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People with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2) inhibitors show a significantly reduced risk of developing kidney stones compared with those treated with other commonly used diabetes drugs.

“To our knowledge, this study is the first and largest to assess the association between SGLT2 inhibitors use and risk of nephrolithiasis [kidney stones] in patients with type 2 diabetes in routine US clinical practice,” said the authors of the study, published in JAMA Internal Medicine. 

“Our results suggest that for patients with type 2 diabetes, the individual risk profile for developing nephrolithiasis could be a consideration when deciding which glucose-lowering agent patients should initiate,” they wrote.

The prevalence of kidney stones has been on the rise, and the problem is especially relevant to those with type 2 diabetes, which is known to have an increased risk of kidney stones, potentially causing severe pain and leading to kidney function decline.

With SGLT2 inhibitors showing renoprotective, in addition to cardiovascular benefits, first author Julie Paik, MD, MPH, an associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics and the Division of Renal (Kidney) Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues conducted an active comparator cohort study using data from three nationwide databases on patients with type 2 diabetes in routine clinical practice.

In the study’s two arms of propensity score-matched patients, 358,203 pairs of patients with type 2 diabetes were matched 1:1 to either those who were new users of SGLT2 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), with patients in those groups having a mean age of 61 and being about 51% female.

In addition, 331,028 pairs matched new SGLT2 inhibitor users 1:1 with didpeptidyl peptidase-4 (DPP4) inhibitor users, who also had a mean age of about 61.5 years and were about 47% female.

Over a median follow-up of 192 days, those treated with SGLT2 inhibitors had about a 31% significantly lower risk of kidney stones than GLP-1RA users (14.9 vs 21.3 events per 1000 person-years; hazard ratio [HR], 0.69).

And the SGLT2 group also had a 26% lower kidney stone risk vs DPP4 inhibitor users (14.6 vs 19.9 events per 1000 person-years; HR, 0.74).

There were no differences in the results with either groups of pairs based on sex, race, ethnicity, a history of chronic kidney disease, or obesity.

Of note, the magnitude of the risk reduction observed with SGLT2 inhibitors was greater in adults aged < 70 years than in those aged ≥ 70 years (HR, 0.85; P for interaction < .001).

The age-related difference could possibly be due to changes in stone composition that occurs with aging, which may influence SGLT2 inhibitor response, Dr Paik told this news organization.

“However, we did not have information on stone composition in our study.”

In the study, patients were taking, on average, more than two antidiabetic medications upon entrance to the study, with 13% taking thiazides and 12% taking loop diuretics. In addition, approximately half of patients discontinued SGLT2 inhibitors (52.6%) and DPP4 inhibitors (53.2%).

However, the results remained consistent after adjusting for those factors, Dr. Paik noted.
 

Mechanisms: Urinary Citrate Excretion?

Among key possible explanations for the lower risk of kidney stones with SGLT2 inhibitors is that the drugs have increased urinary citrate excretion, with one study showing a nearly 50% increase in urinary citrate excretion among patients treated with empagliflozin vs placebo over 4 weeks and other studies also showing similar increases.

“This increased urinary citrate excretion may play a pivotal role in decreasing stone risk by inhibiting supersaturation and crystallization of calcium crystals,” the authors explained.

In addition, the urinary citrate excretion could further play a role by “forming complexes with calcium and thus lowering urinary calcium concentration, and raising urinary pH, thereby reducing the risk of uric acid stones,” they added.

SGLT inhibitors’ anti-inflammatory effects could also reduce stone formation by “suppressing the expression of a stone core matrix protein, osteopontin, and markers of kidney injury, inflammation, and macrophages that promote stone formation,” the authors noted.

Ultimately, however, “while we found a lower risk of kidney stones in our study, we don’t fully understand how they lower the risk,” Dr. Paik said. The potential explanations “remain to be studied further.”

Either way, “the risk of kidney stones in a patient might be one additional consideration for a clinician to take into account when choosing among the different glucose-lowering agents for patients with type 2 diabetes,” Dr. Paik said.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, the National Institute of Aging the Patient-Centered Outcomes Research Institute, the US Food and Drug Administration, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. 

A version of this article appeared on Medscape.com .

People with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2) inhibitors show a significantly reduced risk of developing kidney stones compared with those treated with other commonly used diabetes drugs.

“To our knowledge, this study is the first and largest to assess the association between SGLT2 inhibitors use and risk of nephrolithiasis [kidney stones] in patients with type 2 diabetes in routine US clinical practice,” said the authors of the study, published in JAMA Internal Medicine. 

“Our results suggest that for patients with type 2 diabetes, the individual risk profile for developing nephrolithiasis could be a consideration when deciding which glucose-lowering agent patients should initiate,” they wrote.

The prevalence of kidney stones has been on the rise, and the problem is especially relevant to those with type 2 diabetes, which is known to have an increased risk of kidney stones, potentially causing severe pain and leading to kidney function decline.

With SGLT2 inhibitors showing renoprotective, in addition to cardiovascular benefits, first author Julie Paik, MD, MPH, an associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics and the Division of Renal (Kidney) Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues conducted an active comparator cohort study using data from three nationwide databases on patients with type 2 diabetes in routine clinical practice.

In the study’s two arms of propensity score-matched patients, 358,203 pairs of patients with type 2 diabetes were matched 1:1 to either those who were new users of SGLT2 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), with patients in those groups having a mean age of 61 and being about 51% female.

In addition, 331,028 pairs matched new SGLT2 inhibitor users 1:1 with didpeptidyl peptidase-4 (DPP4) inhibitor users, who also had a mean age of about 61.5 years and were about 47% female.

Over a median follow-up of 192 days, those treated with SGLT2 inhibitors had about a 31% significantly lower risk of kidney stones than GLP-1RA users (14.9 vs 21.3 events per 1000 person-years; hazard ratio [HR], 0.69).

And the SGLT2 group also had a 26% lower kidney stone risk vs DPP4 inhibitor users (14.6 vs 19.9 events per 1000 person-years; HR, 0.74).

There were no differences in the results with either groups of pairs based on sex, race, ethnicity, a history of chronic kidney disease, or obesity.

Of note, the magnitude of the risk reduction observed with SGLT2 inhibitors was greater in adults aged < 70 years than in those aged ≥ 70 years (HR, 0.85; P for interaction < .001).

The age-related difference could possibly be due to changes in stone composition that occurs with aging, which may influence SGLT2 inhibitor response, Dr Paik told this news organization.

“However, we did not have information on stone composition in our study.”

In the study, patients were taking, on average, more than two antidiabetic medications upon entrance to the study, with 13% taking thiazides and 12% taking loop diuretics. In addition, approximately half of patients discontinued SGLT2 inhibitors (52.6%) and DPP4 inhibitors (53.2%).

However, the results remained consistent after adjusting for those factors, Dr. Paik noted.
 

Mechanisms: Urinary Citrate Excretion?

Among key possible explanations for the lower risk of kidney stones with SGLT2 inhibitors is that the drugs have increased urinary citrate excretion, with one study showing a nearly 50% increase in urinary citrate excretion among patients treated with empagliflozin vs placebo over 4 weeks and other studies also showing similar increases.

“This increased urinary citrate excretion may play a pivotal role in decreasing stone risk by inhibiting supersaturation and crystallization of calcium crystals,” the authors explained.

In addition, the urinary citrate excretion could further play a role by “forming complexes with calcium and thus lowering urinary calcium concentration, and raising urinary pH, thereby reducing the risk of uric acid stones,” they added.

SGLT inhibitors’ anti-inflammatory effects could also reduce stone formation by “suppressing the expression of a stone core matrix protein, osteopontin, and markers of kidney injury, inflammation, and macrophages that promote stone formation,” the authors noted.

Ultimately, however, “while we found a lower risk of kidney stones in our study, we don’t fully understand how they lower the risk,” Dr. Paik said. The potential explanations “remain to be studied further.”

Either way, “the risk of kidney stones in a patient might be one additional consideration for a clinician to take into account when choosing among the different glucose-lowering agents for patients with type 2 diabetes,” Dr. Paik said.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, the National Institute of Aging the Patient-Centered Outcomes Research Institute, the US Food and Drug Administration, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. 

A version of this article appeared on Medscape.com .

People with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2) inhibitors show a significantly reduced risk of developing kidney stones compared with those treated with other commonly used diabetes drugs.

“To our knowledge, this study is the first and largest to assess the association between SGLT2 inhibitors use and risk of nephrolithiasis [kidney stones] in patients with type 2 diabetes in routine US clinical practice,” said the authors of the study, published in JAMA Internal Medicine. 

“Our results suggest that for patients with type 2 diabetes, the individual risk profile for developing nephrolithiasis could be a consideration when deciding which glucose-lowering agent patients should initiate,” they wrote.

The prevalence of kidney stones has been on the rise, and the problem is especially relevant to those with type 2 diabetes, which is known to have an increased risk of kidney stones, potentially causing severe pain and leading to kidney function decline.

With SGLT2 inhibitors showing renoprotective, in addition to cardiovascular benefits, first author Julie Paik, MD, MPH, an associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics and the Division of Renal (Kidney) Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues conducted an active comparator cohort study using data from three nationwide databases on patients with type 2 diabetes in routine clinical practice.

In the study’s two arms of propensity score-matched patients, 358,203 pairs of patients with type 2 diabetes were matched 1:1 to either those who were new users of SGLT2 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), with patients in those groups having a mean age of 61 and being about 51% female.

In addition, 331,028 pairs matched new SGLT2 inhibitor users 1:1 with didpeptidyl peptidase-4 (DPP4) inhibitor users, who also had a mean age of about 61.5 years and were about 47% female.

Over a median follow-up of 192 days, those treated with SGLT2 inhibitors had about a 31% significantly lower risk of kidney stones than GLP-1RA users (14.9 vs 21.3 events per 1000 person-years; hazard ratio [HR], 0.69).

And the SGLT2 group also had a 26% lower kidney stone risk vs DPP4 inhibitor users (14.6 vs 19.9 events per 1000 person-years; HR, 0.74).

There were no differences in the results with either groups of pairs based on sex, race, ethnicity, a history of chronic kidney disease, or obesity.

Of note, the magnitude of the risk reduction observed with SGLT2 inhibitors was greater in adults aged < 70 years than in those aged ≥ 70 years (HR, 0.85; P for interaction < .001).

The age-related difference could possibly be due to changes in stone composition that occurs with aging, which may influence SGLT2 inhibitor response, Dr Paik told this news organization.

“However, we did not have information on stone composition in our study.”

In the study, patients were taking, on average, more than two antidiabetic medications upon entrance to the study, with 13% taking thiazides and 12% taking loop diuretics. In addition, approximately half of patients discontinued SGLT2 inhibitors (52.6%) and DPP4 inhibitors (53.2%).

However, the results remained consistent after adjusting for those factors, Dr. Paik noted.
 

Mechanisms: Urinary Citrate Excretion?

Among key possible explanations for the lower risk of kidney stones with SGLT2 inhibitors is that the drugs have increased urinary citrate excretion, with one study showing a nearly 50% increase in urinary citrate excretion among patients treated with empagliflozin vs placebo over 4 weeks and other studies also showing similar increases.

“This increased urinary citrate excretion may play a pivotal role in decreasing stone risk by inhibiting supersaturation and crystallization of calcium crystals,” the authors explained.

In addition, the urinary citrate excretion could further play a role by “forming complexes with calcium and thus lowering urinary calcium concentration, and raising urinary pH, thereby reducing the risk of uric acid stones,” they added.

SGLT inhibitors’ anti-inflammatory effects could also reduce stone formation by “suppressing the expression of a stone core matrix protein, osteopontin, and markers of kidney injury, inflammation, and macrophages that promote stone formation,” the authors noted.

Ultimately, however, “while we found a lower risk of kidney stones in our study, we don’t fully understand how they lower the risk,” Dr. Paik said. The potential explanations “remain to be studied further.”

Either way, “the risk of kidney stones in a patient might be one additional consideration for a clinician to take into account when choosing among the different glucose-lowering agents for patients with type 2 diabetes,” Dr. Paik said.

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, the National Institute of Aging the Patient-Centered Outcomes Research Institute, the US Food and Drug Administration, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. 

A version of this article appeared on Medscape.com .

TOPLINE:

Once-weekly insulin icodec shows a higher glycated A1c reduction than once-daily basal insulin analogs in patients with type 2 diabetes (T2D), without major safety concerns.

METHODOLOGY:

• A meta-analysis of five phase 3 ONWARDS randomized controlled trials included 3764 patients with T2D.
• The trials compared the effects of the weekly insulin icodec with those of the daily basal insulin analogs glargine and degludec over 26-78 months.
• The primary outcome was the change in A1c levels.
• Secondary outcomes included fasting plasma glucose levels, A1c levels < 7%, time in target glycemic range, body weight changes, insulin dose, hypoglycemia events, and adverse events.

TAKEAWAY:

• A1c levels < 7% were observed in a higher percentage of patients in the insulin icodec group than in the comparator group (odds ratio, 1.51; P = .004).
• In subgroup analyses, insulin icodec was superior to insulin degludec by several measures but comparatively similar to glargine.
• Insulin icodec was associated with no major safety concerns and had a slightly higher incidence of levels 1, 2, and combined 2/3 than degludec but no significant differences compared with glargine.

IN PRACTICE:

“Sustained glycemic control with once-weekly injections of insulin icodec would lead to better patient acceptance and treatment satisfaction,” the authors wrote.

SOURCE:

This study, authored by Sahana Shetty, MD, and Renuka Suvarna, MSc, Manipal Academy of Higher Education, Department of Endocrinology, Kasturba Medical College, Manipal, Karnataka, was published online on January 8, 2024, in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The comparator group included individuals who used different basal insulin analogs. This heterogeneity in the comparator group introduced a potential source of variability, making it challenging to isolate the specific effects of insulin icodec compared with a standardized comparator. Blinding or masking of participants was performed in only one of the five trials.

DISCLOSURES:

The authors declared no conflicts of interest. All five clinical trials in the meta-analysis were sponsored by Novo Nordisk.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Once-weekly insulin icodec shows a higher glycated A1c reduction than once-daily basal insulin analogs in patients with type 2 diabetes (T2D), without major safety concerns.

METHODOLOGY:

• A meta-analysis of five phase 3 ONWARDS randomized controlled trials included 3764 patients with T2D.
• The trials compared the effects of the weekly insulin icodec with those of the daily basal insulin analogs glargine and degludec over 26-78 months.
• The primary outcome was the change in A1c levels.
• Secondary outcomes included fasting plasma glucose levels, A1c levels < 7%, time in target glycemic range, body weight changes, insulin dose, hypoglycemia events, and adverse events.

TAKEAWAY:

• A1c levels < 7% were observed in a higher percentage of patients in the insulin icodec group than in the comparator group (odds ratio, 1.51; P = .004).
• In subgroup analyses, insulin icodec was superior to insulin degludec by several measures but comparatively similar to glargine.
• Insulin icodec was associated with no major safety concerns and had a slightly higher incidence of levels 1, 2, and combined 2/3 than degludec but no significant differences compared with glargine.

IN PRACTICE:

“Sustained glycemic control with once-weekly injections of insulin icodec would lead to better patient acceptance and treatment satisfaction,” the authors wrote.

SOURCE:

This study, authored by Sahana Shetty, MD, and Renuka Suvarna, MSc, Manipal Academy of Higher Education, Department of Endocrinology, Kasturba Medical College, Manipal, Karnataka, was published online on January 8, 2024, in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The comparator group included individuals who used different basal insulin analogs. This heterogeneity in the comparator group introduced a potential source of variability, making it challenging to isolate the specific effects of insulin icodec compared with a standardized comparator. Blinding or masking of participants was performed in only one of the five trials.

DISCLOSURES:

The authors declared no conflicts of interest. All five clinical trials in the meta-analysis were sponsored by Novo Nordisk.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Once-weekly insulin icodec shows a higher glycated A1c reduction than once-daily basal insulin analogs in patients with type 2 diabetes (T2D), without major safety concerns.

METHODOLOGY:

• A meta-analysis of five phase 3 ONWARDS randomized controlled trials included 3764 patients with T2D.
• The trials compared the effects of the weekly insulin icodec with those of the daily basal insulin analogs glargine and degludec over 26-78 months.
• The primary outcome was the change in A1c levels.
• Secondary outcomes included fasting plasma glucose levels, A1c levels < 7%, time in target glycemic range, body weight changes, insulin dose, hypoglycemia events, and adverse events.

TAKEAWAY:

• A1c levels < 7% were observed in a higher percentage of patients in the insulin icodec group than in the comparator group (odds ratio, 1.51; P = .004).
• In subgroup analyses, insulin icodec was superior to insulin degludec by several measures but comparatively similar to glargine.
• Insulin icodec was associated with no major safety concerns and had a slightly higher incidence of levels 1, 2, and combined 2/3 than degludec but no significant differences compared with glargine.

IN PRACTICE:

“Sustained glycemic control with once-weekly injections of insulin icodec would lead to better patient acceptance and treatment satisfaction,” the authors wrote.

SOURCE:

This study, authored by Sahana Shetty, MD, and Renuka Suvarna, MSc, Manipal Academy of Higher Education, Department of Endocrinology, Kasturba Medical College, Manipal, Karnataka, was published online on January 8, 2024, in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The comparator group included individuals who used different basal insulin analogs. This heterogeneity in the comparator group introduced a potential source of variability, making it challenging to isolate the specific effects of insulin icodec compared with a standardized comparator. Blinding or masking of participants was performed in only one of the five trials.

DISCLOSURES:

The authors declared no conflicts of interest. All five clinical trials in the meta-analysis were sponsored by Novo Nordisk.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A meta-analysis showed that all doses of tirzepatide, a novel twincretin molecule, reduced albuminuria levels without affecting renal function in patients with type 2 diabetes (T2D).

METHODOLOGY:

• A meta-analysis of eight randomized controlled trials compared the effects of tirzepatide and control treatment (placebo or any active comparator) on albuminuria levels and renal function in patients with T2D.
• The pooled data included 6226 patients with T2D who received tirzepatide (5, 10, or 15 mg) and 3307 participants in the control group who received placebo, semaglutide, or insulin.
• The primary outcome was the difference in absolute change in urinary albumin-creatinine ratio (UACR) from baseline between the tirzepatide and control groups.
• The secondary efficacy endpoint was the comparative change in estimated glomerular filtration rate (eGFR) between the two groups.

TAKEAWAY:

• Overall, tirzepatide reduced UACR by ~27% (mean difference [MD], −26.9%; P < .001) compared with controls.
• The reduction in UACR was consistent across all tirzepatide doses (5 mg: MD, −23.12%; 10 mg: MD, −27.87%; 15 mg: MD, −27.15).
• Benefits of tirzepatide were even more pronounced in patients with increased albuminuria levels (UACR ≥ 30 mg/g) at baseline (MD, −41.42%; P < .001) than in controls.
• However, tirzepatide vs control treatment did not have a significant effect on eGFR levels (P = .46), which indicated no negative effect of tirzepatide on renal function.

IN PRACTICE:

“Tirzepatide seems to be a ‘rising star’ for the prevention and delaying of chronic kidney disease and related, surrogate renal outcomes in patients with T2DM,” the authors wrote.

SOURCE:

Paschalis Karakasis, MD, Aristotle University of Thessaloniki, Thessaloniki, Greece, led this study, which was published online December 20, 2023, in the journal Diabetes, Obesity and Metabolism.

LIMITATIONS:

There was significant heterogeneity between the studies. Bias may have come from the open-label design in the included randomized controlled trials. The pathophysiological mechanisms underlying the effect of tirzepatide on chronic kidney disease pathogenesis are speculative.

DISCLOSURES:

The paper did not receive any specific funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A meta-analysis showed that all doses of tirzepatide, a novel twincretin molecule, reduced albuminuria levels without affecting renal function in patients with type 2 diabetes (T2D).

METHODOLOGY:

• A meta-analysis of eight randomized controlled trials compared the effects of tirzepatide and control treatment (placebo or any active comparator) on albuminuria levels and renal function in patients with T2D.
• The pooled data included 6226 patients with T2D who received tirzepatide (5, 10, or 15 mg) and 3307 participants in the control group who received placebo, semaglutide, or insulin.
• The primary outcome was the difference in absolute change in urinary albumin-creatinine ratio (UACR) from baseline between the tirzepatide and control groups.
• The secondary efficacy endpoint was the comparative change in estimated glomerular filtration rate (eGFR) between the two groups.

TAKEAWAY:

• Overall, tirzepatide reduced UACR by ~27% (mean difference [MD], −26.9%; P < .001) compared with controls.
• The reduction in UACR was consistent across all tirzepatide doses (5 mg: MD, −23.12%; 10 mg: MD, −27.87%; 15 mg: MD, −27.15).
• Benefits of tirzepatide were even more pronounced in patients with increased albuminuria levels (UACR ≥ 30 mg/g) at baseline (MD, −41.42%; P < .001) than in controls.
• However, tirzepatide vs control treatment did not have a significant effect on eGFR levels (P = .46), which indicated no negative effect of tirzepatide on renal function.

IN PRACTICE:

“Tirzepatide seems to be a ‘rising star’ for the prevention and delaying of chronic kidney disease and related, surrogate renal outcomes in patients with T2DM,” the authors wrote.

SOURCE:

Paschalis Karakasis, MD, Aristotle University of Thessaloniki, Thessaloniki, Greece, led this study, which was published online December 20, 2023, in the journal Diabetes, Obesity and Metabolism.

LIMITATIONS:

There was significant heterogeneity between the studies. Bias may have come from the open-label design in the included randomized controlled trials. The pathophysiological mechanisms underlying the effect of tirzepatide on chronic kidney disease pathogenesis are speculative.

DISCLOSURES:

The paper did not receive any specific funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A meta-analysis showed that all doses of tirzepatide, a novel twincretin molecule, reduced albuminuria levels without affecting renal function in patients with type 2 diabetes (T2D).

METHODOLOGY:

• A meta-analysis of eight randomized controlled trials compared the effects of tirzepatide and control treatment (placebo or any active comparator) on albuminuria levels and renal function in patients with T2D.
• The pooled data included 6226 patients with T2D who received tirzepatide (5, 10, or 15 mg) and 3307 participants in the control group who received placebo, semaglutide, or insulin.
• The primary outcome was the difference in absolute change in urinary albumin-creatinine ratio (UACR) from baseline between the tirzepatide and control groups.
• The secondary efficacy endpoint was the comparative change in estimated glomerular filtration rate (eGFR) between the two groups.

TAKEAWAY:

• Overall, tirzepatide reduced UACR by ~27% (mean difference [MD], −26.9%; P < .001) compared with controls.
• The reduction in UACR was consistent across all tirzepatide doses (5 mg: MD, −23.12%; 10 mg: MD, −27.87%; 15 mg: MD, −27.15).
• Benefits of tirzepatide were even more pronounced in patients with increased albuminuria levels (UACR ≥ 30 mg/g) at baseline (MD, −41.42%; P < .001) than in controls.
• However, tirzepatide vs control treatment did not have a significant effect on eGFR levels (P = .46), which indicated no negative effect of tirzepatide on renal function.

IN PRACTICE:

“Tirzepatide seems to be a ‘rising star’ for the prevention and delaying of chronic kidney disease and related, surrogate renal outcomes in patients with T2DM,” the authors wrote.

SOURCE:

Paschalis Karakasis, MD, Aristotle University of Thessaloniki, Thessaloniki, Greece, led this study, which was published online December 20, 2023, in the journal Diabetes, Obesity and Metabolism.

LIMITATIONS:

There was significant heterogeneity between the studies. Bias may have come from the open-label design in the included randomized controlled trials. The pathophysiological mechanisms underlying the effect of tirzepatide on chronic kidney disease pathogenesis are speculative.

DISCLOSURES:

The paper did not receive any specific funding. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.

FAIRFAX, VIRGINIA — The lack of data on optimal timing of delivery for pregnancies complicated by diabetes remains a major challenge in obstetrics — one with considerable implications given the high and rising prevalence of pregestational and gestational diabetes, Katherine Laughon Grantz, MD, MS, of the National Institute of Child Health and Human Development, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“While 39-40 weeks might be ideal for low-risk pregnancies, the optimal timing for pregnancies with complications [like diabetes] is unknown,” said Dr. Grantz, a senior investigator in the NICHD’s epidemiology branch.

The percentage of mothers with gestational diabetes mellitus (GDM) increased from 6% in 2016 to 8% in 2021, according to the most recent data from the National Vital Statistics System of the Centers for Disease Control and Prevention (MMWR Morb Mortal Wkly Rep. 2023;72:16). Meanwhile, the prevalence of prepregnancy obesity, which raises the risk of gestational and type 2 diabetes, was 29% in 2019; this represents an 11% increase from 2015 (NCHS Data Brief. 2020;392:1-8) and has occurred across all maternal ages, races, ethnic groups, and educational levels, she said.

“The reason clinicians deliver pregnancies with diabetes earlier is because there’s a decreased risk of macrosomia, shoulder dystocia, and stillbirth. And these risks need to be balanced with the increased risk of neonatal morbidity and mortality associated with earlier delivery,” said Dr. Grantz, who noted during her talk that delivery timing also appears to influence long-term neurodevelopmental outcomes. “Yet despite [diabetes in pregnancy] being so common, there is complete uncertainty about when to deliver.”
 

ACOG Recommendations, Randomized Trials (New And Old)

The American College of Obstetricians and Gynecologists, in a Committee Opinion on Medically Indicated Late-Preterm and Early-Term Deliveries, published in collaboration with the Society of Maternal-Fetal Medicine, offers recommendations based on the type of diabetes and the level of control. For instance, the suggested delivery timing for well-controlled GDM is full term (39 0/7 to 40 6/7 weeks of gestation), while the recommendation for poorly controlled diabetes is individualized late preterm/early term management (Obstet Gynecol. 2021;138:e35-9).

In defining and evaluating control, she noted, “the clinical focus is on glucose, but there are likely other important parameters that are not taken into account ... which [could be] important when considering the timing of delivery.” Potentially important factors include estimated fetal weight, fetal growth velocity, lipids, and amino acids, she said.

ACOG’s recommendations are based mainly on retrospective data, Dr. Grantz said. Only two randomized controlled trials have investigated the timing of delivery in the context of diabetes, and both focused on cesarean section and were “generally underpowered to study neonatal outcomes,” she said.

The first RCT, published in 1993, enrolled 200 women with uncomplicated insulin-requiring diabetes (187 with GDM and 13 with pregestational diabetes) at 38 weeks of gestation, and compared active induction of labor within 5 days to expectant management. There was no significant difference in the cesarean delivery rate (the primary outcome), but rates of macrosomia and large for gestational age were higher in the expectant management group (27% vs. 15%, P = .05, and 23% vs. 10%, P = .02, respectively). Shoulder dystocia occurred in three deliveries, each of which was expectantly managed (Am J Obstet Gynecol. 1993;169[3]:611-5). Notably, the study included “only women with excellent glucose control,” Dr. Grantz said.

The second RCT, published in 2017 by a group in Italy, enrolled 425 patients with GDM (diagnosed by the International Association of Diabetes and Pregnancy Study Groups criteria) between week 38 and week 39 of gestation and similarly randomized them to induction of labor or expectant management. No difference in cesarean delivery was found (BJOG. 2017;124[4]:669-77). Induction of labor was associated with a higher risk of hyperbilirubinemia, and there was a trend toward a decreased risk of macrosomia, but again, the study was underpowered to detect differences in most outcomes, she said. (The study also was stopped early because of an inability to recruit, she noted.)

Dr. Grantz is currently recruiting for a randomized trial aimed at determining the optimal time between 37 and 39 weeks to initiate delivery — the time when neonatal morbidity and perinatal mortality risk is the lowest – for uncontrolled GDM-complicated pregnancies. The trial is designed to recruit up to 3,450 pregnant women with uncontrolled GDM and randomize the timing of their delivery (NCT05515744).

Those who are eligible for the study but do not consent to participate in randomization for delivery will be asked about chart review only (an estimated additional 3,000). The SPAN TIME study will also assess newborn development and behavior outcomes, as well as anthropometric measures, as secondary outcomes. An exploratory analysis will look for clinical, nonclinical or biochemical factors that could be helpful in optimizing delivery timing.

What Retrospective Studies Reveal

Factors that may influence the timing of delivery include the duration of neonatal exposure to hyperglycemia/hyperinsulinemia (pregestational vs. gestational diabetes), the level of diabetes control, and comorbidities (e.g. maternal renal disease or chronic hypertension). However, research “investigating how these factors influence morbidity and the timing of delivery is limited,” said Dr. Grantz.

Overall, it has been difficult through retrospective studies, she said, to investigate neonatal morbidity in diabetic pregnancies and tease apart the relative effects of diabetes as a precursor for early delivery and prematurity itself. Among the studies suggesting an independent risk of diabetes is a retrospective study focusing on neonatal respiratory morbidity — “one of the most common adverse outcomes associated with diabetes.”

The study, an analysis of the Consortium on Safe Labor study (an electronic medical record study of more than 220,000 singleton pregnancies), stratified morbidity by the probability of delivering at term (≥ 37 weeks). GDM and pregestational diabetes complicated 5.1% and 1.5% of the pregnancies, respectively, and were found to be associated with increased risks of neonatal respiratory morbidity compared to women without diabetes — regardless of the probability of delivering at term.

However, these associations were stronger with a higher probability of delivering at term, which suggests that the neonatal respiratory morbidity associated with diabetes is not fully explained by a greater propensity for prematurity (Am J Perinatol. 2017;34[11]:1160-8).

In addition, the rates of all neonatal respiratory morbidities and mortality were higher for pregestational diabetes compared with gestational diabetes, said Dr. Grantz, a senior author of the study. (Morbidities included neonatal intensive care unit admission, transient tachypnea of newborn, apnea, respiratory distress syndrome, mechanical ventilation, and stillbirth.)

The pathophysiology of diabetes and neonatal respiratory morbidity is “not fully known,” she said. It is believed that fetal hyperinsulinemia may cause delayed pulmonary maturation and there is evidence from animal studies that insulin decreases the incorporation of glucose and fatty acids into phospholipid phosphatidylglycerol. Indirect effects stem from the physiologic immaturity of earlier delivery and a higher cesarean delivery rate in pregnancies complicated by diabetes, Dr. Grantz said.

Among other retrospective studies was a population-based study from Canada (2004-2014), published in 2020, of large numbers of women with all types of diabetes and a comparison group of over 2.5 million without diabetes. For maternal morbidity/mortality, there were no significant differences by gestational age between iatrogenic delivery and expectant management among any form of diabetes. But for neonatal morbidity and mortality, the study found differences.

In women with gestational diabetes, iatrogenic delivery was associated with increased risk of neonatal morbidity/mortality at 36 and 37 weeks’ gestation and with decreased risk at weeks 38-40. Increased risk with iatrogenic delivery was also found for women with type 1 and type 2 diabetes at weeks 36 and 37 (Acta Obstet Gynecol Scand. 2020;99[3]:341-9).

Another retrospective study using California vital statistics (1997-2006) examined rates of stillbirth and infant death in women with GDM by gestational age at delivery (Am J Obstet Gynecol. 2012;206[4]:309.e1-e7). The 190,000-plus women with GDM had elevated risk of stillbirth at each gestational age compared to those without GDM, but “the [excess] risk for GDM was lowest at 38 weeks and again at 40 weeks,” Dr. Grantz said. The investigators concluded, she said, “that the risk of expectant management exceeded that of delivery at 38 weeks and beyond.”

Dr. Grantz reported no disclosures.

Over just a decade, sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the second-line treatment of type 2 diabetes by improving the control of blood sugar, and they’re also being used to treat heart failure and chronic kidney disease. Now, there’s growing evidence that the medications have the potential to play a role in the treatment of a variety of rheumatologic diseases — gout, systemic lupus erythematosus (SLE), and lupus nephritis.

“I suspect that SGLT2 inhibitors may have a role in multiple rheumatic diseases,” said rheumatologist April Jorge, MD, of Harvard Medical School and Massachusetts General Hospital, Boston.

Jorge_April_MA_2_web.jpg

In gout, for example, “SGLT2 inhibitors hold great promise as a multipurpose treatment option,” said rheumatologist Chio Yokose, MD, MSc, also of Harvard Medical School and Massachusetts General Hospital. Both Dr. Jorge and Dr. Yokose spoke at recent medical conferences and in interviews about the potential value of the drugs in rheumatology.
 

There’s a big caveat. For the moment, SGLT2 inhibitors aren’t cleared for use in the treatment of rheumatologic conditions, and neither physician is ready to recommend prescribing them off-label outside of their FDA-approved indications.

But studies could pave the way toward more approved uses in rheumatology. And there’s good news for now: Many rheumatology patients may already be eligible to take the drugs because of other medical conditions. In gout, for example, “sizable proportions of patients have comorbidities for which they are already indicated,” Dr. Yokose said.
 

Research Hints at Gout-Busting Potential

The first SGLT2 inhibitor canagliflozin (Invokana), received FDA approval in 2013, followed by dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro), and bexagliflozin (Brenzavvy). The drugs “lower blood sugar by causing the kidneys to remove sugar from the body through urine,” reports the National Kidney Foundation, and they “help to protect the kidneys and heart in people with CKD [chronic kidney disease].”

Yokose_Chio_MA_web.jpg

As Dr. Yokose noted in a presentation at the 2023 Gout Hyperuricemia and Crystal Associated Disease Network research symposium, SGLT2 inhibitors “have really become blockbuster drugs, and they’ve now been integrated into multiple professional society guidelines and recommendations.”

These drugs should not be confused with the wildly popular medications known as glucagon-like peptide-1 (GLP1) agonists, which include medications such as semaglutide (Ozempic and Wegovy). These drugs are generally administered via injection — unlike the oral SGLT2 inhibitors — and they’re variously indicated for type 2 diabetes and obesity.

Dr. Yokose highlighted research findings about the drugs in gout. A 2020 study, for example, tracked 295,907 US adults with type 2 diabetes who received a new prescription for an SGLT2 inhibitor or GLP1 agonist during 2013-2017. Those in the SGLT2 inhibitor group had a 36% lower risk of newly diagnosed gout (hazard ratio [HR], 0.64; 95% CI, 0.57-0.72), the researchers reported.

A similar study, a 2021 report from Taiwan, also linked SGLT2 inhibitors to improvement in gout incidence vs. dipeptidyl peptidase 4 (DPP4) inhibitors, diabetes drugs that are not linked to lower serum urate levels. In an adjusted analysis, the risk of gout was 11% lower in the SGLT2 inhibitor group (adjusted HR, 0.86; 95% CI, 0.78-0.95).

What about recurrent gout? In a 2023 study, Dr. Yokose and colleagues tracked patients with type 2 diabetes who began SGLT2 inhibitors or DPP4 inhibitors. Over the period from 2013 to 2017, those who took SGLT2 inhibitors were less likely to have gout flares (rate ratio [RR], 0.66; 95% CI, 0.57-0.75) and gout-primary emergency department visits/hospitalizations (RR, 0.52; 95% CI, 0.32-0.84).

“This finding requires further replication in other populations and compared to other drugs,” Dr. Yokose cautioned.

Another 2023 study analyzed UK data and reached similar results regarding risk of recurrent gout.

Lower Urate Levels and Less Inflammation Could Be Key

How might SGLT2 inhibitors reduce the risk of gout? Multiple studies have linked the drugs to lower serum urate levels, Dr. Yokose said, but researchers often excluded patients with gout.

For a small new study presented at the 2023 annual meeting of the American College of Rheumatology but not yet published, Dr. Yokose and colleagues reported that patients with gout who began SGLT2 inhibitors had lower urate levels than those who began a sulfonylurea, another second-line agent for type 2 diabetes. During the study period, up to 3 months before and after initiation, 43.5% of patients in the SGLT2 inhibitor group reached a target serum urate of < 6 mg/dL vs. 4.2% of sulfonylurea initiators.

“The magnitude of this reduction, while not as large as what can be achieved with appropriately titrated urate-lowering therapy such as allopurinol or febuxostat, is also not negligible. It’s believed to be between 1.5-2.0 mg/dL among patients with gout,” Dr. Yokose said. “Also, SGLT2 inhibitors are purported to have some anti-inflammatory effects that may target the same pathways responsible for the profound inflammation associated with acute gout flares. However, both the exact mechanisms underlying the serum urate-lowering and anti-inflammatory effects of SGLT2 [inhibitors] require further research and clarification.”

Moving forward, she said, “I would love to see some prospective studies of SGLT2 inhibitor use among patients with gout, looking at serum urate and clinical gout endpoints, as well as biomarkers to understand better the beneficial effects of SGLT2 inhibitors as it pertains to patients with gout.”

In Lupus, Findings Are More Mixed

Studies of SGLT2 inhibitors have excluded patients with lupus, limiting insight into their benefits in that specific population, said Dr. Jorge of Massachusetts General Hospital and Harvard Medical School. However, “one small phase I/II trial showed an acceptable safety profile of dapagliflozin add-on therapy in adult patients with SLE,” she said.

Her team is working to expand understanding about the drugs in people with lupus. At the 2023 ACR annual meeting, she presented the findings of a study that tracked patients with SLE who took SGLT2 inhibitors (n = 426, including 154 with lupus nephritis) or DPP4 inhibitors (n = 865, including 270 with lupus nephritis). Patients who took SGLT2 inhibitors had lower risks of major adverse cardiac events (HR, 0.69; 95% CI, 0.48-0.99) and renal progression (HR, 0.71; 95% CI, 0.51-0.98).

“Our results are promising, but the majority of patient with lupus who had received SGLT2 inhibitors also had the comorbidity of type 2 diabetes as a separate indication for SGLT2 inhibitor use,” Dr. Jorge said. “We still need to study the impact of SGLT2 inhibitors in patients with SLE and lupus nephritis who do not have a separate indication for the medication.”

Dr. Jorge added that “we do not yet know the ideal time to initiate SGLT2 inhibitors in the treatment of lupus nephritis. Specifically, it is not yet known whether these medications should be used in patients with persistent proteinuria due to damage from lupus nephritis or whether there is also a role to start these medications in patients with active lupus nephritis who are undergoing induction immunosuppression regimens.”

However, another study released at the 2023 ACR annual meeting suggested that SGLT2 inhibitors may not have a beneficial effect in lupus nephritis: “We observed a reduction in decline in eGFR [estimated glomerular filtration rate] after starting SGLT2 inhibitors; however, this reduction was not statistically significant … early experience suggested marginal benefit of SGLT2 inhibitors in SLE,” researchers from Johns Hopkins University, and the University of Maryland, Baltimore, reported.

“My cohort is not showing miracles from SGLT2 inhibitors,” study lead author Michelle Petri, MD, MPH, of Johns Hopkins, said in an interview.

Still, new European Alliance of Associations for Rheumatology recommendations for SLE now advise to consider the use of the drugs in patients with lupus nephritis who have reduced eGFR. Meanwhile, “the American College of Rheumatology is currently developing new treatment guidelines for SLE and for lupus nephritis, and SGLT2 inhibitors will likely be a topic of consideration,” Dr. Jorge added.

As for mechanism, Dr. Jorge said it’s not clear how the drugs may affect lupus. “It’s proposed that they have benefits in hemodynamic effects as well as potentially anti-inflammatory effects. The hemodynamic effects, including reducing intraglomerular hyperfiltration and reducing blood pressure, likely have similar benefits in patients with chronic kidney disease due to diabetic nephropathy or due to lupus nephritis with damage/scarring and persistent proteinuria. Patients with SLE and other chronic, systemic rheumatic diseases such as ANCA [antineutrophilic cytoplasmic antibody]-associated vasculitis also develop kidney disease and cardiovascular events mediated by inflammatory processes.”
 

Side Effects and Cost: Where Do They Fit In?

According to Dr. Yokose, SGLT2 inhibitors “are generally quite well-tolerated, and very serious adverse effects are rare.” Side effects include disrupted urination, increased thirst, genital infections, flu-like symptoms, and swelling.

Urinary-related problems are understandable “because these drugs cause the kidneys to pass more glucose into the urine,” University of Hong Kong cardiac specialist Bernard Cheung, MBBCh, PhD, who has studied SGLT2 inhibitors, said in an interview.

In Dr. Yokose’s 2023 study of SGLT2 inhibitors in recurrent gout, patients who took the drugs were 2.15 times more likely than the comparison group to have genital infections (hazard ratio, 2.15; 95% CI, 1.39-3.30). This finding “was what we’d expect,” she said.

She added that genital infection rates were higher among patients with diabetes, women, and uncircumcised men. “Fortunately, most experienced just a single mild episode that can readily be treated with topical therapy. There does not appear to be an increased risk of urinary tract infections.”

Dr. Cheung added that “doctors should be aware of a rare adverse effect called euglycemic ketoacidosis, in which the patient has increased ketones in the blood causing it to be more acidic than normal, but the blood glucose remains within the normal range.”

As for cost, goodrx.com reports that several SGLT2 inhibitors run about $550-$683 per month, making them expensive but still cheaper than GLP-1 agonists, which can cost $1,000 or more per month. Unlike the most popular GLP-1 agonists such as Ozempic, none of the SGLT2 inhibitors are in short supply, according to the American Society of Health-System Pharmacists.

“If someone with gout already has a cardiovascular-kidney-metabolic indication for SGLT2 inhibitors and also stands to benefit in terms of lowering serum urate and risk of recurrent gout flares, there is potential for high benefit relative to cost,” Dr. Yokose said.

She added: “It is well-documented that current gout care is suboptimal, and many patients end up in the emergency room or hospitalized for gout, which in and of itself is quite costly both for the patient and the health care system. Therefore, streamlining or integrating gout and comorbidity care with SGLT2 inhibitors could potentially be quite beneficial for patients with gout.”

In regard to lupus, “many patients with lupus undergo multiple hospitalizations related to their disease, which is a source of high health care costs,” Dr. Jorge said. “Additionally, chronic kidney disease and cardiovascular disease are major causes of disability and premature mortality. Further studies will be needed to better understand whether benefits of SGLT2 inhibitors may outweigh the costs of treatment.”

As for prescribing the drugs in lupus now, Dr. Jorge said they can be an option in lupus nephritis. “There is not a clear consensus of the ideal timing to initiate SGLT2 inhibitors — e.g., degree of proteinuria or eGFR range,” she said. “However, it is less controversial that SGLT2 inhibitors should be considered in particular for patients with lupus nephritis with ongoing proteinuria despite adequate treatment with conventional therapies.”

As for gout, Dr. Yokose isn’t ready to prescribe the drugs to patients who don’t have comorbidities that can be treated by the medications. However, she noted that those patients are rare.

“If I see a patient with gout with one or more of these comorbidities, and I see that they are not already on an SGLT2 inhibitor, I definitely take the time to talk to the patient about this exciting class of drugs and will consult with their other physicians about getting them started on an SGLT2 inhibitor.”

Dr. Yokose, Dr. Petri, and Dr. Cheung have no relevant disclosures. Dr. Jorge disclosed serving as a site investigator for SLE clinical trials funded by Bristol-Myers Squibb and Cabaletta Bio; the trials are not related to SGLT2 inhibitors.

Over just a decade, sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the second-line treatment of type 2 diabetes by improving the control of blood sugar, and they’re also being used to treat heart failure and chronic kidney disease. Now, there’s growing evidence that the medications have the potential to play a role in the treatment of a variety of rheumatologic diseases — gout, systemic lupus erythematosus (SLE), and lupus nephritis.

“I suspect that SGLT2 inhibitors may have a role in multiple rheumatic diseases,” said rheumatologist April Jorge, MD, of Harvard Medical School and Massachusetts General Hospital, Boston.

Jorge_April_MA_2_web.jpg

In gout, for example, “SGLT2 inhibitors hold great promise as a multipurpose treatment option,” said rheumatologist Chio Yokose, MD, MSc, also of Harvard Medical School and Massachusetts General Hospital. Both Dr. Jorge and Dr. Yokose spoke at recent medical conferences and in interviews about the potential value of the drugs in rheumatology.
 

There’s a big caveat. For the moment, SGLT2 inhibitors aren’t cleared for use in the treatment of rheumatologic conditions, and neither physician is ready to recommend prescribing them off-label outside of their FDA-approved indications.

But studies could pave the way toward more approved uses in rheumatology. And there’s good news for now: Many rheumatology patients may already be eligible to take the drugs because of other medical conditions. In gout, for example, “sizable proportions of patients have comorbidities for which they are already indicated,” Dr. Yokose said.
 

Research Hints at Gout-Busting Potential

The first SGLT2 inhibitor canagliflozin (Invokana), received FDA approval in 2013, followed by dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro), and bexagliflozin (Brenzavvy). The drugs “lower blood sugar by causing the kidneys to remove sugar from the body through urine,” reports the National Kidney Foundation, and they “help to protect the kidneys and heart in people with CKD [chronic kidney disease].”

Yokose_Chio_MA_web.jpg

As Dr. Yokose noted in a presentation at the 2023 Gout Hyperuricemia and Crystal Associated Disease Network research symposium, SGLT2 inhibitors “have really become blockbuster drugs, and they’ve now been integrated into multiple professional society guidelines and recommendations.”

These drugs should not be confused with the wildly popular medications known as glucagon-like peptide-1 (GLP1) agonists, which include medications such as semaglutide (Ozempic and Wegovy). These drugs are generally administered via injection — unlike the oral SGLT2 inhibitors — and they’re variously indicated for type 2 diabetes and obesity.

Dr. Yokose highlighted research findings about the drugs in gout. A 2020 study, for example, tracked 295,907 US adults with type 2 diabetes who received a new prescription for an SGLT2 inhibitor or GLP1 agonist during 2013-2017. Those in the SGLT2 inhibitor group had a 36% lower risk of newly diagnosed gout (hazard ratio [HR], 0.64; 95% CI, 0.57-0.72), the researchers reported.

A similar study, a 2021 report from Taiwan, also linked SGLT2 inhibitors to improvement in gout incidence vs. dipeptidyl peptidase 4 (DPP4) inhibitors, diabetes drugs that are not linked to lower serum urate levels. In an adjusted analysis, the risk of gout was 11% lower in the SGLT2 inhibitor group (adjusted HR, 0.86; 95% CI, 0.78-0.95).

What about recurrent gout? In a 2023 study, Dr. Yokose and colleagues tracked patients with type 2 diabetes who began SGLT2 inhibitors or DPP4 inhibitors. Over the period from 2013 to 2017, those who took SGLT2 inhibitors were less likely to have gout flares (rate ratio [RR], 0.66; 95% CI, 0.57-0.75) and gout-primary emergency department visits/hospitalizations (RR, 0.52; 95% CI, 0.32-0.84).

“This finding requires further replication in other populations and compared to other drugs,” Dr. Yokose cautioned.

Another 2023 study analyzed UK data and reached similar results regarding risk of recurrent gout.

Lower Urate Levels and Less Inflammation Could Be Key

How might SGLT2 inhibitors reduce the risk of gout? Multiple studies have linked the drugs to lower serum urate levels, Dr. Yokose said, but researchers often excluded patients with gout.

For a small new study presented at the 2023 annual meeting of the American College of Rheumatology but not yet published, Dr. Yokose and colleagues reported that patients with gout who began SGLT2 inhibitors had lower urate levels than those who began a sulfonylurea, another second-line agent for type 2 diabetes. During the study period, up to 3 months before and after initiation, 43.5% of patients in the SGLT2 inhibitor group reached a target serum urate of < 6 mg/dL vs. 4.2% of sulfonylurea initiators.

“The magnitude of this reduction, while not as large as what can be achieved with appropriately titrated urate-lowering therapy such as allopurinol or febuxostat, is also not negligible. It’s believed to be between 1.5-2.0 mg/dL among patients with gout,” Dr. Yokose said. “Also, SGLT2 inhibitors are purported to have some anti-inflammatory effects that may target the same pathways responsible for the profound inflammation associated with acute gout flares. However, both the exact mechanisms underlying the serum urate-lowering and anti-inflammatory effects of SGLT2 [inhibitors] require further research and clarification.”

Moving forward, she said, “I would love to see some prospective studies of SGLT2 inhibitor use among patients with gout, looking at serum urate and clinical gout endpoints, as well as biomarkers to understand better the beneficial effects of SGLT2 inhibitors as it pertains to patients with gout.”

In Lupus, Findings Are More Mixed

Studies of SGLT2 inhibitors have excluded patients with lupus, limiting insight into their benefits in that specific population, said Dr. Jorge of Massachusetts General Hospital and Harvard Medical School. However, “one small phase I/II trial showed an acceptable safety profile of dapagliflozin add-on therapy in adult patients with SLE,” she said.

Her team is working to expand understanding about the drugs in people with lupus. At the 2023 ACR annual meeting, she presented the findings of a study that tracked patients with SLE who took SGLT2 inhibitors (n = 426, including 154 with lupus nephritis) or DPP4 inhibitors (n = 865, including 270 with lupus nephritis). Patients who took SGLT2 inhibitors had lower risks of major adverse cardiac events (HR, 0.69; 95% CI, 0.48-0.99) and renal progression (HR, 0.71; 95% CI, 0.51-0.98).

“Our results are promising, but the majority of patient with lupus who had received SGLT2 inhibitors also had the comorbidity of type 2 diabetes as a separate indication for SGLT2 inhibitor use,” Dr. Jorge said. “We still need to study the impact of SGLT2 inhibitors in patients with SLE and lupus nephritis who do not have a separate indication for the medication.”

Dr. Jorge added that “we do not yet know the ideal time to initiate SGLT2 inhibitors in the treatment of lupus nephritis. Specifically, it is not yet known whether these medications should be used in patients with persistent proteinuria due to damage from lupus nephritis or whether there is also a role to start these medications in patients with active lupus nephritis who are undergoing induction immunosuppression regimens.”

However, another study released at the 2023 ACR annual meeting suggested that SGLT2 inhibitors may not have a beneficial effect in lupus nephritis: “We observed a reduction in decline in eGFR [estimated glomerular filtration rate] after starting SGLT2 inhibitors; however, this reduction was not statistically significant … early experience suggested marginal benefit of SGLT2 inhibitors in SLE,” researchers from Johns Hopkins University, and the University of Maryland, Baltimore, reported.

“My cohort is not showing miracles from SGLT2 inhibitors,” study lead author Michelle Petri, MD, MPH, of Johns Hopkins, said in an interview.

Still, new European Alliance of Associations for Rheumatology recommendations for SLE now advise to consider the use of the drugs in patients with lupus nephritis who have reduced eGFR. Meanwhile, “the American College of Rheumatology is currently developing new treatment guidelines for SLE and for lupus nephritis, and SGLT2 inhibitors will likely be a topic of consideration,” Dr. Jorge added.

As for mechanism, Dr. Jorge said it’s not clear how the drugs may affect lupus. “It’s proposed that they have benefits in hemodynamic effects as well as potentially anti-inflammatory effects. The hemodynamic effects, including reducing intraglomerular hyperfiltration and reducing blood pressure, likely have similar benefits in patients with chronic kidney disease due to diabetic nephropathy or due to lupus nephritis with damage/scarring and persistent proteinuria. Patients with SLE and other chronic, systemic rheumatic diseases such as ANCA [antineutrophilic cytoplasmic antibody]-associated vasculitis also develop kidney disease and cardiovascular events mediated by inflammatory processes.”
 

Side Effects and Cost: Where Do They Fit In?

According to Dr. Yokose, SGLT2 inhibitors “are generally quite well-tolerated, and very serious adverse effects are rare.” Side effects include disrupted urination, increased thirst, genital infections, flu-like symptoms, and swelling.

Urinary-related problems are understandable “because these drugs cause the kidneys to pass more glucose into the urine,” University of Hong Kong cardiac specialist Bernard Cheung, MBBCh, PhD, who has studied SGLT2 inhibitors, said in an interview.

In Dr. Yokose’s 2023 study of SGLT2 inhibitors in recurrent gout, patients who took the drugs were 2.15 times more likely than the comparison group to have genital infections (hazard ratio, 2.15; 95% CI, 1.39-3.30). This finding “was what we’d expect,” she said.

She added that genital infection rates were higher among patients with diabetes, women, and uncircumcised men. “Fortunately, most experienced just a single mild episode that can readily be treated with topical therapy. There does not appear to be an increased risk of urinary tract infections.”

Dr. Cheung added that “doctors should be aware of a rare adverse effect called euglycemic ketoacidosis, in which the patient has increased ketones in the blood causing it to be more acidic than normal, but the blood glucose remains within the normal range.”

As for cost, goodrx.com reports that several SGLT2 inhibitors run about $550-$683 per month, making them expensive but still cheaper than GLP-1 agonists, which can cost $1,000 or more per month. Unlike the most popular GLP-1 agonists such as Ozempic, none of the SGLT2 inhibitors are in short supply, according to the American Society of Health-System Pharmacists.

“If someone with gout already has a cardiovascular-kidney-metabolic indication for SGLT2 inhibitors and also stands to benefit in terms of lowering serum urate and risk of recurrent gout flares, there is potential for high benefit relative to cost,” Dr. Yokose said.

She added: “It is well-documented that current gout care is suboptimal, and many patients end up in the emergency room or hospitalized for gout, which in and of itself is quite costly both for the patient and the health care system. Therefore, streamlining or integrating gout and comorbidity care with SGLT2 inhibitors could potentially be quite beneficial for patients with gout.”

In regard to lupus, “many patients with lupus undergo multiple hospitalizations related to their disease, which is a source of high health care costs,” Dr. Jorge said. “Additionally, chronic kidney disease and cardiovascular disease are major causes of disability and premature mortality. Further studies will be needed to better understand whether benefits of SGLT2 inhibitors may outweigh the costs of treatment.”

As for prescribing the drugs in lupus now, Dr. Jorge said they can be an option in lupus nephritis. “There is not a clear consensus of the ideal timing to initiate SGLT2 inhibitors — e.g., degree of proteinuria or eGFR range,” she said. “However, it is less controversial that SGLT2 inhibitors should be considered in particular for patients with lupus nephritis with ongoing proteinuria despite adequate treatment with conventional therapies.”

As for gout, Dr. Yokose isn’t ready to prescribe the drugs to patients who don’t have comorbidities that can be treated by the medications. However, she noted that those patients are rare.

“If I see a patient with gout with one or more of these comorbidities, and I see that they are not already on an SGLT2 inhibitor, I definitely take the time to talk to the patient about this exciting class of drugs and will consult with their other physicians about getting them started on an SGLT2 inhibitor.”

Dr. Yokose, Dr. Petri, and Dr. Cheung have no relevant disclosures. Dr. Jorge disclosed serving as a site investigator for SLE clinical trials funded by Bristol-Myers Squibb and Cabaletta Bio; the trials are not related to SGLT2 inhibitors.

Over just a decade, sodium-glucose cotransporter-2 (SGLT2) inhibitors have revolutionized the second-line treatment of type 2 diabetes by improving the control of blood sugar, and they’re also being used to treat heart failure and chronic kidney disease. Now, there’s growing evidence that the medications have the potential to play a role in the treatment of a variety of rheumatologic diseases — gout, systemic lupus erythematosus (SLE), and lupus nephritis.

“I suspect that SGLT2 inhibitors may have a role in multiple rheumatic diseases,” said rheumatologist April Jorge, MD, of Harvard Medical School and Massachusetts General Hospital, Boston.

Jorge_April_MA_2_web.jpg

In gout, for example, “SGLT2 inhibitors hold great promise as a multipurpose treatment option,” said rheumatologist Chio Yokose, MD, MSc, also of Harvard Medical School and Massachusetts General Hospital. Both Dr. Jorge and Dr. Yokose spoke at recent medical conferences and in interviews about the potential value of the drugs in rheumatology.
 

There’s a big caveat. For the moment, SGLT2 inhibitors aren’t cleared for use in the treatment of rheumatologic conditions, and neither physician is ready to recommend prescribing them off-label outside of their FDA-approved indications.

But studies could pave the way toward more approved uses in rheumatology. And there’s good news for now: Many rheumatology patients may already be eligible to take the drugs because of other medical conditions. In gout, for example, “sizable proportions of patients have comorbidities for which they are already indicated,” Dr. Yokose said.
 

Research Hints at Gout-Busting Potential

The first SGLT2 inhibitor canagliflozin (Invokana), received FDA approval in 2013, followed by dapagliflozin (Farxiga), empagliflozin (Jardiance), ertugliflozin (Steglatro), and bexagliflozin (Brenzavvy). The drugs “lower blood sugar by causing the kidneys to remove sugar from the body through urine,” reports the National Kidney Foundation, and they “help to protect the kidneys and heart in people with CKD [chronic kidney disease].”

Yokose_Chio_MA_web.jpg

As Dr. Yokose noted in a presentation at the 2023 Gout Hyperuricemia and Crystal Associated Disease Network research symposium, SGLT2 inhibitors “have really become blockbuster drugs, and they’ve now been integrated into multiple professional society guidelines and recommendations.”

These drugs should not be confused with the wildly popular medications known as glucagon-like peptide-1 (GLP1) agonists, which include medications such as semaglutide (Ozempic and Wegovy). These drugs are generally administered via injection — unlike the oral SGLT2 inhibitors — and they’re variously indicated for type 2 diabetes and obesity.

Dr. Yokose highlighted research findings about the drugs in gout. A 2020 study, for example, tracked 295,907 US adults with type 2 diabetes who received a new prescription for an SGLT2 inhibitor or GLP1 agonist during 2013-2017. Those in the SGLT2 inhibitor group had a 36% lower risk of newly diagnosed gout (hazard ratio [HR], 0.64; 95% CI, 0.57-0.72), the researchers reported.

A similar study, a 2021 report from Taiwan, also linked SGLT2 inhibitors to improvement in gout incidence vs. dipeptidyl peptidase 4 (DPP4) inhibitors, diabetes drugs that are not linked to lower serum urate levels. In an adjusted analysis, the risk of gout was 11% lower in the SGLT2 inhibitor group (adjusted HR, 0.86; 95% CI, 0.78-0.95).

What about recurrent gout? In a 2023 study, Dr. Yokose and colleagues tracked patients with type 2 diabetes who began SGLT2 inhibitors or DPP4 inhibitors. Over the period from 2013 to 2017, those who took SGLT2 inhibitors were less likely to have gout flares (rate ratio [RR], 0.66; 95% CI, 0.57-0.75) and gout-primary emergency department visits/hospitalizations (RR, 0.52; 95% CI, 0.32-0.84).

“This finding requires further replication in other populations and compared to other drugs,” Dr. Yokose cautioned.

Another 2023 study analyzed UK data and reached similar results regarding risk of recurrent gout.

Lower Urate Levels and Less Inflammation Could Be Key

How might SGLT2 inhibitors reduce the risk of gout? Multiple studies have linked the drugs to lower serum urate levels, Dr. Yokose said, but researchers often excluded patients with gout.

For a small new study presented at the 2023 annual meeting of the American College of Rheumatology but not yet published, Dr. Yokose and colleagues reported that patients with gout who began SGLT2 inhibitors had lower urate levels than those who began a sulfonylurea, another second-line agent for type 2 diabetes. During the study period, up to 3 months before and after initiation, 43.5% of patients in the SGLT2 inhibitor group reached a target serum urate of < 6 mg/dL vs. 4.2% of sulfonylurea initiators.

“The magnitude of this reduction, while not as large as what can be achieved with appropriately titrated urate-lowering therapy such as allopurinol or febuxostat, is also not negligible. It’s believed to be between 1.5-2.0 mg/dL among patients with gout,” Dr. Yokose said. “Also, SGLT2 inhibitors are purported to have some anti-inflammatory effects that may target the same pathways responsible for the profound inflammation associated with acute gout flares. However, both the exact mechanisms underlying the serum urate-lowering and anti-inflammatory effects of SGLT2 [inhibitors] require further research and clarification.”

Moving forward, she said, “I would love to see some prospective studies of SGLT2 inhibitor use among patients with gout, looking at serum urate and clinical gout endpoints, as well as biomarkers to understand better the beneficial effects of SGLT2 inhibitors as it pertains to patients with gout.”

In Lupus, Findings Are More Mixed

Studies of SGLT2 inhibitors have excluded patients with lupus, limiting insight into their benefits in that specific population, said Dr. Jorge of Massachusetts General Hospital and Harvard Medical School. However, “one small phase I/II trial showed an acceptable safety profile of dapagliflozin add-on therapy in adult patients with SLE,” she said.

Her team is working to expand understanding about the drugs in people with lupus. At the 2023 ACR annual meeting, she presented the findings of a study that tracked patients with SLE who took SGLT2 inhibitors (n = 426, including 154 with lupus nephritis) or DPP4 inhibitors (n = 865, including 270 with lupus nephritis). Patients who took SGLT2 inhibitors had lower risks of major adverse cardiac events (HR, 0.69; 95% CI, 0.48-0.99) and renal progression (HR, 0.71; 95% CI, 0.51-0.98).

“Our results are promising, but the majority of patient with lupus who had received SGLT2 inhibitors also had the comorbidity of type 2 diabetes as a separate indication for SGLT2 inhibitor use,” Dr. Jorge said. “We still need to study the impact of SGLT2 inhibitors in patients with SLE and lupus nephritis who do not have a separate indication for the medication.”

Dr. Jorge added that “we do not yet know the ideal time to initiate SGLT2 inhibitors in the treatment of lupus nephritis. Specifically, it is not yet known whether these medications should be used in patients with persistent proteinuria due to damage from lupus nephritis or whether there is also a role to start these medications in patients with active lupus nephritis who are undergoing induction immunosuppression regimens.”

However, another study released at the 2023 ACR annual meeting suggested that SGLT2 inhibitors may not have a beneficial effect in lupus nephritis: “We observed a reduction in decline in eGFR [estimated glomerular filtration rate] after starting SGLT2 inhibitors; however, this reduction was not statistically significant … early experience suggested marginal benefit of SGLT2 inhibitors in SLE,” researchers from Johns Hopkins University, and the University of Maryland, Baltimore, reported.

“My cohort is not showing miracles from SGLT2 inhibitors,” study lead author Michelle Petri, MD, MPH, of Johns Hopkins, said in an interview.

Still, new European Alliance of Associations for Rheumatology recommendations for SLE now advise to consider the use of the drugs in patients with lupus nephritis who have reduced eGFR. Meanwhile, “the American College of Rheumatology is currently developing new treatment guidelines for SLE and for lupus nephritis, and SGLT2 inhibitors will likely be a topic of consideration,” Dr. Jorge added.

As for mechanism, Dr. Jorge said it’s not clear how the drugs may affect lupus. “It’s proposed that they have benefits in hemodynamic effects as well as potentially anti-inflammatory effects. The hemodynamic effects, including reducing intraglomerular hyperfiltration and reducing blood pressure, likely have similar benefits in patients with chronic kidney disease due to diabetic nephropathy or due to lupus nephritis with damage/scarring and persistent proteinuria. Patients with SLE and other chronic, systemic rheumatic diseases such as ANCA [antineutrophilic cytoplasmic antibody]-associated vasculitis also develop kidney disease and cardiovascular events mediated by inflammatory processes.”
 

Side Effects and Cost: Where Do They Fit In?

According to Dr. Yokose, SGLT2 inhibitors “are generally quite well-tolerated, and very serious adverse effects are rare.” Side effects include disrupted urination, increased thirst, genital infections, flu-like symptoms, and swelling.

Urinary-related problems are understandable “because these drugs cause the kidneys to pass more glucose into the urine,” University of Hong Kong cardiac specialist Bernard Cheung, MBBCh, PhD, who has studied SGLT2 inhibitors, said in an interview.

In Dr. Yokose’s 2023 study of SGLT2 inhibitors in recurrent gout, patients who took the drugs were 2.15 times more likely than the comparison group to have genital infections (hazard ratio, 2.15; 95% CI, 1.39-3.30). This finding “was what we’d expect,” she said.

She added that genital infection rates were higher among patients with diabetes, women, and uncircumcised men. “Fortunately, most experienced just a single mild episode that can readily be treated with topical therapy. There does not appear to be an increased risk of urinary tract infections.”

Dr. Cheung added that “doctors should be aware of a rare adverse effect called euglycemic ketoacidosis, in which the patient has increased ketones in the blood causing it to be more acidic than normal, but the blood glucose remains within the normal range.”

As for cost, goodrx.com reports that several SGLT2 inhibitors run about $550-$683 per month, making them expensive but still cheaper than GLP-1 agonists, which can cost $1,000 or more per month. Unlike the most popular GLP-1 agonists such as Ozempic, none of the SGLT2 inhibitors are in short supply, according to the American Society of Health-System Pharmacists.

“If someone with gout already has a cardiovascular-kidney-metabolic indication for SGLT2 inhibitors and also stands to benefit in terms of lowering serum urate and risk of recurrent gout flares, there is potential for high benefit relative to cost,” Dr. Yokose said.

She added: “It is well-documented that current gout care is suboptimal, and many patients end up in the emergency room or hospitalized for gout, which in and of itself is quite costly both for the patient and the health care system. Therefore, streamlining or integrating gout and comorbidity care with SGLT2 inhibitors could potentially be quite beneficial for patients with gout.”

In regard to lupus, “many patients with lupus undergo multiple hospitalizations related to their disease, which is a source of high health care costs,” Dr. Jorge said. “Additionally, chronic kidney disease and cardiovascular disease are major causes of disability and premature mortality. Further studies will be needed to better understand whether benefits of SGLT2 inhibitors may outweigh the costs of treatment.”

As for prescribing the drugs in lupus now, Dr. Jorge said they can be an option in lupus nephritis. “There is not a clear consensus of the ideal timing to initiate SGLT2 inhibitors — e.g., degree of proteinuria or eGFR range,” she said. “However, it is less controversial that SGLT2 inhibitors should be considered in particular for patients with lupus nephritis with ongoing proteinuria despite adequate treatment with conventional therapies.”

As for gout, Dr. Yokose isn’t ready to prescribe the drugs to patients who don’t have comorbidities that can be treated by the medications. However, she noted that those patients are rare.

“If I see a patient with gout with one or more of these comorbidities, and I see that they are not already on an SGLT2 inhibitor, I definitely take the time to talk to the patient about this exciting class of drugs and will consult with their other physicians about getting them started on an SGLT2 inhibitor.”

Dr. Yokose, Dr. Petri, and Dr. Cheung have no relevant disclosures. Dr. Jorge disclosed serving as a site investigator for SLE clinical trials funded by Bristol-Myers Squibb and Cabaletta Bio; the trials are not related to SGLT2 inhibitors.

Walking is a simple, cost-free form of exercise that benefits physical, social, and mental health in many ways. Several clinical trials have shown that walking regularly is associated with a lower risk for cardiovascular events and all-cause mortality, and having a higher daily step count is linked to a decreased risk for premature death.

Walking and Diabetes

In recent years, the link between walking speed and the risk for multiple health problems has sparked keen interest. Data suggest that a faster walking pace may have a greater physiological response and may be associated with more favorable health advantages than a slow walking pace. A previous meta-analysis of eight cohort studies suggested that individuals in the fastest walking-pace category (median = 5.6 km/h) had a 44% lower risk for stroke than those in the slowest walking-pace category (median = 1.6 km/h). The risk for the former decreased by 13% for every 1 km/h increment in baseline walking pace.

Type 2 diabetes (T2D) is one of the most common metabolic diseases in the world. People with this type of diabetes have an increased risk for microvascular and macrovascular complications and a shorter life expectancy. Approximately 537 million adults are estimated to be living with diabetes worldwide, and this number is expected to reach 783 million by 2045.

Physical activity is an essential component of T2D prevention programs and can favorably affect blood sugar control. A meta-analysis of cohort studies showed that being physically active was associated with a 35% reduction in the risk of acquiring T2D in the general population, and regular walking was associated with a 15% reduction in the risk of developing T2D.

However, no studies have investigated the link between different walking speeds and the risk for T2D. A team from the Research Center at the Semnan University of Medical Sciences in Iran carried out a systematic review of the association between walking speed and the risk of developing T2D in adults; this review was published in the British Journal of Sports Medicine.
 

10 Cohort Studies

This systematic review used publications (1999-2022) available in the usual data sources (PubMed, Scopus, CENTRAL, and Web of Science). Random-effects meta-analyses were used to calculate relative risk (RR) and risk difference (RD) based on different walking speeds. The researchers rated the credibility of subgroup differences and the certainty of evidence using the Instrument to assess the Credibility of Effect Modification ANalyses (ICEMAN) and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools, respectively.

Of the 508,121 potential participants, 18,410 adults from 10 prospective cohort studies conducted in the United States, Japan, and the United Kingdom were deemed eligible. The proportion of women was between 52% and 73%, depending on the cohort. Follow-up duration varied from 3 to 11.1 years (median, 8 years).

Five cohort studies measured walking speed using stopwatch testing, while the other five used self-assessed questionnaires. To define cases of T2D, seven studies used objective methods such as blood glucose measurement or linkage with medical records, and in three cohorts, self-assessment questionnaires were used (these were checked against patient records). All studies controlled age, sex, and tobacco consumption in the multivariate analyses, and some controlled just alcohol consumption, blood pressure, total physical activity volume, body mass index, time spent walking or daily step count, and a family history of diabetes.

The Right Speed

The authors first categorized walking speed into four prespecified levels: Easy or casual (< 2 mph or 3.2 km/h), average or normal (2-3 mph or 3.2-4.8 km/h), fairly brisk (3-4 mph or 4.8-6.4 km/h), and very brisk or brisk/striding (> 4 mph or > 6.4 km/h).

Four cohort studies with 6,520 cases of T2D among 160,321 participants reported information on average or normal walking. Participants with average or normal walking were at a 15% lower risk for T2D than those with easy or casual walking (RR = 0.85 [95% CI, 0.70-1.00]; RD = 0.86 [1.72-0]). Ten cohort studies with 18,410 cases among 508,121 participants reported information on fairly brisk walking. Those with fairly brisk walking were at a 24% lower risk for T2D than those with easy or casual walking (RR = 0.76 [0.65-0.87]; I2 = 90%; RD = 1.38 [2.01-0.75]).

There was no significant or credible subgroup difference by adjustment for the total physical activity or time spent walking per day. The dose-response analysis suggested that the risk for T2D decreased significantly at a walking speed of 4 km/h and above.

Study Limitations

This meta-analysis has strengths that may increase the generalizability of its results. The researchers included cohort studies, which allowed them to consider the temporal sequence of exposure and outcome. Cohort studies are less affected by recall and selection biases compared with retrospective case–control studies, which increase the likelihood of causality. The researchers also assessed the credibility of subgroup differences using the recently developed ICEMAN tool, calculated both relative and absolute risks, and rated the certainty of evidence using the GRADE approach.

Some shortcomings must be considered. Most of the studies included in the present review were rated as having a serious risk for bias, with the most important biases resulting from inadequate adjustment for potential confounders and the methods used for walking speed assessment and diagnosis of T2D. In addition, the findings could have been subject to reverse causality bias because participants with faster walking speed are more likely to perform more physical activity and have better cardiorespiratory fitness, greater muscle mass, and better health status. However, the subgroup analyses of fairly brisk and brisk/striding walking indicated that there were no significant subgroup differences by follow-up duration and that the significant inverse associations remained stable in the subgroup of cohort studies with a follow-up duration of > 10 years.

The authors concluded that “the present meta-analysis of cohort studies suggested that fairly brisk and brisk/striding walking, independent of the total volume of physical activity or time spent walking per day, may be associated with a lower risk of T2D in adults. While current strategies to increase total walking time are beneficial, it may also be reasonable to encourage people to walk at faster speeds to further increase the health benefits of walking.”

This article was translated from JIM, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

Walking is a simple, cost-free form of exercise that benefits physical, social, and mental health in many ways. Several clinical trials have shown that walking regularly is associated with a lower risk for cardiovascular events and all-cause mortality, and having a higher daily step count is linked to a decreased risk for premature death.

Walking and Diabetes

In recent years, the link between walking speed and the risk for multiple health problems has sparked keen interest. Data suggest that a faster walking pace may have a greater physiological response and may be associated with more favorable health advantages than a slow walking pace. A previous meta-analysis of eight cohort studies suggested that individuals in the fastest walking-pace category (median = 5.6 km/h) had a 44% lower risk for stroke than those in the slowest walking-pace category (median = 1.6 km/h). The risk for the former decreased by 13% for every 1 km/h increment in baseline walking pace.

Type 2 diabetes (T2D) is one of the most common metabolic diseases in the world. People with this type of diabetes have an increased risk for microvascular and macrovascular complications and a shorter life expectancy. Approximately 537 million adults are estimated to be living with diabetes worldwide, and this number is expected to reach 783 million by 2045.

Physical activity is an essential component of T2D prevention programs and can favorably affect blood sugar control. A meta-analysis of cohort studies showed that being physically active was associated with a 35% reduction in the risk of acquiring T2D in the general population, and regular walking was associated with a 15% reduction in the risk of developing T2D.

However, no studies have investigated the link between different walking speeds and the risk for T2D. A team from the Research Center at the Semnan University of Medical Sciences in Iran carried out a systematic review of the association between walking speed and the risk of developing T2D in adults; this review was published in the British Journal of Sports Medicine.
 

10 Cohort Studies

This systematic review used publications (1999-2022) available in the usual data sources (PubMed, Scopus, CENTRAL, and Web of Science). Random-effects meta-analyses were used to calculate relative risk (RR) and risk difference (RD) based on different walking speeds. The researchers rated the credibility of subgroup differences and the certainty of evidence using the Instrument to assess the Credibility of Effect Modification ANalyses (ICEMAN) and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools, respectively.

Of the 508,121 potential participants, 18,410 adults from 10 prospective cohort studies conducted in the United States, Japan, and the United Kingdom were deemed eligible. The proportion of women was between 52% and 73%, depending on the cohort. Follow-up duration varied from 3 to 11.1 years (median, 8 years).

Five cohort studies measured walking speed using stopwatch testing, while the other five used self-assessed questionnaires. To define cases of T2D, seven studies used objective methods such as blood glucose measurement or linkage with medical records, and in three cohorts, self-assessment questionnaires were used (these were checked against patient records). All studies controlled age, sex, and tobacco consumption in the multivariate analyses, and some controlled just alcohol consumption, blood pressure, total physical activity volume, body mass index, time spent walking or daily step count, and a family history of diabetes.

The Right Speed

The authors first categorized walking speed into four prespecified levels: Easy or casual (< 2 mph or 3.2 km/h), average or normal (2-3 mph or 3.2-4.8 km/h), fairly brisk (3-4 mph or 4.8-6.4 km/h), and very brisk or brisk/striding (> 4 mph or > 6.4 km/h).

Four cohort studies with 6,520 cases of T2D among 160,321 participants reported information on average or normal walking. Participants with average or normal walking were at a 15% lower risk for T2D than those with easy or casual walking (RR = 0.85 [95% CI, 0.70-1.00]; RD = 0.86 [1.72-0]). Ten cohort studies with 18,410 cases among 508,121 participants reported information on fairly brisk walking. Those with fairly brisk walking were at a 24% lower risk for T2D than those with easy or casual walking (RR = 0.76 [0.65-0.87]; I2 = 90%; RD = 1.38 [2.01-0.75]).

There was no significant or credible subgroup difference by adjustment for the total physical activity or time spent walking per day. The dose-response analysis suggested that the risk for T2D decreased significantly at a walking speed of 4 km/h and above.

Study Limitations

This meta-analysis has strengths that may increase the generalizability of its results. The researchers included cohort studies, which allowed them to consider the temporal sequence of exposure and outcome. Cohort studies are less affected by recall and selection biases compared with retrospective case–control studies, which increase the likelihood of causality. The researchers also assessed the credibility of subgroup differences using the recently developed ICEMAN tool, calculated both relative and absolute risks, and rated the certainty of evidence using the GRADE approach.

Some shortcomings must be considered. Most of the studies included in the present review were rated as having a serious risk for bias, with the most important biases resulting from inadequate adjustment for potential confounders and the methods used for walking speed assessment and diagnosis of T2D. In addition, the findings could have been subject to reverse causality bias because participants with faster walking speed are more likely to perform more physical activity and have better cardiorespiratory fitness, greater muscle mass, and better health status. However, the subgroup analyses of fairly brisk and brisk/striding walking indicated that there were no significant subgroup differences by follow-up duration and that the significant inverse associations remained stable in the subgroup of cohort studies with a follow-up duration of > 10 years.

The authors concluded that “the present meta-analysis of cohort studies suggested that fairly brisk and brisk/striding walking, independent of the total volume of physical activity or time spent walking per day, may be associated with a lower risk of T2D in adults. While current strategies to increase total walking time are beneficial, it may also be reasonable to encourage people to walk at faster speeds to further increase the health benefits of walking.”

This article was translated from JIM, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

Walking is a simple, cost-free form of exercise that benefits physical, social, and mental health in many ways. Several clinical trials have shown that walking regularly is associated with a lower risk for cardiovascular events and all-cause mortality, and having a higher daily step count is linked to a decreased risk for premature death.

Walking and Diabetes

In recent years, the link between walking speed and the risk for multiple health problems has sparked keen interest. Data suggest that a faster walking pace may have a greater physiological response and may be associated with more favorable health advantages than a slow walking pace. A previous meta-analysis of eight cohort studies suggested that individuals in the fastest walking-pace category (median = 5.6 km/h) had a 44% lower risk for stroke than those in the slowest walking-pace category (median = 1.6 km/h). The risk for the former decreased by 13% for every 1 km/h increment in baseline walking pace.

Type 2 diabetes (T2D) is one of the most common metabolic diseases in the world. People with this type of diabetes have an increased risk for microvascular and macrovascular complications and a shorter life expectancy. Approximately 537 million adults are estimated to be living with diabetes worldwide, and this number is expected to reach 783 million by 2045.

Physical activity is an essential component of T2D prevention programs and can favorably affect blood sugar control. A meta-analysis of cohort studies showed that being physically active was associated with a 35% reduction in the risk of acquiring T2D in the general population, and regular walking was associated with a 15% reduction in the risk of developing T2D.

However, no studies have investigated the link between different walking speeds and the risk for T2D. A team from the Research Center at the Semnan University of Medical Sciences in Iran carried out a systematic review of the association between walking speed and the risk of developing T2D in adults; this review was published in the British Journal of Sports Medicine.
 

10 Cohort Studies

This systematic review used publications (1999-2022) available in the usual data sources (PubMed, Scopus, CENTRAL, and Web of Science). Random-effects meta-analyses were used to calculate relative risk (RR) and risk difference (RD) based on different walking speeds. The researchers rated the credibility of subgroup differences and the certainty of evidence using the Instrument to assess the Credibility of Effect Modification ANalyses (ICEMAN) and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tools, respectively.

Of the 508,121 potential participants, 18,410 adults from 10 prospective cohort studies conducted in the United States, Japan, and the United Kingdom were deemed eligible. The proportion of women was between 52% and 73%, depending on the cohort. Follow-up duration varied from 3 to 11.1 years (median, 8 years).

Five cohort studies measured walking speed using stopwatch testing, while the other five used self-assessed questionnaires. To define cases of T2D, seven studies used objective methods such as blood glucose measurement or linkage with medical records, and in three cohorts, self-assessment questionnaires were used (these were checked against patient records). All studies controlled age, sex, and tobacco consumption in the multivariate analyses, and some controlled just alcohol consumption, blood pressure, total physical activity volume, body mass index, time spent walking or daily step count, and a family history of diabetes.

The Right Speed

The authors first categorized walking speed into four prespecified levels: Easy or casual (< 2 mph or 3.2 km/h), average or normal (2-3 mph or 3.2-4.8 km/h), fairly brisk (3-4 mph or 4.8-6.4 km/h), and very brisk or brisk/striding (> 4 mph or > 6.4 km/h).

Four cohort studies with 6,520 cases of T2D among 160,321 participants reported information on average or normal walking. Participants with average or normal walking were at a 15% lower risk for T2D than those with easy or casual walking (RR = 0.85 [95% CI, 0.70-1.00]; RD = 0.86 [1.72-0]). Ten cohort studies with 18,410 cases among 508,121 participants reported information on fairly brisk walking. Those with fairly brisk walking were at a 24% lower risk for T2D than those with easy or casual walking (RR = 0.76 [0.65-0.87]; I2 = 90%; RD = 1.38 [2.01-0.75]).

There was no significant or credible subgroup difference by adjustment for the total physical activity or time spent walking per day. The dose-response analysis suggested that the risk for T2D decreased significantly at a walking speed of 4 km/h and above.

Study Limitations

This meta-analysis has strengths that may increase the generalizability of its results. The researchers included cohort studies, which allowed them to consider the temporal sequence of exposure and outcome. Cohort studies are less affected by recall and selection biases compared with retrospective case–control studies, which increase the likelihood of causality. The researchers also assessed the credibility of subgroup differences using the recently developed ICEMAN tool, calculated both relative and absolute risks, and rated the certainty of evidence using the GRADE approach.

Some shortcomings must be considered. Most of the studies included in the present review were rated as having a serious risk for bias, with the most important biases resulting from inadequate adjustment for potential confounders and the methods used for walking speed assessment and diagnosis of T2D. In addition, the findings could have been subject to reverse causality bias because participants with faster walking speed are more likely to perform more physical activity and have better cardiorespiratory fitness, greater muscle mass, and better health status. However, the subgroup analyses of fairly brisk and brisk/striding walking indicated that there were no significant subgroup differences by follow-up duration and that the significant inverse associations remained stable in the subgroup of cohort studies with a follow-up duration of > 10 years.

The authors concluded that “the present meta-analysis of cohort studies suggested that fairly brisk and brisk/striding walking, independent of the total volume of physical activity or time spent walking per day, may be associated with a lower risk of T2D in adults. While current strategies to increase total walking time are beneficial, it may also be reasonable to encourage people to walk at faster speeds to further increase the health benefits of walking.”

This article was translated from JIM, which is part of the Medscape Professional Network. A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has issued a warning to the public about counterfeit semaglutide (Ozempic) products that have entered the US drug supply. 

Clinicians and patients are advised to check the product packages they have received and not to use those labeled with lot number NAR0074 and serial number 430834149057. Some of these counterfeit products may still be available for purchase, the FDA said in a statement. 

Together with Ozempic manufacturer Novo Nordisk, the FDA is investigating “thousands of units” of the 1-mg injection product. Information is not yet available regarding the drugs’ identity, quality, or safety. However, the pen needles have been confirmed as fake — thereby raising the potential risk for infection — as have the pen labels, accompanying health care professional and patient label information, and carton. 

“FDA takes reports of possible counterfeit products seriously and works closely with other federal agencies and the private sector to help protect the nation’s drug supply. FDA’s investigation is ongoing, and the agency is working with Novo Nordisk to identify, investigate, and remove further suspected counterfeit semaglutide injectable products found in the US,” the statement says. 

Patients are advised to only obtain Ozempic with a valid prescription through state-licensed pharmacies and to check the product before using for any signs of counterfeiting. There are several differences between the genuine and counterfeit products in the way the pen needle is packaged. The most obvious is that the paper tab covering the fake needle says “Novofine®” whereas the genuine one says “Novofine® Plus.” 

There have been at least five adverse events reported from this lot; none were serious and all were consistent with gastrointestinal issues known to occur with the genuine product. 

Counterfeit products should be reported to the FDA ‘s consumer complaint coordinator or to the criminal activity division.

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

The US Food and Drug Administration (FDA) has issued a warning to the public about counterfeit semaglutide (Ozempic) products that have entered the US drug supply. 

Clinicians and patients are advised to check the product packages they have received and not to use those labeled with lot number NAR0074 and serial number 430834149057. Some of these counterfeit products may still be available for purchase, the FDA said in a statement. 

Together with Ozempic manufacturer Novo Nordisk, the FDA is investigating “thousands of units” of the 1-mg injection product. Information is not yet available regarding the drugs’ identity, quality, or safety. However, the pen needles have been confirmed as fake — thereby raising the potential risk for infection — as have the pen labels, accompanying health care professional and patient label information, and carton. 

“FDA takes reports of possible counterfeit products seriously and works closely with other federal agencies and the private sector to help protect the nation’s drug supply. FDA’s investigation is ongoing, and the agency is working with Novo Nordisk to identify, investigate, and remove further suspected counterfeit semaglutide injectable products found in the US,” the statement says. 

Patients are advised to only obtain Ozempic with a valid prescription through state-licensed pharmacies and to check the product before using for any signs of counterfeiting. There are several differences between the genuine and counterfeit products in the way the pen needle is packaged. The most obvious is that the paper tab covering the fake needle says “Novofine®” whereas the genuine one says “Novofine® Plus.” 

There have been at least five adverse events reported from this lot; none were serious and all were consistent with gastrointestinal issues known to occur with the genuine product. 

Counterfeit products should be reported to the FDA ‘s consumer complaint coordinator or to the criminal activity division.

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

The US Food and Drug Administration (FDA) has issued a warning to the public about counterfeit semaglutide (Ozempic) products that have entered the US drug supply. 

Clinicians and patients are advised to check the product packages they have received and not to use those labeled with lot number NAR0074 and serial number 430834149057. Some of these counterfeit products may still be available for purchase, the FDA said in a statement. 

Together with Ozempic manufacturer Novo Nordisk, the FDA is investigating “thousands of units” of the 1-mg injection product. Information is not yet available regarding the drugs’ identity, quality, or safety. However, the pen needles have been confirmed as fake — thereby raising the potential risk for infection — as have the pen labels, accompanying health care professional and patient label information, and carton. 

“FDA takes reports of possible counterfeit products seriously and works closely with other federal agencies and the private sector to help protect the nation’s drug supply. FDA’s investigation is ongoing, and the agency is working with Novo Nordisk to identify, investigate, and remove further suspected counterfeit semaglutide injectable products found in the US,” the statement says. 

Patients are advised to only obtain Ozempic with a valid prescription through state-licensed pharmacies and to check the product before using for any signs of counterfeiting. There are several differences between the genuine and counterfeit products in the way the pen needle is packaged. The most obvious is that the paper tab covering the fake needle says “Novofine®” whereas the genuine one says “Novofine® Plus.” 

There have been at least five adverse events reported from this lot; none were serious and all were consistent with gastrointestinal issues known to occur with the genuine product. 

Counterfeit products should be reported to the FDA ‘s consumer complaint coordinator or to the criminal activity division.

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

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

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

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

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

SAN DIEGO – An investigational allogeneic stem cell–derived pancreatic islet cell replacement therapy (VX-880, Vertex Pharmaceuticals) continues to show promise as a treatment for type 1 diabetes, according to the latest data, from six patients thus far.

Two of the six are insulin-independent beyond 1 year after receiving the VX-880 infusions, and three others who received them more recently are on a similar trajectory. One dropped out because of reasons unrelated to the therapy. The remaining five are continuing to receive immunosuppressive treatment to prevent rejection of the islets. The six all had undetectable insulin secretion, impaired hypoglycemic awareness, and severe hypoglycemia as the criterion to enter the phase 1/2 study.

“These new findings demonstrate the potential of stem cell–derived islets as a future treatment for patients with type 1 diabetes, signaling a new era that could potentially remove the need for exogenously administered insulin to achieve glycemic control,” said lead investigator Trevor W. Reichman, MD, PhD, surgical director of Pancreas and Islet Cell Transplantation at the University of Toronto.

Dr. Reichman presented the data at the annual scientific sessions of the American Diabetes Association, as an update to the report of the first two patients at last year’s ADA meeting. “We are hopeful that this first-of-its-kind research could be a game-changer for the treatment of type 1 diabetes,” he emphasized.

Co-investigator Maria Cristina Nostro, PhD, senior scientist at McEwen Stem Cell Institute, Toronto, told this news organization: “The clinical trial data are extremely exciting ... I think what was very beautiful is the glucose tolerance test where the insulin secretion was almost like a person without type 1 diabetes. For someone who is in the lab doing basic science research ... all the work we’ve put into this, it’s a labor of love. We’ve been trying to generate the cells for so long, and now to see this, it’s fantastic.”  
 

Two meet primary endpoint, three more on the right path

The six patients had a mean age of 44 years and mean 23 years’ diabetes duration. Three each were male and female. Their mean baseline A1c was 8.1%, and fasting C-peptide was undetectable. They had experienced a mean of 3.3 severe hypoglycemia episodes in the year prior to receiving the infusion, which was delivered to the portal vein similarly to the procedure with cadaveric donor islets, Dr. Reichman said.

The first two patients, including the one who dropped out, received half target doses of VX-880 (trial part A), while the rest, enrolled sequentially (part B), were each administered the full target dose of VX-880 given as a single infusion.

Induction with anti-thymocyte globulin and maintenance immunosuppressants, tacrolimus/sirolimus, was used to protect the cells from the recipient’s immune system. After the infusion, all six participants had C-peptide production, reduction in A1c despite reduced insulin use, and no severe hypoglycemia episodes from day 90 onwards.

Both participants with at least a year of follow-up met the criteria for the primary endpoint of A1c less than 7% with no severe hypoglycemic episodes. The first participant had an A1c of 5.3% at month 21, and the second 6.0% at 12 months. Both had sustained glucose-responsive insulin production with a mixed-meal tolerance test and exceeded the ADA target of more than 70% time-in blood glucose range assessed with continuous glucose monitoring.  
 

Safety: No major concerns thus far

Among all six, adverse events included elevations in the liver enzyme transaminase, occurring shortly after VX-880 infusion that were transient and resolved. No serious adverse events were considered related to the therapy.

Regarding safety, Dr. Nostro said, “With this trial, I have no concerns, because they’re using immunosuppression, so should anything go bad, you remove immunosuppression and the cells would be destroyed by the immune system. So it’s a perfect trial in a way.”

However, she noted, “Moving forward, as we develop something that will be genetically modified ... I think this is the future, because if you’re going to treat people with type 1 diabetes, we have to eliminate the immune suppression. I think the concern would be making sure the genetically modified cells are safe.”

Dr. Nostro, who gave an introductory presentation at the beginning of the symposium where the VX-880 data were presented, explained that in a current trial of genetically modified cells, “they’re placing the product inside a device so that the cells would be retrievable. It might not be perfect, but at least it’s going to tell us whether the genetically modified product is safe, which I think is what we need to use.”

In her talk, Dr. Nostro also summarized ongoing work in this field involving efforts to improve the generation of stem cell–derived islets with no “off target” non-beta cells to ensure consistency, optimization of engraftment, and elimination of immunosuppression. “[VX-880] is the beginning. This is the first product that’s going to be in the clinic, but I can imagine how 5, 10 years from now we will have different and more enhanced solutions for type 1 diabetes and who knows, maybe even for type 2.” 

Based on the data so far, the VX-880 trial is now moving to part C, in which 10 concurrently enrolled participants will receive the full target dose of the product. The trial, previously exclusively in the United States, has now expanded to additional sites in Norway, Switzerland, and the Netherlands. 

The study was funded by Vertex. Dr. Reichman is on advisory boards for Vertex and Sernova. Dr. Nostro was a consultant for Sigilon Therapeutics from 2018-2022, currently receives research support from Universal Cells, and has a patent licensed to Sernova.

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

A new study provides the first comprehensive safety profile of sodium-glucose cotransporter 2 (SGLT2) inhibitors in U.S. patients with chronic kidney disease (CKD) and type 2 diabetes receiving routine care and suggests that the benefits outweigh the risks.

Starting therapy with an SGLT2 inhibitor versus a glucagon-like peptide-1 (GLP-1) receptor agonist was associated with more lower limb amputations, nonvertebral fractures, and genital infections, but these risks need to be balanced against cardiovascular and renoprotective benefits, according to the researchers.

The analysis showed that there would be 2.1 more lower limb amputations, 2.5 more nonvertebral fractures, and 41 more genital infections per 1,000 patients per year among those receiving SGLT2 inhibitors versus an equal number of patients receiving GLP-1 agonists, lead author Edouard Fu, PhD, explained to this news organization in an email.

“On the other hand, we know from the evidence from randomized controlled trials that taking an SGLT2 inhibitor compared with placebo lowers the risk of developing kidney failure,” said Dr. Fu, who is a research fellow in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.

“For instance,” he continued, “in the DAPA-CKD clinical trial, dapagliflozin versus placebo led to 29 fewer events per 1,000 patients per year of the composite outcome (50% decline in estimated glomerular filtration rate [eGFR], kidney failure, cardiovascular or kidney death).”

In the CREDENCE trial, canagliflozin versus placebo led to 18 fewer events per 1,000 person-years for the composite outcome of doubling of serum creatinine, kidney failure, and cardiovascular or kidney death.

And in the EMPA-KIDNEY study, empagliflozin versus placebo led to 21 fewer events per 1,000 person-years for the composite outcome of progression of kidney disease or cardiovascular death.

“Thus, benefits would still outweigh the risks,” Dr. Fu emphasized.
 

‘Quantifies absolute rate of events among routine care patients’

“The importance of our paper,” he summarized, “is that it quantifies the absolute rate of events among routine care patients and may be used to inform shared decision-making.”

The analysis also found that the risks of diabetic ketoacidosis (DKA), hypovolemia, hypoglycemia, and severe urinary tract infection (UTI) were similar with SGLT2 inhibitors versus GLP-1 agonists, but the risk of developing acute kidney injury (AKI) was lower with an SGLT2 inhibitor.

“Our study can help inform patient-physician decision-making regarding risks and benefits before prescribing SGLT2 inhibitors in this population” of patients with CKD and diabetes treated in clinical practice, the researchers conclude, “but needs to be interpreted in light of its limitations, including residual confounding, short follow-up time, and the use of diagnosis codes to identify patients with CKD.”

The study was recently published in the Clinical Journal of the American Society of Nephrology.
 

Slow uptake, safety concerns

SGLT2 inhibitors are recommended as first-line therapy in patients with type 2 diabetes and CKD who have an eGFR equal to or greater than 20 mL/min per 1.73 m², and thus are at high risk for cardiovascular disease and kidney disease progression, Dr. Fu and colleagues write.

However, studies report that as few as 6% of patients with CKD and type 2 diabetes are currently prescribed SGLT2 inhibitors in the United States.

This slow uptake of SGLT2 inhibitors among patients with CKD may be partly due to concerns about DKA, fractures, amputations, and urogenital infections observed in clinical trials.

However, such trials are generally underpowered to assess rare adverse events, use monitoring protocols to lower the risk of adverse events, and include a highly selected patient population, and so safety in routine clinical practice is often unclear.

To examine this, the researchers identified health insurance claims data from 96,128 individuals (from Optum, IBM MarketScan, and Medicare databases) who were 18 years or older (65 years or older for Medicare) and had type 2 diabetes and at least one inpatient or two outpatient diagnostic codes for stage 3 or 4 CKD.

Of these patients, 32,192 had a newly filled prescription for an SGLT2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, or ertugliflozin) and 63,936 had a newly filled prescription for a GLP-1 agonist (liraglutide, dulaglutide, semaglutide, exenatide, albiglutide, or lixisenatide) between April 2013, when the first SGLT2 inhibitor was available in the United States, and 2021.

The researchers matched 28,847 individuals who were initiated on an SGLT2 inhibitor with an equal number who were initiated on a GLP-1 agonist, based on propensity scores, adjusting for more than 120 baseline characteristics.

Safety outcomes were based on previously identified potential safety signals.

Patients who were initiated on an SGLT2 inhibitor had 1.30-fold, 2.13-fold, and 3.08-fold higher risks of having a nonvertebral fracture, a lower limb amputation, and a genital infection, respectively, compared with patients who were initiated on a GLP-1 agonist, after a mean on-treatment time of 7.5 months,

Risks of DKA, hypovolemia, hypoglycemia, and severe UTI were similar in both groups.

Patients initiated on an SGLT2 inhibitor versus a GLP-1 agonist had a lower risk of AKI (hazard ratio, 0.93) equivalent to 6.75 fewer cases of AKI per 1,000 patients per year.

Patients had higher risks for lower limb amputation, genital infections, and nonvertebral fractures with SGLT2 inhibitors versus GLP-1 agonists across most of the prespecified subgroups by age, sex, cardiovascular disease, heart failure, and use of metformin, insulin, or sulfonylurea, but with wider confidence intervals.

Dr. Fu was supported by a Rubicon grant from the Dutch Research Council and has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

A new study provides the first comprehensive safety profile of sodium-glucose cotransporter 2 (SGLT2) inhibitors in U.S. patients with chronic kidney disease (CKD) and type 2 diabetes receiving routine care and suggests that the benefits outweigh the risks.

Starting therapy with an SGLT2 inhibitor versus a glucagon-like peptide-1 (GLP-1) receptor agonist was associated with more lower limb amputations, nonvertebral fractures, and genital infections, but these risks need to be balanced against cardiovascular and renoprotective benefits, according to the researchers.

The analysis showed that there would be 2.1 more lower limb amputations, 2.5 more nonvertebral fractures, and 41 more genital infections per 1,000 patients per year among those receiving SGLT2 inhibitors versus an equal number of patients receiving GLP-1 agonists, lead author Edouard Fu, PhD, explained to this news organization in an email.

“On the other hand, we know from the evidence from randomized controlled trials that taking an SGLT2 inhibitor compared with placebo lowers the risk of developing kidney failure,” said Dr. Fu, who is a research fellow in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.

“For instance,” he continued, “in the DAPA-CKD clinical trial, dapagliflozin versus placebo led to 29 fewer events per 1,000 patients per year of the composite outcome (50% decline in estimated glomerular filtration rate [eGFR], kidney failure, cardiovascular or kidney death).”

In the CREDENCE trial, canagliflozin versus placebo led to 18 fewer events per 1,000 person-years for the composite outcome of doubling of serum creatinine, kidney failure, and cardiovascular or kidney death.

And in the EMPA-KIDNEY study, empagliflozin versus placebo led to 21 fewer events per 1,000 person-years for the composite outcome of progression of kidney disease or cardiovascular death.

“Thus, benefits would still outweigh the risks,” Dr. Fu emphasized.
 

‘Quantifies absolute rate of events among routine care patients’

“The importance of our paper,” he summarized, “is that it quantifies the absolute rate of events among routine care patients and may be used to inform shared decision-making.”

The analysis also found that the risks of diabetic ketoacidosis (DKA), hypovolemia, hypoglycemia, and severe urinary tract infection (UTI) were similar with SGLT2 inhibitors versus GLP-1 agonists, but the risk of developing acute kidney injury (AKI) was lower with an SGLT2 inhibitor.

“Our study can help inform patient-physician decision-making regarding risks and benefits before prescribing SGLT2 inhibitors in this population” of patients with CKD and diabetes treated in clinical practice, the researchers conclude, “but needs to be interpreted in light of its limitations, including residual confounding, short follow-up time, and the use of diagnosis codes to identify patients with CKD.”

The study was recently published in the Clinical Journal of the American Society of Nephrology.
 

Slow uptake, safety concerns

SGLT2 inhibitors are recommended as first-line therapy in patients with type 2 diabetes and CKD who have an eGFR equal to or greater than 20 mL/min per 1.73 m², and thus are at high risk for cardiovascular disease and kidney disease progression, Dr. Fu and colleagues write.

However, studies report that as few as 6% of patients with CKD and type 2 diabetes are currently prescribed SGLT2 inhibitors in the United States.

This slow uptake of SGLT2 inhibitors among patients with CKD may be partly due to concerns about DKA, fractures, amputations, and urogenital infections observed in clinical trials.

However, such trials are generally underpowered to assess rare adverse events, use monitoring protocols to lower the risk of adverse events, and include a highly selected patient population, and so safety in routine clinical practice is often unclear.

To examine this, the researchers identified health insurance claims data from 96,128 individuals (from Optum, IBM MarketScan, and Medicare databases) who were 18 years or older (65 years or older for Medicare) and had type 2 diabetes and at least one inpatient or two outpatient diagnostic codes for stage 3 or 4 CKD.

Of these patients, 32,192 had a newly filled prescription for an SGLT2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, or ertugliflozin) and 63,936 had a newly filled prescription for a GLP-1 agonist (liraglutide, dulaglutide, semaglutide, exenatide, albiglutide, or lixisenatide) between April 2013, when the first SGLT2 inhibitor was available in the United States, and 2021.

The researchers matched 28,847 individuals who were initiated on an SGLT2 inhibitor with an equal number who were initiated on a GLP-1 agonist, based on propensity scores, adjusting for more than 120 baseline characteristics.

Safety outcomes were based on previously identified potential safety signals.

Patients who were initiated on an SGLT2 inhibitor had 1.30-fold, 2.13-fold, and 3.08-fold higher risks of having a nonvertebral fracture, a lower limb amputation, and a genital infection, respectively, compared with patients who were initiated on a GLP-1 agonist, after a mean on-treatment time of 7.5 months,

Risks of DKA, hypovolemia, hypoglycemia, and severe UTI were similar in both groups.

Patients initiated on an SGLT2 inhibitor versus a GLP-1 agonist had a lower risk of AKI (hazard ratio, 0.93) equivalent to 6.75 fewer cases of AKI per 1,000 patients per year.

Patients had higher risks for lower limb amputation, genital infections, and nonvertebral fractures with SGLT2 inhibitors versus GLP-1 agonists across most of the prespecified subgroups by age, sex, cardiovascular disease, heart failure, and use of metformin, insulin, or sulfonylurea, but with wider confidence intervals.

Dr. Fu was supported by a Rubicon grant from the Dutch Research Council and has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

A new study provides the first comprehensive safety profile of sodium-glucose cotransporter 2 (SGLT2) inhibitors in U.S. patients with chronic kidney disease (CKD) and type 2 diabetes receiving routine care and suggests that the benefits outweigh the risks.

Starting therapy with an SGLT2 inhibitor versus a glucagon-like peptide-1 (GLP-1) receptor agonist was associated with more lower limb amputations, nonvertebral fractures, and genital infections, but these risks need to be balanced against cardiovascular and renoprotective benefits, according to the researchers.

The analysis showed that there would be 2.1 more lower limb amputations, 2.5 more nonvertebral fractures, and 41 more genital infections per 1,000 patients per year among those receiving SGLT2 inhibitors versus an equal number of patients receiving GLP-1 agonists, lead author Edouard Fu, PhD, explained to this news organization in an email.

“On the other hand, we know from the evidence from randomized controlled trials that taking an SGLT2 inhibitor compared with placebo lowers the risk of developing kidney failure,” said Dr. Fu, who is a research fellow in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston.

“For instance,” he continued, “in the DAPA-CKD clinical trial, dapagliflozin versus placebo led to 29 fewer events per 1,000 patients per year of the composite outcome (50% decline in estimated glomerular filtration rate [eGFR], kidney failure, cardiovascular or kidney death).”

In the CREDENCE trial, canagliflozin versus placebo led to 18 fewer events per 1,000 person-years for the composite outcome of doubling of serum creatinine, kidney failure, and cardiovascular or kidney death.

And in the EMPA-KIDNEY study, empagliflozin versus placebo led to 21 fewer events per 1,000 person-years for the composite outcome of progression of kidney disease or cardiovascular death.

“Thus, benefits would still outweigh the risks,” Dr. Fu emphasized.
 

‘Quantifies absolute rate of events among routine care patients’

“The importance of our paper,” he summarized, “is that it quantifies the absolute rate of events among routine care patients and may be used to inform shared decision-making.”

The analysis also found that the risks of diabetic ketoacidosis (DKA), hypovolemia, hypoglycemia, and severe urinary tract infection (UTI) were similar with SGLT2 inhibitors versus GLP-1 agonists, but the risk of developing acute kidney injury (AKI) was lower with an SGLT2 inhibitor.

“Our study can help inform patient-physician decision-making regarding risks and benefits before prescribing SGLT2 inhibitors in this population” of patients with CKD and diabetes treated in clinical practice, the researchers conclude, “but needs to be interpreted in light of its limitations, including residual confounding, short follow-up time, and the use of diagnosis codes to identify patients with CKD.”

The study was recently published in the Clinical Journal of the American Society of Nephrology.
 

Slow uptake, safety concerns

SGLT2 inhibitors are recommended as first-line therapy in patients with type 2 diabetes and CKD who have an eGFR equal to or greater than 20 mL/min per 1.73 m², and thus are at high risk for cardiovascular disease and kidney disease progression, Dr. Fu and colleagues write.

However, studies report that as few as 6% of patients with CKD and type 2 diabetes are currently prescribed SGLT2 inhibitors in the United States.

This slow uptake of SGLT2 inhibitors among patients with CKD may be partly due to concerns about DKA, fractures, amputations, and urogenital infections observed in clinical trials.

However, such trials are generally underpowered to assess rare adverse events, use monitoring protocols to lower the risk of adverse events, and include a highly selected patient population, and so safety in routine clinical practice is often unclear.

To examine this, the researchers identified health insurance claims data from 96,128 individuals (from Optum, IBM MarketScan, and Medicare databases) who were 18 years or older (65 years or older for Medicare) and had type 2 diabetes and at least one inpatient or two outpatient diagnostic codes for stage 3 or 4 CKD.

Of these patients, 32,192 had a newly filled prescription for an SGLT2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, or ertugliflozin) and 63,936 had a newly filled prescription for a GLP-1 agonist (liraglutide, dulaglutide, semaglutide, exenatide, albiglutide, or lixisenatide) between April 2013, when the first SGLT2 inhibitor was available in the United States, and 2021.

The researchers matched 28,847 individuals who were initiated on an SGLT2 inhibitor with an equal number who were initiated on a GLP-1 agonist, based on propensity scores, adjusting for more than 120 baseline characteristics.

Safety outcomes were based on previously identified potential safety signals.

Patients who were initiated on an SGLT2 inhibitor had 1.30-fold, 2.13-fold, and 3.08-fold higher risks of having a nonvertebral fracture, a lower limb amputation, and a genital infection, respectively, compared with patients who were initiated on a GLP-1 agonist, after a mean on-treatment time of 7.5 months,

Risks of DKA, hypovolemia, hypoglycemia, and severe UTI were similar in both groups.

Patients initiated on an SGLT2 inhibitor versus a GLP-1 agonist had a lower risk of AKI (hazard ratio, 0.93) equivalent to 6.75 fewer cases of AKI per 1,000 patients per year.

Patients had higher risks for lower limb amputation, genital infections, and nonvertebral fractures with SGLT2 inhibitors versus GLP-1 agonists across most of the prespecified subgroups by age, sex, cardiovascular disease, heart failure, and use of metformin, insulin, or sulfonylurea, but with wider confidence intervals.

Dr. Fu was supported by a Rubicon grant from the Dutch Research Council and has reported no relevant financial relationships. Disclosures for the other authors are listed with the article.

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

Nearly one in four children diagnosed with type 2 diabetes for 5 years or more develop diabetic retinopathy, according to a new report.

The global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes is about 7%, which appears to increase with age.

“In our clinical practice, we have seen an increase in children presenting with type 2 diabetes over the past few years. These patients present with multiple simultaneous comorbidities and complications like hypertension, fatty liver, and other conditions,” senior author M. Constantine Samaan, MD, told this news organization.

“The exact scale of diabetes-related eye disease was not clear, and we decided to quantify it,” said Dr. Samaan, associate professor of pediatrics at McMaster University and pediatric endocrinologist at McMaster Children’s Hospital in Hamilton, Ont.

“What we found was that in pediatric patients with type 2 diabetes, diabetic retinopathy is present in 1 in 14 youth. The risk of retinopathy increased significantly 5 years after diagnosis to almost one in four,” he noted.

“While we acknowledged that the number of diabetic retinopathy cases was relatively small and there was heterogeneity in studies, we were surprised that retinopathy rates rose so fast in the first few years after diabetes diagnosis,” Dr. Samaan indicated.

The findings signal that the increase in the prevalence of diabetic retinopathy is emerging decades earlier among children compared with adults with type 2 diabetes, the authors wrote in their article published online in JAMA Network Open.

“While the guidelines for eye care in children with type 2 diabetes recommend screening at diagnosis and annually afterward, these recommendations are not followed in almost half of these patients,” Dr. Samaan said. “There is a need to ensure that patients get screened to try and prevent or delay retinopathy onset and progression.”
 

Analyzing prevalence rates

Diabetic retinopathy is the leading cause of blindness in patients with type 2 diabetes. Between 21% and 39% of adults have diabetic retinopathy at diagnosis, with rates subsequently increasing, the authors wrote.

Dr. Samaan and colleagues conducted a systematic review and meta-analysis to estimate the global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes. They included studies that had a study population of at least 10 participants diagnosed at age 21 and younger, an observational study design, and prevalence data on diabetic retinopathy.

Among the 29 studies included, 6 were cross-sectional, 13 had a retrospective cohort design, and 10 had a prospective cohort design. Patients were diagnosed between age 6.5 and 21 years, and the diabetes duration ranged from 0 to 15 years after diagnosis.

The overall global prevalence of diabetic retinopathy in 5,924 pediatric patients was 7.0%. Prevalence varied by study design, ranging from 1.1% in cross-sectional studies to 6.5% in prospective cohort studies and 11.3% in retrospective cohort studies.

In the nine studies that reported diabetic retinopathy classification based on criteria, the prevalence of minimal-to-moderate nonproliferative diabetic retinopathy was 11.2%, the prevalence of severe nonproliferative diabetic retinopathy was 2.6%, the prevalence of proliferative diabetic retinopathy was 2.4%, and the prevalence of macular edema was 3.1%.

In the five studies that reported diabetic retinopathy diagnosis using fundoscopy, the prevalence was 0.5%. In the four studies that used 7-field stereoscopic fundus photography, the prevalence was 13.6%.

In the pooled analysis of 27 studies, the prevalence of diabetic retinopathy was 1.8% less than 2.5 years after diabetes diagnosis but more than doubled to 5.1% in years 2.5 to 5 and jumped to 28.8% more than 5 years after diagnosis.
 

Differences by sex, ethnicity

“We were also surprised that there was very limited evidence to understand the sex and race differences in retinopathy risk,” said Dr. Samaan. “Further research is warranted, considering that more girls develop type 2 diabetes than boys, and the risk of type 2 diabetes is higher in some racial groups.”

In addition, older age, longer diabetes duration, and higher hypertension prevalence were associated with diabetic retinopathy prevalence. There were no associations with obesity prevalence or mean age at diabetes diagnosis. However, patients who developed diabetic retinopathy had a higher mean A1c level of 1.4% compared to those without retinopathy.

Dr. Samaan and colleagues are continuing to research the comorbidities and complications that children with type 2 diabetes face as well as mechanisms that drive diabetes outcomes among children and adolescents.

For now, the findings highlight the importance of retinopathy screening and personalized diabetes treatment to protect vision, Dr. Samaan reiterated.

No funding source for the study was reported. The authors have reported no relevant financial relationships.
 

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

Nearly one in four children diagnosed with type 2 diabetes for 5 years or more develop diabetic retinopathy, according to a new report.

The global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes is about 7%, which appears to increase with age.

“In our clinical practice, we have seen an increase in children presenting with type 2 diabetes over the past few years. These patients present with multiple simultaneous comorbidities and complications like hypertension, fatty liver, and other conditions,” senior author M. Constantine Samaan, MD, told this news organization.

“The exact scale of diabetes-related eye disease was not clear, and we decided to quantify it,” said Dr. Samaan, associate professor of pediatrics at McMaster University and pediatric endocrinologist at McMaster Children’s Hospital in Hamilton, Ont.

“What we found was that in pediatric patients with type 2 diabetes, diabetic retinopathy is present in 1 in 14 youth. The risk of retinopathy increased significantly 5 years after diagnosis to almost one in four,” he noted.

“While we acknowledged that the number of diabetic retinopathy cases was relatively small and there was heterogeneity in studies, we were surprised that retinopathy rates rose so fast in the first few years after diabetes diagnosis,” Dr. Samaan indicated.

The findings signal that the increase in the prevalence of diabetic retinopathy is emerging decades earlier among children compared with adults with type 2 diabetes, the authors wrote in their article published online in JAMA Network Open.

“While the guidelines for eye care in children with type 2 diabetes recommend screening at diagnosis and annually afterward, these recommendations are not followed in almost half of these patients,” Dr. Samaan said. “There is a need to ensure that patients get screened to try and prevent or delay retinopathy onset and progression.”
 

Analyzing prevalence rates

Diabetic retinopathy is the leading cause of blindness in patients with type 2 diabetes. Between 21% and 39% of adults have diabetic retinopathy at diagnosis, with rates subsequently increasing, the authors wrote.

Dr. Samaan and colleagues conducted a systematic review and meta-analysis to estimate the global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes. They included studies that had a study population of at least 10 participants diagnosed at age 21 and younger, an observational study design, and prevalence data on diabetic retinopathy.

Among the 29 studies included, 6 were cross-sectional, 13 had a retrospective cohort design, and 10 had a prospective cohort design. Patients were diagnosed between age 6.5 and 21 years, and the diabetes duration ranged from 0 to 15 years after diagnosis.

The overall global prevalence of diabetic retinopathy in 5,924 pediatric patients was 7.0%. Prevalence varied by study design, ranging from 1.1% in cross-sectional studies to 6.5% in prospective cohort studies and 11.3% in retrospective cohort studies.

In the nine studies that reported diabetic retinopathy classification based on criteria, the prevalence of minimal-to-moderate nonproliferative diabetic retinopathy was 11.2%, the prevalence of severe nonproliferative diabetic retinopathy was 2.6%, the prevalence of proliferative diabetic retinopathy was 2.4%, and the prevalence of macular edema was 3.1%.

In the five studies that reported diabetic retinopathy diagnosis using fundoscopy, the prevalence was 0.5%. In the four studies that used 7-field stereoscopic fundus photography, the prevalence was 13.6%.

In the pooled analysis of 27 studies, the prevalence of diabetic retinopathy was 1.8% less than 2.5 years after diabetes diagnosis but more than doubled to 5.1% in years 2.5 to 5 and jumped to 28.8% more than 5 years after diagnosis.
 

Differences by sex, ethnicity

“We were also surprised that there was very limited evidence to understand the sex and race differences in retinopathy risk,” said Dr. Samaan. “Further research is warranted, considering that more girls develop type 2 diabetes than boys, and the risk of type 2 diabetes is higher in some racial groups.”

In addition, older age, longer diabetes duration, and higher hypertension prevalence were associated with diabetic retinopathy prevalence. There were no associations with obesity prevalence or mean age at diabetes diagnosis. However, patients who developed diabetic retinopathy had a higher mean A1c level of 1.4% compared to those without retinopathy.

Dr. Samaan and colleagues are continuing to research the comorbidities and complications that children with type 2 diabetes face as well as mechanisms that drive diabetes outcomes among children and adolescents.

For now, the findings highlight the importance of retinopathy screening and personalized diabetes treatment to protect vision, Dr. Samaan reiterated.

No funding source for the study was reported. The authors have reported no relevant financial relationships.
 

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

Nearly one in four children diagnosed with type 2 diabetes for 5 years or more develop diabetic retinopathy, according to a new report.

The global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes is about 7%, which appears to increase with age.

“In our clinical practice, we have seen an increase in children presenting with type 2 diabetes over the past few years. These patients present with multiple simultaneous comorbidities and complications like hypertension, fatty liver, and other conditions,” senior author M. Constantine Samaan, MD, told this news organization.

“The exact scale of diabetes-related eye disease was not clear, and we decided to quantify it,” said Dr. Samaan, associate professor of pediatrics at McMaster University and pediatric endocrinologist at McMaster Children’s Hospital in Hamilton, Ont.

“What we found was that in pediatric patients with type 2 diabetes, diabetic retinopathy is present in 1 in 14 youth. The risk of retinopathy increased significantly 5 years after diagnosis to almost one in four,” he noted.

“While we acknowledged that the number of diabetic retinopathy cases was relatively small and there was heterogeneity in studies, we were surprised that retinopathy rates rose so fast in the first few years after diabetes diagnosis,” Dr. Samaan indicated.

The findings signal that the increase in the prevalence of diabetic retinopathy is emerging decades earlier among children compared with adults with type 2 diabetes, the authors wrote in their article published online in JAMA Network Open.

“While the guidelines for eye care in children with type 2 diabetes recommend screening at diagnosis and annually afterward, these recommendations are not followed in almost half of these patients,” Dr. Samaan said. “There is a need to ensure that patients get screened to try and prevent or delay retinopathy onset and progression.”
 

Analyzing prevalence rates

Diabetic retinopathy is the leading cause of blindness in patients with type 2 diabetes. Between 21% and 39% of adults have diabetic retinopathy at diagnosis, with rates subsequently increasing, the authors wrote.

Dr. Samaan and colleagues conducted a systematic review and meta-analysis to estimate the global prevalence of diabetic retinopathy in pediatric patients with type 2 diabetes. They included studies that had a study population of at least 10 participants diagnosed at age 21 and younger, an observational study design, and prevalence data on diabetic retinopathy.

Among the 29 studies included, 6 were cross-sectional, 13 had a retrospective cohort design, and 10 had a prospective cohort design. Patients were diagnosed between age 6.5 and 21 years, and the diabetes duration ranged from 0 to 15 years after diagnosis.

The overall global prevalence of diabetic retinopathy in 5,924 pediatric patients was 7.0%. Prevalence varied by study design, ranging from 1.1% in cross-sectional studies to 6.5% in prospective cohort studies and 11.3% in retrospective cohort studies.

In the nine studies that reported diabetic retinopathy classification based on criteria, the prevalence of minimal-to-moderate nonproliferative diabetic retinopathy was 11.2%, the prevalence of severe nonproliferative diabetic retinopathy was 2.6%, the prevalence of proliferative diabetic retinopathy was 2.4%, and the prevalence of macular edema was 3.1%.

In the five studies that reported diabetic retinopathy diagnosis using fundoscopy, the prevalence was 0.5%. In the four studies that used 7-field stereoscopic fundus photography, the prevalence was 13.6%.

In the pooled analysis of 27 studies, the prevalence of diabetic retinopathy was 1.8% less than 2.5 years after diabetes diagnosis but more than doubled to 5.1% in years 2.5 to 5 and jumped to 28.8% more than 5 years after diagnosis.
 

Differences by sex, ethnicity

“We were also surprised that there was very limited evidence to understand the sex and race differences in retinopathy risk,” said Dr. Samaan. “Further research is warranted, considering that more girls develop type 2 diabetes than boys, and the risk of type 2 diabetes is higher in some racial groups.”

In addition, older age, longer diabetes duration, and higher hypertension prevalence were associated with diabetic retinopathy prevalence. There were no associations with obesity prevalence or mean age at diabetes diagnosis. However, patients who developed diabetic retinopathy had a higher mean A1c level of 1.4% compared to those without retinopathy.

Dr. Samaan and colleagues are continuing to research the comorbidities and complications that children with type 2 diabetes face as well as mechanisms that drive diabetes outcomes among children and adolescents.

For now, the findings highlight the importance of retinopathy screening and personalized diabetes treatment to protect vision, Dr. Samaan reiterated.

No funding source for the study was reported. The authors have reported no relevant financial relationships.
 

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