Nephrology

Low dietary calcium and potassium intake are important risk factors for the development of incident kidney stones as well as their symptomatic recurrence, a population-based study of dietary factors shows.

“Our research is of particular importance as recommendations for preventing symptomatic recurrence of kidney stones has largely been based on dietary factors associated with the incidence rather than the recurrence of stone formation,” Api Chewcharat, MD, Mayo Clinic, Rochester, Minn., said in a video discussing the study.

“We recommend a daily intake of calcium of approximately 1,200 mg and a diet that is high in potassium, especially high in fruits and vegetables, in order to prevent both incident and recurrent symptomatic kidney stone formation,” he stressed.

The study was published online in Mayo Clinic Proceedings.
 

Lower dietary calcium, potassium, and fluid associated with increased incidence

Some 411 patients with incident symptomatic kidney stone formation were recruited. Diets were compared between them and 384 controls. Patients were seen at the Mayo Clinic in either Minnesota or Florida between Jan. 1, 2009, and Aug. 31, 2018. “Dietary factors were based on a Viocare food frequency questionnaire administered during a baseline in-person study visit,” Dr. Chewcharat and colleagues observed.

During a median follow-up of 4.1 years, 73 patients experienced a symptomatic recurrence. In a fully adjusted analysis, a dietary calcium intake less than 1,200 mg/d was associated with incident stone formation. Similarly, among participants with a fluid intake less than 3,400 mL/d – about nine 12-oz glasses of fluid – was also associated with incident stone formation, as was a lower intake of dietary potassium, caffeine, and phytate. Phytate is an antioxidant found in whole grains, nuts, and other foods that can increase calcium absorption and urinary calcium excretion.

After excluding patients who were taking either a thiazide diuretic or a calcium supplement, lower dietary calcium and potassium, fluid, and phytate intake remained significantly associated with incident stone formation.

However, only lower dietary calcium intake was associated with a higher risk for symptomatic recurrence, although a lower dietary potassium intake was also associated with a higher risk for symptomatic recurrence in an analysis that adjusted for body mass index, fluid, and energy intake.

As the authors suggested, patients may be less keen to adjust their diet to prevent the development of incident kidney stones. On the other hand, they may be much more willing to adjust their diet to prevent their symptomatic recurrence. The Department of Agriculture currently recommends that individuals get approximately 1,200 mg/d of dietary calcium which, given the study results, appears to be justified for the prevention of symptomatic stone recurrence.

A higher-calcium diet is associated with a higher urinary pH, and citrate confers an alkali load which helps protect against the formation of calcium oxalate stones. Foods that are high in potassium also contain more fluid, citrate, and phytate, which, again, have been reported to be protective against kidney stones. “Changing your diet to prevent kidney stones can be very difficult,” Andrew Rule, MD, a nephrologist at the Mayo Clinic said in a statement.

“Thus, knowing the dietary factors that are most important for preventing kidney stone recurrence can help patients and providers know what to prioritize,” he added.

The authors have no conflicts of interest to declare.

A version of this article first appeared on Medscape.com.

Low dietary calcium and potassium intake are important risk factors for the development of incident kidney stones as well as their symptomatic recurrence, a population-based study of dietary factors shows.

“Our research is of particular importance as recommendations for preventing symptomatic recurrence of kidney stones has largely been based on dietary factors associated with the incidence rather than the recurrence of stone formation,” Api Chewcharat, MD, Mayo Clinic, Rochester, Minn., said in a video discussing the study.

“We recommend a daily intake of calcium of approximately 1,200 mg and a diet that is high in potassium, especially high in fruits and vegetables, in order to prevent both incident and recurrent symptomatic kidney stone formation,” he stressed.

The study was published online in Mayo Clinic Proceedings.
 

Lower dietary calcium, potassium, and fluid associated with increased incidence

Some 411 patients with incident symptomatic kidney stone formation were recruited. Diets were compared between them and 384 controls. Patients were seen at the Mayo Clinic in either Minnesota or Florida between Jan. 1, 2009, and Aug. 31, 2018. “Dietary factors were based on a Viocare food frequency questionnaire administered during a baseline in-person study visit,” Dr. Chewcharat and colleagues observed.

During a median follow-up of 4.1 years, 73 patients experienced a symptomatic recurrence. In a fully adjusted analysis, a dietary calcium intake less than 1,200 mg/d was associated with incident stone formation. Similarly, among participants with a fluid intake less than 3,400 mL/d – about nine 12-oz glasses of fluid – was also associated with incident stone formation, as was a lower intake of dietary potassium, caffeine, and phytate. Phytate is an antioxidant found in whole grains, nuts, and other foods that can increase calcium absorption and urinary calcium excretion.

After excluding patients who were taking either a thiazide diuretic or a calcium supplement, lower dietary calcium and potassium, fluid, and phytate intake remained significantly associated with incident stone formation.

However, only lower dietary calcium intake was associated with a higher risk for symptomatic recurrence, although a lower dietary potassium intake was also associated with a higher risk for symptomatic recurrence in an analysis that adjusted for body mass index, fluid, and energy intake.

As the authors suggested, patients may be less keen to adjust their diet to prevent the development of incident kidney stones. On the other hand, they may be much more willing to adjust their diet to prevent their symptomatic recurrence. The Department of Agriculture currently recommends that individuals get approximately 1,200 mg/d of dietary calcium which, given the study results, appears to be justified for the prevention of symptomatic stone recurrence.

A higher-calcium diet is associated with a higher urinary pH, and citrate confers an alkali load which helps protect against the formation of calcium oxalate stones. Foods that are high in potassium also contain more fluid, citrate, and phytate, which, again, have been reported to be protective against kidney stones. “Changing your diet to prevent kidney stones can be very difficult,” Andrew Rule, MD, a nephrologist at the Mayo Clinic said in a statement.

“Thus, knowing the dietary factors that are most important for preventing kidney stone recurrence can help patients and providers know what to prioritize,” he added.

The authors have no conflicts of interest to declare.

A version of this article first appeared on Medscape.com.

Low dietary calcium and potassium intake are important risk factors for the development of incident kidney stones as well as their symptomatic recurrence, a population-based study of dietary factors shows.

“Our research is of particular importance as recommendations for preventing symptomatic recurrence of kidney stones has largely been based on dietary factors associated with the incidence rather than the recurrence of stone formation,” Api Chewcharat, MD, Mayo Clinic, Rochester, Minn., said in a video discussing the study.

“We recommend a daily intake of calcium of approximately 1,200 mg and a diet that is high in potassium, especially high in fruits and vegetables, in order to prevent both incident and recurrent symptomatic kidney stone formation,” he stressed.

The study was published online in Mayo Clinic Proceedings.
 

Lower dietary calcium, potassium, and fluid associated with increased incidence

Some 411 patients with incident symptomatic kidney stone formation were recruited. Diets were compared between them and 384 controls. Patients were seen at the Mayo Clinic in either Minnesota or Florida between Jan. 1, 2009, and Aug. 31, 2018. “Dietary factors were based on a Viocare food frequency questionnaire administered during a baseline in-person study visit,” Dr. Chewcharat and colleagues observed.

During a median follow-up of 4.1 years, 73 patients experienced a symptomatic recurrence. In a fully adjusted analysis, a dietary calcium intake less than 1,200 mg/d was associated with incident stone formation. Similarly, among participants with a fluid intake less than 3,400 mL/d – about nine 12-oz glasses of fluid – was also associated with incident stone formation, as was a lower intake of dietary potassium, caffeine, and phytate. Phytate is an antioxidant found in whole grains, nuts, and other foods that can increase calcium absorption and urinary calcium excretion.

After excluding patients who were taking either a thiazide diuretic or a calcium supplement, lower dietary calcium and potassium, fluid, and phytate intake remained significantly associated with incident stone formation.

However, only lower dietary calcium intake was associated with a higher risk for symptomatic recurrence, although a lower dietary potassium intake was also associated with a higher risk for symptomatic recurrence in an analysis that adjusted for body mass index, fluid, and energy intake.

As the authors suggested, patients may be less keen to adjust their diet to prevent the development of incident kidney stones. On the other hand, they may be much more willing to adjust their diet to prevent their symptomatic recurrence. The Department of Agriculture currently recommends that individuals get approximately 1,200 mg/d of dietary calcium which, given the study results, appears to be justified for the prevention of symptomatic stone recurrence.

A higher-calcium diet is associated with a higher urinary pH, and citrate confers an alkali load which helps protect against the formation of calcium oxalate stones. Foods that are high in potassium also contain more fluid, citrate, and phytate, which, again, have been reported to be protective against kidney stones. “Changing your diet to prevent kidney stones can be very difficult,” Andrew Rule, MD, a nephrologist at the Mayo Clinic said in a statement.

“Thus, knowing the dietary factors that are most important for preventing kidney stone recurrence can help patients and providers know what to prioritize,” he added.

The authors have no conflicts of interest to declare.

A version of this article first appeared on Medscape.com.

From Memora Health (Dr. Flyckt and Dr. Colbert), San Francisco, CA; and Harvard Medical School (Dr. Colbert), Boston, MA.

A close relative was recently diagnosed with follicular lymphoma. He was cared for at a high-ranked cancer center by physicians with demonstrated expertise, and even had the support of a care navigator. Still, he was often left feeling overwhelmed and confused, holding an inch-thick stack of papers, instructions, and pamphlets. As he left his treatment planning visit, reeling from the emotional burden of his diagnosis and all the unfamiliar terminology, he didn’t know what to do or what to expect. Later, when he experienced early signs of tumor lysis syndrome, he struggled to reach his care team for triage and guidance. When he went to the emergency room, his oncologist was never informed.

This scenario is unfortunately common, and versions of this scenario play out thousands of times each day across the US health system. Within the clinic and hospital setting, patients receive excellent care from their providers, but a disconnect emerges once the patient leaves these medical settings: patients at home struggle to find guidance and support, while care teams lack the tools to engage patients between visits or monitor their health across care settings, providers, or episodes of care.

Leveraging Technology to Move From Episodes of Care to Complex Care Journeys

The use of automated messaging, artificial intelligence and natural language processing–driven chat experiences, and text-based support is becoming more common. However, health care lags behind other industries in the adoption of these technologies.^1,2 The slow pace can be warranted, given that health care is more complicated and higher risk than inquiring about a lost package, ordering groceries, or applying for a mortgage. At the same time, many of the consumer engagement tools used to guide an applicant through the multiple steps and complexities of their home loan process or to prompt viewers to select new shows to binge have applications in health care.

Over the past few years, technologies have emerged that guide patients through complex care journeys and allow care teams to monitor and engage patients between visits. These solutions come in different formats, but generally patients can receive messages on their phones that contain disease-specific educational content, prompts to fill prescriptions and take medications, and reminders and guidance on how to prepare for appointments and procedures. These programs also collect relevant data from patients through survey and electronic patient-reported outcomes instruments, as well as connected patient monitoring devices, that help track patient progress and identify issues as they arise. Many programs also incorporate symptom triage pathways and use natural language processing to respond automatically to patient questions and concerns.^3,4

These technology solutions can automate many tasks that in the past required a care team member to spend hours on the phone. Newly freed from such repetitive tasks, care teams can now focus on more in-depth interactions with those patients who are most in need—the types of interactions that are more satisfying and rewarding. Such assistance is particularly needed today with the staffing shortages faced by most health systems.⁵

In addition, technology allows teams to see the panel of patients they are caring for and to quickly identify and take action on any specific needs or issues. Care teams can focus on any patient and see where they are in their journey. When appropriate, some solutions also allow care teams to engage directly with patients through text-messaging, creating a seamless experience and unified communication channel. Ideally, these solutions should be linked or embedded within the electronic health record or other primary system of record, so that teams can easily access these tools through their existing workflows and avoid creating yet another interface to navigate.

The Impact of Low-Tech Solutions to Deliver High-Touch Support

There is evidence showing that digital patient navigation tools impact patient care. In the oncology setting, patients with a digital navigator have achieved over 95% adherence rates with complex oral chemotherapy regimens (Memora Health Unpublished Data. 2022.). In the postpartum setting, a text message–based program improved screening rates for postpartum depression and did so with very high patient satisfaction ratings.⁶ Particularly notable is the fact that this depression screening program achieved these results in a population that was predominantly low income, with more than half belonging to underrepresented minority populations.⁶

We believe these digital patient navigation technologies, specifically low-tech solutions that don’t require app downloads, portal log-ins, or high-speed internet, will transform care delivery over the next 5 to 10 years. Successful management of complex conditions like diabetes or cancer requires more than 3 hours of care each day,⁷ yet most patients spend only 1 or 2 hours per month directly interacting with their health care providers. However, most patients carry their phones with them at all times, and artificial intelligence–enabled text support is “always on” to provide support, monitoring, and guidance, wherever a patient happens to be when assistance is needed.

Shifting the Model to Support a Lifetime of Care

While still in the early stages of development, these tools have the potential to radically alter the practice of medicine, shifting the focus from episodic interactions to continuous journey-based care delivery. Outside of an acute event bringing a patient into the clinic or emergency room, many patients go a year or more without seeing their primary care providers.⁸ During that time, an immense amount of information is underreported or completely lost. Capturing this information in real-time and more holistically over a person’s lifetime of care could provide physicians better insight to both better manage and more fully evaluate the success of treatment plans by tracking patient symptoms, pain, and functional status over time. With this more longitudinal view of the patient, we see a pathway towards achieving the Quadruple Aim: patients who are more supported will achieve better outcomes at lower cost, they will have a better experience, and care teams will be empowered to focus their time on more satisfying activities rather than repetitive administrative tasks.

Corresponding author: James A. Colbert, MD, MBA; jamie@memorahealth.com

Disclosures: Dr. Flyckt and Dr. Colbert are employed by Memora Health, an organization that helps health care systems digitize and automate care journeys.

From Memora Health (Dr. Flyckt and Dr. Colbert), San Francisco, CA; and Harvard Medical School (Dr. Colbert), Boston, MA.

A close relative was recently diagnosed with follicular lymphoma. He was cared for at a high-ranked cancer center by physicians with demonstrated expertise, and even had the support of a care navigator. Still, he was often left feeling overwhelmed and confused, holding an inch-thick stack of papers, instructions, and pamphlets. As he left his treatment planning visit, reeling from the emotional burden of his diagnosis and all the unfamiliar terminology, he didn’t know what to do or what to expect. Later, when he experienced early signs of tumor lysis syndrome, he struggled to reach his care team for triage and guidance. When he went to the emergency room, his oncologist was never informed.

This scenario is unfortunately common, and versions of this scenario play out thousands of times each day across the US health system. Within the clinic and hospital setting, patients receive excellent care from their providers, but a disconnect emerges once the patient leaves these medical settings: patients at home struggle to find guidance and support, while care teams lack the tools to engage patients between visits or monitor their health across care settings, providers, or episodes of care.

Leveraging Technology to Move From Episodes of Care to Complex Care Journeys

The use of automated messaging, artificial intelligence and natural language processing–driven chat experiences, and text-based support is becoming more common. However, health care lags behind other industries in the adoption of these technologies.^1,2 The slow pace can be warranted, given that health care is more complicated and higher risk than inquiring about a lost package, ordering groceries, or applying for a mortgage. At the same time, many of the consumer engagement tools used to guide an applicant through the multiple steps and complexities of their home loan process or to prompt viewers to select new shows to binge have applications in health care.

Over the past few years, technologies have emerged that guide patients through complex care journeys and allow care teams to monitor and engage patients between visits. These solutions come in different formats, but generally patients can receive messages on their phones that contain disease-specific educational content, prompts to fill prescriptions and take medications, and reminders and guidance on how to prepare for appointments and procedures. These programs also collect relevant data from patients through survey and electronic patient-reported outcomes instruments, as well as connected patient monitoring devices, that help track patient progress and identify issues as they arise. Many programs also incorporate symptom triage pathways and use natural language processing to respond automatically to patient questions and concerns.^3,4

These technology solutions can automate many tasks that in the past required a care team member to spend hours on the phone. Newly freed from such repetitive tasks, care teams can now focus on more in-depth interactions with those patients who are most in need—the types of interactions that are more satisfying and rewarding. Such assistance is particularly needed today with the staffing shortages faced by most health systems.⁵

In addition, technology allows teams to see the panel of patients they are caring for and to quickly identify and take action on any specific needs or issues. Care teams can focus on any patient and see where they are in their journey. When appropriate, some solutions also allow care teams to engage directly with patients through text-messaging, creating a seamless experience and unified communication channel. Ideally, these solutions should be linked or embedded within the electronic health record or other primary system of record, so that teams can easily access these tools through their existing workflows and avoid creating yet another interface to navigate.

The Impact of Low-Tech Solutions to Deliver High-Touch Support

There is evidence showing that digital patient navigation tools impact patient care. In the oncology setting, patients with a digital navigator have achieved over 95% adherence rates with complex oral chemotherapy regimens (Memora Health Unpublished Data. 2022.). In the postpartum setting, a text message–based program improved screening rates for postpartum depression and did so with very high patient satisfaction ratings.⁶ Particularly notable is the fact that this depression screening program achieved these results in a population that was predominantly low income, with more than half belonging to underrepresented minority populations.⁶

We believe these digital patient navigation technologies, specifically low-tech solutions that don’t require app downloads, portal log-ins, or high-speed internet, will transform care delivery over the next 5 to 10 years. Successful management of complex conditions like diabetes or cancer requires more than 3 hours of care each day,⁷ yet most patients spend only 1 or 2 hours per month directly interacting with their health care providers. However, most patients carry their phones with them at all times, and artificial intelligence–enabled text support is “always on” to provide support, monitoring, and guidance, wherever a patient happens to be when assistance is needed.

Shifting the Model to Support a Lifetime of Care

While still in the early stages of development, these tools have the potential to radically alter the practice of medicine, shifting the focus from episodic interactions to continuous journey-based care delivery. Outside of an acute event bringing a patient into the clinic or emergency room, many patients go a year or more without seeing their primary care providers.⁸ During that time, an immense amount of information is underreported or completely lost. Capturing this information in real-time and more holistically over a person’s lifetime of care could provide physicians better insight to both better manage and more fully evaluate the success of treatment plans by tracking patient symptoms, pain, and functional status over time. With this more longitudinal view of the patient, we see a pathway towards achieving the Quadruple Aim: patients who are more supported will achieve better outcomes at lower cost, they will have a better experience, and care teams will be empowered to focus their time on more satisfying activities rather than repetitive administrative tasks.

Corresponding author: James A. Colbert, MD, MBA; jamie@memorahealth.com

Disclosures: Dr. Flyckt and Dr. Colbert are employed by Memora Health, an organization that helps health care systems digitize and automate care journeys.

From Memora Health (Dr. Flyckt and Dr. Colbert), San Francisco, CA; and Harvard Medical School (Dr. Colbert), Boston, MA.

A close relative was recently diagnosed with follicular lymphoma. He was cared for at a high-ranked cancer center by physicians with demonstrated expertise, and even had the support of a care navigator. Still, he was often left feeling overwhelmed and confused, holding an inch-thick stack of papers, instructions, and pamphlets. As he left his treatment planning visit, reeling from the emotional burden of his diagnosis and all the unfamiliar terminology, he didn’t know what to do or what to expect. Later, when he experienced early signs of tumor lysis syndrome, he struggled to reach his care team for triage and guidance. When he went to the emergency room, his oncologist was never informed.

This scenario is unfortunately common, and versions of this scenario play out thousands of times each day across the US health system. Within the clinic and hospital setting, patients receive excellent care from their providers, but a disconnect emerges once the patient leaves these medical settings: patients at home struggle to find guidance and support, while care teams lack the tools to engage patients between visits or monitor their health across care settings, providers, or episodes of care.

Leveraging Technology to Move From Episodes of Care to Complex Care Journeys

The use of automated messaging, artificial intelligence and natural language processing–driven chat experiences, and text-based support is becoming more common. However, health care lags behind other industries in the adoption of these technologies.^1,2 The slow pace can be warranted, given that health care is more complicated and higher risk than inquiring about a lost package, ordering groceries, or applying for a mortgage. At the same time, many of the consumer engagement tools used to guide an applicant through the multiple steps and complexities of their home loan process or to prompt viewers to select new shows to binge have applications in health care.

Over the past few years, technologies have emerged that guide patients through complex care journeys and allow care teams to monitor and engage patients between visits. These solutions come in different formats, but generally patients can receive messages on their phones that contain disease-specific educational content, prompts to fill prescriptions and take medications, and reminders and guidance on how to prepare for appointments and procedures. These programs also collect relevant data from patients through survey and electronic patient-reported outcomes instruments, as well as connected patient monitoring devices, that help track patient progress and identify issues as they arise. Many programs also incorporate symptom triage pathways and use natural language processing to respond automatically to patient questions and concerns.^3,4

These technology solutions can automate many tasks that in the past required a care team member to spend hours on the phone. Newly freed from such repetitive tasks, care teams can now focus on more in-depth interactions with those patients who are most in need—the types of interactions that are more satisfying and rewarding. Such assistance is particularly needed today with the staffing shortages faced by most health systems.⁵

In addition, technology allows teams to see the panel of patients they are caring for and to quickly identify and take action on any specific needs or issues. Care teams can focus on any patient and see where they are in their journey. When appropriate, some solutions also allow care teams to engage directly with patients through text-messaging, creating a seamless experience and unified communication channel. Ideally, these solutions should be linked or embedded within the electronic health record or other primary system of record, so that teams can easily access these tools through their existing workflows and avoid creating yet another interface to navigate.

The Impact of Low-Tech Solutions to Deliver High-Touch Support

There is evidence showing that digital patient navigation tools impact patient care. In the oncology setting, patients with a digital navigator have achieved over 95% adherence rates with complex oral chemotherapy regimens (Memora Health Unpublished Data. 2022.). In the postpartum setting, a text message–based program improved screening rates for postpartum depression and did so with very high patient satisfaction ratings.⁶ Particularly notable is the fact that this depression screening program achieved these results in a population that was predominantly low income, with more than half belonging to underrepresented minority populations.⁶

We believe these digital patient navigation technologies, specifically low-tech solutions that don’t require app downloads, portal log-ins, or high-speed internet, will transform care delivery over the next 5 to 10 years. Successful management of complex conditions like diabetes or cancer requires more than 3 hours of care each day,⁷ yet most patients spend only 1 or 2 hours per month directly interacting with their health care providers. However, most patients carry their phones with them at all times, and artificial intelligence–enabled text support is “always on” to provide support, monitoring, and guidance, wherever a patient happens to be when assistance is needed.

Shifting the Model to Support a Lifetime of Care

While still in the early stages of development, these tools have the potential to radically alter the practice of medicine, shifting the focus from episodic interactions to continuous journey-based care delivery. Outside of an acute event bringing a patient into the clinic or emergency room, many patients go a year or more without seeing their primary care providers.⁸ During that time, an immense amount of information is underreported or completely lost. Capturing this information in real-time and more holistically over a person’s lifetime of care could provide physicians better insight to both better manage and more fully evaluate the success of treatment plans by tracking patient symptoms, pain, and functional status over time. With this more longitudinal view of the patient, we see a pathway towards achieving the Quadruple Aim: patients who are more supported will achieve better outcomes at lower cost, they will have a better experience, and care teams will be empowered to focus their time on more satisfying activities rather than repetitive administrative tasks.

Corresponding author: James A. Colbert, MD, MBA; jamie@memorahealth.com

Disclosures: Dr. Flyckt and Dr. Colbert are employed by Memora Health, an organization that helps health care systems digitize and automate care journeys.

The Food and Drug Administration has approved belimumab (Benlysta) for treating active lupus nephritis (LN) in children aged 5-17 years. The drug can now be used to treat adult and pediatric patients with systemic lupus erythematosus (SLE) and LN. The decision expands therapeutic options for the estimated 1.5 million Americans currently living with lupus.

“This approval marks a significant step forward in providing treatment options to these children at risk of incurring kidney damage early on in life,” Stevan W. Gibson, president and CEO of the Lupus Foundation of America, said in a press release issued by the manufacturer, GlaxoSmithKline. LN is a condition that sometimes develops in people with lupus. In LN, the autoimmune cells produced by the disease attack the kidney. Roughly 40% of people with SLE experience LN.

Olivier Le Moal/Getty Images

Damage to the kidneys causes the body to have difficulty processing waste and toxins. This can create a host of problems, including end-stage kidney disease, which may be treated only with dialysis or kidney transplant. These situations significantly increase mortality among people with lupus, especially children.

Prior to the approval, the only treatment pathway for children with active LN included immunosuppressants and corticosteroids. While they may be effective, use of these classes of drugs may come with many side effects, including susceptibility to other diseases and infections. Belimumab, by contrast, is a B-lymphocyte stimulator protein inhibitor. It inhibits the survival of B cells, which are thought to play a role in the disease’s pathophysiology.

Belimumab was first approved to treat patients with SLE in 2011. It was approved for children with SLE 8 years later. The drug’s indications were expanded to include adults with LN in 2020.

Organizations within the lupus research community have communicated their support of the FDA’s decision. “Our community has much to celebrate with the approval of the first and much-needed treatment for children with lupus nephritis,” Lupus Research Alliance President and CEO Kenneth M. Farber said in a release from the organization.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved belimumab (Benlysta) for treating active lupus nephritis (LN) in children aged 5-17 years. The drug can now be used to treat adult and pediatric patients with systemic lupus erythematosus (SLE) and LN. The decision expands therapeutic options for the estimated 1.5 million Americans currently living with lupus.

“This approval marks a significant step forward in providing treatment options to these children at risk of incurring kidney damage early on in life,” Stevan W. Gibson, president and CEO of the Lupus Foundation of America, said in a press release issued by the manufacturer, GlaxoSmithKline. LN is a condition that sometimes develops in people with lupus. In LN, the autoimmune cells produced by the disease attack the kidney. Roughly 40% of people with SLE experience LN.

Olivier Le Moal/Getty Images

Damage to the kidneys causes the body to have difficulty processing waste and toxins. This can create a host of problems, including end-stage kidney disease, which may be treated only with dialysis or kidney transplant. These situations significantly increase mortality among people with lupus, especially children.

Prior to the approval, the only treatment pathway for children with active LN included immunosuppressants and corticosteroids. While they may be effective, use of these classes of drugs may come with many side effects, including susceptibility to other diseases and infections. Belimumab, by contrast, is a B-lymphocyte stimulator protein inhibitor. It inhibits the survival of B cells, which are thought to play a role in the disease’s pathophysiology.

Belimumab was first approved to treat patients with SLE in 2011. It was approved for children with SLE 8 years later. The drug’s indications were expanded to include adults with LN in 2020.

Organizations within the lupus research community have communicated their support of the FDA’s decision. “Our community has much to celebrate with the approval of the first and much-needed treatment for children with lupus nephritis,” Lupus Research Alliance President and CEO Kenneth M. Farber said in a release from the organization.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved belimumab (Benlysta) for treating active lupus nephritis (LN) in children aged 5-17 years. The drug can now be used to treat adult and pediatric patients with systemic lupus erythematosus (SLE) and LN. The decision expands therapeutic options for the estimated 1.5 million Americans currently living with lupus.

“This approval marks a significant step forward in providing treatment options to these children at risk of incurring kidney damage early on in life,” Stevan W. Gibson, president and CEO of the Lupus Foundation of America, said in a press release issued by the manufacturer, GlaxoSmithKline. LN is a condition that sometimes develops in people with lupus. In LN, the autoimmune cells produced by the disease attack the kidney. Roughly 40% of people with SLE experience LN.

Olivier Le Moal/Getty Images

Damage to the kidneys causes the body to have difficulty processing waste and toxins. This can create a host of problems, including end-stage kidney disease, which may be treated only with dialysis or kidney transplant. These situations significantly increase mortality among people with lupus, especially children.

Prior to the approval, the only treatment pathway for children with active LN included immunosuppressants and corticosteroids. While they may be effective, use of these classes of drugs may come with many side effects, including susceptibility to other diseases and infections. Belimumab, by contrast, is a B-lymphocyte stimulator protein inhibitor. It inhibits the survival of B cells, which are thought to play a role in the disease’s pathophysiology.

Belimumab was first approved to treat patients with SLE in 2011. It was approved for children with SLE 8 years later. The drug’s indications were expanded to include adults with LN in 2020.

Organizations within the lupus research community have communicated their support of the FDA’s decision. “Our community has much to celebrate with the approval of the first and much-needed treatment for children with lupus nephritis,” Lupus Research Alliance President and CEO Kenneth M. Farber said in a release from the organization.

A version of this article first appeared on Medscape.com.

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Rosuvastatin for cholesterol lowering was associated with slightly greater risks for kidney harm than atorvastatin, risks that were greater at higher-dose levels, in a large retrospective cohort study.

The most potent statin on the market, rosuvastatin has been linked with excess risk for kidney damage compared with atorvastatin in case reports and small trials, but there has been little surveillance of the issue following its approval in 2003.

The current analysis “is one of the first and largest real-world studies” examining rosuvastatin versus atorvastatin for risk for hematuria, proteinuria, and kidney failure with replacement therapy – dialysis or transplantation – across a range of estimated glomerular filtration rates (eGFR) in a heterogeneous population, the researchers write.

“Our findings suggest the need for greater care in prescribing and monitoring of rosuvastatin, particularly in patients who are receiving high doses” or have severe chronic kidney disease (CKD), they concluded in their report published online in the Journal of the American Society of Nephrology.

The analysis included close to 1 million patients in the United States who were newly prescribed rosuvastatin or atorvastatin from 2011 through 2019; they were followed a median of 3.1 years. Among the findings:

• Users of rosuvastatin had an 8% higher risk for hematuria, a 17% higher risk for proteinuria, and a 15% higher risk for kidney failure with replacement therapy, compared with those on atorvastatin
• The two groups avoided MI and stroke to similar extents
• About 44% of patients with severe CKD G4+ (eGFR < 30 mL/min per 1.73 m2) were prescribed a higher rosuvastatin dosage than the maximum 10 mg/day recommended for such patients by the Food and Drug Administration.

From this study, “we do not know why the adherence of FDA dosing recommendation for rosuvastatin in patients with severe CKD is low,” lead author Jung-Im Shin, MD, PhD, said in an interview.

“It is likely that not many clinicians are aware of rosuvastatin’s dosing recommendations [in severe CKD], or potential risks of hematuria or proteinuria,” speculated Dr. Shin, assistant professor at Johns Hopkins University, Baltimore.

“High-dose rosuvastatin [and its cardiovascular benefits] may not merit the risk, even if small, particularly in low eGFR,” she said. “Our study provides the opportunity to increase awareness of this clinical issue.”

“Future studies are warranted to shed light on the discrepancy between real-world practice and FDA dosing recommendations for high-dose rosuvastatin,” the researchers noted.

‘Greater awareness and education are key’

Invited to comment, Swapnil Hiremath, MD, a nephrologist at the Ottawa Hospital Research Institute, noted that the higher risk for nephrotoxicity with high-dose rosuvastatin versus high-dose atorvastatin was shown in the PLANET 1 trial published in 2015 and in, for example, a case report published in 2016 – which the researchers also mention.

“I was personally surprised” at the high proportion of patients with severe CKD who received higher than recommended doses of rosuvastatin, said Dr. Hiremath, who is also an associate professor at the University of Ottawa and a Freely Filtered podcaster, and not associated with the current study.

“We do see this occasionally,” he continued, “but either because someone is targeting LDL [cholesterol] and hasn’t noted the GFR, or possibly the patient was started on a high dose a long time ago and the kidney function has declined, and no one has noted the high dose.”

“Greater awareness and education are key,” observed Dr. Hiremath. “My personal bias is to have renal pharmacists involved in multidisciplinary clinics when GFR [is] less than 30 or so,” he said. “There are so many other tricky medicine/interaction issues” in patients with kidney disease.

Nevertheless, “I would be careful in drawing too many conclusions from an observational study,” Dr. Hiremath added. “There’s always the threat of residual confounding and selection bias,” which the researchers acknowledge, “and especially competing risks.”

For example, “if there is less cardiovascular death with rosuvastatin, then more people will remain alive to develop kidney failure.”
 

Dosing in practice unclear

Atorvastatin at 40-mg and 80-mg dosages and rosuvastatin at 20 mg and 40 mg are the only two statins considered high-intensity, the researchers noted.

Development of an 80-mg dosage for rosuvastatin was dropped because of hematuria and proteinuria safety signals highlighted at the time of rosuvastatin’s FDA approval.

However, there has been little postmarketing surveillance to assess real-world risk from high-intensity rosuvastatin, and it remains unclear whether and to what extent clinical practice adheres to the starting dosage recommended by the FDA in severe CKD, 5 mg/day with a maximum of 10 mg/day, the report noted.

The researchers analyzed deidentified electronic health record data from 40 health care organizations in the United States from the OptumLabs Data Warehouse database. They entered 152,101 new rosuvastatin users and 795,799 new atorvastatin users, and excluded patients with a history of rhabdomyolysis.

Patients in the two groups were similar with respect to CKD prevalence, cardiovascular risk factors, and demographics. Their age averaged 60 years, 48% were women, and 82% were White.

Hematuria was defined as dipstick hematuria > + or the presence of more than 3 red blood cells per high-power field in urine microscopy, at least twice. Proteinuria was defined as dipstick proteinuria > ++ or urine albumin-to-creatinine ratio greater than 300 mg/g at least twice.

Overall, 2.9% of patients had hematuria (3.4% of the rosuvastatin group and 2.8% of those taking atorvastatin) and 1% of patients had proteinuria (1.2% and 0.9%, respectively).

After balancing baseline characteristics in both groups using inverse probability of treatment weighting, rosuvastatin treatment, compared with atorvastatin, was associated with significantly greater risks for hematuria (hazard ratio, 1.08), proteinuria (HR, 1.17), and kidney failure requiring replacement therapy (HR, 1.15).  

Patients with eGFR less than 30 mL/min per 1.73 m2 had an approximately twofold higher risk for hematuria and ninefold higher risk for proteinuria during the follow-up compared with patients with eGFR of at least 60 mL/min per 1.73 m2.

Patients with eGFR less than 30 mL/min per 1.73 m2 were commonly prescribed high-dose rosuvastatin (29.9% received the 20-mg dose and 14% the 40-mg dose), contrary to the labeling recommendation.

Dr. Shin reported receiving research Funding from the National Institutes of Health and Merck; disclosures for the other authors are in the report. Dr. Hiremath reported having no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with type 2 diabetes who received empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, were almost 40% less likely to have a kidney stone than patients who received placebo during a median 1.5 years of treatment.

These findings are from an analysis of pooled data from phase 1-4 clinical trials of empagliflozin for blood glucose control in 15,081 patients with type 2 diabetes.  

Priyadarshini Balasubramanian, MD, presented the study as a poster at the annual meeting of the Endocrine Society; the study also was published online in the Journal of Clinical Endocrinology & Metabolism.

The researchers acknowledge this was a retrospective, post-hoc analysis and that urolithiasis – a stone in the urinary tract, which includes nephrolithiasis, a kidney stone – was an adverse event, not a primary or secondary outcome.

Also, the stone composition, which might help explain how the drug may affect stone formation, is unknown.

Therefore, “dedicated randomized prospective clinical trials are needed to confirm these initial observations in patients both with and without type 2 diabetes,” said Dr. Balasubramanian, a clinical fellow in the section of endocrinology & metabolism, department of internal medicine at Yale University, New Haven, Conn.

However, “if this association is proven, empagliflozin may be used to decrease the risk of kidney stones at least in those with type 2 diabetes, but maybe also in those without diabetes,” Dr. Balasubramanian said in an interview.

Further trials are also needed to determine if this is a class effect, which is likely, she speculated, and to unravel the potential mechanism.

This is important because of the prevalence of kidney stones, which affect up to 15% of the general population and 15%-20% of patients with diabetes, she explained.
 

‘Provocative’ earlier findings

The current study was prompted by a recent observational study by Kasper B. Kristensen, MD, PhD, and colleagues.

Because SGLT2 inhibitors increase urinary glucose excretion through reduced renal reabsorption of glucose leading to osmotic diuresis and increased urinary flow, they hypothesized that these therapies “may reduce the risk of upper urinary tract stones (nephrolithiasis) by reducing the concentration of lithogenic substances in urine.” 

Using data from Danish Health registries, they matched 12,325 individuals newly prescribed an SGLT2 inhibitor 1:1 with patients newly prescribed a glucagonlike peptide-1 (GLP1) agonist, another new class of drugs for treating type 2 diabetes.

They found a hazard ratio of 0.51 (95% confidence interval, 0.37-0.71) for incident nephrolithiasis and a hazard ratio of 0.68 (95% CI, 0.48-0.97) for recurrent nephrolithiasis for patients taking SGLT2 inhibitors versus GLP-1 agonists.

These findings are “striking,” according to Dr. Balasubramanian and colleagues. However, “these data, while provocative, were entirely retrospective and therefore possibly prone to bias,” they add.
 

Pooled data from 20 trials

The current study analyzed data from 20 randomized controlled trials of glycemic control in type 2 diabetes, in which 10,177 patients had received empagliflozin 10 mg or 25 mg and 4,904 patients had received placebo.

Most patients (46.5%) had participated in the EMPA-REG OUTCOMES trial, which also had the longest follow-up (2.6 years).

The researchers identified patients with a new stone from the urinary tract (including the kidney, ureter, and urethra). Patients had received either the study drug for a median of 543 days or placebo for a median of 549 days.

During treatment, 104 of 10,177 patients in the pooled empagliflozin groups and 79 of 4,904 patients in the pooled placebo groups developed a stone in the urinary tract.

This was equivalent to 0.63 new urinary-tract stones per 100 patient-years in the pooled empagliflozin groups versus 1.01 new urinary-tract stones per 100 patient-years in the pooled placebo groups.

The incidence rate ratio was 0.64 (95% CI, 0.48-0.86), in favor of empagliflozin.

When the analysis was restricted to new kidney stones, the results were similar: 75 of 10,177 patients in the pooled empagliflozin groups and 57 of 4,904 patients in the pooled placebo groups developed a kidney stone.

This was equivalent to 0.45 new kidney stones per 100 patient-years in the pooled empagliflozin groups versus 0.72 new kidney stones per 100 patient-years in the pooled placebo groups.

The IRR was 0.65 (95% CI, 0.46-0.92), in favor of empagliflozin.
 

Upcoming small RCT in adults without diabetes

Invited to comment on the new study, Dr. Kristensen said: “The reduced risk of SGLT2 inhibitors towards nephrolithiasis is now reported in at least two studies with different methodology, different populations, and different exposure and outcome definitions.”

“I agree that randomized clinical trials designed specifically to confirm these findings appear warranted,” added Dr. Kristensen, from the Institute of Public Health, Clinical Pharmacology, Pharmacy, and Environmental Medicine, University of Southern Denmark in Odense.

There is a need for studies in patients with and without diabetes, he added, especially ones that focus on prevention of nephrolithiasis in patients with kidney stone disease.

A new trial should shed further light on this.

Results are expected by the end of 2022 for SWEETSTONE (Impact of the SGLT2 Inhibitor Empagliflozin on Urinary Supersaturations in Kidney Stone Formers), a randomized, double-blind crossover exploratory study in 46 patients without diabetes.

This should provide preliminary data to “establish the relevance for larger trials assessing the prophylactic potential of empagliflozin in kidney stone disease,” according to an article on the trial protocol recently published in BMJ.

The trials included in the pooled dataset were funded by Boehringer Ingelheim or the Boehringer Ingelheim and Eli Lilly Diabetes Alliance. Dr. Balasubramanian has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with type 2 diabetes who received empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, were almost 40% less likely to have a kidney stone than patients who received placebo during a median 1.5 years of treatment.

These findings are from an analysis of pooled data from phase 1-4 clinical trials of empagliflozin for blood glucose control in 15,081 patients with type 2 diabetes.  

Priyadarshini Balasubramanian, MD, presented the study as a poster at the annual meeting of the Endocrine Society; the study also was published online in the Journal of Clinical Endocrinology & Metabolism.

The researchers acknowledge this was a retrospective, post-hoc analysis and that urolithiasis – a stone in the urinary tract, which includes nephrolithiasis, a kidney stone – was an adverse event, not a primary or secondary outcome.

Also, the stone composition, which might help explain how the drug may affect stone formation, is unknown.

Therefore, “dedicated randomized prospective clinical trials are needed to confirm these initial observations in patients both with and without type 2 diabetes,” said Dr. Balasubramanian, a clinical fellow in the section of endocrinology & metabolism, department of internal medicine at Yale University, New Haven, Conn.

However, “if this association is proven, empagliflozin may be used to decrease the risk of kidney stones at least in those with type 2 diabetes, but maybe also in those without diabetes,” Dr. Balasubramanian said in an interview.

Further trials are also needed to determine if this is a class effect, which is likely, she speculated, and to unravel the potential mechanism.

This is important because of the prevalence of kidney stones, which affect up to 15% of the general population and 15%-20% of patients with diabetes, she explained.
 

‘Provocative’ earlier findings

The current study was prompted by a recent observational study by Kasper B. Kristensen, MD, PhD, and colleagues.

Because SGLT2 inhibitors increase urinary glucose excretion through reduced renal reabsorption of glucose leading to osmotic diuresis and increased urinary flow, they hypothesized that these therapies “may reduce the risk of upper urinary tract stones (nephrolithiasis) by reducing the concentration of lithogenic substances in urine.” 

Using data from Danish Health registries, they matched 12,325 individuals newly prescribed an SGLT2 inhibitor 1:1 with patients newly prescribed a glucagonlike peptide-1 (GLP1) agonist, another new class of drugs for treating type 2 diabetes.

They found a hazard ratio of 0.51 (95% confidence interval, 0.37-0.71) for incident nephrolithiasis and a hazard ratio of 0.68 (95% CI, 0.48-0.97) for recurrent nephrolithiasis for patients taking SGLT2 inhibitors versus GLP-1 agonists.

These findings are “striking,” according to Dr. Balasubramanian and colleagues. However, “these data, while provocative, were entirely retrospective and therefore possibly prone to bias,” they add.
 

Pooled data from 20 trials

The current study analyzed data from 20 randomized controlled trials of glycemic control in type 2 diabetes, in which 10,177 patients had received empagliflozin 10 mg or 25 mg and 4,904 patients had received placebo.

Most patients (46.5%) had participated in the EMPA-REG OUTCOMES trial, which also had the longest follow-up (2.6 years).

The researchers identified patients with a new stone from the urinary tract (including the kidney, ureter, and urethra). Patients had received either the study drug for a median of 543 days or placebo for a median of 549 days.

During treatment, 104 of 10,177 patients in the pooled empagliflozin groups and 79 of 4,904 patients in the pooled placebo groups developed a stone in the urinary tract.

This was equivalent to 0.63 new urinary-tract stones per 100 patient-years in the pooled empagliflozin groups versus 1.01 new urinary-tract stones per 100 patient-years in the pooled placebo groups.

The incidence rate ratio was 0.64 (95% CI, 0.48-0.86), in favor of empagliflozin.

When the analysis was restricted to new kidney stones, the results were similar: 75 of 10,177 patients in the pooled empagliflozin groups and 57 of 4,904 patients in the pooled placebo groups developed a kidney stone.

This was equivalent to 0.45 new kidney stones per 100 patient-years in the pooled empagliflozin groups versus 0.72 new kidney stones per 100 patient-years in the pooled placebo groups.

The IRR was 0.65 (95% CI, 0.46-0.92), in favor of empagliflozin.
 

Upcoming small RCT in adults without diabetes

Invited to comment on the new study, Dr. Kristensen said: “The reduced risk of SGLT2 inhibitors towards nephrolithiasis is now reported in at least two studies with different methodology, different populations, and different exposure and outcome definitions.”

“I agree that randomized clinical trials designed specifically to confirm these findings appear warranted,” added Dr. Kristensen, from the Institute of Public Health, Clinical Pharmacology, Pharmacy, and Environmental Medicine, University of Southern Denmark in Odense.

There is a need for studies in patients with and without diabetes, he added, especially ones that focus on prevention of nephrolithiasis in patients with kidney stone disease.

A new trial should shed further light on this.

Results are expected by the end of 2022 for SWEETSTONE (Impact of the SGLT2 Inhibitor Empagliflozin on Urinary Supersaturations in Kidney Stone Formers), a randomized, double-blind crossover exploratory study in 46 patients without diabetes.

This should provide preliminary data to “establish the relevance for larger trials assessing the prophylactic potential of empagliflozin in kidney stone disease,” according to an article on the trial protocol recently published in BMJ.

The trials included in the pooled dataset were funded by Boehringer Ingelheim or the Boehringer Ingelheim and Eli Lilly Diabetes Alliance. Dr. Balasubramanian has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Patients with type 2 diabetes who received empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, were almost 40% less likely to have a kidney stone than patients who received placebo during a median 1.5 years of treatment.

These findings are from an analysis of pooled data from phase 1-4 clinical trials of empagliflozin for blood glucose control in 15,081 patients with type 2 diabetes.  

Priyadarshini Balasubramanian, MD, presented the study as a poster at the annual meeting of the Endocrine Society; the study also was published online in the Journal of Clinical Endocrinology & Metabolism.

The researchers acknowledge this was a retrospective, post-hoc analysis and that urolithiasis – a stone in the urinary tract, which includes nephrolithiasis, a kidney stone – was an adverse event, not a primary or secondary outcome.

Also, the stone composition, which might help explain how the drug may affect stone formation, is unknown.

Therefore, “dedicated randomized prospective clinical trials are needed to confirm these initial observations in patients both with and without type 2 diabetes,” said Dr. Balasubramanian, a clinical fellow in the section of endocrinology & metabolism, department of internal medicine at Yale University, New Haven, Conn.

However, “if this association is proven, empagliflozin may be used to decrease the risk of kidney stones at least in those with type 2 diabetes, but maybe also in those without diabetes,” Dr. Balasubramanian said in an interview.

Further trials are also needed to determine if this is a class effect, which is likely, she speculated, and to unravel the potential mechanism.

This is important because of the prevalence of kidney stones, which affect up to 15% of the general population and 15%-20% of patients with diabetes, she explained.
 

‘Provocative’ earlier findings

The current study was prompted by a recent observational study by Kasper B. Kristensen, MD, PhD, and colleagues.

Because SGLT2 inhibitors increase urinary glucose excretion through reduced renal reabsorption of glucose leading to osmotic diuresis and increased urinary flow, they hypothesized that these therapies “may reduce the risk of upper urinary tract stones (nephrolithiasis) by reducing the concentration of lithogenic substances in urine.” 

Using data from Danish Health registries, they matched 12,325 individuals newly prescribed an SGLT2 inhibitor 1:1 with patients newly prescribed a glucagonlike peptide-1 (GLP1) agonist, another new class of drugs for treating type 2 diabetes.

They found a hazard ratio of 0.51 (95% confidence interval, 0.37-0.71) for incident nephrolithiasis and a hazard ratio of 0.68 (95% CI, 0.48-0.97) for recurrent nephrolithiasis for patients taking SGLT2 inhibitors versus GLP-1 agonists.

These findings are “striking,” according to Dr. Balasubramanian and colleagues. However, “these data, while provocative, were entirely retrospective and therefore possibly prone to bias,” they add.
 

Pooled data from 20 trials

The current study analyzed data from 20 randomized controlled trials of glycemic control in type 2 diabetes, in which 10,177 patients had received empagliflozin 10 mg or 25 mg and 4,904 patients had received placebo.

Most patients (46.5%) had participated in the EMPA-REG OUTCOMES trial, which also had the longest follow-up (2.6 years).

The researchers identified patients with a new stone from the urinary tract (including the kidney, ureter, and urethra). Patients had received either the study drug for a median of 543 days or placebo for a median of 549 days.

During treatment, 104 of 10,177 patients in the pooled empagliflozin groups and 79 of 4,904 patients in the pooled placebo groups developed a stone in the urinary tract.

This was equivalent to 0.63 new urinary-tract stones per 100 patient-years in the pooled empagliflozin groups versus 1.01 new urinary-tract stones per 100 patient-years in the pooled placebo groups.

The incidence rate ratio was 0.64 (95% CI, 0.48-0.86), in favor of empagliflozin.

When the analysis was restricted to new kidney stones, the results were similar: 75 of 10,177 patients in the pooled empagliflozin groups and 57 of 4,904 patients in the pooled placebo groups developed a kidney stone.

This was equivalent to 0.45 new kidney stones per 100 patient-years in the pooled empagliflozin groups versus 0.72 new kidney stones per 100 patient-years in the pooled placebo groups.

The IRR was 0.65 (95% CI, 0.46-0.92), in favor of empagliflozin.
 

Upcoming small RCT in adults without diabetes

Invited to comment on the new study, Dr. Kristensen said: “The reduced risk of SGLT2 inhibitors towards nephrolithiasis is now reported in at least two studies with different methodology, different populations, and different exposure and outcome definitions.”

“I agree that randomized clinical trials designed specifically to confirm these findings appear warranted,” added Dr. Kristensen, from the Institute of Public Health, Clinical Pharmacology, Pharmacy, and Environmental Medicine, University of Southern Denmark in Odense.

There is a need for studies in patients with and without diabetes, he added, especially ones that focus on prevention of nephrolithiasis in patients with kidney stone disease.

A new trial should shed further light on this.

Results are expected by the end of 2022 for SWEETSTONE (Impact of the SGLT2 Inhibitor Empagliflozin on Urinary Supersaturations in Kidney Stone Formers), a randomized, double-blind crossover exploratory study in 46 patients without diabetes.

This should provide preliminary data to “establish the relevance for larger trials assessing the prophylactic potential of empagliflozin in kidney stone disease,” according to an article on the trial protocol recently published in BMJ.

The trials included in the pooled dataset were funded by Boehringer Ingelheim or the Boehringer Ingelheim and Eli Lilly Diabetes Alliance. Dr. Balasubramanian has reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The following highlights are a brief overview of guideline updates, drug approvals, and diagnostics relevant to geriatric medicine from June 2021 to April 2022, some of which were discussed at the American Geriatrics Society conference in May. I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).

Aspirin for primary prevention

It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.¹

The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.

While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.²

Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
 

Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia

One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.

Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.⁴

Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.

Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.⁵

Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.

In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.⁶
 

Overdiagnosis of CKD in older adults

The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m² for adults aged 65 and older.⁷

The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.⁸ In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.

A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.

These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
 

Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.

References

1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.

2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.

3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.

4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.

5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.

6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.

7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.

8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.

The following highlights are a brief overview of guideline updates, drug approvals, and diagnostics relevant to geriatric medicine from June 2021 to April 2022, some of which were discussed at the American Geriatrics Society conference in May. I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).

Aspirin for primary prevention

It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.¹

The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.

While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.²

Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
 

Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia

One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.

Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.⁴

Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.

Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.⁵

Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.

In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.⁶
 

Overdiagnosis of CKD in older adults

The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m² for adults aged 65 and older.⁷

The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.⁸ In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.

A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.

These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
 

Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.

References

1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.

2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.

3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.

4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.

5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.

6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.

7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.

8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.

The following highlights are a brief overview of guideline updates, drug approvals, and diagnostics relevant to geriatric medicine from June 2021 to April 2022, some of which were discussed at the American Geriatrics Society conference in May. I selected these topics as they were among the most discussed by my colleagues in geriatric medicine and inquired about by my primary care patients in geriatric medicine clinic. I hope that these updates provide primary care clinicians who care for older adults with more context and background information regarding new Alzheimer’s disease therapy to better answer patient inquiries, and to feel empowered to deprescribe aspirin and reframe the diagnostic criteria of chronic kidney disease (CKD).

Aspirin for primary prevention

It was welcome news in the geriatrics community when the United States Preventive Services Task Force updated their guidelines in April 2022 to recommend against the initiation of aspirin for primary prevention in adults aged 60 or older. This recommendation was based on studies that found that net benefits of CVD prevention in older adults are outweighed by risk of bleeding.¹

The risk of bleeding increases with age and can occur in individuals without common risk factors for bleeding, such as prior gastrointestinal bleeding, peptic ulcer disease, concurrent NSAID use, or corticosteroid use.

While it may be easier to not initiate aspirin for primary prevention, deprescribing aspirin for patients who have been on aspirin long term for primary prevention presents more of a challenge. Modeling data from the USPTSF suggest stopping aspirin at age 75 for those taking aspirin for primary prevention.²

Behavioral change, particularly for patients who have been on aspirin for decades, can be difficult. A 2021 study by Green et al. found that language that resonates the most with older adults when deprescribing emphasized the side effects rather than statements such as “this will not help you” or “do not need anymore.”3
 

Aducanumab for mild cognitive impairment and mild Alzheimer’s dementia

One of the most discussed topics this past year is the Food and Drug Administration approval of aducanumab (brand name Aduhelm) in June 2021. Aducanumab is the first approved disease-modifying therapy for Alzheimer’s disease and the first drug approved for the treatment of Alzheimer’s disease since 2003. Aducanumab is an antiamyloid monoclonal antibody that was developed to reduce amyloid plaque in the brain, one of the features of Alzheimer’s disease pathology.

Uptake of aducanumab by dementia providers has been limited for several reasons. Firstly, the clinical significance of the drug remains in question. ENGAGE and EMERGE were the two main randomized clinical trials that studied the effect of aducanumab on amyloid burden and clinical stages of dementia over 18 months. While both studies demonstrated that aducanumab reduced amyloid burden based on neuroimaging and in cerebrospinal fluid, the ENGAGE trial found no difference in the stage of dementia. The EMERGE trial did note a small, statistically significant difference in stage of dementia, however the participants of the EMERGE trial had a faster rate of progression of dementia than the placebo participants in the ENGAGE trial, which could have contributed to the difference detected.⁴

Additionally, exclusion criteria for both trials call into question the generalizability of this study. Participants over age 85, with CKD, prior stroke, or transient ischemic attacks, or on anticoagulation were excluded. One of the drivers for the exclusion criteria is the increased risk of macro and microhemorrhages.

Thirty-five percent of research participants were incidentally noted to have brain edema, an abnormality called amyloid-related imaging abnormality or ARIA-E, that necessitated serial monitoring with brain MRIs. It is also important to highlight that inclusion of African American, Hispanic, and Latinx participants in these studies was less than 5%, despite a higher incidence of Alzheimer’s disease in these populations.⁵

Lastly, economic implications for the U.S. health care system with increased uptake of aducanumab could be enormous. Originally quoted at $56,000 yearly, Biogen, the maker of aducanumab, recently reduced annual costs to $28,200 per patient.

In April 2022, CMS released a statement that antiamyloid monoclonal antibodies and related services, including PET scans, would be covered under Medicare for those with mild cognitive impairment and mild Alzheimer’s dementia with confirmed presence of amyloid. A study by Mafi et al. estimated that aducanumab could cost Medicare between $7 billion and $37.4 billion annually based on lower and upper bound estimates of eligible Medicare beneficiaries.⁶
 

Overdiagnosis of CKD in older adults

The current diagnostic criteria of CKD, which is based on an estimated glomerular filtration rate (eGFR) of less than 60, has been up for debate, as glomerular filtration rate (GFR) physiologically decreases with age. Fixed thresholds can lead to underdiagnosis of CKD in younger adults and overdiagnosis of CKD in older adults. Age-adapted thresholds for the diagnosis of CKD have been proposed, with the suggestion of an eGFR threshold of 45mL/min/1.73 m² for adults aged 65 and older.⁷

The clinical implication of using an age-adapted eGFR threshold definition was investigated in a 2021 cohort study by Liu et al.⁸ In this study, outcomes of adults diagnosed with CKD using a fixed threshold versus age-adapted threshold were compared with a healthy cohort.

A fixed threshold led to a 60% higher incidence of CKD diagnosis. However, incidence of renal failure and all-cause mortality in older adults with an eGFR between 45-59 /min/1.73 m2 with normal or mild albuminuria was of similar magnitude to the healthy cohort at 5 years of follow-up.

These findings support the use of age-adapted thresholds for the diagnosis of CKD in older adults, as an earlier diagnosis of mild CKD does not equate to clinical benefits, but could lead to harms of unnecessary interventions and patient anxiety.
 

Dr. Mengru “Ruru” Wang is a geriatrician and internist at the University of Washington, Seattle. She practices full-spectrum medicine, seeing patients in primary care, nursing homes, and acute care. Dr. Wang has no disclosures related to this piece.

References

1. Selak Vet al. Predicting bleeding risk to guide aspirin use for the primary prevention of cardiovascular disease: A cohort study. Ann Intern Med. 2019;170(6):357-68. doi: 10.7326/M18-2808.

2. US Preventive Services Task Force. Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement. JAMA. 2022;327(16):1577-84. doi: 10.1001/jama.2022.4983.

3. Green AR et al. Assessment of patient-preferred language to achieve goal-aligned deprescribing in older adults. JAMA Netw Open. 2021;4(4):e212633. doi: 10.1001/jamanetworkopen.2021.2633.

4. Oh ES. Use of anti-amyloid therapy for Alzheimer’s disease in clinical practice. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at American Geriatrics Society Meeting, 2022. Orlando.

5. Amjad H. Issues of Access and Marginalization. An update on Alzheimer’s disease diagnosis and therapeutics. Presentation at: American Geriatrics Society Meeting, 2022. Orlando.

6. Mafi JN et al. Estimated annual spending on aducanumab in the U.S. Medicare program. JAMA Health Forum. 2022;3(1):e214495. doi: 10.1001/jamahealthforum.2021.4495.

7. Delanaye P et al. CKD: A call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805. doi: 10.1681/ASN.2019030238.

8. Liu Pet al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-66. doi: 10.1001/jamainternmed.2021.4813.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Mitchel L. Zoler/MDedge News

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Mitchel L. Zoler/MDedge News

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Mitchel L. Zoler/MDedge News

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

As it gears up for the first in-person scientific sessions for 3 years, the American Diabetes Association has issued an addendum to its most recent annual clinical practice recommendations published in December 2021, the 2022 Standards of Medical Care in Diabetes, based on recent trial evidence and consensus.

The update informs clinicians about:

• The effect of the nonsteroidal mineralocorticoid antagonist (Kerendia) on cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease.
• The effect of a sodium-glucose cotransporter 2 (SGLT2) inhibitor on heart failure and renal outcomes in patients with type 2 diabetes.

The National Kidney Foundation and the American Society of Nephrology Task Force recommendation to remove race in the formula for calculating estimated glomerular filtration rate (eGFR).

Checking with Dr Gabbay -- RM 08/16

“This is the fifth year that we are able to update the Standards of Care after it has been published through our Living Standards of Care updates, making it possible to give diabetes care providers the most important information and the latest evidence relevant to their practice,” Robert A. Gabbay, MD, PhD, ADA chief scientific and medical officer, said in a press release from the organization.

The addendum, entitled, “Living Standards of Care,” updates Section 10, “Cardiovascular Disease and Risk Management,” and Section 11, “Chronic Kidney Disease and Risk Management” of the 2022 Standards of Medical Care in Diabetes. 

The amendments were approved by the ADA Professional Practice Committee, which is responsible for developing the Standards of Care. The American College of Cardiology reviewed and endorsed the section on CVD and risk management.

The Living Standards Update was published online in Diabetes Care.
 

CVD and risk management

In the Addendum to Section 10, “Cardiovascular Disease and Risk Management,” the committee writes:

• “For patients with type 2 diabetes and chronic kidney disease treated with maximum tolerated doses of ACE inhibitors or angiotensin receptor blockers, addition of finerenone should be considered to improve cardiovascular outcomes and reduce the risk of chronic kidney disease progression. A”
• “Patients with type 2 diabetes and chronic kidney disease should be considered for treatment with finerenone to reduce cardiovascular outcomes and the risk of chronic kidney disease progression.”
• “In patients with type 2 diabetes and established heart failure with either preserved or reduced ejection fraction, an SGLT2 inhibitor [with proven benefit in this patient population] is recommended to reduce risk of worsening heart failure, hospitalizations for heart failure, and cardiovascular death. ”

In the section “Statin Treatment,” the addendum no longer states that “a prospective trial of a newer fibrate ... is ongoing,” because that trial investigating pemafibrate (Kowa), a novel selective peroxisome proliferator-activated receptor alpha modulator (or fibrate), has been discontinued.
 

Chronic kidney disease and risk management

In the Addendum to Section 11, “Chronic Kidney Disease and Risk Management,” the committee writes: 

• “Traditionally, eGFR is calculated from serum creatinine using a validated formula. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is preferred. ... Historically, a correction factor for muscle mass was included in a modified equation for African Americans; however, due to various issues with inequities, it was decided to the equation such that it applies to all. Hence, a committee was convened, resulting in the recommendation for immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the U.S.” (This is based on an National Kidney Foundation and American Society of Nephrology Task Force recommendation.)
• “Additionally, increased use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone.” 

Evidence from clinical trials

The update is based on findings from the following clinical trials:

• Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD)
• Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease (FIGARO-DKD)
• FIDELITY, a prespecified pooled analysis of FIDELIO-DKD and FIGARO-DKD
• Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved)
• Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients with PRESERVED Ejection Fraction Heart Failure (PRESERVED-HF)
• Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT).

A version of this article first appeared on Medscape.com.

As it gears up for the first in-person scientific sessions for 3 years, the American Diabetes Association has issued an addendum to its most recent annual clinical practice recommendations published in December 2021, the 2022 Standards of Medical Care in Diabetes, based on recent trial evidence and consensus.

The update informs clinicians about:

• The effect of the nonsteroidal mineralocorticoid antagonist (Kerendia) on cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease.
• The effect of a sodium-glucose cotransporter 2 (SGLT2) inhibitor on heart failure and renal outcomes in patients with type 2 diabetes.

The National Kidney Foundation and the American Society of Nephrology Task Force recommendation to remove race in the formula for calculating estimated glomerular filtration rate (eGFR).

Checking with Dr Gabbay -- RM 08/16

“This is the fifth year that we are able to update the Standards of Care after it has been published through our Living Standards of Care updates, making it possible to give diabetes care providers the most important information and the latest evidence relevant to their practice,” Robert A. Gabbay, MD, PhD, ADA chief scientific and medical officer, said in a press release from the organization.

The addendum, entitled, “Living Standards of Care,” updates Section 10, “Cardiovascular Disease and Risk Management,” and Section 11, “Chronic Kidney Disease and Risk Management” of the 2022 Standards of Medical Care in Diabetes. 

The amendments were approved by the ADA Professional Practice Committee, which is responsible for developing the Standards of Care. The American College of Cardiology reviewed and endorsed the section on CVD and risk management.

The Living Standards Update was published online in Diabetes Care.
 

CVD and risk management

In the Addendum to Section 10, “Cardiovascular Disease and Risk Management,” the committee writes:

• “For patients with type 2 diabetes and chronic kidney disease treated with maximum tolerated doses of ACE inhibitors or angiotensin receptor blockers, addition of finerenone should be considered to improve cardiovascular outcomes and reduce the risk of chronic kidney disease progression. A”
• “Patients with type 2 diabetes and chronic kidney disease should be considered for treatment with finerenone to reduce cardiovascular outcomes and the risk of chronic kidney disease progression.”
• “In patients with type 2 diabetes and established heart failure with either preserved or reduced ejection fraction, an SGLT2 inhibitor [with proven benefit in this patient population] is recommended to reduce risk of worsening heart failure, hospitalizations for heart failure, and cardiovascular death. ”

In the section “Statin Treatment,” the addendum no longer states that “a prospective trial of a newer fibrate ... is ongoing,” because that trial investigating pemafibrate (Kowa), a novel selective peroxisome proliferator-activated receptor alpha modulator (or fibrate), has been discontinued.
 

Chronic kidney disease and risk management

In the Addendum to Section 11, “Chronic Kidney Disease and Risk Management,” the committee writes: 

• “Traditionally, eGFR is calculated from serum creatinine using a validated formula. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is preferred. ... Historically, a correction factor for muscle mass was included in a modified equation for African Americans; however, due to various issues with inequities, it was decided to the equation such that it applies to all. Hence, a committee was convened, resulting in the recommendation for immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the U.S.” (This is based on an National Kidney Foundation and American Society of Nephrology Task Force recommendation.)
• “Additionally, increased use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone.” 

Evidence from clinical trials

The update is based on findings from the following clinical trials:

• Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD)
• Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease (FIGARO-DKD)
• FIDELITY, a prespecified pooled analysis of FIDELIO-DKD and FIGARO-DKD
• Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved)
• Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients with PRESERVED Ejection Fraction Heart Failure (PRESERVED-HF)
• Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT).

A version of this article first appeared on Medscape.com.

As it gears up for the first in-person scientific sessions for 3 years, the American Diabetes Association has issued an addendum to its most recent annual clinical practice recommendations published in December 2021, the 2022 Standards of Medical Care in Diabetes, based on recent trial evidence and consensus.

The update informs clinicians about:

• The effect of the nonsteroidal mineralocorticoid antagonist (Kerendia) on cardiovascular outcomes in patients with type 2 diabetes and chronic kidney disease.
• The effect of a sodium-glucose cotransporter 2 (SGLT2) inhibitor on heart failure and renal outcomes in patients with type 2 diabetes.

The National Kidney Foundation and the American Society of Nephrology Task Force recommendation to remove race in the formula for calculating estimated glomerular filtration rate (eGFR).

Checking with Dr Gabbay -- RM 08/16

“This is the fifth year that we are able to update the Standards of Care after it has been published through our Living Standards of Care updates, making it possible to give diabetes care providers the most important information and the latest evidence relevant to their practice,” Robert A. Gabbay, MD, PhD, ADA chief scientific and medical officer, said in a press release from the organization.

The addendum, entitled, “Living Standards of Care,” updates Section 10, “Cardiovascular Disease and Risk Management,” and Section 11, “Chronic Kidney Disease and Risk Management” of the 2022 Standards of Medical Care in Diabetes. 

The amendments were approved by the ADA Professional Practice Committee, which is responsible for developing the Standards of Care. The American College of Cardiology reviewed and endorsed the section on CVD and risk management.

The Living Standards Update was published online in Diabetes Care.
 

CVD and risk management

In the Addendum to Section 10, “Cardiovascular Disease and Risk Management,” the committee writes:

• “For patients with type 2 diabetes and chronic kidney disease treated with maximum tolerated doses of ACE inhibitors or angiotensin receptor blockers, addition of finerenone should be considered to improve cardiovascular outcomes and reduce the risk of chronic kidney disease progression. A”
• “Patients with type 2 diabetes and chronic kidney disease should be considered for treatment with finerenone to reduce cardiovascular outcomes and the risk of chronic kidney disease progression.”
• “In patients with type 2 diabetes and established heart failure with either preserved or reduced ejection fraction, an SGLT2 inhibitor [with proven benefit in this patient population] is recommended to reduce risk of worsening heart failure, hospitalizations for heart failure, and cardiovascular death. ”

In the section “Statin Treatment,” the addendum no longer states that “a prospective trial of a newer fibrate ... is ongoing,” because that trial investigating pemafibrate (Kowa), a novel selective peroxisome proliferator-activated receptor alpha modulator (or fibrate), has been discontinued.
 

Chronic kidney disease and risk management

In the Addendum to Section 11, “Chronic Kidney Disease and Risk Management,” the committee writes: 

• “Traditionally, eGFR is calculated from serum creatinine using a validated formula. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is preferred. ... Historically, a correction factor for muscle mass was included in a modified equation for African Americans; however, due to various issues with inequities, it was decided to the equation such that it applies to all. Hence, a committee was convened, resulting in the recommendation for immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the U.S.” (This is based on an National Kidney Foundation and American Society of Nephrology Task Force recommendation.)
• “Additionally, increased use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone.” 

Evidence from clinical trials

The update is based on findings from the following clinical trials:

• Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD)
• Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and the Clinical Diagnosis of Diabetic Kidney Disease (FIGARO-DKD)
• FIDELITY, a prespecified pooled analysis of FIDELIO-DKD and FIGARO-DKD
• Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved)
• Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients with PRESERVED Ejection Fraction Heart Failure (PRESERVED-HF)
• Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT).

A version of this article first appeared on Medscape.com.

COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.

Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.

The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.

“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”

Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.

Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.

He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”

Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”

Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”

Maintenance therapy in lupus nephritis: To continue or not?

Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).

A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.

Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m². The mean SLE Disease Activity Index score was around 2.

Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.

Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m² or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
 

Noninferiority of discontinuation versus continuation not shown

A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).

“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.

Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).

However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”

No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.

The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
 

Longer immunosuppressive therapy prediscontinuation leads to better results

Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”

Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”

Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.

“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.

Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.

COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.

Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.

The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.

“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”

Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.

Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.

He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”

Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”

Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”

Maintenance therapy in lupus nephritis: To continue or not?

Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).

A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.

Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m². The mean SLE Disease Activity Index score was around 2.

Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.

Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m² or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
 

Noninferiority of discontinuation versus continuation not shown

A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).

“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.

Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).

However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”

No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.

The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
 

Longer immunosuppressive therapy prediscontinuation leads to better results

Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”

Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”

Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.

“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.

Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.

COPENHAGEN – Discontinuing maintenance immunosuppressive therapy (IST) in patients with proliferative lupus nephritis in remission proved less effective than continuing it in terms of the rates of renal relapse and severe systemic lupus erythematosus (SLE) flare, results from the WIN-Lupus trial show.

Lead researcher Noemie Jourde-Chiche, MD, assistant professor at Aix-Marseille (France) University, presented the results at the annual European Congress of Rheumatology.

The randomized, controlled trial aimed to determine the optimal duration of maintenance IST for proliferative lupus nephritis, by asking whether discontinuation of such therapy after 2-3 years was noninferior to IST continuation for 2 more years.

“This is the first randomized IST trial in proliferative lupus nephritis,” Dr. Jourde-Chiche reported. “We found that noninferiority of IST discontinuation was not demonstrated, and those who discontinued had a higher risk of SLE flares, but the majority of patients who discontinued did not experience flare.”

Regarding the incidence of renal relapse, no statistically significant difference was found between patients who continued versus those who discontinued IST.

Rheumatologist Christophe Richez, MD, of the Groupe Hospitalier Pellegrin-CHU de Bordeaux (France) welcomed the trial. “The work does not find a significant difference but suggests that with more power, the difference would have been significant,” he said in an interview.

He added that a significant number of patients refused to enter the study for several reasons, including scheduling a pregnancy and fear of relapse after stopping the treatment. “This in itself shows that we need this type of study to know if we can stop the treatment to plan a pregnancy or if a relay treatment is necessary. These data also mean we can now better inform our patients about the benefit-risk [profile] of continuing treatment or not.”

Dr. Richez, who was not involved in the trial, noted that the data provide information that strongly suggest more research is needed to better determine which patients are at risk of relapse, and consequently, for which patients is discontinuation possible. “There’s also a need for further analysis of tolerance to the immunosuppressive drugs according to the strategy.”

Finally, he referred to the issue around therapeutic adherence that is often faced with management of lupus. “The data from this study will allow us to better explain to patients the need to continue or discontinue their treatments, including hydroxychloroquine, and also the possibility of decreasing the immunosuppressive drugs to half-dose.”

Maintenance therapy in lupus nephritis: To continue or not?

Conducted in 28 French centers, participants had class III or IV lupus nephritis with active lesions and had previously received induction IST of cyclophosphamide or mycophenolate mofetil with hydroxychloroquine and glucocorticoids. Maintenance IST was azathioprine or mycophenolate mofetil, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day).

A total of 96 patients were randomized into two groups: continuation of maintenance therapy (azathioprine or mycophenolate mofetil for 2-3 more years, hydroxychloroquine, and possibly low-dose glucocorticoids (below 10 mg/day), or discontinuation of maintenance therapy (azathioprine or mycophenolate mofetil) over 3 months.

Both study arms were similar with a mean age of 36-37 years, and 82%-86% of patients were female, 59%-67% were White. They had a mean disease duration of 7-9 years, and 72%-80% had experienced their first flare of proliferative nephritis. A total of 54%-65% had received cyclophosphamide induction therapy, and 75%-81% were on mycophenolate mofetil maintenance therapy that had been ongoing for a mean of 2.8 years. Tests of patients’ kidney function revealed a mean serum creatinine of 67-72 micromol/L and estimated glomerular filtration rate (eGFR) of 94-101 mL/min per 1.73 m². The mean SLE Disease Activity Index score was around 2.

Follow-up visits were conducted every 3 months for 2 years, and the trial had a primary end point of renal relapse rate at 24 months (confirmed by kidney biopsy), while secondary endpoints included rate of severe SLE flares, survival without renal relapse, or severe flare and adverse events, among others.

Patients were excluded if they were not taking hydroxychloroquine, had extrarenal SLE, an eGFR less than 30 mL/min per 1.73 m² or stage VI disease. After some participants did not finish the trial because of pregnancy, wish for pregnancy, or adverse events, data from a total of 40 in the IST continuation group and 44 in the discontinuation group were analyzed.
 

Noninferiority of discontinuation versus continuation not shown

A total of 12.5% in the continuation arm experienced renal relapse over 24 months, compared with 27.3% in the discontinuation arm (P = .079).

“The endpoint of noninferiority of discontinuation of immunosuppressive therapy was not shown, but no statistically significant difference was found between groups for renal relapse,” Dr. Jourde-Chiche said.

Severe SLE flares (renal or extrarenal) occurred significantly less often over 24 months in the continuation arm at 12.5% versus 31.8% in the discontinuation arm (P = .034).

However, Dr. Jourde-Chiche pointed out that “the majority of patients who discontinued treatment did not experience a flare.”

No differences were seen between groups with respect to any secondary endpoints. “Fortunately, no patients died or reached end-stage renal disease, and overall, the adverse events did not differ between groups,” she reported.

The study identified several risk factors for renal relapse, among which were low complement component 3 and higher baseline urinary protein to creatinine ratio.
 

Longer immunosuppressive therapy prediscontinuation leads to better results

Gabriella Moroni, MD, of the nephrology unit at Ospedale Maggiore Policlinico, Milan, authored a review of studies that attempted to interrupt glucocorticoids and other immunosuppressive agents in lupus nephritis and in SLE. Her review concluded that “the available data suggest that therapy withdrawal is feasible at least in patients enjoying a complete clinical remission after a prolonged therapy.”

Asked to comment on the French study, Dr. Moroni said the trial was very welcome. “In our long-term experience, we have stopped IST in 73 patients with lupus nephritis, followed for a mean of 23 years. Of these, 32 never reassumed therapy and 20 had at least one flare.”

Dr. Moroni noted that those participants who did not experience flares had significantly longer IST and longer remission before discontinuation and took hydroxychloroquine more frequently.

“We feel that, to prevent severe flares, firstly, lupus nephritis should be in complete remission for at least 3 years, and secondly, patients should have received IST for at least 5 years before discontinuation; immunosuppressive drugs should be tapered off very slowly and after strict clinical surveillance, and finally, hydroxychloroquine can prevent extrarenal flares.

Dr. Jourde-Chiche reported serving on a speakers bureau for Vifor Pharma and receiving grant/research support from Fresenius Medical Care. Some coauthors reported financial ties to many pharmaceutical companies. Dr. Richez said he has received fees for lectures or boards from GlaxoSmithKline, AstraZeneca, and Novartis. Dr. Moroni had no relevant disclosures.