Nephrology

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

A previously healthy 44-year-old woman presents to the emergency department with 1 day of fever, flank pain, dysuria, and persistent nausea and vomiting. Her temperature is 38.7°C (101.7°F), heart rate 102 beats per minute, and blood pressure 120/70 mm Hg. She has costovertebral angle tenderness. Laboratory testing reveals mild leukocytosis and a normal serum creatinine level; urinalysis shows leukocytes, as well as leukocyte esterase and nitrites. She has no personal or family history of nephrolithiasis. Urine cultures are obtained, and she is started on intravenous antibiotics and intravenous hydration to treat pyelonephritis.

Is imaging indicated at this point? And if so, which study is recommended?

KEY FEATURES

Acute pyelonephritis, infection of the renal parenchyma and collecting system, most often results from an ascending infection of the lower urinary tract. It is estimated to account for 250,000 office visits and 200,000 hospital admissions each year in the United States.¹

Lower urinary tract symptoms such as urinary frequency, urgency, and dysuria accompanied by fever, nausea, vomiting, and flank pain raise suspicion for acute pyelonephritis. Flank pain is a key, nearly universal feature of upper urinary tract infection in patients without diabetes, though it may be absent in up to 50% of patients with diabetes.²

Additional findings include costovertebral angle tenderness on physical examination and leukocytosis, pyuria, and bacteriuria on laboratory studies.

PREDICTING THE NEED FOR EARLY IMAGING

Though guidelines state that imaging is inappropriate in most patients with pyeloneph­ritis,^2–4 it is nevertheless often done for diagnosis or identification of complications, which have been reported in more than two-thirds of patients.^2–4

Acute pyelonephritis is generally classified as complicated or uncomplicated, though different definitions exist with regard to these classifications. The American College of Radiology’s Appropriateness Criteria2 consider patients with diabetes, immune compromise, a history of urolithiasis, or anatomic abnormality to be at highest risk for complications, and therefore recommend early imaging to assess for hydronephrosis, pyonephrosis, emphysematous pyelonephritis, and intrinsic or perinephric abscess.²

A clinical rule for predicting the need for imaging in acute pyelonephritis was developed and validated in an emergency department population in the Netherlands.³ The study suggested that restricting early imaging to patients with a history of urolithiasis, a urine pH of 7.0 or higher, or renal insufficiency—defined as a glomerular filtration rate (GFR) of 40 mL/min/1.73m² or lower as estimated by the Modification of Diet in Renal Disease formula—would provide a negative predictive value of 94% to 100% for detection of an urgent urologic disorder (pyonephrosis, renal abscess, or urolithiasis). This high negative predictive value highlights that an absence of these signs and symptoms can safely identify patients who do not need renal imaging.

The positive predictive value was less useful, as only 5% to 23% of patients who had at least 1 risk factor went on to have urgent urologic risk factors.³

Implementation of this prediction rule would have resulted in a relative reduction in imaging of 40% and an absolute reduction of 28%. Of note, use of reduced GFR in this prediction rule is not clearly validated for patients with chronic kidney disease, as the previous GFR for most patients in this study was unknown.³

Based on these data, initial imaging is recommended in patients with diabetes, immune compromise, a history of urolithiasis, anatomic abnormality, a urine pH 7.0 or higher, or a GFR 40 mL/min or lower in a patient with no history of significant renal dysfunction. Early imaging would also be reasonable in patients with a complex clinical presentation, early recurrence of symptoms after treatment, clinical decompensation, or critical illness.

In a retrospective review of 62 patients hospitalized for acute renal infection, Soulen et al5 found that the most reliable indicator of complicated acute pyelonephritis was the persistence of fever and leukocytosis at 72 hours. And another small prospective study of patients with uncomplicated pyelonephritis reported a time to defervescence of no more than 4 days.⁶

In accordance with the Appropriateness Criteria2 and based on the best available evidence, imaging is recommended in all patients who remain febrile or have persistent leukocytosis after 72 hours of antibiotic therapy. In such cases, there should be high suspicion for a complication requiring treatment.

OPTIONS FOR IMAGING

Computed tomography

Computed tomography (CT) of the abdomen and pelvis with contrast is considered the study of choice in complicated acute pyelonephritis. CT can detect focal parenchymal abnormalities, emphysematous changes, and anatomic anomalies, and can also define the extent of disease. It can also detect perinephric fluid collections and abscesses that necessitate a change in management.^2,5

A retrospective study in 2017 found that contrast-enhanced CT done without the usual noncontrast and excretory phases had an accuracy of 90% to 92% for pyelonephritis and 96% to 99% for urolithiasis, suggesting that reduction in radiation exposure through use of only the contrast-enhanced phase of CT imaging may be reasonable.⁷

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is increasingly acknowledged as effective in the evaluation of renal pathology, including the diagnosis of pyelonephritis; but it lacks the level of evidence that CT provides for detecting renal abscesses, calculi, and emphysematous pyelonephritis.^2,8,9

Though it is more costly and time-consuming than CT with contrast enhancement, MRI is nevertheless the imaging study of choice if iodinated contrast or ionizing radiation must be avoided.

MRI typically involves a precontrast phase and a gadolinium contrast-enhanced phase, though there are data to support diffusion-weighted MRI when exposure to gadolinium poses a risk to the patient, such as in pregnancy or renal impairment (particularly when the estimated GFR is < 30 mL/min/1.73 m²).¹⁰

Ultrasonography

Conventional ultrasonography is appealing due to its relatively low cost, its availability and portability, and the lack of radiation and contrast exposure. It is most helpful in detecting hydronephrosis and pyonephrosis rather than intrarenal or perinephric abscess.^2,9

Color and power Doppler ultrasonography may improve testing characteristics but not to the level of CT; in one study, sensitivity for detection of pyelonephritis was 33.3% with ultrasonography vs 81.0% with CT.¹¹

Recent studies of ultrasonography with contrast enhancement show promising results,² and it may ultimately prove to have a similar efficacy with lower risk for patients, but this has not been validated in large studies, and its availability remains limited.

Ultrasonography should be considered for patients in whom obstruction (with resulting hydronephrosis or pyonephrosis) is a primary concern, particularly when contrast exposure or radiation is contraindicated and MRI is unavailable.²

Abdominal radiography

While emphysematous pyelonephritis or a large staghorn calculus may be seen on abdominal radiography, it is not recommended for the assessment of complications in acute pyelonephritis because it lacks sensitivity.²

RETURN TO THE CASE SCENARIO

The patient in our case scenario meets the clinical criteria for uncomplicated pyelo­nephritis and is therefore not a candidate for imaging. Intravenous antibiotics should be started and should lead to rapid improvement in her condition.

Acknowledgment: The authors would like to thank Dr. Lisa Blacklock for her review of the radiology section of this paper.

Sodium-glucose cotransporter 2 inhibitors do not appear to increase the risk of urinary tract infections, compared with other antidiabetic medications, new research has found.

In a paper published in Annals of Internal Medicine, researchers reported the outcomes of a population-based, propensity-matched cohort study in which the analyzed data from 235,730 individuals newly prescribed sodium-glucose cotransporter 2 (SGLT-2) inhibitors, dipeptidyl peptidase–4 (DPP-4) inhibitors, and glucagonlike peptide–1 receptor (GLP-1) agonists.

In the first cohort, comparing SGLT-2 inhibitors with DDP-4 inhibitors, there were no significant differences between the two groups in the incidence rate of severe urinary tract infections (UTIs) (adjusted hazard ratio, 0.98; 95% confidence interval, 0.68-1.41).

In the second cohort, which compared patients taking GLP-1 receptor agonists with those taking SGLT-2 inhibitors, researchers saw a slightly lower incidence of severe UTIs among individuals on SGLT-2 inhibitors (HR, 0.72; 95% CI, 0.53-0.99; P = .04).

The analysis also failed to find any evidence that SGLT-2 inhibitors were associated with an increase in the risk of hospitalization or outpatient treatment for a UTI.

Chintan V. Dave, PharmD – now at Rutgers University, New Brunswick, N.J. – and colleagues from Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote that the findings have significant clinical implications.

“Patients who may be good candidates to receive SGLT-2 inhibitors for diabetes control but who have a history of recurrent UTIs may be precluded from being prescribed these agents; because UTIs are highly prevalent in patients with diabetes, this could exclude a substantial number of patients from receiving an entire class of medications that has been shown to decrease risk for major cardiovascular events and death,” they wrote.

The researchers stressed that “other factors beyond risk for UTI events should be considered in decisions about whether to prescribe SGLT-2 therapy for patients with diabetes.”

The authors did note that their study was subject to the usual limitations of observational studies, such as susceptibility to confounding, and was also limited to people with health insurance.

An accompanying editorial by Kristian B. Filion, PhD, and Oriana H. Yu, MD, of McGill University, Montreal, commented that the data provided reassuring, real-world evidence on the potential safety issue of UTI risk with SGLT-2 inhibitors.

However, they also stressed that the study excluded individuals at high risk or with a history of UTIs, and that these were subgroups who required further investigation.

The study was supported by the Harvard Medical School and the National Institute on Aging. Three authors reported support from private industry outside the submitted work.

SOURCE: Dave CV et al. Ann Intern Med. 2019 Jul 29. doi: 10.7326/M18-3136.

Sodium-glucose cotransporter 2 inhibitors do not appear to increase the risk of urinary tract infections, compared with other antidiabetic medications, new research has found.

In a paper published in Annals of Internal Medicine, researchers reported the outcomes of a population-based, propensity-matched cohort study in which the analyzed data from 235,730 individuals newly prescribed sodium-glucose cotransporter 2 (SGLT-2) inhibitors, dipeptidyl peptidase–4 (DPP-4) inhibitors, and glucagonlike peptide–1 receptor (GLP-1) agonists.

In the first cohort, comparing SGLT-2 inhibitors with DDP-4 inhibitors, there were no significant differences between the two groups in the incidence rate of severe urinary tract infections (UTIs) (adjusted hazard ratio, 0.98; 95% confidence interval, 0.68-1.41).

In the second cohort, which compared patients taking GLP-1 receptor agonists with those taking SGLT-2 inhibitors, researchers saw a slightly lower incidence of severe UTIs among individuals on SGLT-2 inhibitors (HR, 0.72; 95% CI, 0.53-0.99; P = .04).

The analysis also failed to find any evidence that SGLT-2 inhibitors were associated with an increase in the risk of hospitalization or outpatient treatment for a UTI.

Chintan V. Dave, PharmD – now at Rutgers University, New Brunswick, N.J. – and colleagues from Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote that the findings have significant clinical implications.

“Patients who may be good candidates to receive SGLT-2 inhibitors for diabetes control but who have a history of recurrent UTIs may be precluded from being prescribed these agents; because UTIs are highly prevalent in patients with diabetes, this could exclude a substantial number of patients from receiving an entire class of medications that has been shown to decrease risk for major cardiovascular events and death,” they wrote.

The researchers stressed that “other factors beyond risk for UTI events should be considered in decisions about whether to prescribe SGLT-2 therapy for patients with diabetes.”

The authors did note that their study was subject to the usual limitations of observational studies, such as susceptibility to confounding, and was also limited to people with health insurance.

An accompanying editorial by Kristian B. Filion, PhD, and Oriana H. Yu, MD, of McGill University, Montreal, commented that the data provided reassuring, real-world evidence on the potential safety issue of UTI risk with SGLT-2 inhibitors.

However, they also stressed that the study excluded individuals at high risk or with a history of UTIs, and that these were subgroups who required further investigation.

The study was supported by the Harvard Medical School and the National Institute on Aging. Three authors reported support from private industry outside the submitted work.

SOURCE: Dave CV et al. Ann Intern Med. 2019 Jul 29. doi: 10.7326/M18-3136.

Sodium-glucose cotransporter 2 inhibitors do not appear to increase the risk of urinary tract infections, compared with other antidiabetic medications, new research has found.

In a paper published in Annals of Internal Medicine, researchers reported the outcomes of a population-based, propensity-matched cohort study in which the analyzed data from 235,730 individuals newly prescribed sodium-glucose cotransporter 2 (SGLT-2) inhibitors, dipeptidyl peptidase–4 (DPP-4) inhibitors, and glucagonlike peptide–1 receptor (GLP-1) agonists.

In the first cohort, comparing SGLT-2 inhibitors with DDP-4 inhibitors, there were no significant differences between the two groups in the incidence rate of severe urinary tract infections (UTIs) (adjusted hazard ratio, 0.98; 95% confidence interval, 0.68-1.41).

In the second cohort, which compared patients taking GLP-1 receptor agonists with those taking SGLT-2 inhibitors, researchers saw a slightly lower incidence of severe UTIs among individuals on SGLT-2 inhibitors (HR, 0.72; 95% CI, 0.53-0.99; P = .04).

The analysis also failed to find any evidence that SGLT-2 inhibitors were associated with an increase in the risk of hospitalization or outpatient treatment for a UTI.

Chintan V. Dave, PharmD – now at Rutgers University, New Brunswick, N.J. – and colleagues from Brigham and Women’s Hospital and Harvard Medical School, Boston, wrote that the findings have significant clinical implications.

“Patients who may be good candidates to receive SGLT-2 inhibitors for diabetes control but who have a history of recurrent UTIs may be precluded from being prescribed these agents; because UTIs are highly prevalent in patients with diabetes, this could exclude a substantial number of patients from receiving an entire class of medications that has been shown to decrease risk for major cardiovascular events and death,” they wrote.

The researchers stressed that “other factors beyond risk for UTI events should be considered in decisions about whether to prescribe SGLT-2 therapy for patients with diabetes.”

The authors did note that their study was subject to the usual limitations of observational studies, such as susceptibility to confounding, and was also limited to people with health insurance.

An accompanying editorial by Kristian B. Filion, PhD, and Oriana H. Yu, MD, of McGill University, Montreal, commented that the data provided reassuring, real-world evidence on the potential safety issue of UTI risk with SGLT-2 inhibitors.

However, they also stressed that the study excluded individuals at high risk or with a history of UTIs, and that these were subgroups who required further investigation.

The study was supported by the Harvard Medical School and the National Institute on Aging. Three authors reported support from private industry outside the submitted work.

SOURCE: Dave CV et al. Ann Intern Med. 2019 Jul 29. doi: 10.7326/M18-3136.

LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

SAN FRANCISCO – The sodium-glucose transporter 2 inhibitor (SGLT2) dapagliflozin (Farxiga) was better than placebo at slowing down kidney disease in patients with type 2 diabetes, and it showed reductions in the relative risk of renal-specific and cardiorenal outcomes of 47% and 24%, respectively, over 4 years, according to an analysis of the DECLARE-TIMI58 trial presented at the annual scientific sessions of the American Diabetes Association.

M. Alexander Otto

The findings add to a message physicians are hearing more and more frequently – that SGLT2 inhibitors, which also include empagliflozin (Jardiance) and canagliflozin (Invokana), could be useful for the early prevention of chronic kidney disease in patients who have type 2 diabetes. The main difference between the DECLARE-TIMI58 and previous study data was that most of its population did not have chronic kidney disease.

The drug should be given “at a very early stage of disease – it can reverse the disease and its complications [and] change the outcomes of patients,” said investigator Itamar Raz, MD, of Hebrew University, Jerusalem, in presenting the findings, which were published simultaneously in the Lancet Diabetes & Endocrinology (2019 Jun 10. doi: 10.1016/S2213-8587[19]30180-9).

What’s new in this renal analysis of DECLARE-TIMI58 is that patients were relatively healthy – 60% of them were without established cardiovascular disease and had much better renal function at baseline, compared with patients in other studies. About half of the patients started out with an estimated glomerular filtration rate (eGFR) more than 90 mL/min per 1.73 m², which means that they had normal kidney function, and most of the rest of the patients had normal to near-normal renal function or mild renal failure. Findings from previous trials with SGLT2 inhibitors that showed renal protection generally included patients with established cardiovascular disease who started out with greater kidney impairment.

Previous findings have also demonstrated cardioprotective effects with SGLT2 inhibitors in patients with type 2 diabetes. For instance, in earlier results from the DECLARE-TIMI58 trial, dapagliflozin reduced the frequency of cardiovascular death or hospitalization for heart failure, compared with placebo (4.9% vs. 5.8%, respectively; New Engl J Med. 2019;380:347-57), although it did not significantly reduce the frequency of stroke, heart attack, or all-cause death, unlike the results from glucagonlike peptide–1 receptor agonists in much sicker patients (Circulation. 2019;139[17]:2022-31).

Taken as a whole, Dr. Raz said that findings for SGLT2 inhibitors, which, like the glucagonlike peptide–1 receptor agonists, are indicated as second-line therapy in type 2 diabetes after metformin, suggest that they should be used sooner in type 2 disease, perhaps in patients with a hemoglobin A_1c level as low at 6.5%.

The absolute benefits of dapagliflozin, compared with placebo, notwithstanding, there are safety concerns with SGLT2s, including genitourinary infections, acute kidney injury, Fournier gangrene, diabetic ketoacidosis, bone fractures, and leg amputations (the latter two only with canagliflozin), many of which have been subject to warnings from the Food and Drug Administration.

Safety outcomes for dapagliflozin, compared with placebo, were not tabulated in the new renal report, but the authors noted a previously reported decrease of 30% in risk for acute kidney injury and major hypoglycemia with dapagliflozin over placebo. There was 1 case of Fournier gangrene with the drug versus 5 with placebo; 27 cases of diabetic ketoacidosis versus 12, respectively; 123 amputations versus 113; and 76 genital infections versus 9.

M. Alexander Otto

Matthew Riddle, MD, of Oregon Health and Science University, Portland, said SGLT2 studies “have shown important short-term benefit, but we have no information on long-term safety. These drugs are not physiologic; they do something powerful, but it’s nothing you see in nature. We don’t really know what they do yet; the physiology is still being worked out.”

DECLARE-TIMI58 randomized 8,582 patients with type 2 diabetes to receive dapagliflozin 10 mg orally daily and 8,578 patients to receive placebo. The patients remained on routine diabetes and cardiovascular care. Inclusion criteria included either established atherosclerotic cardiovascular disease (41% of patients) or cardiovascular risk factors (almost 60%), and creatinine clearance of at least 60 mL/min. Median follow-up was 4.2 years.

Overall, 4.2% of patients receiving dapagliflozin and 5.3% of those receiving placebo, met a prespecified secondary cardiorenal composite outcome of end-stage renal disease; death from renal or cardiovascular causes; or a decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m² according to two tests at least 4 weeks apart (hazard ratio, 0.76; P less than .0001).

Similarly, 1.5% of dapagliflozin patients and 2.6% of those on placebo met a prespecified renal-specific composite of those factors minus death from cardiovascular causes (HR, 0.53; P less than .0001).

Among placebo-treated patients, 2.5% had a sustained decline in eGFR of at least 40% to less than 60 mL/min per 1.73 m², compared with 1.4% in the dapagliflozin group (HR, 0.54; P less than .0001). There were 11 cases of end-stage renal disease or renal death with dapagliflozin (0.1%), compared with 27 (0.3%) with placebo (HR, 0.41; P = .012).

Among patients who entered the trial with significant renal impairment – an eGFR of less than 60 mL/min per 1.73 m² – the difference in further renal decline with dapagliflozin was not statistically significant against placebo because of the small number of patients, but Dr. Raz said the drug should still be used earlier in type 2 disease.

Dapagliflozin patients fared worse on renal measurements at 6 months, but caught up by year 2, and surpassed placebo at years 3 and 4, the authors wrote in the latest report.

Just more than 60% of participants were men; patients were in their 60s, on average, and overweight. About 80% of the patients were white.

AstraZeneca, which makes dapagliflozin, was involved with study design, data collection, data analysis, interpretation, and writing of the report. Four authors were employees of the company, and all but two of the 17 others, including Dr. Raz, disclosed personal payments from the company and/or research funding. Dr. Riddle disclosed receiving research funding from AstraZeneca.
 

[email protected]

SAN FRANCISCO – The sodium-glucose transporter 2 inhibitor (SGLT2) dapagliflozin (Farxiga) was better than placebo at slowing down kidney disease in patients with type 2 diabetes, and it showed reductions in the relative risk of renal-specific and cardiorenal outcomes of 47% and 24%, respectively, over 4 years, according to an analysis of the DECLARE-TIMI58 trial presented at the annual scientific sessions of the American Diabetes Association.

M. Alexander Otto

The findings add to a message physicians are hearing more and more frequently – that SGLT2 inhibitors, which also include empagliflozin (Jardiance) and canagliflozin (Invokana), could be useful for the early prevention of chronic kidney disease in patients who have type 2 diabetes. The main difference between the DECLARE-TIMI58 and previous study data was that most of its population did not have chronic kidney disease.

The drug should be given “at a very early stage of disease – it can reverse the disease and its complications [and] change the outcomes of patients,” said investigator Itamar Raz, MD, of Hebrew University, Jerusalem, in presenting the findings, which were published simultaneously in the Lancet Diabetes & Endocrinology (2019 Jun 10. doi: 10.1016/S2213-8587[19]30180-9).

What’s new in this renal analysis of DECLARE-TIMI58 is that patients were relatively healthy – 60% of them were without established cardiovascular disease and had much better renal function at baseline, compared with patients in other studies. About half of the patients started out with an estimated glomerular filtration rate (eGFR) more than 90 mL/min per 1.73 m², which means that they had normal kidney function, and most of the rest of the patients had normal to near-normal renal function or mild renal failure. Findings from previous trials with SGLT2 inhibitors that showed renal protection generally included patients with established cardiovascular disease who started out with greater kidney impairment.

Previous findings have also demonstrated cardioprotective effects with SGLT2 inhibitors in patients with type 2 diabetes. For instance, in earlier results from the DECLARE-TIMI58 trial, dapagliflozin reduced the frequency of cardiovascular death or hospitalization for heart failure, compared with placebo (4.9% vs. 5.8%, respectively; New Engl J Med. 2019;380:347-57), although it did not significantly reduce the frequency of stroke, heart attack, or all-cause death, unlike the results from glucagonlike peptide–1 receptor agonists in much sicker patients (Circulation. 2019;139[17]:2022-31).

Taken as a whole, Dr. Raz said that findings for SGLT2 inhibitors, which, like the glucagonlike peptide–1 receptor agonists, are indicated as second-line therapy in type 2 diabetes after metformin, suggest that they should be used sooner in type 2 disease, perhaps in patients with a hemoglobin A_1c level as low at 6.5%.

The absolute benefits of dapagliflozin, compared with placebo, notwithstanding, there are safety concerns with SGLT2s, including genitourinary infections, acute kidney injury, Fournier gangrene, diabetic ketoacidosis, bone fractures, and leg amputations (the latter two only with canagliflozin), many of which have been subject to warnings from the Food and Drug Administration.

Safety outcomes for dapagliflozin, compared with placebo, were not tabulated in the new renal report, but the authors noted a previously reported decrease of 30% in risk for acute kidney injury and major hypoglycemia with dapagliflozin over placebo. There was 1 case of Fournier gangrene with the drug versus 5 with placebo; 27 cases of diabetic ketoacidosis versus 12, respectively; 123 amputations versus 113; and 76 genital infections versus 9.

M. Alexander Otto

Matthew Riddle, MD, of Oregon Health and Science University, Portland, said SGLT2 studies “have shown important short-term benefit, but we have no information on long-term safety. These drugs are not physiologic; they do something powerful, but it’s nothing you see in nature. We don’t really know what they do yet; the physiology is still being worked out.”

DECLARE-TIMI58 randomized 8,582 patients with type 2 diabetes to receive dapagliflozin 10 mg orally daily and 8,578 patients to receive placebo. The patients remained on routine diabetes and cardiovascular care. Inclusion criteria included either established atherosclerotic cardiovascular disease (41% of patients) or cardiovascular risk factors (almost 60%), and creatinine clearance of at least 60 mL/min. Median follow-up was 4.2 years.

Overall, 4.2% of patients receiving dapagliflozin and 5.3% of those receiving placebo, met a prespecified secondary cardiorenal composite outcome of end-stage renal disease; death from renal or cardiovascular causes; or a decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m² according to two tests at least 4 weeks apart (hazard ratio, 0.76; P less than .0001).

Similarly, 1.5% of dapagliflozin patients and 2.6% of those on placebo met a prespecified renal-specific composite of those factors minus death from cardiovascular causes (HR, 0.53; P less than .0001).

Among placebo-treated patients, 2.5% had a sustained decline in eGFR of at least 40% to less than 60 mL/min per 1.73 m², compared with 1.4% in the dapagliflozin group (HR, 0.54; P less than .0001). There were 11 cases of end-stage renal disease or renal death with dapagliflozin (0.1%), compared with 27 (0.3%) with placebo (HR, 0.41; P = .012).

Among patients who entered the trial with significant renal impairment – an eGFR of less than 60 mL/min per 1.73 m² – the difference in further renal decline with dapagliflozin was not statistically significant against placebo because of the small number of patients, but Dr. Raz said the drug should still be used earlier in type 2 disease.

Dapagliflozin patients fared worse on renal measurements at 6 months, but caught up by year 2, and surpassed placebo at years 3 and 4, the authors wrote in the latest report.

Just more than 60% of participants were men; patients were in their 60s, on average, and overweight. About 80% of the patients were white.

AstraZeneca, which makes dapagliflozin, was involved with study design, data collection, data analysis, interpretation, and writing of the report. Four authors were employees of the company, and all but two of the 17 others, including Dr. Raz, disclosed personal payments from the company and/or research funding. Dr. Riddle disclosed receiving research funding from AstraZeneca.
 

[email protected]

SAN FRANCISCO – The sodium-glucose transporter 2 inhibitor (SGLT2) dapagliflozin (Farxiga) was better than placebo at slowing down kidney disease in patients with type 2 diabetes, and it showed reductions in the relative risk of renal-specific and cardiorenal outcomes of 47% and 24%, respectively, over 4 years, according to an analysis of the DECLARE-TIMI58 trial presented at the annual scientific sessions of the American Diabetes Association.

M. Alexander Otto

The findings add to a message physicians are hearing more and more frequently – that SGLT2 inhibitors, which also include empagliflozin (Jardiance) and canagliflozin (Invokana), could be useful for the early prevention of chronic kidney disease in patients who have type 2 diabetes. The main difference between the DECLARE-TIMI58 and previous study data was that most of its population did not have chronic kidney disease.

The drug should be given “at a very early stage of disease – it can reverse the disease and its complications [and] change the outcomes of patients,” said investigator Itamar Raz, MD, of Hebrew University, Jerusalem, in presenting the findings, which were published simultaneously in the Lancet Diabetes & Endocrinology (2019 Jun 10. doi: 10.1016/S2213-8587[19]30180-9).

What’s new in this renal analysis of DECLARE-TIMI58 is that patients were relatively healthy – 60% of them were without established cardiovascular disease and had much better renal function at baseline, compared with patients in other studies. About half of the patients started out with an estimated glomerular filtration rate (eGFR) more than 90 mL/min per 1.73 m², which means that they had normal kidney function, and most of the rest of the patients had normal to near-normal renal function or mild renal failure. Findings from previous trials with SGLT2 inhibitors that showed renal protection generally included patients with established cardiovascular disease who started out with greater kidney impairment.

Previous findings have also demonstrated cardioprotective effects with SGLT2 inhibitors in patients with type 2 diabetes. For instance, in earlier results from the DECLARE-TIMI58 trial, dapagliflozin reduced the frequency of cardiovascular death or hospitalization for heart failure, compared with placebo (4.9% vs. 5.8%, respectively; New Engl J Med. 2019;380:347-57), although it did not significantly reduce the frequency of stroke, heart attack, or all-cause death, unlike the results from glucagonlike peptide–1 receptor agonists in much sicker patients (Circulation. 2019;139[17]:2022-31).

Taken as a whole, Dr. Raz said that findings for SGLT2 inhibitors, which, like the glucagonlike peptide–1 receptor agonists, are indicated as second-line therapy in type 2 diabetes after metformin, suggest that they should be used sooner in type 2 disease, perhaps in patients with a hemoglobin A_1c level as low at 6.5%.

The absolute benefits of dapagliflozin, compared with placebo, notwithstanding, there are safety concerns with SGLT2s, including genitourinary infections, acute kidney injury, Fournier gangrene, diabetic ketoacidosis, bone fractures, and leg amputations (the latter two only with canagliflozin), many of which have been subject to warnings from the Food and Drug Administration.

Safety outcomes for dapagliflozin, compared with placebo, were not tabulated in the new renal report, but the authors noted a previously reported decrease of 30% in risk for acute kidney injury and major hypoglycemia with dapagliflozin over placebo. There was 1 case of Fournier gangrene with the drug versus 5 with placebo; 27 cases of diabetic ketoacidosis versus 12, respectively; 123 amputations versus 113; and 76 genital infections versus 9.

M. Alexander Otto

Matthew Riddle, MD, of Oregon Health and Science University, Portland, said SGLT2 studies “have shown important short-term benefit, but we have no information on long-term safety. These drugs are not physiologic; they do something powerful, but it’s nothing you see in nature. We don’t really know what they do yet; the physiology is still being worked out.”

DECLARE-TIMI58 randomized 8,582 patients with type 2 diabetes to receive dapagliflozin 10 mg orally daily and 8,578 patients to receive placebo. The patients remained on routine diabetes and cardiovascular care. Inclusion criteria included either established atherosclerotic cardiovascular disease (41% of patients) or cardiovascular risk factors (almost 60%), and creatinine clearance of at least 60 mL/min. Median follow-up was 4.2 years.

Overall, 4.2% of patients receiving dapagliflozin and 5.3% of those receiving placebo, met a prespecified secondary cardiorenal composite outcome of end-stage renal disease; death from renal or cardiovascular causes; or a decline of at least 40% in eGFR to less than 60 mL/min per 1.73 m² according to two tests at least 4 weeks apart (hazard ratio, 0.76; P less than .0001).

Similarly, 1.5% of dapagliflozin patients and 2.6% of those on placebo met a prespecified renal-specific composite of those factors minus death from cardiovascular causes (HR, 0.53; P less than .0001).

Among placebo-treated patients, 2.5% had a sustained decline in eGFR of at least 40% to less than 60 mL/min per 1.73 m², compared with 1.4% in the dapagliflozin group (HR, 0.54; P less than .0001). There were 11 cases of end-stage renal disease or renal death with dapagliflozin (0.1%), compared with 27 (0.3%) with placebo (HR, 0.41; P = .012).

Among patients who entered the trial with significant renal impairment – an eGFR of less than 60 mL/min per 1.73 m² – the difference in further renal decline with dapagliflozin was not statistically significant against placebo because of the small number of patients, but Dr. Raz said the drug should still be used earlier in type 2 disease.

Dapagliflozin patients fared worse on renal measurements at 6 months, but caught up by year 2, and surpassed placebo at years 3 and 4, the authors wrote in the latest report.

Just more than 60% of participants were men; patients were in their 60s, on average, and overweight. About 80% of the patients were white.

AstraZeneca, which makes dapagliflozin, was involved with study design, data collection, data analysis, interpretation, and writing of the report. Four authors were employees of the company, and all but two of the 17 others, including Dr. Raz, disclosed personal payments from the company and/or research funding. Dr. Riddle disclosed receiving research funding from AstraZeneca.
 

[email protected]

Non–vitamin K oral anticoagulants (NOACs) significantly reduced the risk of stroke or systemic embolism compared to vitamin K antagonists (VKAs) for patients in the early stages of chronic kidney disease and comorbid atrial fibrillation, based on data from a meta-analysis of roughly 34,000 patients.

Chronic kidney disease increases the risk of complications including stroke, congestive heart failure, and death in patients who also have atrial fibrillation, but most trials of anticoagulant therapy to reduce the risk of such events have excluded these patients, wrote Jeffrey T. Ha, MBBS, of the George Institute for Global Health, Newtown, Australia, and colleagues.

To assess the benefits and harms of oral anticoagulants for multiple indications in chronic kidney disease patients, the researchers conducted a meta-analysis of 45 studies including 34,082 individuals. The findings were published in the Annals of Internal Medicine. The analysis included 8 trials of end stage kidney disease patients on dialysis; the remaining trials excluded patients with creatinine clearance less than 20 mL/min or an estimated glomerular filtration rate less than 15 mL/min per 1.73 m². The interventional agents were rivaroxaban, dabigatran, apixaban, edoxaban, betrixaban, warfarin, and acenocoumarol.

A notable finding was the significant reduction in relative risk of stroke or systemic embolism (21%), hemorrhagic stroke (52%), and intracranial hemorrhage (51%) for early-stage chronic kidney disease patients with atrial fibrillation given NOACs, compared with those given VKAs.

The evidence for the superiority of NOACs over VKAs for reducing risk of venous thromboembolism (VTE) or VTE-related death was uncertain, as was the evidence to draw any conclusions about benefits and harms of either NOACs or VKAs for patients with advanced or end-stage kidney disease.

Across all trials, NOACs appeared to reduce the relative risk of major bleeding, compared with VKAs by roughly 25%, but the difference was not statistically significant, the researchers noted.

The findings were limited by the lack of evidence for oral anticoagulant use in patients with advanced chronic or end-stage kidney disease, as well as inability to assess differences among NOACs, the researchers noted. However, the results suggest that NOACs may be recommended over VKAs for the subgroup of early-stage chronic kidney disease patients with atrial fibrillation, they said.

Several additional trials are in progress, and future trials “should include not only participants with dialysis-dependent ESKD [end-stage kidney disease] but also those with CrCl [creatinine clearance of] less than 25 mL/min,” and compare NOACs with placebo as well, they noted.

Lead author Dr. Ha is supported by a University Postgraduate Award from University of New South Wales, Sydney, but had no financial conflicts to disclose; coauthors disclosed support from various organizations as well as pharmaceutical companies including Baxter, Amgen, Eli Lilly, Boehringer Ingelheim, Vifor Pharma, Janssen, Pfizer, Bristol-Myers Squibb, and GlaxoSmithKline.
 

SOURCE: Ha JT et al. Ann Intern Med. 2019 July 15. doi: 10.7326/M19-0087

Non–vitamin K oral anticoagulants (NOACs) significantly reduced the risk of stroke or systemic embolism compared to vitamin K antagonists (VKAs) for patients in the early stages of chronic kidney disease and comorbid atrial fibrillation, based on data from a meta-analysis of roughly 34,000 patients.

Chronic kidney disease increases the risk of complications including stroke, congestive heart failure, and death in patients who also have atrial fibrillation, but most trials of anticoagulant therapy to reduce the risk of such events have excluded these patients, wrote Jeffrey T. Ha, MBBS, of the George Institute for Global Health, Newtown, Australia, and colleagues.

To assess the benefits and harms of oral anticoagulants for multiple indications in chronic kidney disease patients, the researchers conducted a meta-analysis of 45 studies including 34,082 individuals. The findings were published in the Annals of Internal Medicine. The analysis included 8 trials of end stage kidney disease patients on dialysis; the remaining trials excluded patients with creatinine clearance less than 20 mL/min or an estimated glomerular filtration rate less than 15 mL/min per 1.73 m². The interventional agents were rivaroxaban, dabigatran, apixaban, edoxaban, betrixaban, warfarin, and acenocoumarol.

A notable finding was the significant reduction in relative risk of stroke or systemic embolism (21%), hemorrhagic stroke (52%), and intracranial hemorrhage (51%) for early-stage chronic kidney disease patients with atrial fibrillation given NOACs, compared with those given VKAs.

The evidence for the superiority of NOACs over VKAs for reducing risk of venous thromboembolism (VTE) or VTE-related death was uncertain, as was the evidence to draw any conclusions about benefits and harms of either NOACs or VKAs for patients with advanced or end-stage kidney disease.

Across all trials, NOACs appeared to reduce the relative risk of major bleeding, compared with VKAs by roughly 25%, but the difference was not statistically significant, the researchers noted.

The findings were limited by the lack of evidence for oral anticoagulant use in patients with advanced chronic or end-stage kidney disease, as well as inability to assess differences among NOACs, the researchers noted. However, the results suggest that NOACs may be recommended over VKAs for the subgroup of early-stage chronic kidney disease patients with atrial fibrillation, they said.

Several additional trials are in progress, and future trials “should include not only participants with dialysis-dependent ESKD [end-stage kidney disease] but also those with CrCl [creatinine clearance of] less than 25 mL/min,” and compare NOACs with placebo as well, they noted.

Lead author Dr. Ha is supported by a University Postgraduate Award from University of New South Wales, Sydney, but had no financial conflicts to disclose; coauthors disclosed support from various organizations as well as pharmaceutical companies including Baxter, Amgen, Eli Lilly, Boehringer Ingelheim, Vifor Pharma, Janssen, Pfizer, Bristol-Myers Squibb, and GlaxoSmithKline.
 

SOURCE: Ha JT et al. Ann Intern Med. 2019 July 15. doi: 10.7326/M19-0087

Non–vitamin K oral anticoagulants (NOACs) significantly reduced the risk of stroke or systemic embolism compared to vitamin K antagonists (VKAs) for patients in the early stages of chronic kidney disease and comorbid atrial fibrillation, based on data from a meta-analysis of roughly 34,000 patients.

Chronic kidney disease increases the risk of complications including stroke, congestive heart failure, and death in patients who also have atrial fibrillation, but most trials of anticoagulant therapy to reduce the risk of such events have excluded these patients, wrote Jeffrey T. Ha, MBBS, of the George Institute for Global Health, Newtown, Australia, and colleagues.

To assess the benefits and harms of oral anticoagulants for multiple indications in chronic kidney disease patients, the researchers conducted a meta-analysis of 45 studies including 34,082 individuals. The findings were published in the Annals of Internal Medicine. The analysis included 8 trials of end stage kidney disease patients on dialysis; the remaining trials excluded patients with creatinine clearance less than 20 mL/min or an estimated glomerular filtration rate less than 15 mL/min per 1.73 m². The interventional agents were rivaroxaban, dabigatran, apixaban, edoxaban, betrixaban, warfarin, and acenocoumarol.

A notable finding was the significant reduction in relative risk of stroke or systemic embolism (21%), hemorrhagic stroke (52%), and intracranial hemorrhage (51%) for early-stage chronic kidney disease patients with atrial fibrillation given NOACs, compared with those given VKAs.

The evidence for the superiority of NOACs over VKAs for reducing risk of venous thromboembolism (VTE) or VTE-related death was uncertain, as was the evidence to draw any conclusions about benefits and harms of either NOACs or VKAs for patients with advanced or end-stage kidney disease.

Across all trials, NOACs appeared to reduce the relative risk of major bleeding, compared with VKAs by roughly 25%, but the difference was not statistically significant, the researchers noted.

The findings were limited by the lack of evidence for oral anticoagulant use in patients with advanced chronic or end-stage kidney disease, as well as inability to assess differences among NOACs, the researchers noted. However, the results suggest that NOACs may be recommended over VKAs for the subgroup of early-stage chronic kidney disease patients with atrial fibrillation, they said.

Several additional trials are in progress, and future trials “should include not only participants with dialysis-dependent ESKD [end-stage kidney disease] but also those with CrCl [creatinine clearance of] less than 25 mL/min,” and compare NOACs with placebo as well, they noted.

Lead author Dr. Ha is supported by a University Postgraduate Award from University of New South Wales, Sydney, but had no financial conflicts to disclose; coauthors disclosed support from various organizations as well as pharmaceutical companies including Baxter, Amgen, Eli Lilly, Boehringer Ingelheim, Vifor Pharma, Janssen, Pfizer, Bristol-Myers Squibb, and GlaxoSmithKline.
 

SOURCE: Ha JT et al. Ann Intern Med. 2019 July 15. doi: 10.7326/M19-0087

The options for treating type 2 diabetes without insulin have grown beyond metformin to include a long list of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide–1 (GLP-1) receptor agonists that can be taken with or without metformin. These new drugs have cardiovascular and kidney benefits and help with weight loss, but they also carry risks and, according to some experts, their costs can be prohibitively expensive.
 

Given the medical community’s long-term experience with treating patients with metformin, and metformin’s lower cost, most of the physicians interviewed for this article advise using SGLT2 inhibitors and GLP-1 receptor agonists as second-line treatments. Others said that they would prefer to use the newer drugs as first-line therapies in select high-risk patients, but prior authorization hurdles created by insurance companies make that approach too burdensome.

“The economics of U.S. health care is stacked against many of our patients with diabetes in the current era,” Robert H. Hopkins Jr., MD, said in an interview.

Even when their insurance approves the drugs, patients still may not be able to afford the copay, explained Dr. Hopkins, professor of internal medicine and pediatrics and director of the division of general internal medicine at the University of Arkansas for Medical Sciences, Little Rock. “Sometimes patients can purchase drugs at a lower cost than the copay to purchase with the ‘drug coverage’ in their insurance plan – unfortunately, this is not the case with the newer diabetes medications we are discussing here.”

“SGLT2 inhibitors and GLP-1 agonists can cost several hundred dollars a month, and insurers often balk at paying for them. They’ll say, ‘Have you tried metformin?’ ” explained endocrinologist Victor Lawrence Roberts, MD, in a interview. “We have to work with insurance companies the best we can in a stepwise fashion.”

According to Dr. Roberts, 80% of his patients with diabetes struggle with the cost of medicine in general. “They’re either underinsured or not insured or their formulary is limited.

Douglas S. Paauw, MD, agreed in an interview that the newer drugs can be problematic on the insurance front.

“For some patients they aren’t affordable, especially for the uninsured if you can’t get them on an assistance program,” said Dr. Paauw, who is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the university.

Dr. Hopkins, who is on the Internal Medicine News board, noted that “unfortunately, the treatment of type 2 diabetes in patients who cannot achieve control with metformin, diet, weight control, and exercise is a story of the ‘haves’ and the ‘have nots.’ The ‘haves’ are those who have pharmacy benefits which make access to newer agents like SGLT2 inhibitors and GLP-1 agonists a possibility.”

“Most insurance companies are now covering select SGLT2 inhibitors and GLP-1 receptor agonists for appropriate patients and those companies that currently do not will soon have to,” said Dr. Skolnik, who is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

“The outcomes [associated with use of the new drugs] are robust, the benefits are large, and are well worth the cost,” he added.
 

The side effects

While others praised these drugs for their beneficial effects, they also noted that the side effects of these drugs are serious and must be discussed with patients.

GLP-1 receptor agonists are linked to gastrointestinal symptoms, especially nausea, while SGLT2 inhibitors have been linked to kidney failure, ketoacidosis, and more. The Food and Drug Administration warned in 2018 that the SGLT2 inhibitors can cause a rare serious infection known as Fournier’s gangrene – necrotizing fasciitis of the perineum.

“We have to tell our patients to let us know right away if they get pain or swelling in the genital area,” Dr. Paauw, who is on the Internal Medicine News board, noted. “The chance that an infection could explode quickly is higher in those who take these drugs.”

Amputation risks also are associated with taking the SGLT2 inhibitor canagliflozin (Invokana). The FDA requires the manufacturer of this drug to include a black-box warning about the risk of “lower-limb amputations, most frequently of the toe and midfoot,” but also the leg. In approval trials, the risk doubled versus placebo.

These amputation risks “put a damper on some of the enthusiasm on behalf of physicians and patients ... for taking this drug,” noted Dr. Roberts, who is a professor of internal medicine at the University of Central Florida, Orlando.

While a manufacturer-funded study released last year found no link to amputations, the results weren’t powerful enough to rule out a moderately increased risk.

“[If] you are at high risk for having an amputation, we really have to take this risk very seriously,” said John B. Buse, MD, chief of the division of endocrinology at the University of North Carolina at Chapel Hill, in a presentation about the study at the 2018 annual scientific sessions of the American Diabetes Association.
 

The benefits

Despite these risks of adverse events, most interviewed agreed that the many benefits observed in those taking SGLT2 inhibitors or GLP-1 receptor agonists make them worth prescribing, at least to those who are able to afford them.

Both SGLT2 inhibitors and GLP-1 receptor agonists appear to have significant cardiovascular benefits. A 2019 meta-­analysis and systematic review found that both drugs reduced major adverse cardiac events by about 12% (Circulation. 2019 Apr 23;139[17]:2022-31).

“They don’t cause hypoglycemia, they lower blood pressure, they don’t cause weight gain, and they might promote weight loss,” noted Dr. Paauw.

SGLT2 inhibitors also have shown signs of kidney benefits. The CREDENCE trial linked canagliflozin to a lowering of kidney disorders versus placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). “The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% confidence interval, 0.53-0.81; P less than .001), and the relative risk of end-stage kidney disease was lower by 32% (HR, 0.68; 95% CI, 0.54-0.86; P = .002),” the trial investigators wrote.

“They showed very nicely that the drug improved the kidney function of those patients and reduced the kidney deterioration,” said Yehuda Handelsman, MD, an endocrinologist in Tarzana, Calif., who chaired the 2011 and 2015 American Association of Clinical Endocrinologists’ Comprehensive Diabetes Guidelines. The study was especially impressive, he added, because it included patients with low kidney function.

SGLT2 inhibitors’ “diuretic mechanism explains why there is a substantial reduction in heart failure hospitalizations in patients who take these drugs,” said cardiologist Marc E. Goldschmidt, MD, director of the Heart Success Program at Atlantic Health System’s Morristown (N.J.) Medical Center, in an interview. “Both the EMPA-REG Outcome and the CREDENCE trials demonstrated substantial benefit of this class of medications by showing a lower risk of cardiovascular death as well as death from any cause and a lower risk of hospitalization for heart failure."

Overall, the SGLT2 trial data have been very consistent with a benefit for cardiovascular risk reduction, particularly in regard to heart failure hospitalizations and even in potentially preventing heart failure in diabetics,” he added.

Dr. Skolnik, a columnist for Family Practice News, cited SGLT2 inhibitors and GLP-1 receptor agonists’ ability to slow renal disease progression, promote weight loss, and prevent poor cardiac outcomes.“These drugs should be used, in addition to metformin, in all patients with diabetes and vascular disease. These proven outcomes are far better than we ever were able to achieve previously and the strength of the evidence at this point is very strong,” said Dr. Skolnik. “In addition to the benefits of decreasing the development of cardiovascular disease, serious heart failure, and slowing progression of renal disease, these two classes of medication have additional benefits. Both classes help patients lose weight, which is very different from what was found with either sulfonylureas or insulin, which cause patients to gain weight. Also both the SGLT2 inhibitors and the GLP-1 RAs [receptor agonists] have a low incidence of hypoglycemia. For all these reasons, these have become important medications for us to use in primary care.”

Other recent trials offer “very powerful data” about SGLT2 inhibitors, Dr. Roberts said. That’s good news, since “our approach needs to be toward cardiovascular protection and preservation as well as managing blood sugar.”An Israeli trial, whose results were released in May 2019 at the annual meeting of the American College of Cardiology, found that, compared with other glucose-lowering drugs, taking an SGLT2 inhibitor was associated with lower risks of heart failure hospitalization and all-cause mortality (HR, 0.54; 95% CI, 0.44-0.65; P less than .001). This trial also offered a new detail: The patients gained the benefit regardless of whether their baseline left ventricular ejection fraction was preserved or reduced (J Coll Cardiol. 2019 Mar;73[9]:suppl 1). The SGLT2 inhibitors used in this trial included dapagliflozin (Farxiga) and empagliflozin (Jardiance).

In another study released this year, a subanalysis of the DECLARE-TIMI 58 trial, researchers reported that the SGLT2 inhibitor dapagliflozin reduced risks of both major adverse cardiovascular events and heart failure hospitalization in the subset of patients with type 2 diabetes and prior myocardial infarction versus controls (Circulation. 2019 May 28;139[22]:2516-27). The absolute risk reduction for major adverse cardiovascular events was 1.9% (HR, 0.81; 95% CI, 0.65-1.00; P = .046), while it was 0.6% for heart failure hospitalization (HR, 0.85; 95% CI, 0.72-1.00; P = .055).

These and other studies “speak volumes about the efficacy of managing blood sugar and addressing our biggest nemesis, which is cardiovascular disease,” Dr. Roberts said. “It’s irrefutable. The data [are] very good.”

Dr. Paauw said an SGLT2 inhibitor or GLP-1 receptor agonist is best reserved for use in select patients with cardiovascular risks and type 2 diabetes that need management beyond metformin.

For example, they might fit a 70-year-old with persistent hypertension who’s already taking a couple of blood pressure medications. “If they have another cardiovascular risk factor, the cardiovascular protection piece will be a bigger deal,” he said. Also, “it will probably help lower their blood pressure so they can avoid taking another blood pressure medicine.”

Trials of both GLP-1 receptor agonists and SGLT2 inhibitors have shown benefits “in improving [major adverse cardiac events], with the SGLT2 class showing substantial benefit in improving both heart failure and renal outcomes as well,” noted Dr. Skolnik. “It is in this context that one must address the question of whether the price of the medications are worthwhile. With such substantial benefit, there is no question in my mind that – for patients who have underlying cardiovascular illness, which includes patients with existent coronary disease, history of stroke, transient ischemic attack, or peripheral vascular disease – it is far and away worth it to prescribe these classes of medications.”

Indeed, the American Diabetes Association and the European Association for the Study of Diabetes’ most recent guidelines now call for a GLP-1 receptor agonist – instead of insulin – to be the first injectable used to treat type 2 diabetes (Diabetes Care 2018 Dec; 41[12]:2669-701).

“For the relatively small number of my patients who have been able to access and use these medications for months or longer, more have tolerated the GLP-1 agonists than SGLT2 inhibitors primarily due to urinary issues,” noted Dr. Hopkins.

Dipeptidyl peptidase–4 inhibitors are another option in patients with type 2 diabetes, but research suggests they may not be a top option for patients with cardiovascular risk. A 2018 review noted that cardiovascular outcome trials for alogliptin (Nesina), saxagliptin (Onglyza), and sitagliptin (Januvia) showed noninferiority but failed to demonstrate any superiority, compared with placebo in patients with type 2 diabetes mellitus and high cardiovascular risk (Circ Res. 2018 May 11;122[10]:1439-59).
 

The combination therapies

Many of the newer drugs are available as combinations with other types of diabetes drugs. In some cases, physicians create their own form of combination therapy by separately prescribing two or more diabetes drugs. Earlier this year, a study suggested the benefits of this kind of add-on therapy: Diabetes outcomes improved in patients who took the GLP-1 receptor agonist semaglutide and an SGLT2 inhibitor (Lancet Diabetes Endocrinol. 2019 Mar 1. doi: 10.1016/S2213-8587[19]30066-X).

Dr. Roberts suggested caution, however, when prescribing combination therapies. “My recommendation is always to begin with the individual medications to see if the patient tolerates the drugs and then decide which component needs to be titrated. It’s hard to titrate a combination drug, and it doesn’t leave a lot of flexibility. You never know which drug is doing what.
 

Dr. Handelsman said some patients may need to take three medications such as metformin, an SGLT2 inhibitor, and a GLP-1 receptor agonist.

“I don’t recommend using the combinations if you’re not familiar with the drugs ... These are relatively new pharmaceuticals, and most of us are on a learning curve as to how they fit into the armamentarium. If a drug is tolerated with a good response, you can certainly consider going to the combination tablets,” he added.

There is at least one drug that combines these three classes: The newly FDA-approved Qternmet XR, which combines dapagliflozin (an SGLT2 inhibitor), saxagliptin (a GLP-1 receptor agonist), and metformin. As of mid-June 2019, it was not yet available in the United States. Its sister drug Qtern, which combines dapagliflozin and saxagliptin, costs more than $500 a month with a free coupon, according to goodrx.com. In contrast, metformin is extremely inexpensive, costing just a few dollars a month for a common starting dose.
 

What about adding insulin?

“Both [SGLT2 inhibitors and GLP-1 receptor agonists] work very well with insulin,” Dr. Handelsman said. “There is a nice additive effect on the reduction of [hemoglobin] A_1c. The only caution is that, although neither SGLT2 inhibitors nor GLP-1 receptor agonists cause hypoglycemia, in combination with insulin they do increase the risk of hypoglycemia. You may have to adjust the dose of insulin.”

Dr. Hopkins warned that cost becomes an even bigger issue when you add insulin into the mix.

“When insulin comes into the discussion, we are again stuck with astronomical costs which many struggle to afford,” he explained.

Indeed, the price tag on these drugs seems to be the biggest problem physicians have with them.

“The challenges in managing patients with diabetes aren’t the risks associated with the drugs. It’s dealing with their insurers,” noted Dr. Roberts.

Dr. Hopkins, Dr. Paauw, Dr. Roberts, and Dr. Syed reported no disclosures. Dr. Buse is an investigator for Johnson and Johnson. Dr. Goldschmidt is paid to speak by Novartis. Dr. Handelsman reported research grants, consulting work, and speaker honoraria from Amgen, Gilead, Lilly, Merck, Novo Nordisk, and others. Dr Skolnik reported nonfinancial support from AstraZeneca, Boehringer Ingelheim, Sanofi, and GlaxoSmithKline and personal fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. He also serves on the advisory boards of AstraZeneca, Boehringer Ingelheim, Teva Pharmaceutical, Eli Lilly, Sanofi, Janssen Pharmaceuticals, Intarcia, Mylan, and GlaxoSmithKline.

Dr. Paauw and Dr. Skolnik are columnists for Family Practice News and Internal Medicine News.

M. Alexander Otto contributed to this report.

[email protected]

The options for treating type 2 diabetes without insulin have grown beyond metformin to include a long list of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide–1 (GLP-1) receptor agonists that can be taken with or without metformin. These new drugs have cardiovascular and kidney benefits and help with weight loss, but they also carry risks and, according to some experts, their costs can be prohibitively expensive.
 

Given the medical community’s long-term experience with treating patients with metformin, and metformin’s lower cost, most of the physicians interviewed for this article advise using SGLT2 inhibitors and GLP-1 receptor agonists as second-line treatments. Others said that they would prefer to use the newer drugs as first-line therapies in select high-risk patients, but prior authorization hurdles created by insurance companies make that approach too burdensome.

“The economics of U.S. health care is stacked against many of our patients with diabetes in the current era,” Robert H. Hopkins Jr., MD, said in an interview.

Even when their insurance approves the drugs, patients still may not be able to afford the copay, explained Dr. Hopkins, professor of internal medicine and pediatrics and director of the division of general internal medicine at the University of Arkansas for Medical Sciences, Little Rock. “Sometimes patients can purchase drugs at a lower cost than the copay to purchase with the ‘drug coverage’ in their insurance plan – unfortunately, this is not the case with the newer diabetes medications we are discussing here.”

“SGLT2 inhibitors and GLP-1 agonists can cost several hundred dollars a month, and insurers often balk at paying for them. They’ll say, ‘Have you tried metformin?’ ” explained endocrinologist Victor Lawrence Roberts, MD, in a interview. “We have to work with insurance companies the best we can in a stepwise fashion.”

According to Dr. Roberts, 80% of his patients with diabetes struggle with the cost of medicine in general. “They’re either underinsured or not insured or their formulary is limited.

Douglas S. Paauw, MD, agreed in an interview that the newer drugs can be problematic on the insurance front.

“For some patients they aren’t affordable, especially for the uninsured if you can’t get them on an assistance program,” said Dr. Paauw, who is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the university.

Dr. Hopkins, who is on the Internal Medicine News board, noted that “unfortunately, the treatment of type 2 diabetes in patients who cannot achieve control with metformin, diet, weight control, and exercise is a story of the ‘haves’ and the ‘have nots.’ The ‘haves’ are those who have pharmacy benefits which make access to newer agents like SGLT2 inhibitors and GLP-1 agonists a possibility.”

“Most insurance companies are now covering select SGLT2 inhibitors and GLP-1 receptor agonists for appropriate patients and those companies that currently do not will soon have to,” said Dr. Skolnik, who is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

“The outcomes [associated with use of the new drugs] are robust, the benefits are large, and are well worth the cost,” he added.
 

The side effects

While others praised these drugs for their beneficial effects, they also noted that the side effects of these drugs are serious and must be discussed with patients.

GLP-1 receptor agonists are linked to gastrointestinal symptoms, especially nausea, while SGLT2 inhibitors have been linked to kidney failure, ketoacidosis, and more. The Food and Drug Administration warned in 2018 that the SGLT2 inhibitors can cause a rare serious infection known as Fournier’s gangrene – necrotizing fasciitis of the perineum.

“We have to tell our patients to let us know right away if they get pain or swelling in the genital area,” Dr. Paauw, who is on the Internal Medicine News board, noted. “The chance that an infection could explode quickly is higher in those who take these drugs.”

Amputation risks also are associated with taking the SGLT2 inhibitor canagliflozin (Invokana). The FDA requires the manufacturer of this drug to include a black-box warning about the risk of “lower-limb amputations, most frequently of the toe and midfoot,” but also the leg. In approval trials, the risk doubled versus placebo.

These amputation risks “put a damper on some of the enthusiasm on behalf of physicians and patients ... for taking this drug,” noted Dr. Roberts, who is a professor of internal medicine at the University of Central Florida, Orlando.

While a manufacturer-funded study released last year found no link to amputations, the results weren’t powerful enough to rule out a moderately increased risk.

“[If] you are at high risk for having an amputation, we really have to take this risk very seriously,” said John B. Buse, MD, chief of the division of endocrinology at the University of North Carolina at Chapel Hill, in a presentation about the study at the 2018 annual scientific sessions of the American Diabetes Association.
 

The benefits

Despite these risks of adverse events, most interviewed agreed that the many benefits observed in those taking SGLT2 inhibitors or GLP-1 receptor agonists make them worth prescribing, at least to those who are able to afford them.

Both SGLT2 inhibitors and GLP-1 receptor agonists appear to have significant cardiovascular benefits. A 2019 meta-­analysis and systematic review found that both drugs reduced major adverse cardiac events by about 12% (Circulation. 2019 Apr 23;139[17]:2022-31).

“They don’t cause hypoglycemia, they lower blood pressure, they don’t cause weight gain, and they might promote weight loss,” noted Dr. Paauw.

SGLT2 inhibitors also have shown signs of kidney benefits. The CREDENCE trial linked canagliflozin to a lowering of kidney disorders versus placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). “The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% confidence interval, 0.53-0.81; P less than .001), and the relative risk of end-stage kidney disease was lower by 32% (HR, 0.68; 95% CI, 0.54-0.86; P = .002),” the trial investigators wrote.

“They showed very nicely that the drug improved the kidney function of those patients and reduced the kidney deterioration,” said Yehuda Handelsman, MD, an endocrinologist in Tarzana, Calif., who chaired the 2011 and 2015 American Association of Clinical Endocrinologists’ Comprehensive Diabetes Guidelines. The study was especially impressive, he added, because it included patients with low kidney function.

SGLT2 inhibitors’ “diuretic mechanism explains why there is a substantial reduction in heart failure hospitalizations in patients who take these drugs,” said cardiologist Marc E. Goldschmidt, MD, director of the Heart Success Program at Atlantic Health System’s Morristown (N.J.) Medical Center, in an interview. “Both the EMPA-REG Outcome and the CREDENCE trials demonstrated substantial benefit of this class of medications by showing a lower risk of cardiovascular death as well as death from any cause and a lower risk of hospitalization for heart failure."

Overall, the SGLT2 trial data have been very consistent with a benefit for cardiovascular risk reduction, particularly in regard to heart failure hospitalizations and even in potentially preventing heart failure in diabetics,” he added.

Dr. Skolnik, a columnist for Family Practice News, cited SGLT2 inhibitors and GLP-1 receptor agonists’ ability to slow renal disease progression, promote weight loss, and prevent poor cardiac outcomes.“These drugs should be used, in addition to metformin, in all patients with diabetes and vascular disease. These proven outcomes are far better than we ever were able to achieve previously and the strength of the evidence at this point is very strong,” said Dr. Skolnik. “In addition to the benefits of decreasing the development of cardiovascular disease, serious heart failure, and slowing progression of renal disease, these two classes of medication have additional benefits. Both classes help patients lose weight, which is very different from what was found with either sulfonylureas or insulin, which cause patients to gain weight. Also both the SGLT2 inhibitors and the GLP-1 RAs [receptor agonists] have a low incidence of hypoglycemia. For all these reasons, these have become important medications for us to use in primary care.”

Other recent trials offer “very powerful data” about SGLT2 inhibitors, Dr. Roberts said. That’s good news, since “our approach needs to be toward cardiovascular protection and preservation as well as managing blood sugar.”An Israeli trial, whose results were released in May 2019 at the annual meeting of the American College of Cardiology, found that, compared with other glucose-lowering drugs, taking an SGLT2 inhibitor was associated with lower risks of heart failure hospitalization and all-cause mortality (HR, 0.54; 95% CI, 0.44-0.65; P less than .001). This trial also offered a new detail: The patients gained the benefit regardless of whether their baseline left ventricular ejection fraction was preserved or reduced (J Coll Cardiol. 2019 Mar;73[9]:suppl 1). The SGLT2 inhibitors used in this trial included dapagliflozin (Farxiga) and empagliflozin (Jardiance).

In another study released this year, a subanalysis of the DECLARE-TIMI 58 trial, researchers reported that the SGLT2 inhibitor dapagliflozin reduced risks of both major adverse cardiovascular events and heart failure hospitalization in the subset of patients with type 2 diabetes and prior myocardial infarction versus controls (Circulation. 2019 May 28;139[22]:2516-27). The absolute risk reduction for major adverse cardiovascular events was 1.9% (HR, 0.81; 95% CI, 0.65-1.00; P = .046), while it was 0.6% for heart failure hospitalization (HR, 0.85; 95% CI, 0.72-1.00; P = .055).

These and other studies “speak volumes about the efficacy of managing blood sugar and addressing our biggest nemesis, which is cardiovascular disease,” Dr. Roberts said. “It’s irrefutable. The data [are] very good.”

Dr. Paauw said an SGLT2 inhibitor or GLP-1 receptor agonist is best reserved for use in select patients with cardiovascular risks and type 2 diabetes that need management beyond metformin.

For example, they might fit a 70-year-old with persistent hypertension who’s already taking a couple of blood pressure medications. “If they have another cardiovascular risk factor, the cardiovascular protection piece will be a bigger deal,” he said. Also, “it will probably help lower their blood pressure so they can avoid taking another blood pressure medicine.”

Trials of both GLP-1 receptor agonists and SGLT2 inhibitors have shown benefits “in improving [major adverse cardiac events], with the SGLT2 class showing substantial benefit in improving both heart failure and renal outcomes as well,” noted Dr. Skolnik. “It is in this context that one must address the question of whether the price of the medications are worthwhile. With such substantial benefit, there is no question in my mind that – for patients who have underlying cardiovascular illness, which includes patients with existent coronary disease, history of stroke, transient ischemic attack, or peripheral vascular disease – it is far and away worth it to prescribe these classes of medications.”

Indeed, the American Diabetes Association and the European Association for the Study of Diabetes’ most recent guidelines now call for a GLP-1 receptor agonist – instead of insulin – to be the first injectable used to treat type 2 diabetes (Diabetes Care 2018 Dec; 41[12]:2669-701).

“For the relatively small number of my patients who have been able to access and use these medications for months or longer, more have tolerated the GLP-1 agonists than SGLT2 inhibitors primarily due to urinary issues,” noted Dr. Hopkins.

Dipeptidyl peptidase–4 inhibitors are another option in patients with type 2 diabetes, but research suggests they may not be a top option for patients with cardiovascular risk. A 2018 review noted that cardiovascular outcome trials for alogliptin (Nesina), saxagliptin (Onglyza), and sitagliptin (Januvia) showed noninferiority but failed to demonstrate any superiority, compared with placebo in patients with type 2 diabetes mellitus and high cardiovascular risk (Circ Res. 2018 May 11;122[10]:1439-59).
 

The combination therapies

Many of the newer drugs are available as combinations with other types of diabetes drugs. In some cases, physicians create their own form of combination therapy by separately prescribing two or more diabetes drugs. Earlier this year, a study suggested the benefits of this kind of add-on therapy: Diabetes outcomes improved in patients who took the GLP-1 receptor agonist semaglutide and an SGLT2 inhibitor (Lancet Diabetes Endocrinol. 2019 Mar 1. doi: 10.1016/S2213-8587[19]30066-X).

Dr. Roberts suggested caution, however, when prescribing combination therapies. “My recommendation is always to begin with the individual medications to see if the patient tolerates the drugs and then decide which component needs to be titrated. It’s hard to titrate a combination drug, and it doesn’t leave a lot of flexibility. You never know which drug is doing what.
 

Dr. Handelsman said some patients may need to take three medications such as metformin, an SGLT2 inhibitor, and a GLP-1 receptor agonist.

“I don’t recommend using the combinations if you’re not familiar with the drugs ... These are relatively new pharmaceuticals, and most of us are on a learning curve as to how they fit into the armamentarium. If a drug is tolerated with a good response, you can certainly consider going to the combination tablets,” he added.

There is at least one drug that combines these three classes: The newly FDA-approved Qternmet XR, which combines dapagliflozin (an SGLT2 inhibitor), saxagliptin (a GLP-1 receptor agonist), and metformin. As of mid-June 2019, it was not yet available in the United States. Its sister drug Qtern, which combines dapagliflozin and saxagliptin, costs more than $500 a month with a free coupon, according to goodrx.com. In contrast, metformin is extremely inexpensive, costing just a few dollars a month for a common starting dose.
 

What about adding insulin?

“Both [SGLT2 inhibitors and GLP-1 receptor agonists] work very well with insulin,” Dr. Handelsman said. “There is a nice additive effect on the reduction of [hemoglobin] A_1c. The only caution is that, although neither SGLT2 inhibitors nor GLP-1 receptor agonists cause hypoglycemia, in combination with insulin they do increase the risk of hypoglycemia. You may have to adjust the dose of insulin.”

Dr. Hopkins warned that cost becomes an even bigger issue when you add insulin into the mix.

“When insulin comes into the discussion, we are again stuck with astronomical costs which many struggle to afford,” he explained.

Indeed, the price tag on these drugs seems to be the biggest problem physicians have with them.

“The challenges in managing patients with diabetes aren’t the risks associated with the drugs. It’s dealing with their insurers,” noted Dr. Roberts.

Dr. Hopkins, Dr. Paauw, Dr. Roberts, and Dr. Syed reported no disclosures. Dr. Buse is an investigator for Johnson and Johnson. Dr. Goldschmidt is paid to speak by Novartis. Dr. Handelsman reported research grants, consulting work, and speaker honoraria from Amgen, Gilead, Lilly, Merck, Novo Nordisk, and others. Dr Skolnik reported nonfinancial support from AstraZeneca, Boehringer Ingelheim, Sanofi, and GlaxoSmithKline and personal fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. He also serves on the advisory boards of AstraZeneca, Boehringer Ingelheim, Teva Pharmaceutical, Eli Lilly, Sanofi, Janssen Pharmaceuticals, Intarcia, Mylan, and GlaxoSmithKline.

Dr. Paauw and Dr. Skolnik are columnists for Family Practice News and Internal Medicine News.

M. Alexander Otto contributed to this report.

[email protected]

The options for treating type 2 diabetes without insulin have grown beyond metformin to include a long list of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagonlike peptide–1 (GLP-1) receptor agonists that can be taken with or without metformin. These new drugs have cardiovascular and kidney benefits and help with weight loss, but they also carry risks and, according to some experts, their costs can be prohibitively expensive.
 

Given the medical community’s long-term experience with treating patients with metformin, and metformin’s lower cost, most of the physicians interviewed for this article advise using SGLT2 inhibitors and GLP-1 receptor agonists as second-line treatments. Others said that they would prefer to use the newer drugs as first-line therapies in select high-risk patients, but prior authorization hurdles created by insurance companies make that approach too burdensome.

“The economics of U.S. health care is stacked against many of our patients with diabetes in the current era,” Robert H. Hopkins Jr., MD, said in an interview.

Even when their insurance approves the drugs, patients still may not be able to afford the copay, explained Dr. Hopkins, professor of internal medicine and pediatrics and director of the division of general internal medicine at the University of Arkansas for Medical Sciences, Little Rock. “Sometimes patients can purchase drugs at a lower cost than the copay to purchase with the ‘drug coverage’ in their insurance plan – unfortunately, this is not the case with the newer diabetes medications we are discussing here.”

“SGLT2 inhibitors and GLP-1 agonists can cost several hundred dollars a month, and insurers often balk at paying for them. They’ll say, ‘Have you tried metformin?’ ” explained endocrinologist Victor Lawrence Roberts, MD, in a interview. “We have to work with insurance companies the best we can in a stepwise fashion.”

According to Dr. Roberts, 80% of his patients with diabetes struggle with the cost of medicine in general. “They’re either underinsured or not insured or their formulary is limited.

Douglas S. Paauw, MD, agreed in an interview that the newer drugs can be problematic on the insurance front.

“For some patients they aren’t affordable, especially for the uninsured if you can’t get them on an assistance program,” said Dr. Paauw, who is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and serves as third-year medical student clerkship director at the university.

Dr. Hopkins, who is on the Internal Medicine News board, noted that “unfortunately, the treatment of type 2 diabetes in patients who cannot achieve control with metformin, diet, weight control, and exercise is a story of the ‘haves’ and the ‘have nots.’ The ‘haves’ are those who have pharmacy benefits which make access to newer agents like SGLT2 inhibitors and GLP-1 agonists a possibility.”

“Most insurance companies are now covering select SGLT2 inhibitors and GLP-1 receptor agonists for appropriate patients and those companies that currently do not will soon have to,” said Dr. Skolnik, who is a professor of family and community medicine at Jefferson Medical College, Philadelphia, and an associate director of the family medicine residency program at Abington (Pa.) Jefferson Health.

“The outcomes [associated with use of the new drugs] are robust, the benefits are large, and are well worth the cost,” he added.
 

The side effects

While others praised these drugs for their beneficial effects, they also noted that the side effects of these drugs are serious and must be discussed with patients.

GLP-1 receptor agonists are linked to gastrointestinal symptoms, especially nausea, while SGLT2 inhibitors have been linked to kidney failure, ketoacidosis, and more. The Food and Drug Administration warned in 2018 that the SGLT2 inhibitors can cause a rare serious infection known as Fournier’s gangrene – necrotizing fasciitis of the perineum.

“We have to tell our patients to let us know right away if they get pain or swelling in the genital area,” Dr. Paauw, who is on the Internal Medicine News board, noted. “The chance that an infection could explode quickly is higher in those who take these drugs.”

Amputation risks also are associated with taking the SGLT2 inhibitor canagliflozin (Invokana). The FDA requires the manufacturer of this drug to include a black-box warning about the risk of “lower-limb amputations, most frequently of the toe and midfoot,” but also the leg. In approval trials, the risk doubled versus placebo.

These amputation risks “put a damper on some of the enthusiasm on behalf of physicians and patients ... for taking this drug,” noted Dr. Roberts, who is a professor of internal medicine at the University of Central Florida, Orlando.

While a manufacturer-funded study released last year found no link to amputations, the results weren’t powerful enough to rule out a moderately increased risk.

“[If] you are at high risk for having an amputation, we really have to take this risk very seriously,” said John B. Buse, MD, chief of the division of endocrinology at the University of North Carolina at Chapel Hill, in a presentation about the study at the 2018 annual scientific sessions of the American Diabetes Association.
 

The benefits

Despite these risks of adverse events, most interviewed agreed that the many benefits observed in those taking SGLT2 inhibitors or GLP-1 receptor agonists make them worth prescribing, at least to those who are able to afford them.

Both SGLT2 inhibitors and GLP-1 receptor agonists appear to have significant cardiovascular benefits. A 2019 meta-­analysis and systematic review found that both drugs reduced major adverse cardiac events by about 12% (Circulation. 2019 Apr 23;139[17]:2022-31).

“They don’t cause hypoglycemia, they lower blood pressure, they don’t cause weight gain, and they might promote weight loss,” noted Dr. Paauw.

SGLT2 inhibitors also have shown signs of kidney benefits. The CREDENCE trial linked canagliflozin to a lowering of kidney disorders versus placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). “The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% confidence interval, 0.53-0.81; P less than .001), and the relative risk of end-stage kidney disease was lower by 32% (HR, 0.68; 95% CI, 0.54-0.86; P = .002),” the trial investigators wrote.

“They showed very nicely that the drug improved the kidney function of those patients and reduced the kidney deterioration,” said Yehuda Handelsman, MD, an endocrinologist in Tarzana, Calif., who chaired the 2011 and 2015 American Association of Clinical Endocrinologists’ Comprehensive Diabetes Guidelines. The study was especially impressive, he added, because it included patients with low kidney function.

SGLT2 inhibitors’ “diuretic mechanism explains why there is a substantial reduction in heart failure hospitalizations in patients who take these drugs,” said cardiologist Marc E. Goldschmidt, MD, director of the Heart Success Program at Atlantic Health System’s Morristown (N.J.) Medical Center, in an interview. “Both the EMPA-REG Outcome and the CREDENCE trials demonstrated substantial benefit of this class of medications by showing a lower risk of cardiovascular death as well as death from any cause and a lower risk of hospitalization for heart failure."

Overall, the SGLT2 trial data have been very consistent with a benefit for cardiovascular risk reduction, particularly in regard to heart failure hospitalizations and even in potentially preventing heart failure in diabetics,” he added.

Dr. Skolnik, a columnist for Family Practice News, cited SGLT2 inhibitors and GLP-1 receptor agonists’ ability to slow renal disease progression, promote weight loss, and prevent poor cardiac outcomes.“These drugs should be used, in addition to metformin, in all patients with diabetes and vascular disease. These proven outcomes are far better than we ever were able to achieve previously and the strength of the evidence at this point is very strong,” said Dr. Skolnik. “In addition to the benefits of decreasing the development of cardiovascular disease, serious heart failure, and slowing progression of renal disease, these two classes of medication have additional benefits. Both classes help patients lose weight, which is very different from what was found with either sulfonylureas or insulin, which cause patients to gain weight. Also both the SGLT2 inhibitors and the GLP-1 RAs [receptor agonists] have a low incidence of hypoglycemia. For all these reasons, these have become important medications for us to use in primary care.”

Other recent trials offer “very powerful data” about SGLT2 inhibitors, Dr. Roberts said. That’s good news, since “our approach needs to be toward cardiovascular protection and preservation as well as managing blood sugar.”An Israeli trial, whose results were released in May 2019 at the annual meeting of the American College of Cardiology, found that, compared with other glucose-lowering drugs, taking an SGLT2 inhibitor was associated with lower risks of heart failure hospitalization and all-cause mortality (HR, 0.54; 95% CI, 0.44-0.65; P less than .001). This trial also offered a new detail: The patients gained the benefit regardless of whether their baseline left ventricular ejection fraction was preserved or reduced (J Coll Cardiol. 2019 Mar;73[9]:suppl 1). The SGLT2 inhibitors used in this trial included dapagliflozin (Farxiga) and empagliflozin (Jardiance).

In another study released this year, a subanalysis of the DECLARE-TIMI 58 trial, researchers reported that the SGLT2 inhibitor dapagliflozin reduced risks of both major adverse cardiovascular events and heart failure hospitalization in the subset of patients with type 2 diabetes and prior myocardial infarction versus controls (Circulation. 2019 May 28;139[22]:2516-27). The absolute risk reduction for major adverse cardiovascular events was 1.9% (HR, 0.81; 95% CI, 0.65-1.00; P = .046), while it was 0.6% for heart failure hospitalization (HR, 0.85; 95% CI, 0.72-1.00; P = .055).

These and other studies “speak volumes about the efficacy of managing blood sugar and addressing our biggest nemesis, which is cardiovascular disease,” Dr. Roberts said. “It’s irrefutable. The data [are] very good.”

Dr. Paauw said an SGLT2 inhibitor or GLP-1 receptor agonist is best reserved for use in select patients with cardiovascular risks and type 2 diabetes that need management beyond metformin.

For example, they might fit a 70-year-old with persistent hypertension who’s already taking a couple of blood pressure medications. “If they have another cardiovascular risk factor, the cardiovascular protection piece will be a bigger deal,” he said. Also, “it will probably help lower their blood pressure so they can avoid taking another blood pressure medicine.”

Trials of both GLP-1 receptor agonists and SGLT2 inhibitors have shown benefits “in improving [major adverse cardiac events], with the SGLT2 class showing substantial benefit in improving both heart failure and renal outcomes as well,” noted Dr. Skolnik. “It is in this context that one must address the question of whether the price of the medications are worthwhile. With such substantial benefit, there is no question in my mind that – for patients who have underlying cardiovascular illness, which includes patients with existent coronary disease, history of stroke, transient ischemic attack, or peripheral vascular disease – it is far and away worth it to prescribe these classes of medications.”

Indeed, the American Diabetes Association and the European Association for the Study of Diabetes’ most recent guidelines now call for a GLP-1 receptor agonist – instead of insulin – to be the first injectable used to treat type 2 diabetes (Diabetes Care 2018 Dec; 41[12]:2669-701).

“For the relatively small number of my patients who have been able to access and use these medications for months or longer, more have tolerated the GLP-1 agonists than SGLT2 inhibitors primarily due to urinary issues,” noted Dr. Hopkins.

Dipeptidyl peptidase–4 inhibitors are another option in patients with type 2 diabetes, but research suggests they may not be a top option for patients with cardiovascular risk. A 2018 review noted that cardiovascular outcome trials for alogliptin (Nesina), saxagliptin (Onglyza), and sitagliptin (Januvia) showed noninferiority but failed to demonstrate any superiority, compared with placebo in patients with type 2 diabetes mellitus and high cardiovascular risk (Circ Res. 2018 May 11;122[10]:1439-59).
 

The combination therapies

Many of the newer drugs are available as combinations with other types of diabetes drugs. In some cases, physicians create their own form of combination therapy by separately prescribing two or more diabetes drugs. Earlier this year, a study suggested the benefits of this kind of add-on therapy: Diabetes outcomes improved in patients who took the GLP-1 receptor agonist semaglutide and an SGLT2 inhibitor (Lancet Diabetes Endocrinol. 2019 Mar 1. doi: 10.1016/S2213-8587[19]30066-X).

Dr. Roberts suggested caution, however, when prescribing combination therapies. “My recommendation is always to begin with the individual medications to see if the patient tolerates the drugs and then decide which component needs to be titrated. It’s hard to titrate a combination drug, and it doesn’t leave a lot of flexibility. You never know which drug is doing what.
 

Dr. Handelsman said some patients may need to take three medications such as metformin, an SGLT2 inhibitor, and a GLP-1 receptor agonist.

“I don’t recommend using the combinations if you’re not familiar with the drugs ... These are relatively new pharmaceuticals, and most of us are on a learning curve as to how they fit into the armamentarium. If a drug is tolerated with a good response, you can certainly consider going to the combination tablets,” he added.

There is at least one drug that combines these three classes: The newly FDA-approved Qternmet XR, which combines dapagliflozin (an SGLT2 inhibitor), saxagliptin (a GLP-1 receptor agonist), and metformin. As of mid-June 2019, it was not yet available in the United States. Its sister drug Qtern, which combines dapagliflozin and saxagliptin, costs more than $500 a month with a free coupon, according to goodrx.com. In contrast, metformin is extremely inexpensive, costing just a few dollars a month for a common starting dose.
 

What about adding insulin?

“Both [SGLT2 inhibitors and GLP-1 receptor agonists] work very well with insulin,” Dr. Handelsman said. “There is a nice additive effect on the reduction of [hemoglobin] A_1c. The only caution is that, although neither SGLT2 inhibitors nor GLP-1 receptor agonists cause hypoglycemia, in combination with insulin they do increase the risk of hypoglycemia. You may have to adjust the dose of insulin.”

Dr. Hopkins warned that cost becomes an even bigger issue when you add insulin into the mix.

“When insulin comes into the discussion, we are again stuck with astronomical costs which many struggle to afford,” he explained.

Indeed, the price tag on these drugs seems to be the biggest problem physicians have with them.

“The challenges in managing patients with diabetes aren’t the risks associated with the drugs. It’s dealing with their insurers,” noted Dr. Roberts.

Dr. Hopkins, Dr. Paauw, Dr. Roberts, and Dr. Syed reported no disclosures. Dr. Buse is an investigator for Johnson and Johnson. Dr. Goldschmidt is paid to speak by Novartis. Dr. Handelsman reported research grants, consulting work, and speaker honoraria from Amgen, Gilead, Lilly, Merck, Novo Nordisk, and others. Dr Skolnik reported nonfinancial support from AstraZeneca, Boehringer Ingelheim, Sanofi, and GlaxoSmithKline and personal fees from AstraZeneca, Boehringer Ingelheim, and Eli Lilly. He also serves on the advisory boards of AstraZeneca, Boehringer Ingelheim, Teva Pharmaceutical, Eli Lilly, Sanofi, Janssen Pharmaceuticals, Intarcia, Mylan, and GlaxoSmithKline.

Dr. Paauw and Dr. Skolnik are columnists for Family Practice News and Internal Medicine News.

M. Alexander Otto contributed to this report.

[email protected]

President Trump on July 10 announced a bold plan to improve care to patients with kidney disease, which he claimed would save thousands of lives each year and billions of dollars for taxpayers.

“It could be higher if it works the way we anticipate,” Mr. Trump boasted in a 25-minute speech to dozens of kidney patients, their families, and kidney care providers in Washington.

The initiative aims to dramatically increase the number of patients getting dialysis at home, rather than in costly dialysis centers, and double the annual number of kidneys available for transplants. About 100,000 Americans are waiting for a kidney transplant. Ten Americans die each day because of the shortage of organs, Mr. Trump said.

Kidney disease is the ninth-leading cause of death in the United States and accounts for 20% of annual Medicare spending, or about $110 billion, administration officials said.

Mr. Trump’s strategy centers on changing how Medicare pays doctors and dialysis centers to boost their incentives to help patients get dialysis at home and keep them healthy enough to be eligible for transplantation. This would be a far cry from the current system, which focuses on in-patient dialysis center treatment.

Mark E. Rosenberg, MD, president of the American Society of Nephrology, said he was pleased that some of the new payment models offered by the Centers for Medicare & Medicaid Services have only “upside” potential for doctors. He said doctors now get paid more to see their patients at the dialysis center than at home. As a result, there is little incentive to promote home dialysis options.

“I have been a kidney doctor for 35 years, and this is the most game-changing thing ever to happen,” he said.

The authority to make such major changes without congressional approval comes from the Centers for Medicare and Medicaid Innovation (CMMI), which was created by the 2010 Affordable Care Act.

On Tuesday, the Trump administration was in a federal appeals court in New Orleans arguing the entire health law should be declared unconstitutional.

“If the law is invalidated, the Innovation Center, and all its authorities, would be eliminated,” said Nicholas Bagley, a University of Michigan law professor.

In touting the new effort, Health and Human Services Secretary Alex M. Azar II and CMMI Director Adam Boehler spoke about how kidney disease has affected their families. Mr. Azar noted his father was on dialysis for several years before receiving a kidney transplant. Mr. Boehler said an aunt died while on dialysis.

Since 1973, all Americans with end-stage kidney disease have been entitled to coverage through Medicare.

The administration said it would expand the number of kidneys available for transplant by increasing public awareness about the need for living donors and help those who donate a kidney. Currently, their medical costs are covered, but the president’s plan would provide financial assistance to cover day care and time missed from work. Mr. Trump said the initiative would also hold organ procurement organizations more accountable so that fewer usable organs are discarded.

Trump said his plan would help 17,000 additional Americans get a kidney transplant each year by 2030. The policy would also help 11,000 more Americans get hearts, lungs, and livers annually.

Kidney transplants cost less than having patients spend years on dialysis, according to government figures. Dialysis treatment runs on average about $89,000 a year, while a kidney transplant surgery averages about $32,000 and postsurgery care runs about $25,000 per year. Mr. Trump estimated his plan would save families and taxpayers $4.2 billion a year. “This is a dramatic and long overdue reform,” he said.

In the United States, only about 12% of patients get dialysis at home, far lower than in other countries, Mr. Trump said. The plan calls for increasing that share to 80% by 2025.

Nichole Jefferson, 47 years, of Dallas, who is awaiting a second transplant to replace a transplanted kidney that is failing, said getting the treatment at home is much less taxing. She had home dialysis for 4 years before her initial transplant in 2008.

“It’s great to be at home where I was more comfortable and more relaxed and the care was in my hands,” she said in an interview at the Trump event. By getting dialysis at night while she slept, she was able to work during the day and take part in family events.

She had to go to a center for the dialysis when the home dialysis stopped working. “I was depressed to be in the center tied to a chair for 4 hours next to people I did not know,” she said. Patients often have dialysis several days a week.

Other patient advocates applauded Mr. Trump’s plan.

“The administration’s commitment to charting a new course for kidney health will help revolutionize transplantation and dialysis and advance new innovations, therapies and treatments, which patients everywhere have been waiting on for far too long,” said Kevin Longino, CEO of the National Kidney Foundation and a kidney transplant patient.

DaVita, the Denver-based company that is the largest provider of home dialysis in the country, offered a more muted response, saying it looked forward to working with the administration. The company’s stock, which fell in recent days ahead of the announcement, rose about 5% Wednesday.

Administration officials said many aspects of their plan would begin next year. Health providers in half the country will be required to participate in one of the new payment models in which they will face some financial risk for caring for patients. Doctors and health systems will have options to take on more financial risk, which means they could make more money or lose more money based on the health of their kidney patients.

Patients, however, will continue to be able to choose their doctors and dialysis providers.

Joe Grogan, head of the White House Domestic Policy Council, said the kidney disease issue “fits in the wheelhouse of items the president likes to confront. ... The current quality of outcomes are pathetic in this area.”

About half of patients on dialysis die within 5 years, Mr. Azar said.
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

President Trump on July 10 announced a bold plan to improve care to patients with kidney disease, which he claimed would save thousands of lives each year and billions of dollars for taxpayers.

“It could be higher if it works the way we anticipate,” Mr. Trump boasted in a 25-minute speech to dozens of kidney patients, their families, and kidney care providers in Washington.

The initiative aims to dramatically increase the number of patients getting dialysis at home, rather than in costly dialysis centers, and double the annual number of kidneys available for transplants. About 100,000 Americans are waiting for a kidney transplant. Ten Americans die each day because of the shortage of organs, Mr. Trump said.

Kidney disease is the ninth-leading cause of death in the United States and accounts for 20% of annual Medicare spending, or about $110 billion, administration officials said.

Mr. Trump’s strategy centers on changing how Medicare pays doctors and dialysis centers to boost their incentives to help patients get dialysis at home and keep them healthy enough to be eligible for transplantation. This would be a far cry from the current system, which focuses on in-patient dialysis center treatment.

Mark E. Rosenberg, MD, president of the American Society of Nephrology, said he was pleased that some of the new payment models offered by the Centers for Medicare & Medicaid Services have only “upside” potential for doctors. He said doctors now get paid more to see their patients at the dialysis center than at home. As a result, there is little incentive to promote home dialysis options.

“I have been a kidney doctor for 35 years, and this is the most game-changing thing ever to happen,” he said.

The authority to make such major changes without congressional approval comes from the Centers for Medicare and Medicaid Innovation (CMMI), which was created by the 2010 Affordable Care Act.

On Tuesday, the Trump administration was in a federal appeals court in New Orleans arguing the entire health law should be declared unconstitutional.

“If the law is invalidated, the Innovation Center, and all its authorities, would be eliminated,” said Nicholas Bagley, a University of Michigan law professor.

In touting the new effort, Health and Human Services Secretary Alex M. Azar II and CMMI Director Adam Boehler spoke about how kidney disease has affected their families. Mr. Azar noted his father was on dialysis for several years before receiving a kidney transplant. Mr. Boehler said an aunt died while on dialysis.

Since 1973, all Americans with end-stage kidney disease have been entitled to coverage through Medicare.

The administration said it would expand the number of kidneys available for transplant by increasing public awareness about the need for living donors and help those who donate a kidney. Currently, their medical costs are covered, but the president’s plan would provide financial assistance to cover day care and time missed from work. Mr. Trump said the initiative would also hold organ procurement organizations more accountable so that fewer usable organs are discarded.

Trump said his plan would help 17,000 additional Americans get a kidney transplant each year by 2030. The policy would also help 11,000 more Americans get hearts, lungs, and livers annually.

Kidney transplants cost less than having patients spend years on dialysis, according to government figures. Dialysis treatment runs on average about $89,000 a year, while a kidney transplant surgery averages about $32,000 and postsurgery care runs about $25,000 per year. Mr. Trump estimated his plan would save families and taxpayers $4.2 billion a year. “This is a dramatic and long overdue reform,” he said.

In the United States, only about 12% of patients get dialysis at home, far lower than in other countries, Mr. Trump said. The plan calls for increasing that share to 80% by 2025.

Nichole Jefferson, 47 years, of Dallas, who is awaiting a second transplant to replace a transplanted kidney that is failing, said getting the treatment at home is much less taxing. She had home dialysis for 4 years before her initial transplant in 2008.

“It’s great to be at home where I was more comfortable and more relaxed and the care was in my hands,” she said in an interview at the Trump event. By getting dialysis at night while she slept, she was able to work during the day and take part in family events.

She had to go to a center for the dialysis when the home dialysis stopped working. “I was depressed to be in the center tied to a chair for 4 hours next to people I did not know,” she said. Patients often have dialysis several days a week.

Other patient advocates applauded Mr. Trump’s plan.

“The administration’s commitment to charting a new course for kidney health will help revolutionize transplantation and dialysis and advance new innovations, therapies and treatments, which patients everywhere have been waiting on for far too long,” said Kevin Longino, CEO of the National Kidney Foundation and a kidney transplant patient.

DaVita, the Denver-based company that is the largest provider of home dialysis in the country, offered a more muted response, saying it looked forward to working with the administration. The company’s stock, which fell in recent days ahead of the announcement, rose about 5% Wednesday.

Administration officials said many aspects of their plan would begin next year. Health providers in half the country will be required to participate in one of the new payment models in which they will face some financial risk for caring for patients. Doctors and health systems will have options to take on more financial risk, which means they could make more money or lose more money based on the health of their kidney patients.

Patients, however, will continue to be able to choose their doctors and dialysis providers.

Joe Grogan, head of the White House Domestic Policy Council, said the kidney disease issue “fits in the wheelhouse of items the president likes to confront. ... The current quality of outcomes are pathetic in this area.”

About half of patients on dialysis die within 5 years, Mr. Azar said.
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

President Trump on July 10 announced a bold plan to improve care to patients with kidney disease, which he claimed would save thousands of lives each year and billions of dollars for taxpayers.

“It could be higher if it works the way we anticipate,” Mr. Trump boasted in a 25-minute speech to dozens of kidney patients, their families, and kidney care providers in Washington.

The initiative aims to dramatically increase the number of patients getting dialysis at home, rather than in costly dialysis centers, and double the annual number of kidneys available for transplants. About 100,000 Americans are waiting for a kidney transplant. Ten Americans die each day because of the shortage of organs, Mr. Trump said.

Kidney disease is the ninth-leading cause of death in the United States and accounts for 20% of annual Medicare spending, or about $110 billion, administration officials said.

Mr. Trump’s strategy centers on changing how Medicare pays doctors and dialysis centers to boost their incentives to help patients get dialysis at home and keep them healthy enough to be eligible for transplantation. This would be a far cry from the current system, which focuses on in-patient dialysis center treatment.

Mark E. Rosenberg, MD, president of the American Society of Nephrology, said he was pleased that some of the new payment models offered by the Centers for Medicare & Medicaid Services have only “upside” potential for doctors. He said doctors now get paid more to see their patients at the dialysis center than at home. As a result, there is little incentive to promote home dialysis options.

“I have been a kidney doctor for 35 years, and this is the most game-changing thing ever to happen,” he said.

The authority to make such major changes without congressional approval comes from the Centers for Medicare and Medicaid Innovation (CMMI), which was created by the 2010 Affordable Care Act.

On Tuesday, the Trump administration was in a federal appeals court in New Orleans arguing the entire health law should be declared unconstitutional.

“If the law is invalidated, the Innovation Center, and all its authorities, would be eliminated,” said Nicholas Bagley, a University of Michigan law professor.

In touting the new effort, Health and Human Services Secretary Alex M. Azar II and CMMI Director Adam Boehler spoke about how kidney disease has affected their families. Mr. Azar noted his father was on dialysis for several years before receiving a kidney transplant. Mr. Boehler said an aunt died while on dialysis.

Since 1973, all Americans with end-stage kidney disease have been entitled to coverage through Medicare.

The administration said it would expand the number of kidneys available for transplant by increasing public awareness about the need for living donors and help those who donate a kidney. Currently, their medical costs are covered, but the president’s plan would provide financial assistance to cover day care and time missed from work. Mr. Trump said the initiative would also hold organ procurement organizations more accountable so that fewer usable organs are discarded.

Trump said his plan would help 17,000 additional Americans get a kidney transplant each year by 2030. The policy would also help 11,000 more Americans get hearts, lungs, and livers annually.

Kidney transplants cost less than having patients spend years on dialysis, according to government figures. Dialysis treatment runs on average about $89,000 a year, while a kidney transplant surgery averages about $32,000 and postsurgery care runs about $25,000 per year. Mr. Trump estimated his plan would save families and taxpayers $4.2 billion a year. “This is a dramatic and long overdue reform,” he said.

In the United States, only about 12% of patients get dialysis at home, far lower than in other countries, Mr. Trump said. The plan calls for increasing that share to 80% by 2025.

Nichole Jefferson, 47 years, of Dallas, who is awaiting a second transplant to replace a transplanted kidney that is failing, said getting the treatment at home is much less taxing. She had home dialysis for 4 years before her initial transplant in 2008.

“It’s great to be at home where I was more comfortable and more relaxed and the care was in my hands,” she said in an interview at the Trump event. By getting dialysis at night while she slept, she was able to work during the day and take part in family events.

She had to go to a center for the dialysis when the home dialysis stopped working. “I was depressed to be in the center tied to a chair for 4 hours next to people I did not know,” she said. Patients often have dialysis several days a week.

Other patient advocates applauded Mr. Trump’s plan.

“The administration’s commitment to charting a new course for kidney health will help revolutionize transplantation and dialysis and advance new innovations, therapies and treatments, which patients everywhere have been waiting on for far too long,” said Kevin Longino, CEO of the National Kidney Foundation and a kidney transplant patient.

DaVita, the Denver-based company that is the largest provider of home dialysis in the country, offered a more muted response, saying it looked forward to working with the administration. The company’s stock, which fell in recent days ahead of the announcement, rose about 5% Wednesday.

Administration officials said many aspects of their plan would begin next year. Health providers in half the country will be required to participate in one of the new payment models in which they will face some financial risk for caring for patients. Doctors and health systems will have options to take on more financial risk, which means they could make more money or lose more money based on the health of their kidney patients.

Patients, however, will continue to be able to choose their doctors and dialysis providers.

Joe Grogan, head of the White House Domestic Policy Council, said the kidney disease issue “fits in the wheelhouse of items the president likes to confront. ... The current quality of outcomes are pathetic in this area.”

About half of patients on dialysis die within 5 years, Mr. Azar said.
 

Kaiser Health News is a nonprofit national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

LJUBLJANA, SLOVENIA – The dogma of the “Golden Hour” for the immediate management of pediatric sepsis has been oversold and actually is based upon weak evidence, Luregn J. Schlapbach, MD, asserted at the annual meeting of the European Society for Paediatric Infectious Diseases.

The true Golden Hour – that is, the time frame within which it’s imperative to administer the sepsis bundle comprised of appropriate antibiotics, fluids, and inotropes – is probably more like 3 hours.

Bruce Jancin/MDedge News

“The evidence suggests that up to 3 hours you don’t really have a big difference in outcomes for sepsis. If you recognize shock there’s no question: You should not even wait 1 hour. But if you’re not certain, it may be better to give up to 3 hours to work up the child and get the senior clinician involved before you make decisions about treatment. So I’m not advocating to delay anything, I’m advocating that if you’re not sure this is sepsis, allow yourself an hour or 2 to make a proper investigation,” said Dr. Schlapbach, a pediatric intensivist at the Child Health Research Center at the University of Queensland in South Brisbane, Australia.

The problem with a 1-hour mandate for delivery of the sepsis bundle, as recommended in guidelines by the Surviving Sepsis Campaign and the American College of Critical Care Medicine, and endorsed in quality improvement initiatives, is that the time pressure pushes physicians to overprescribe antibiotics to children who don’t actually have a serious bacterial infection. And that, he noted, contributes to the growing problem of antimicrobial resistance.

“You may have a child where you’re not too sure. Usually you would have done a urine culture because UTI [urinary tract infection] is quite a common cause of these infections, and many of these kids aren’t necessarily septic. But if people tell you that within 1 hour you need to treat, are you going to take the time to do the urine culture, or are you just going to decide to treat?” he asked rhetorically.

Dr. Schlapbach is a world-renowned pediatric sepsis researcher. He is far from alone in his reservations about the Golden Hour mandate.

“This is one of the reasons why IDSA [the Infectious Diseases Society of America] has not endorsed the Surviving Sepsis Campaign,” according to the physician, who noted that, in a position statement, IDSA officials have declared that discrimination of sepsis from noninfectious conditions remains a challenge, and that a 60-minute time to antibiotics may jeopardize patient reassessment (Clin Infect Dis. 2018 May 15;66[10]:1631-5).

Dr. Schlapbach highlighted other recent developments in pediatric sepsis.

The definition of adult sepsis has changed, and the pediatric version needs to as well

The revised definition of sepsis, known as Sepsis-3, issued by the International Sepsis Definition Task Force in 2016 notably dropped systemic inflammatory response syndrome (SIRS), as a requirement for sepsis (JAMA. 2016;315[8]:801-10). The revised definition characterizes sepsis as a dysregulated host response to infection resulting in life-threatening organ dysfunction. But Sepsis-3 is based entirely on adult data and is not considered applicable to children.

The current Pediatric Sepsis Consensus Conference definition dates back to 2005. A comprehensive revision is getting underway. It, too, is likely to drop SIRS into the wastebasket, Dr. Schlapbach said.

“It is probably time to abandon the old view of sepsis disease progression, which proposes a progression from infection to SIRS to severe sepsis with organ dysfunction to septic shock, because most children with infection do manifest signs of SIRS, such as tachycardia, tachypnea, and fever, and these probably should be considered as more of an adaptive rather than a maladaptive response,” he explained.

The goal of the pediatric sepsis redefinition project is to come up with something more useful for clinicians than the Sepsis-3 definition. While the Sepsis-3 concept of a dysregulated host response to infection sounds nice, he explained, “we don’t actually know what it is.

“One of the challenges that you all know as pediatricians is that children who develop sepsis get sick very, very quickly. We all have memories of children who we saw and may have discharged, and they were dead 12 hours later,” he noted.

Indeed, he and others have shown in multiple studies that up to 50% of pediatric deaths caused by sepsis happen within 24 hours of presentation.

“So whatever happens, it happens very quickly. The true question for us is actually how and why do children progress from no organ dysfunction, where the mortality is close to zero, to organ dysfunction, where all of a sudden mortality jumps up dramatically. It’s this progression that we don’t understand at all,” according to Dr. Schlapbach.

The genetic contribution to fulminant sepsis in children may be substantial

One-third of pediatric sepsis deaths in high-income countries happen in previously healthy children. In a proof-of-concept study, Dr. Schlapbach and coinvestigators in the Swiss Pediatric Sepsis Study Group conducted exome-sequencing genetic studies in eight previously healthy children with no family history of immunodeficiency who died of severe sepsis because of community-acquired Pseudomonas aeruginosa infection. Two of the eight had rare loss-of-function mutations in genes known to cause primary immunodeficiencies. The investigators proposed that unusually severe sepsis in previously healthy children warrants exome sequencing to look for underlying previously undetected primary immunodeficiencies. That’s important information for survivors and/or affected families to have, they argued (Front Immunol. 2016 Sep 20;7:357. eCollection 2016).

“There are some indications that the genetic contribution in children with sepsis may be larger than previously assumed,” he said.

The longstanding practice of fluid bolus therapy for resuscitation in pediatric sepsis is being reexamined

The FEAST (Fluid Expansion As Supportive Therapy) study, a randomized trial of more than 3,000 children with severe febrile illness and impaired perfusion in sub-Saharan Africa, turned heads with its finding that fluid boluses significantly increased 48-hour mortality (BMC Med. 2013 Mar 14;11:67).

Indeed, the FEAST findings, supported by mechanistic animal studies, were sufficiently compelling that the use of fluid boluses in both pediatric and adult septic shock is now under scrutiny in two major randomized trials: RIFTS (the Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock), and CLOVERS (Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis). Stay tuned.

Dr. Schlapbach reported having no financial conflicts regarding his presentation.

[email protected]

LJUBLJANA, SLOVENIA – The dogma of the “Golden Hour” for the immediate management of pediatric sepsis has been oversold and actually is based upon weak evidence, Luregn J. Schlapbach, MD, asserted at the annual meeting of the European Society for Paediatric Infectious Diseases.

The true Golden Hour – that is, the time frame within which it’s imperative to administer the sepsis bundle comprised of appropriate antibiotics, fluids, and inotropes – is probably more like 3 hours.

Bruce Jancin/MDedge News

“The evidence suggests that up to 3 hours you don’t really have a big difference in outcomes for sepsis. If you recognize shock there’s no question: You should not even wait 1 hour. But if you’re not certain, it may be better to give up to 3 hours to work up the child and get the senior clinician involved before you make decisions about treatment. So I’m not advocating to delay anything, I’m advocating that if you’re not sure this is sepsis, allow yourself an hour or 2 to make a proper investigation,” said Dr. Schlapbach, a pediatric intensivist at the Child Health Research Center at the University of Queensland in South Brisbane, Australia.

The problem with a 1-hour mandate for delivery of the sepsis bundle, as recommended in guidelines by the Surviving Sepsis Campaign and the American College of Critical Care Medicine, and endorsed in quality improvement initiatives, is that the time pressure pushes physicians to overprescribe antibiotics to children who don’t actually have a serious bacterial infection. And that, he noted, contributes to the growing problem of antimicrobial resistance.

“You may have a child where you’re not too sure. Usually you would have done a urine culture because UTI [urinary tract infection] is quite a common cause of these infections, and many of these kids aren’t necessarily septic. But if people tell you that within 1 hour you need to treat, are you going to take the time to do the urine culture, or are you just going to decide to treat?” he asked rhetorically.

Dr. Schlapbach is a world-renowned pediatric sepsis researcher. He is far from alone in his reservations about the Golden Hour mandate.

“This is one of the reasons why IDSA [the Infectious Diseases Society of America] has not endorsed the Surviving Sepsis Campaign,” according to the physician, who noted that, in a position statement, IDSA officials have declared that discrimination of sepsis from noninfectious conditions remains a challenge, and that a 60-minute time to antibiotics may jeopardize patient reassessment (Clin Infect Dis. 2018 May 15;66[10]:1631-5).

Dr. Schlapbach highlighted other recent developments in pediatric sepsis.

The definition of adult sepsis has changed, and the pediatric version needs to as well

The revised definition of sepsis, known as Sepsis-3, issued by the International Sepsis Definition Task Force in 2016 notably dropped systemic inflammatory response syndrome (SIRS), as a requirement for sepsis (JAMA. 2016;315[8]:801-10). The revised definition characterizes sepsis as a dysregulated host response to infection resulting in life-threatening organ dysfunction. But Sepsis-3 is based entirely on adult data and is not considered applicable to children.

The current Pediatric Sepsis Consensus Conference definition dates back to 2005. A comprehensive revision is getting underway. It, too, is likely to drop SIRS into the wastebasket, Dr. Schlapbach said.

“It is probably time to abandon the old view of sepsis disease progression, which proposes a progression from infection to SIRS to severe sepsis with organ dysfunction to septic shock, because most children with infection do manifest signs of SIRS, such as tachycardia, tachypnea, and fever, and these probably should be considered as more of an adaptive rather than a maladaptive response,” he explained.

The goal of the pediatric sepsis redefinition project is to come up with something more useful for clinicians than the Sepsis-3 definition. While the Sepsis-3 concept of a dysregulated host response to infection sounds nice, he explained, “we don’t actually know what it is.

“One of the challenges that you all know as pediatricians is that children who develop sepsis get sick very, very quickly. We all have memories of children who we saw and may have discharged, and they were dead 12 hours later,” he noted.

Indeed, he and others have shown in multiple studies that up to 50% of pediatric deaths caused by sepsis happen within 24 hours of presentation.

“So whatever happens, it happens very quickly. The true question for us is actually how and why do children progress from no organ dysfunction, where the mortality is close to zero, to organ dysfunction, where all of a sudden mortality jumps up dramatically. It’s this progression that we don’t understand at all,” according to Dr. Schlapbach.

The genetic contribution to fulminant sepsis in children may be substantial

One-third of pediatric sepsis deaths in high-income countries happen in previously healthy children. In a proof-of-concept study, Dr. Schlapbach and coinvestigators in the Swiss Pediatric Sepsis Study Group conducted exome-sequencing genetic studies in eight previously healthy children with no family history of immunodeficiency who died of severe sepsis because of community-acquired Pseudomonas aeruginosa infection. Two of the eight had rare loss-of-function mutations in genes known to cause primary immunodeficiencies. The investigators proposed that unusually severe sepsis in previously healthy children warrants exome sequencing to look for underlying previously undetected primary immunodeficiencies. That’s important information for survivors and/or affected families to have, they argued (Front Immunol. 2016 Sep 20;7:357. eCollection 2016).

“There are some indications that the genetic contribution in children with sepsis may be larger than previously assumed,” he said.

The longstanding practice of fluid bolus therapy for resuscitation in pediatric sepsis is being reexamined

The FEAST (Fluid Expansion As Supportive Therapy) study, a randomized trial of more than 3,000 children with severe febrile illness and impaired perfusion in sub-Saharan Africa, turned heads with its finding that fluid boluses significantly increased 48-hour mortality (BMC Med. 2013 Mar 14;11:67).

Indeed, the FEAST findings, supported by mechanistic animal studies, were sufficiently compelling that the use of fluid boluses in both pediatric and adult septic shock is now under scrutiny in two major randomized trials: RIFTS (the Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock), and CLOVERS (Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis). Stay tuned.

Dr. Schlapbach reported having no financial conflicts regarding his presentation.

[email protected]

LJUBLJANA, SLOVENIA – The dogma of the “Golden Hour” for the immediate management of pediatric sepsis has been oversold and actually is based upon weak evidence, Luregn J. Schlapbach, MD, asserted at the annual meeting of the European Society for Paediatric Infectious Diseases.

The true Golden Hour – that is, the time frame within which it’s imperative to administer the sepsis bundle comprised of appropriate antibiotics, fluids, and inotropes – is probably more like 3 hours.

Bruce Jancin/MDedge News

“The evidence suggests that up to 3 hours you don’t really have a big difference in outcomes for sepsis. If you recognize shock there’s no question: You should not even wait 1 hour. But if you’re not certain, it may be better to give up to 3 hours to work up the child and get the senior clinician involved before you make decisions about treatment. So I’m not advocating to delay anything, I’m advocating that if you’re not sure this is sepsis, allow yourself an hour or 2 to make a proper investigation,” said Dr. Schlapbach, a pediatric intensivist at the Child Health Research Center at the University of Queensland in South Brisbane, Australia.

The problem with a 1-hour mandate for delivery of the sepsis bundle, as recommended in guidelines by the Surviving Sepsis Campaign and the American College of Critical Care Medicine, and endorsed in quality improvement initiatives, is that the time pressure pushes physicians to overprescribe antibiotics to children who don’t actually have a serious bacterial infection. And that, he noted, contributes to the growing problem of antimicrobial resistance.

“You may have a child where you’re not too sure. Usually you would have done a urine culture because UTI [urinary tract infection] is quite a common cause of these infections, and many of these kids aren’t necessarily septic. But if people tell you that within 1 hour you need to treat, are you going to take the time to do the urine culture, or are you just going to decide to treat?” he asked rhetorically.

Dr. Schlapbach is a world-renowned pediatric sepsis researcher. He is far from alone in his reservations about the Golden Hour mandate.

“This is one of the reasons why IDSA [the Infectious Diseases Society of America] has not endorsed the Surviving Sepsis Campaign,” according to the physician, who noted that, in a position statement, IDSA officials have declared that discrimination of sepsis from noninfectious conditions remains a challenge, and that a 60-minute time to antibiotics may jeopardize patient reassessment (Clin Infect Dis. 2018 May 15;66[10]:1631-5).

Dr. Schlapbach highlighted other recent developments in pediatric sepsis.

The definition of adult sepsis has changed, and the pediatric version needs to as well

The revised definition of sepsis, known as Sepsis-3, issued by the International Sepsis Definition Task Force in 2016 notably dropped systemic inflammatory response syndrome (SIRS), as a requirement for sepsis (JAMA. 2016;315[8]:801-10). The revised definition characterizes sepsis as a dysregulated host response to infection resulting in life-threatening organ dysfunction. But Sepsis-3 is based entirely on adult data and is not considered applicable to children.

The current Pediatric Sepsis Consensus Conference definition dates back to 2005. A comprehensive revision is getting underway. It, too, is likely to drop SIRS into the wastebasket, Dr. Schlapbach said.

“It is probably time to abandon the old view of sepsis disease progression, which proposes a progression from infection to SIRS to severe sepsis with organ dysfunction to septic shock, because most children with infection do manifest signs of SIRS, such as tachycardia, tachypnea, and fever, and these probably should be considered as more of an adaptive rather than a maladaptive response,” he explained.

The goal of the pediatric sepsis redefinition project is to come up with something more useful for clinicians than the Sepsis-3 definition. While the Sepsis-3 concept of a dysregulated host response to infection sounds nice, he explained, “we don’t actually know what it is.

“One of the challenges that you all know as pediatricians is that children who develop sepsis get sick very, very quickly. We all have memories of children who we saw and may have discharged, and they were dead 12 hours later,” he noted.

Indeed, he and others have shown in multiple studies that up to 50% of pediatric deaths caused by sepsis happen within 24 hours of presentation.

“So whatever happens, it happens very quickly. The true question for us is actually how and why do children progress from no organ dysfunction, where the mortality is close to zero, to organ dysfunction, where all of a sudden mortality jumps up dramatically. It’s this progression that we don’t understand at all,” according to Dr. Schlapbach.

The genetic contribution to fulminant sepsis in children may be substantial

One-third of pediatric sepsis deaths in high-income countries happen in previously healthy children. In a proof-of-concept study, Dr. Schlapbach and coinvestigators in the Swiss Pediatric Sepsis Study Group conducted exome-sequencing genetic studies in eight previously healthy children with no family history of immunodeficiency who died of severe sepsis because of community-acquired Pseudomonas aeruginosa infection. Two of the eight had rare loss-of-function mutations in genes known to cause primary immunodeficiencies. The investigators proposed that unusually severe sepsis in previously healthy children warrants exome sequencing to look for underlying previously undetected primary immunodeficiencies. That’s important information for survivors and/or affected families to have, they argued (Front Immunol. 2016 Sep 20;7:357. eCollection 2016).

“There are some indications that the genetic contribution in children with sepsis may be larger than previously assumed,” he said.

The longstanding practice of fluid bolus therapy for resuscitation in pediatric sepsis is being reexamined

The FEAST (Fluid Expansion As Supportive Therapy) study, a randomized trial of more than 3,000 children with severe febrile illness and impaired perfusion in sub-Saharan Africa, turned heads with its finding that fluid boluses significantly increased 48-hour mortality (BMC Med. 2013 Mar 14;11:67).

Indeed, the FEAST findings, supported by mechanistic animal studies, were sufficiently compelling that the use of fluid boluses in both pediatric and adult septic shock is now under scrutiny in two major randomized trials: RIFTS (the Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock), and CLOVERS (Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis). Stay tuned.

Dr. Schlapbach reported having no financial conflicts regarding his presentation.

[email protected]

Q) What are the current recommendations for the use of DXA and bisphosphonates in patients with chronic kidney disease and end-stage renal disease?

For patients with kidney disease, mineral and bone disorder (MBD) is a common complication, affecting the majority of those with moderate to severe chronic kidney disease (CKD; see Table 1).^1,2 CKD-MBD is a systemic disorder that encompasses abnormalities in mineral metabolism, skeletal health, and soft-tissue calcifications.^1,2 It manifests as one or more of the following:

• Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism
• Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
• Vascular or other soft-tissue calcification.²

The Figure provides an illustration of the effect of CKD on bone health: In the general population, risk for hip fracture increases with age; risk is further exacerbated in those who have CKD.³

To assess for fracture risk in patients with advanced stages of CKD (3-5) who have evidence of CKD-MBD and/or risk factors for osteoporosis, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommends bone mineral density testing with dual-energy X-ray absorptiometry (DXA).² Bone biopsy—the gold standard for diagnosis of renal osteodystrophy, a form of osteoporosis and one type of bone abnormality seen in CKD-MBD—is “reasonable” to perform in cases in which knowing the type of renal osteodystrophy would inform treatment choices.² KDIGO also recognizes limitations in the ability to perform a bone biopsy and therefore recommends monitoring serial PTH and bone-specific alkaline phosphatase to evaluate for bone disease.²

Prevention of fractures and treatment of patients with CKD-MDB has historically been challenging, since many of the available pharmacologic agents have not been developed for or studied in patients with CKD.¹ According to KDIGO, it is acceptable for patients with CKD stages 1 and 2 to receive the same osteoporosis/fracture risk management as recommended for the general population.² Patients with CKD stages 3a and 3b can also receive treatment as recommended for the general population, as long as the patient’s PTH level is in normal range.² Table 2 outlines the FDA-approved glomerular filtration rate cutoffs for some bisphosphonates commonly used to treat osteoporosis.

Before initiating treatment for CKD-associated osteoporosis, no matter what the stage, it is important to manage vitamin D deficiency, hyperphosphatemia, and hyperparathyroidism.¹ In CKD patients with abnormalities of calcium, phosphorus, PTH, and/or vitamin D, involve the nephrology team to assist in providing MBD care. Different approaches to treatment may include, but are not limited to, adjusting phosphorus binders; using vitamin D supplements or analogs; using calcimimetics; prescribing dialysis; providing dietary education; and addressing medication costs.

Q) What are the current recommendations for the use of DXA and bisphosphonates in patients with chronic kidney disease and end-stage renal disease?

For patients with kidney disease, mineral and bone disorder (MBD) is a common complication, affecting the majority of those with moderate to severe chronic kidney disease (CKD; see Table 1).^1,2 CKD-MBD is a systemic disorder that encompasses abnormalities in mineral metabolism, skeletal health, and soft-tissue calcifications.^1,2 It manifests as one or more of the following:

• Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism
• Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
• Vascular or other soft-tissue calcification.²

The Figure provides an illustration of the effect of CKD on bone health: In the general population, risk for hip fracture increases with age; risk is further exacerbated in those who have CKD.³

To assess for fracture risk in patients with advanced stages of CKD (3-5) who have evidence of CKD-MBD and/or risk factors for osteoporosis, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommends bone mineral density testing with dual-energy X-ray absorptiometry (DXA).² Bone biopsy—the gold standard for diagnosis of renal osteodystrophy, a form of osteoporosis and one type of bone abnormality seen in CKD-MBD—is “reasonable” to perform in cases in which knowing the type of renal osteodystrophy would inform treatment choices.² KDIGO also recognizes limitations in the ability to perform a bone biopsy and therefore recommends monitoring serial PTH and bone-specific alkaline phosphatase to evaluate for bone disease.²

Prevention of fractures and treatment of patients with CKD-MDB has historically been challenging, since many of the available pharmacologic agents have not been developed for or studied in patients with CKD.¹ According to KDIGO, it is acceptable for patients with CKD stages 1 and 2 to receive the same osteoporosis/fracture risk management as recommended for the general population.² Patients with CKD stages 3a and 3b can also receive treatment as recommended for the general population, as long as the patient’s PTH level is in normal range.² Table 2 outlines the FDA-approved glomerular filtration rate cutoffs for some bisphosphonates commonly used to treat osteoporosis.

Before initiating treatment for CKD-associated osteoporosis, no matter what the stage, it is important to manage vitamin D deficiency, hyperphosphatemia, and hyperparathyroidism.¹ In CKD patients with abnormalities of calcium, phosphorus, PTH, and/or vitamin D, involve the nephrology team to assist in providing MBD care. Different approaches to treatment may include, but are not limited to, adjusting phosphorus binders; using vitamin D supplements or analogs; using calcimimetics; prescribing dialysis; providing dietary education; and addressing medication costs.

Q) What are the current recommendations for the use of DXA and bisphosphonates in patients with chronic kidney disease and end-stage renal disease?

For patients with kidney disease, mineral and bone disorder (MBD) is a common complication, affecting the majority of those with moderate to severe chronic kidney disease (CKD; see Table 1).^1,2 CKD-MBD is a systemic disorder that encompasses abnormalities in mineral metabolism, skeletal health, and soft-tissue calcifications.^1,2 It manifests as one or more of the following:

• Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism
• Abnormalities in bone turnover, mineralization, volume, linear growth, or strength
• Vascular or other soft-tissue calcification.²

The Figure provides an illustration of the effect of CKD on bone health: In the general population, risk for hip fracture increases with age; risk is further exacerbated in those who have CKD.³

To assess for fracture risk in patients with advanced stages of CKD (3-5) who have evidence of CKD-MBD and/or risk factors for osteoporosis, the Kidney Disease: Improving Global Outcomes (KDIGO) group recommends bone mineral density testing with dual-energy X-ray absorptiometry (DXA).² Bone biopsy—the gold standard for diagnosis of renal osteodystrophy, a form of osteoporosis and one type of bone abnormality seen in CKD-MBD—is “reasonable” to perform in cases in which knowing the type of renal osteodystrophy would inform treatment choices.² KDIGO also recognizes limitations in the ability to perform a bone biopsy and therefore recommends monitoring serial PTH and bone-specific alkaline phosphatase to evaluate for bone disease.²

Prevention of fractures and treatment of patients with CKD-MDB has historically been challenging, since many of the available pharmacologic agents have not been developed for or studied in patients with CKD.¹ According to KDIGO, it is acceptable for patients with CKD stages 1 and 2 to receive the same osteoporosis/fracture risk management as recommended for the general population.² Patients with CKD stages 3a and 3b can also receive treatment as recommended for the general population, as long as the patient’s PTH level is in normal range.² Table 2 outlines the FDA-approved glomerular filtration rate cutoffs for some bisphosphonates commonly used to treat osteoporosis.

Before initiating treatment for CKD-associated osteoporosis, no matter what the stage, it is important to manage vitamin D deficiency, hyperphosphatemia, and hyperparathyroidism.¹ In CKD patients with abnormalities of calcium, phosphorus, PTH, and/or vitamin D, involve the nephrology team to assist in providing MBD care. Different approaches to treatment may include, but are not limited to, adjusting phosphorus binders; using vitamin D supplements or analogs; using calcimimetics; prescribing dialysis; providing dietary education; and addressing medication costs.