impact of seemingly small requests on hospitalist workflow. For example, even adding one required question for every patient at interdisciplinary rounds can meaningfully affect the flow of rounds. Hospitalist leaders are well situated to assess the yield to burden ratio (Y/B) of any requirement. High burden tasks should be justified by substantial benefit, and tasks in which the Y/B is uncertain should be limited in scope until the value proposition is established.

The electronic medical record (EMR) deserves specific attention because it is an established source of annoyance and burnout.³ Leaders should proactively collaborate with administrators to remove EMR requirements with low Y/B. The “Get Rid of Stupid Stuff” (GROSS) program demonstrated the benefits of an innovative approach to eliminating wasteful EMR tasks.⁴ Our own institution discontinued the BPA asking clinicians to add “Chronic Kidney Disease, Stage III” to the Problem List when an assessment revealed that the Problem List was rarely updated and this BPA was frequently presented; the BPA was low yield, high burden.

Lastly, leaders should not become part of the problem. For example, a hospitalist-led quality improvement project may require documentation that a primary care physician has been contacted for each newly admitted patient. Assuming four patients and 5 minutes per call, this ask requires 20 minutes; the burden has been estimated but the yield is unknown, producing an unclear Y/B. Therefore, items generated within the group need to be vetted with the same scrutiny as external tasks.

Explicitly addressing wasteful burdens provides leaders with the opportunity to shift the emphasis from processes that distract from to initiatives that enhance patient care. Promoting a sense of meaning and purpose is an essential component of group success.⁵ Outstanding performance, productivity, and retention can only be realized through a work environment that prioritizes patients and minimizes tasks not aligned with this mission.

The authors have nothing to disclose.

“Time is the coin of your life. It is the only coin you have, and only you can determine how it will be spent. Be careful lest you let other people spend it for you.”

—Carl Sandburg

No one went into the practice of medicine to check off boxes. Clinicians find joy and purpose by connecting with patients and interacting with colleagues. Unfortunately, our goal of practicing in an environment that allows these experiences is threatened by extreme levels of regulatory and administrative oversight.^1,2 Decreased enjoyment and meaning in work may follow and lead to burnout, poor performance, and for some, premature departure from medicine.³ The negative effects on individuals can erode the morale and productivity of the group.

Many administrative requirements add value to clinical care. For example, interdisciplinary rounds may include a mandatory review of urinary catheters that reduces catheter-associated infections. The usefulness of some requirements, however, may promote implementation of other requirements of lesser value that interfere with the positive impact of meaningful interventions. Best Practice Alerts (BPAs) that are “clicked through” sap enthusiasm. Perfunctory monthly meetings that are informational rather than productive and exhaustive e-learning modules on institutional requirements such as “Corporate Compliance” take time away from patient care. Despite being a prominent driver of burnout, the most common approach to nuisances is nihilism. It is unrealistic for anyone with a full clinical slate to tackle pervasive irritations. Similarly, leaders may not see decreasing administrative burdens as a priority; the excitement for decreasing hassles pales relative to the excitement for developing a new vision or strategic plan.

Rather than acceptance, leaders should take proactive steps to decrease wasteful tasks. Begin by explicitly assessing the burden of tasks through dialogue with administrators, such as the chief medical officer. Administrators may not realize the impact of seemingly small requests on hospitalist workflow. For example, even adding one required question for every patient at interdisciplinary rounds can meaningfully affect the flow of rounds. Hospitalist leaders are well situated to assess the yield to burden ratio (Y/B) of any requirement. High burden tasks should be justified by substantial benefit, and tasks in which the Y/B is uncertain should be limited in scope until the value proposition is established.

The electronic medical record (EMR) deserves specific attention because it is an established source of annoyance and burnout.³ Leaders should proactively collaborate with administrators to remove EMR requirements with low Y/B. The “Get Rid of Stupid Stuff” (GROSS) program demonstrated the benefits of an innovative approach to eliminating wasteful EMR tasks.⁴ Our own institution discontinued the BPA asking clinicians to add “Chronic Kidney Disease, Stage III” to the Problem List when an assessment revealed that the Problem List was rarely updated and this BPA was frequently presented; the BPA was low yield, high burden.

Lastly, leaders should not become part of the problem. For example, a hospitalist-led quality improvement project may require documentation that a primary care physician has been contacted for each newly admitted patient. Assuming four patients and 5 minutes per call, this ask requires 20 minutes; the burden has been estimated but the yield is unknown, producing an unclear Y/B. Therefore, items generated within the group need to be vetted with the same scrutiny as external tasks.

Explicitly addressing wasteful burdens provides leaders with the opportunity to shift the emphasis from processes that distract from to initiatives that enhance patient care. Promoting a sense of meaning and purpose is an essential component of group success.⁵ Outstanding performance, productivity, and retention can only be realized through a work environment that prioritizes patients and minimizes tasks not aligned with this mission.

The authors have nothing to disclose.

“Time is the coin of your life. It is the only coin you have, and only you can determine how it will be spent. Be careful lest you let other people spend it for you.”

—Carl Sandburg

No one went into the practice of medicine to check off boxes. Clinicians find joy and purpose by connecting with patients and interacting with colleagues. Unfortunately, our goal of practicing in an environment that allows these experiences is threatened by extreme levels of regulatory and administrative oversight.^1,2 Decreased enjoyment and meaning in work may follow and lead to burnout, poor performance, and for some, premature departure from medicine.³ The negative effects on individuals can erode the morale and productivity of the group.

Many administrative requirements add value to clinical care. For example, interdisciplinary rounds may include a mandatory review of urinary catheters that reduces catheter-associated infections. The usefulness of some requirements, however, may promote implementation of other requirements of lesser value that interfere with the positive impact of meaningful interventions. Best Practice Alerts (BPAs) that are “clicked through” sap enthusiasm. Perfunctory monthly meetings that are informational rather than productive and exhaustive e-learning modules on institutional requirements such as “Corporate Compliance” take time away from patient care. Despite being a prominent driver of burnout, the most common approach to nuisances is nihilism. It is unrealistic for anyone with a full clinical slate to tackle pervasive irritations. Similarly, leaders may not see decreasing administrative burdens as a priority; the excitement for decreasing hassles pales relative to the excitement for developing a new vision or strategic plan.

Rather than acceptance, leaders should take proactive steps to decrease wasteful tasks. Begin by explicitly assessing the burden of tasks through dialogue with administrators, such as the chief medical officer. Administrators may not realize the impact of seemingly small requests on hospitalist workflow. For example, even adding one required question for every patient at interdisciplinary rounds can meaningfully affect the flow of rounds. Hospitalist leaders are well situated to assess the yield to burden ratio (Y/B) of any requirement. High burden tasks should be justified by substantial benefit, and tasks in which the Y/B is uncertain should be limited in scope until the value proposition is established.

The electronic medical record (EMR) deserves specific attention because it is an established source of annoyance and burnout.³ Leaders should proactively collaborate with administrators to remove EMR requirements with low Y/B. The “Get Rid of Stupid Stuff” (GROSS) program demonstrated the benefits of an innovative approach to eliminating wasteful EMR tasks.⁴ Our own institution discontinued the BPA asking clinicians to add “Chronic Kidney Disease, Stage III” to the Problem List when an assessment revealed that the Problem List was rarely updated and this BPA was frequently presented; the BPA was low yield, high burden.

Lastly, leaders should not become part of the problem. For example, a hospitalist-led quality improvement project may require documentation that a primary care physician has been contacted for each newly admitted patient. Assuming four patients and 5 minutes per call, this ask requires 20 minutes; the burden has been estimated but the yield is unknown, producing an unclear Y/B. Therefore, items generated within the group need to be vetted with the same scrutiny as external tasks.

Explicitly addressing wasteful burdens provides leaders with the opportunity to shift the emphasis from processes that distract from to initiatives that enhance patient care. Promoting a sense of meaning and purpose is an essential component of group success.⁵ Outstanding performance, productivity, and retention can only be realized through a work environment that prioritizes patients and minimizes tasks not aligned with this mission.

The authors have nothing to disclose.

Key clinical point: In patients with progressive multiple sclerosis (MS), impaired odor identification is associated with a greater clinical decline and higher risk for death.

Major finding: Impaired Brief-Smell Identification (B-SIT) was associated with higher risk for death (adjusted hazard ratio [aHR], 14.9; P less than .001). Among patients with progressive MS, impaired B-SIT vs normal B-SIT showed greater clinical change per month in terms of Multiple Sclerosis Severity scores (median, 0.62 vs. –0.08; P =.004) and Age-Related Multiple Sclerosis Severity scores (median, 0.54 vs. –0.07; P =.004).

Study details: Findings from a retrospective review on 149 patients with MS during a median follow-up of 121 months.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: da Silva AM et al. Mult Scler Relat Disord. 2020 Sep 3. doi: 10.1016/j.msard.2020.102486.

Key clinical point: In patients with progressive multiple sclerosis (MS), impaired odor identification is associated with a greater clinical decline and higher risk for death.

Major finding: Impaired Brief-Smell Identification (B-SIT) was associated with higher risk for death (adjusted hazard ratio [aHR], 14.9; P less than .001). Among patients with progressive MS, impaired B-SIT vs normal B-SIT showed greater clinical change per month in terms of Multiple Sclerosis Severity scores (median, 0.62 vs. –0.08; P =.004) and Age-Related Multiple Sclerosis Severity scores (median, 0.54 vs. –0.07; P =.004).

Study details: Findings from a retrospective review on 149 patients with MS during a median follow-up of 121 months.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: da Silva AM et al. Mult Scler Relat Disord. 2020 Sep 3. doi: 10.1016/j.msard.2020.102486.

Key clinical point: In patients with progressive multiple sclerosis (MS), impaired odor identification is associated with a greater clinical decline and higher risk for death.

Major finding: Impaired Brief-Smell Identification (B-SIT) was associated with higher risk for death (adjusted hazard ratio [aHR], 14.9; P less than .001). Among patients with progressive MS, impaired B-SIT vs normal B-SIT showed greater clinical change per month in terms of Multiple Sclerosis Severity scores (median, 0.62 vs. –0.08; P =.004) and Age-Related Multiple Sclerosis Severity scores (median, 0.54 vs. –0.07; P =.004).

Study details: Findings from a retrospective review on 149 patients with MS during a median follow-up of 121 months.

Disclosures: No funding source was identified. The authors declared no conflicts of interest.

Citation: da Silva AM et al. Mult Scler Relat Disord. 2020 Sep 3. doi: 10.1016/j.msard.2020.102486.

Treatments in the pipeline may offer more options for rosacea sufferers, according to Linda Stein Gold, MD, director of clinical research, in the department of dermatology, Henry Ford Hospital in Detroit.

sruilk/shutterstock

In addition, topical minocycline has recently been approved by the Food and Drug Administration for the treatment of rosacea in a 1.5% foam formulation. “The reason it has taken so long to have a minocycline product is that it is challenging to deliver it topically,” she said in a presentation at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually. Studies of higher concentrations were not significantly better for rosacea, so development of the 1.5% foam was pursued, although a 4% foam is approved for the treatment of acne.

Dr. Stein Gold shared results from a pair of 12-week randomized trials in which significantly more patients treated with topical minocycline foam showed treatment success, compared with those on vehicle, based on Investigator’s Global Assessment (IGA) scores of clear or almost clear and a decrease of at least two grades from baseline: 52.1% versus 43.0% in one study and 49.1% versus 39.0% in the second, statistically significant differences. The product also was well tolerated, with most patients reporting no side effects or mild side effects.

Research on how to maximize effectiveness of available treatments such as ivermectin is ongoing, but several new treatments in the pipeline continue to show promising results, she noted.

An up-and-coming rosacea treatment is an old product used in a new way: Benzoyl peroxide in a microencapsulated form. “Benzoyl peroxide is encased in silica molecules that allow very slow release of the benzoyl peroxide into the skin and that leads to decreased irritation,” Dr. Stein Gold explained. The deposit of active ingredient on the skin appears to stay below the level of irritation.

Dr. Stein Gold and colleagues conducted two randomized, vehicle-controlled trials in which 733 adults with moderate to severe rosacea were treated with either the encapsulated benzoyl peroxide cream formulation or a vehicle applied once daily for 12 weeks.

At 12 weeks, IGA success increased over the course of the studies, and reached 43.5% in one and 50.1% in the other, compared with 16.1% and 25.9%, respectively, for the vehicle groups in those studies (P < .001 for both). Overall, she described this as “a nice improvement for a drug that we had not considered to be part of our treatment armamentarium for our rosacea patients.”

Dr. Stein Gold also shared data from a phase 2 study of low-dose oral minocycline in adults with papulopustular rosacea. A group of 200 patients used the drug or a placebo once daily for 16 weeks. The study examined 20-mg and 40-mg extended-release formulations, and found a significant improvement with the 40-mg dose over the 20-mg dose and over placebo, in terms of those who reached an IGA of 0 or 1, with a 2 grade improvement. While this is a phase 2 study, it may lead to oral minocycline as another treatment option, she said.

“It is an exciting time for the treatment of rosacea, with a variety of options and an active pipeline, so we can aim for clear skin for our patients,” she commented.

Dr. Stein Gold disclosed serving as an investigator and consultant for Galderma, Vyne, Sun, Sol Gel, and Almirall; she is a consultant and speaker for Ortho.

MedscapeLive and this news organization are owned by the same parent company.
 

Treatments in the pipeline may offer more options for rosacea sufferers, according to Linda Stein Gold, MD, director of clinical research, in the department of dermatology, Henry Ford Hospital in Detroit.

sruilk/shutterstock

In addition, topical minocycline has recently been approved by the Food and Drug Administration for the treatment of rosacea in a 1.5% foam formulation. “The reason it has taken so long to have a minocycline product is that it is challenging to deliver it topically,” she said in a presentation at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually. Studies of higher concentrations were not significantly better for rosacea, so development of the 1.5% foam was pursued, although a 4% foam is approved for the treatment of acne.

Dr. Stein Gold shared results from a pair of 12-week randomized trials in which significantly more patients treated with topical minocycline foam showed treatment success, compared with those on vehicle, based on Investigator’s Global Assessment (IGA) scores of clear or almost clear and a decrease of at least two grades from baseline: 52.1% versus 43.0% in one study and 49.1% versus 39.0% in the second, statistically significant differences. The product also was well tolerated, with most patients reporting no side effects or mild side effects.

Research on how to maximize effectiveness of available treatments such as ivermectin is ongoing, but several new treatments in the pipeline continue to show promising results, she noted.

An up-and-coming rosacea treatment is an old product used in a new way: Benzoyl peroxide in a microencapsulated form. “Benzoyl peroxide is encased in silica molecules that allow very slow release of the benzoyl peroxide into the skin and that leads to decreased irritation,” Dr. Stein Gold explained. The deposit of active ingredient on the skin appears to stay below the level of irritation.

Dr. Stein Gold and colleagues conducted two randomized, vehicle-controlled trials in which 733 adults with moderate to severe rosacea were treated with either the encapsulated benzoyl peroxide cream formulation or a vehicle applied once daily for 12 weeks.

At 12 weeks, IGA success increased over the course of the studies, and reached 43.5% in one and 50.1% in the other, compared with 16.1% and 25.9%, respectively, for the vehicle groups in those studies (P < .001 for both). Overall, she described this as “a nice improvement for a drug that we had not considered to be part of our treatment armamentarium for our rosacea patients.”

Dr. Stein Gold also shared data from a phase 2 study of low-dose oral minocycline in adults with papulopustular rosacea. A group of 200 patients used the drug or a placebo once daily for 16 weeks. The study examined 20-mg and 40-mg extended-release formulations, and found a significant improvement with the 40-mg dose over the 20-mg dose and over placebo, in terms of those who reached an IGA of 0 or 1, with a 2 grade improvement. While this is a phase 2 study, it may lead to oral minocycline as another treatment option, she said.

“It is an exciting time for the treatment of rosacea, with a variety of options and an active pipeline, so we can aim for clear skin for our patients,” she commented.

Dr. Stein Gold disclosed serving as an investigator and consultant for Galderma, Vyne, Sun, Sol Gel, and Almirall; she is a consultant and speaker for Ortho.

MedscapeLive and this news organization are owned by the same parent company.
 

Treatments in the pipeline may offer more options for rosacea sufferers, according to Linda Stein Gold, MD, director of clinical research, in the department of dermatology, Henry Ford Hospital in Detroit.

sruilk/shutterstock

In addition, topical minocycline has recently been approved by the Food and Drug Administration for the treatment of rosacea in a 1.5% foam formulation. “The reason it has taken so long to have a minocycline product is that it is challenging to deliver it topically,” she said in a presentation at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually. Studies of higher concentrations were not significantly better for rosacea, so development of the 1.5% foam was pursued, although a 4% foam is approved for the treatment of acne.

Dr. Stein Gold shared results from a pair of 12-week randomized trials in which significantly more patients treated with topical minocycline foam showed treatment success, compared with those on vehicle, based on Investigator’s Global Assessment (IGA) scores of clear or almost clear and a decrease of at least two grades from baseline: 52.1% versus 43.0% in one study and 49.1% versus 39.0% in the second, statistically significant differences. The product also was well tolerated, with most patients reporting no side effects or mild side effects.

Research on how to maximize effectiveness of available treatments such as ivermectin is ongoing, but several new treatments in the pipeline continue to show promising results, she noted.

An up-and-coming rosacea treatment is an old product used in a new way: Benzoyl peroxide in a microencapsulated form. “Benzoyl peroxide is encased in silica molecules that allow very slow release of the benzoyl peroxide into the skin and that leads to decreased irritation,” Dr. Stein Gold explained. The deposit of active ingredient on the skin appears to stay below the level of irritation.

Dr. Stein Gold and colleagues conducted two randomized, vehicle-controlled trials in which 733 adults with moderate to severe rosacea were treated with either the encapsulated benzoyl peroxide cream formulation or a vehicle applied once daily for 12 weeks.

At 12 weeks, IGA success increased over the course of the studies, and reached 43.5% in one and 50.1% in the other, compared with 16.1% and 25.9%, respectively, for the vehicle groups in those studies (P < .001 for both). Overall, she described this as “a nice improvement for a drug that we had not considered to be part of our treatment armamentarium for our rosacea patients.”

Dr. Stein Gold also shared data from a phase 2 study of low-dose oral minocycline in adults with papulopustular rosacea. A group of 200 patients used the drug or a placebo once daily for 16 weeks. The study examined 20-mg and 40-mg extended-release formulations, and found a significant improvement with the 40-mg dose over the 20-mg dose and over placebo, in terms of those who reached an IGA of 0 or 1, with a 2 grade improvement. While this is a phase 2 study, it may lead to oral minocycline as another treatment option, she said.

“It is an exciting time for the treatment of rosacea, with a variety of options and an active pipeline, so we can aim for clear skin for our patients,” she commented.

Dr. Stein Gold disclosed serving as an investigator and consultant for Galderma, Vyne, Sun, Sol Gel, and Almirall; she is a consultant and speaker for Ortho.

MedscapeLive and this news organization are owned by the same parent company.
 

Key clinical point: Impaired respiratory muscle functions are linked to sleep disturbance and cognitive impairment in patients with multiple sclerosis (MS), warranting early evaluation of respiratory muscle strength.

Major finding: The respiratory muscle function test negatively correlated with the scores of Epworth Sleepiness Scale (ESS) and Perceived Deficits Questionnaire (PDQ) and showed a positive correlation with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scale score (P less than .001 for all).

Study details: The study assessed 146 MS patients with a mean age of 29.3 years and a mean Expanded Disability Status Scale (EDSS) score of 4.11.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interests.

Citation: Hashim NA et al. Mult Scler Relat Dis. 2020 Sep 16. doi: 10.1016/j.msard.2020.102514.

Key clinical point: Impaired respiratory muscle functions are linked to sleep disturbance and cognitive impairment in patients with multiple sclerosis (MS), warranting early evaluation of respiratory muscle strength.

Major finding: The respiratory muscle function test negatively correlated with the scores of Epworth Sleepiness Scale (ESS) and Perceived Deficits Questionnaire (PDQ) and showed a positive correlation with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scale score (P less than .001 for all).

Study details: The study assessed 146 MS patients with a mean age of 29.3 years and a mean Expanded Disability Status Scale (EDSS) score of 4.11.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interests.

Citation: Hashim NA et al. Mult Scler Relat Dis. 2020 Sep 16. doi: 10.1016/j.msard.2020.102514.

Key clinical point: Impaired respiratory muscle functions are linked to sleep disturbance and cognitive impairment in patients with multiple sclerosis (MS), warranting early evaluation of respiratory muscle strength.

Major finding: The respiratory muscle function test negatively correlated with the scores of Epworth Sleepiness Scale (ESS) and Perceived Deficits Questionnaire (PDQ) and showed a positive correlation with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scale score (P less than .001 for all).

Study details: The study assessed 146 MS patients with a mean age of 29.3 years and a mean Expanded Disability Status Scale (EDSS) score of 4.11.

Disclosures: This study did not receive any external funding. The authors declared no conflicts of interests.

Citation: Hashim NA et al. Mult Scler Relat Dis. 2020 Sep 16. doi: 10.1016/j.msard.2020.102514.

Key clinical point: Teriflunomide as a long-term immunomodulatory therapy in patients with relapsing multiple sclerosis (MS) has a favorable benefit-risk profile.

Major finding: The safety profile of teriflunomide 14 mg in the extension study was consistent with that in the core study, with similar incidences of adverse events (AEs) and serious AEs. There were differences in serious AE incidences between the placebo and teriflunomide 14 mg groups (6.4% vs. 12.4%). Teriflunomide was associated with reduction in annualized relapse rates in all treatment groups, irrespective of when treatment was initiated.

Study details: Long-term extension of the phase 3 TOWER study: Patients who received teriflunomide 14 mg in the core study were assigned to their original dose (14 mg/14 mg group); patients who received placebo or teriflunomide 7 mg in the core study were reassigned to teriflunomide 14 mg (placebo/14 mg and 7 mg/14 mg groups, respectively).

Disclosures: Development of the manuscript was supported by Sanofi. AL Lublin, P Truffinet, J Chavin, J Delhay, and A Purvis are employees of Sanofi, with ownership interest. M Benamor is an employee of Sanofi. The remaining authors reported ties with various pharmaceutical companies, including Sanofi.

Citation: Miller AE et al. Mult Scler Relat Disord. 2020 Aug 1. doi: 10.1016/j.msard.2020.102438.

Key clinical point: Teriflunomide as a long-term immunomodulatory therapy in patients with relapsing multiple sclerosis (MS) has a favorable benefit-risk profile.

Major finding: The safety profile of teriflunomide 14 mg in the extension study was consistent with that in the core study, with similar incidences of adverse events (AEs) and serious AEs. There were differences in serious AE incidences between the placebo and teriflunomide 14 mg groups (6.4% vs. 12.4%). Teriflunomide was associated with reduction in annualized relapse rates in all treatment groups, irrespective of when treatment was initiated.

Study details: Long-term extension of the phase 3 TOWER study: Patients who received teriflunomide 14 mg in the core study were assigned to their original dose (14 mg/14 mg group); patients who received placebo or teriflunomide 7 mg in the core study were reassigned to teriflunomide 14 mg (placebo/14 mg and 7 mg/14 mg groups, respectively).

Disclosures: Development of the manuscript was supported by Sanofi. AL Lublin, P Truffinet, J Chavin, J Delhay, and A Purvis are employees of Sanofi, with ownership interest. M Benamor is an employee of Sanofi. The remaining authors reported ties with various pharmaceutical companies, including Sanofi.

Citation: Miller AE et al. Mult Scler Relat Disord. 2020 Aug 1. doi: 10.1016/j.msard.2020.102438.

Key clinical point: Teriflunomide as a long-term immunomodulatory therapy in patients with relapsing multiple sclerosis (MS) has a favorable benefit-risk profile.

Major finding: The safety profile of teriflunomide 14 mg in the extension study was consistent with that in the core study, with similar incidences of adverse events (AEs) and serious AEs. There were differences in serious AE incidences between the placebo and teriflunomide 14 mg groups (6.4% vs. 12.4%). Teriflunomide was associated with reduction in annualized relapse rates in all treatment groups, irrespective of when treatment was initiated.

Study details: Long-term extension of the phase 3 TOWER study: Patients who received teriflunomide 14 mg in the core study were assigned to their original dose (14 mg/14 mg group); patients who received placebo or teriflunomide 7 mg in the core study were reassigned to teriflunomide 14 mg (placebo/14 mg and 7 mg/14 mg groups, respectively).

Disclosures: Development of the manuscript was supported by Sanofi. AL Lublin, P Truffinet, J Chavin, J Delhay, and A Purvis are employees of Sanofi, with ownership interest. M Benamor is an employee of Sanofi. The remaining authors reported ties with various pharmaceutical companies, including Sanofi.

Citation: Miller AE et al. Mult Scler Relat Disord. 2020 Aug 1. doi: 10.1016/j.msard.2020.102438.

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS

Study Overview

Objective. To assess whether dapagliflozin added to guideline-recommended therapies is effective and safe over the long-term to reduce the rate of renal and cardiovascular events in patients across multiple chronic kidney disease (CKD) stages, with and without type 2 diabetes.

Design. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) was a randomized, double-blind, parallel-group, placebo-controlled, multicenter event-driven, clinical trial sponsored by Astra-Zeneca. It was conducted at 386 sites in 21 countries from February 2, 2017, to June 12, 2020. A recruitment period of 24 months and a total study duration of 45 months were initially planned. The primary efficacy analysis was based on the intention-to-treat population. This was the first randomized controlled trial designed to assess the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on renal and cardiovascular outcomes in patients with CKD.

Setting and participants. This trial randomly assigned 4304 adult participants with CKD stages 2 to 4 (an estimated glomerular filtration rate [GFR] of 25 to 75 mL/min/1.73 m² of body-surface area) and elevated urinary albumin excretion (urinary albumin-to-creatinine ratio of 200 to 5000, measured in mg of albumin per g of creatinine) to receive dapagliflozin (10 mg once daily) or placebo. Exclusion criteria included type 1 diabetes, polycystic kidney disease, lupus nephritis, antineutrophil cytoplasmic antibody–associated vasculitis, recent immunosuppressive therapy for primary or secondary kidney disease, New York Heart Association class IV congestive heart failure, myocardial infarction, unstable angina, stroke or transient ischemic attacks, or recent coronary revascularization or valvular repair/replacement. All participants received a stable dose of renin–angiotensin system inhibitor for 4 weeks prior to screening, and the vast majority received a maximum tolerated dose at enrollment. Randomization was monitored to ensure that at least 30% of participants recruited did not have diabetes and that no more than 10% had stage 2 CKD. Participants were randomly assigned to receive dapagliflozin (n = 2152) or matching placebo (n = 2152) to ensure a 1:1 ratio of the 2 regimens. Dapagliflozin and placebo had identical appearance and administration schedules. All participants and trial personnel (except members of the independent data monitoring committee) were unaware of the trial-group assignments. After randomization, in-person study visits were conducted at 2 weeks, at 2, 4, and 8 months, and at 4-month intervals thereafter.

Main outcome measures. The primary outcome was a composite of the first occurrence of either a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. Secondary outcomes, in hierarchical order, were: (1) the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes; (2) a composite cardiovascular outcome defined as hospitalization for heart failure or death from cardiovascular causes; and (3) death from any cause. All outcomes were assessed by time-to-event analyses.

Given the extensive prior experience with dapagliflozin, only selected adverse events were recorded. These included serious adverse events, adverse events resulting in the discontinuation of dapagliflozin or placebo, and adverse events of interest to dapagliflozin (eg, volume depletion symptoms, renal events, major hypoglycemia, fractures, diabetic ketoacidosis, events leading to higher risk of lower limb amputation, and lower limb amputations).

Main results. On March 26, 2020, the independent data monitoring committee recommended stopping the trial because of clear efficacy on the basis of 408 primary outcome events. The participants were 61.8 ± 12.1 years of age, and 1425 participants (33.1%) were female. The baseline mean estimated GFR was 43.1 ± 12.4 mL/min/1.73 m², the median urinary albumin-to-creatinine ratio was 949, and 2906 participants (67.5%) had type 2 diabetes. Over a median of 2.4 years, a primary outcome event occurred in 197 participants (9.2%) in the dapagliflozin group and 312 (14.5%) in the placebo group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.51-0.72; P < 0.001). The number of participants who needed to be treated during the trial period to prevent 1 primary outcome event was 19 (95% CI, 15-27). The beneficial effect of dapagliflozin compared with placebo was consistent across all 8 prespecified subgroups (ie, age, sex, race, geographic region, type 2 diabetes, estimated GFR, urinary albumin-to-creatinine ratio, and systolic blood pressure) for the primary outcome. The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes.

The incidence of each secondary outcome was similarly lower in the dapagliflozin-treated group than in the placebo group. The HR for the composite kidney outcome of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45-0.68; P < 0.001), and the HR for the composite cardiovascular outcome of hospitalization for heart failure or death from cardiovascular causes was 0.71 (95% CI, 0.55-0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (HR, 0.69; 95% CI, 0.53-0.88; P = 0.004). The known safety profile of dapagliflozin was confirmed by the similar overall incidences of adverse events and serious adverse events in the dapagliflozin and placebo groups.

Conclusion. In patients with CKD, with or without type 2 diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lowered by dapagliflozin treatment.

Commentary

Although SGLT2 inhibitors were designed to reduce plasma glucose and hemoglobin A1c (HbA1c) by increasing urinary glucose excretion in a non-insulin-dependent fashion, an increasing number of clinical trials have demonstrated their possible cardiovascular and renal benefits that extend beyond glycemic control. In 2008, the US Food and Drug Administration (FDA) issued a guidance recommending the evaluation of long-term cardiovascular outcomes prior to approval and commercialization of new antidiabetic therapies to ensure minimum cardiovascular risks following the discovery of cardiovascular safety issues associated with antidiabetic compounds, including rosiglitazone, after drug approval. No one foresaw that this recommendation would lead to the discovery of new classes of antidiabetic drugs (glucagon-like peptide 1 [GLP1] and SGLT2 inhibitors) that improve cardiovascular outcomes. A series of clinical trials of SGLT2 inhibitors, including empagliflozin,¹ canagliflozin,² and dapagliflozin,³ showed a reduction in cardiovascular death and hospitalization due to heart failure among patients with type 2 diabetes. Furthermore, a meta-analysis from 2019 found that SGLT2 inhibitors reduced the risk of a composite of cardiovascular death or hospitalization for heart failure by 23% and the risk of progression of kidney failure by 45% in patients with diabetes.⁴ Thus, the strong and consistent evidence from these large and well-designed outcome trials led the American Diabetes Association in its most recent guidelines to recommend adding SGLT2 inhibitors to metformin for the treatment of patients with type 2 diabetes with or at high risk of atherosclerotic cardiovascular disease, heart failure, or CKD, regardless of baseline HbA1c levels or HbA1c target.⁵ As a result of the compelling effects of SGLT2 inhibitors on cardiovascular outcomes in diabetic patients, as well as increasing evidence that these clinical effects were independent of glycemic control, several subsequent trials were conducted to evaluate whether this new class of drugs may improve clinical outcomes in nondiabetic patients.

The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) was the first clinical trial to investigate the effect of SGLT2 inhibitors on cardiovascular disease in nondiabetic patients. Findings from DAPA-HF showed that dapagliflozin reduced the risk of worsening heart failure or death from cardiovascular causes, independent of the presence of underlying diabetes. This initial finding resonates with a growing body of evidence^6,7 that supports the use of SGLT2 inhibitors as an adjunctive therapy for heart failure in the absence of diabetes.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial showed that long-term administration of canagliflozin conferred cardiovascular, as well as renal, protection in patients with type 2 diabetes with CKD.⁸ Similar to the protective effects on heart failure, the renal benefits of SGLT2 inhibitors appeared to be independent of their blood glucose-lowering effects. Thus, these recent discoveries led to the design of the DAPA-CKD trial to further assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with CKD precipitated by causes other than type 2 diabetes. Although diabetes is the most common cause for CKD, it nonetheless only accounts for 40% of all CKD etiologies. To date, the only classes of medication that have been shown to slow a decline in kidney function in patients with diabetes are angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). Given that CKD is an important contributor to illness, is associated with diminished quality of life and reduced life expectancy, and increases health care costs, the findings of the DAPA-CKD trial are particularly significant as they show a renal benefit of dapagliflozin treatment across CKD stages that is independent of underlying diabetes. Therefore, SGLT2 inhibitors may offer a new and unique treatment option for millions of patients with CKD worldwide for whom ACE inhibitors and ARBs were otherwise the only treatments to prevent kidney failure. Moreover, with a number-needed-to-treat of 19 to prevent 1 composite renal vascular event over a period of 2.4 years, dapagliflozin requires a much lower number needed to treat compared to ACE inhibitors and ARBs in similar patients.

The trial has several limitations in study design. For example, the management of diabetes and hypertension were left to the discretion of each trial site, in keeping with local clinical practice and guidelines. It is unknown whether this variability in the management of comorbidities that impact kidney function had an effect on the study’s results. In addition, the trial was stopped early as a result of recommendations from an independent committee due to the demonstrated efficacy of dapagliflozin. This may have reduced the statistical power to assess some of the secondary outcomes. Finally, the authors discussed an initial dip in the estimated GFR after initiation of dapagliflozin treatment, similar to that observed in other SGLT2 inhibitor clinical trials. However, they were unable to ascertain the reversibility of this effect after the discontinuation of dapagliflozin because assessment of GFR was not completed after trial closure. Nonetheless, the authors specified that the reversibility of this initial estimated GFR dip had been assessed and observed in other clinical trials involving dapagliflozin.

The nonglycemic benefits of SGLT2 inhibitors, including improvement in renal outcomes, have strong implications for the future management of patients with CKD. If this indication is approved by the FDA and recommended by clinical guidelines, the ease of SGLT2 inhibitor prescription (eg, minimal drug-drug interaction, no titration), treatment administration (orally once daily), and safety profile may lead to wide use of SGLT2 inhibitors by generalists, nephrologists, and endocrinologists in preserving or improving renal outcomes in patients at risk for end-stage kidney disease. Given that SGLT2 inhibitors are a new class of pharmacologic therapeutics, patient education should include a discussion of the possible side effects, such as euglycemic ketoacidosis, genital and urinary tract infection, and foot and leg amputation. Finally, as Strandberg and colleagues reported in a recent commentary,⁹ the safety of SGLT2 inhibitors in older adults with multimorbidity, frailty, and polypharmacy remains unclear. Thus, future studies of SGLT2 inhibitors are needed to better evaluate their clinical effects in older adults.

Applications for Clinical Practice

This trial enrolled a dedicated patient population with CKD and demonstrated a benefit of dapagliflozin in reducing renal and cardiovascular outcomes, regardless of baseline diabetes status. These drugs (dapagliflozin as well as other SGLT2 inhibitors) will likely have a prominent role in future CKD management guidelines. Until then, several barriers remain before SGLT2 inhibitors can be widely used in clinical practice. Among these barriers are FDA approval for their use in patients with and without diabetes with an estimated GFR < 30 mL/min/1.73 m² and lowering the costs of this class of drugs.

—Rachel Litke, MD, PhD
Icahn School of Medicine at Mount Sinai
Fred Ko, MD, MS