Diabetes

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness. 

What should primary care providers be doing differently? 

The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes. 

And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.

But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags. 

Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with this news organization, she cited several alarming facts about the state of CKD screening in the United States. 

“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Dr. Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease. 

Dr. Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Dr. Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.” 

But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation. 

The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Dr. Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood. 

But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Dr. Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Dr. Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day. 
 

Why Not Screen Everyone?

For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes. 

But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease. 

But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).

“I consider these blockbuster drugs,” Dr. Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”

Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys. 

Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor. 

But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes. 

Dr. Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said. 

Dr. Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia. 

But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes. 
 

EPIC Changes Coming?

In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations. 

The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation. 

A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes. 

The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%. 

More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone. 

The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Ms. Cusick told this news organization.

In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained. 

According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.” 

For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY. 

A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Ms. Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said. 

Although adherence to current recommendations for screening of people at risk is poor, Dr. Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would. 

“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes. 

In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Dr. Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”

Dr. Bansal, Ms. Cusick, and Dr. Owens reported no financial conflicts of interest. Dr. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials. 
 

Dr. Thomas is a pediatrician and epidemiologist living in Portland, Oregon.

A version of this article appeared on Medscape.com.

TOPLINE:

Previous gestational diabetes mellitus (GDM) nearly doubles future chronic kidney disease (CKD) risk, irrespective of subsequent diabetes and hypertension, a study showed.

METHODOLOGY:

• A nationwide, cohort study was based on data from the Danish Medical Birth Register and included 697,622 women who gave birth between 1997 and 2018.
• Of all study participants, 3.4% reported GDM in at least one pregnancy, and 12.8% of women with GDM received insulin, a proxy for a more severe metabolic dysfunction.
• The women were followed up for a median of 11.9 years.
• Researchers studied CKD and acute kidney disease as the outcomes of interest, the mediating effects of subsequent diabetes and hypertension on future CKD, and how GDM severity affected later risk for kidney disease.

TAKEAWAY:

• Women with GDM showed significantly higher CKD risk than those without GDM (adjusted hazard ratio [aHR], 1.92; 95% CI, 1.67-2.21).
• Women who received insulin during pregnancy due to severe metabolic dysfunction but did not develop subsequent diabetes had a proportionally higher risk for CKD (aHR, 2.35; 95% CI, 1.39-3.97).
• Women with GDM who went on to develop diabetes or hypertension faced even higher risks for CKD, suggesting that preventing diabetes and hypertension after GDM may reduce the development of CKD.
• GDM did not affect the risk for acute kidney disease (aHR, 1.08; 95% CI, 0.90-1.29).

IN PRACTICE:

“Women with severe metabolic dysfunction during pregnancy constitute a high-risk group regarding future CKD,” the authors wrote. “The significantly elevated CKD risk was observed from 2 years after pregnancy and beyond.”

SOURCE:

The study, with first author Maria Hornstrup Christensen, of Odense University Hospital, Odense, Denmark, was published online on December 15 in Diabetes Care.

LIMITATIONS:

GDM may be underdiagnosed, and undiagnosed diabetes may be misclassified as GDM. The proxies of GDM and insulin treatment may not have captured the increasing severity of metabolic dysfunction. The prevalence of insulin treatment was lower than expected, perhaps due to the practice of providing a patient’s first insulin pen without a prescription and perhaps not recording it in a patient’s health record.

DISCLOSURES:

This work received financial support from the University of Southern Denmark, the Region of Southern Denmark, and the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Previous gestational diabetes mellitus (GDM) nearly doubles future chronic kidney disease (CKD) risk, irrespective of subsequent diabetes and hypertension, a study showed.

METHODOLOGY:

• A nationwide, cohort study was based on data from the Danish Medical Birth Register and included 697,622 women who gave birth between 1997 and 2018.
• Of all study participants, 3.4% reported GDM in at least one pregnancy, and 12.8% of women with GDM received insulin, a proxy for a more severe metabolic dysfunction.
• The women were followed up for a median of 11.9 years.
• Researchers studied CKD and acute kidney disease as the outcomes of interest, the mediating effects of subsequent diabetes and hypertension on future CKD, and how GDM severity affected later risk for kidney disease.

TAKEAWAY:

• Women with GDM showed significantly higher CKD risk than those without GDM (adjusted hazard ratio [aHR], 1.92; 95% CI, 1.67-2.21).
• Women who received insulin during pregnancy due to severe metabolic dysfunction but did not develop subsequent diabetes had a proportionally higher risk for CKD (aHR, 2.35; 95% CI, 1.39-3.97).
• Women with GDM who went on to develop diabetes or hypertension faced even higher risks for CKD, suggesting that preventing diabetes and hypertension after GDM may reduce the development of CKD.
• GDM did not affect the risk for acute kidney disease (aHR, 1.08; 95% CI, 0.90-1.29).

IN PRACTICE:

“Women with severe metabolic dysfunction during pregnancy constitute a high-risk group regarding future CKD,” the authors wrote. “The significantly elevated CKD risk was observed from 2 years after pregnancy and beyond.”

SOURCE:

The study, with first author Maria Hornstrup Christensen, of Odense University Hospital, Odense, Denmark, was published online on December 15 in Diabetes Care.

LIMITATIONS:

GDM may be underdiagnosed, and undiagnosed diabetes may be misclassified as GDM. The proxies of GDM and insulin treatment may not have captured the increasing severity of metabolic dysfunction. The prevalence of insulin treatment was lower than expected, perhaps due to the practice of providing a patient’s first insulin pen without a prescription and perhaps not recording it in a patient’s health record.

DISCLOSURES:

This work received financial support from the University of Southern Denmark, the Region of Southern Denmark, and the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Previous gestational diabetes mellitus (GDM) nearly doubles future chronic kidney disease (CKD) risk, irrespective of subsequent diabetes and hypertension, a study showed.

METHODOLOGY:

• A nationwide, cohort study was based on data from the Danish Medical Birth Register and included 697,622 women who gave birth between 1997 and 2018.
• Of all study participants, 3.4% reported GDM in at least one pregnancy, and 12.8% of women with GDM received insulin, a proxy for a more severe metabolic dysfunction.
• The women were followed up for a median of 11.9 years.
• Researchers studied CKD and acute kidney disease as the outcomes of interest, the mediating effects of subsequent diabetes and hypertension on future CKD, and how GDM severity affected later risk for kidney disease.

TAKEAWAY:

• Women with GDM showed significantly higher CKD risk than those without GDM (adjusted hazard ratio [aHR], 1.92; 95% CI, 1.67-2.21).
• Women who received insulin during pregnancy due to severe metabolic dysfunction but did not develop subsequent diabetes had a proportionally higher risk for CKD (aHR, 2.35; 95% CI, 1.39-3.97).
• Women with GDM who went on to develop diabetes or hypertension faced even higher risks for CKD, suggesting that preventing diabetes and hypertension after GDM may reduce the development of CKD.
• GDM did not affect the risk for acute kidney disease (aHR, 1.08; 95% CI, 0.90-1.29).

IN PRACTICE:

“Women with severe metabolic dysfunction during pregnancy constitute a high-risk group regarding future CKD,” the authors wrote. “The significantly elevated CKD risk was observed from 2 years after pregnancy and beyond.”

SOURCE:

The study, with first author Maria Hornstrup Christensen, of Odense University Hospital, Odense, Denmark, was published online on December 15 in Diabetes Care.

LIMITATIONS:

GDM may be underdiagnosed, and undiagnosed diabetes may be misclassified as GDM. The proxies of GDM and insulin treatment may not have captured the increasing severity of metabolic dysfunction. The prevalence of insulin treatment was lower than expected, perhaps due to the practice of providing a patient’s first insulin pen without a prescription and perhaps not recording it in a patient’s health record.

DISCLOSURES:

This work received financial support from the University of Southern Denmark, the Region of Southern Denmark, and the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation. The authors declared no conflicts of interest.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with type 2 diabetes (T2D) at an elevated risk for kidney failure may stand to gain the most renal benefit with intensive glycemic control, but they also face the highest overall risk for death and hypoglycemic events.

METHODOLOGY:

• Studies show the primary benefit of intensive glycemic control in T2D is microvascular outcomes, mostly in the kidney, but no clear criteria exist to identify patients who may benefit most.
• Researchers conducted a post hoc analysis of the ACCORD trial, including 9777 patients with diabetes and cardiovascular disease or two or more cardiovascular risk factors.
• The 5-year kidney failure risk was estimated using the validated kidney failure risk equation (KFRE).
• The patients were randomly assigned to receive intensive glycemic control (A1c, < 6.0%) or standard glycemic control (A1c, 7.0%-7.9%).
• The primary outcomes were kidney microvascular events and all-cause mortality.

TAKEAWAY:

• Over a 7-year period, intensive vs standard glycemic control delayed the onset of kidney microvascular outcomes by 48.4 days (corresponding hazard ratio [HR], 0.75; 95% CI, 0.65-0.86) but reduced the time to death by 23.6 days (HR, 1.20; 95% CI, 1.04-1.40).
• Patients in the highest quartile of 5-year kidney failure risk according to KFRE benefited the most with intensive vs standard glycemic control and reported the longest delay in the onset of kidney microvascular outcomes (114.8 days; 95% CI, 58.1-176.4).
• Although renal outcomes improved, the time to death was shortened by 56.7 days in patients with elevated risk for kidney failure receiving intensive glycemic control.

IN PRACTICE:

“The observed effect of intensive glycemic control on kidney microvascular outcomes in ACCORD is almost entirely driven by a subset of patients representing one quarter of the trial eligible population at elevated risk for kidney failure at baseline,” the authors wrote.

SOURCE:

Vivek Charu of Stanford University School of Medicine, Stanford, California, led this study, which was published online on December 11, 2023, in the Journal of the American Society of Nephrology

LIMITATIONS:

The ACCORD study enrolled participants with a low risk for kidney disease. Therefore, this study lacks relevant data that might be needed to analyze the risks and benefits of intensive glycemic control in a population at high risk for kidney disease. Treatment options and monitoring approaches to glycemic control have evolved in the nearly 20 years since the ACCORD trial, which used insulin and sulfonylurea agents for glycemic control.

DISCLOSURES:

This work was supported by several grants secured by the authors. Some authors declared serving in advisory or leadership roles, receiving honoraria and research funding, and other ties with several sources.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with type 2 diabetes (T2D) at an elevated risk for kidney failure may stand to gain the most renal benefit with intensive glycemic control, but they also face the highest overall risk for death and hypoglycemic events.

METHODOLOGY:

• Studies show the primary benefit of intensive glycemic control in T2D is microvascular outcomes, mostly in the kidney, but no clear criteria exist to identify patients who may benefit most.
• Researchers conducted a post hoc analysis of the ACCORD trial, including 9777 patients with diabetes and cardiovascular disease or two or more cardiovascular risk factors.
• The 5-year kidney failure risk was estimated using the validated kidney failure risk equation (KFRE).
• The patients were randomly assigned to receive intensive glycemic control (A1c, < 6.0%) or standard glycemic control (A1c, 7.0%-7.9%).
• The primary outcomes were kidney microvascular events and all-cause mortality.

TAKEAWAY:

• Over a 7-year period, intensive vs standard glycemic control delayed the onset of kidney microvascular outcomes by 48.4 days (corresponding hazard ratio [HR], 0.75; 95% CI, 0.65-0.86) but reduced the time to death by 23.6 days (HR, 1.20; 95% CI, 1.04-1.40).
• Patients in the highest quartile of 5-year kidney failure risk according to KFRE benefited the most with intensive vs standard glycemic control and reported the longest delay in the onset of kidney microvascular outcomes (114.8 days; 95% CI, 58.1-176.4).
• Although renal outcomes improved, the time to death was shortened by 56.7 days in patients with elevated risk for kidney failure receiving intensive glycemic control.

IN PRACTICE:

“The observed effect of intensive glycemic control on kidney microvascular outcomes in ACCORD is almost entirely driven by a subset of patients representing one quarter of the trial eligible population at elevated risk for kidney failure at baseline,” the authors wrote.

SOURCE:

Vivek Charu of Stanford University School of Medicine, Stanford, California, led this study, which was published online on December 11, 2023, in the Journal of the American Society of Nephrology

LIMITATIONS:

The ACCORD study enrolled participants with a low risk for kidney disease. Therefore, this study lacks relevant data that might be needed to analyze the risks and benefits of intensive glycemic control in a population at high risk for kidney disease. Treatment options and monitoring approaches to glycemic control have evolved in the nearly 20 years since the ACCORD trial, which used insulin and sulfonylurea agents for glycemic control.

DISCLOSURES:

This work was supported by several grants secured by the authors. Some authors declared serving in advisory or leadership roles, receiving honoraria and research funding, and other ties with several sources.

A version of this article appeared on Medscape.com.

TOPLINE:

Patients with type 2 diabetes (T2D) at an elevated risk for kidney failure may stand to gain the most renal benefit with intensive glycemic control, but they also face the highest overall risk for death and hypoglycemic events.

METHODOLOGY:

• Studies show the primary benefit of intensive glycemic control in T2D is microvascular outcomes, mostly in the kidney, but no clear criteria exist to identify patients who may benefit most.
• Researchers conducted a post hoc analysis of the ACCORD trial, including 9777 patients with diabetes and cardiovascular disease or two or more cardiovascular risk factors.
• The 5-year kidney failure risk was estimated using the validated kidney failure risk equation (KFRE).
• The patients were randomly assigned to receive intensive glycemic control (A1c, < 6.0%) or standard glycemic control (A1c, 7.0%-7.9%).
• The primary outcomes were kidney microvascular events and all-cause mortality.

TAKEAWAY:

• Over a 7-year period, intensive vs standard glycemic control delayed the onset of kidney microvascular outcomes by 48.4 days (corresponding hazard ratio [HR], 0.75; 95% CI, 0.65-0.86) but reduced the time to death by 23.6 days (HR, 1.20; 95% CI, 1.04-1.40).
• Patients in the highest quartile of 5-year kidney failure risk according to KFRE benefited the most with intensive vs standard glycemic control and reported the longest delay in the onset of kidney microvascular outcomes (114.8 days; 95% CI, 58.1-176.4).
• Although renal outcomes improved, the time to death was shortened by 56.7 days in patients with elevated risk for kidney failure receiving intensive glycemic control.

IN PRACTICE:

“The observed effect of intensive glycemic control on kidney microvascular outcomes in ACCORD is almost entirely driven by a subset of patients representing one quarter of the trial eligible population at elevated risk for kidney failure at baseline,” the authors wrote.

SOURCE:

Vivek Charu of Stanford University School of Medicine, Stanford, California, led this study, which was published online on December 11, 2023, in the Journal of the American Society of Nephrology

LIMITATIONS:

The ACCORD study enrolled participants with a low risk for kidney disease. Therefore, this study lacks relevant data that might be needed to analyze the risks and benefits of intensive glycemic control in a population at high risk for kidney disease. Treatment options and monitoring approaches to glycemic control have evolved in the nearly 20 years since the ACCORD trial, which used insulin and sulfonylurea agents for glycemic control.

DISCLOSURES:

This work was supported by several grants secured by the authors. Some authors declared serving in advisory or leadership roles, receiving honoraria and research funding, and other ties with several sources.

A version of this article appeared on Medscape.com.

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

FAIRFAX, VIRGINIA — Pharmacologic treatment of gestational diabetes mellitus (GDM) remains challenged by overall poor trial quality, clinical practice guidelines that offer differing advice, and a limited ability to predict individual risk and treatment response, but researchers at the biennial meeting of the Diabetes in Pregnancy Study Group of North America expressed hope for more clarity in the near future and the ability to someday individualize treatment to account for what is increasingly viewed as a heterogeneous condition.

Until studies in 2015 and 2018 cast doubt on glyburide, “we used to have 80% [of our GDM patients] on glyburide, and 20% on insulin,” Maisa Feghali, MD, of the University of Pittsburgh, said during a discussion period. “Now we have 95% on insulin and 5% on oral hypoglycemics. I rely on insulin because I don’t have a better option, and I rely on research efforts [underway to provide better options]” in the future.

The American College of Obstetricians and Gynecologists recommends insulin as the preferred first-line pharmacologic therapy for GDM when pharmacologic therapy is needed, with metformin as an option when patients decline or cannot safely use insulin. Glyburide, ACOG said in its 2018 practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64), should not be recommended as a first-line pharmacologic therapy.

The Society of Maternal-Fetal Medicine, on the other hand, has accepted metformin as a “reasonable and safe” first-line alternative to insulin — while recognizing that half of women will still require insulin to achieve glycemic control — and does not rule out consideration of glyburide. In its 2018 statement on the pharmacologic treatment of GDM, the society said that the evidence of benefit of one oral agent over another remains limited.  

“When you have dueling guidelines, it means the data are not that clear,” George Saade, MD, professor and chair of obstetrics and gynecology at the Eastern Virginia School of Medicine, Norfolk, said in a presentation on GDM. An upcoming $12 million multicenter study to be led by the Ohio State University College of Medicine — coined the DECIDE trial — should provide clarity, he said.

The trial, funded by the Patient-Centered Outcomes Research Institute, which funds comparative clinical effectiveness research designed to be broadly applicable to practice, will enroll and randomize over 1500 pregnant individuals with GDM to either oral metformin or insulin and will follow mothers and children until 2 years after delivery.

The study’s primary and secondary hypotheses, respectively, are that metformin is not inferior to insulin in reducing a composite adverse neonatal outcome (large for gestational age, neonatal hypoglycemia and/or hyperbilirubemia) and that metformin does not result in increased child body mass index at 2 years, compared with insulin. It will also look at patient-reported factors associated with metformin use compared to insulin use — factors that “are important ... to enable clinical implementation of study findings,” said Dr. Saade, who played a role in designing the study over the past several years.

The study will take a pragmatic, real-world approach by ensuring racial and ethnic, socioeconomic, urban and rural, and geographic diversity at both large academic and community-based sites across the United States.

The trial, to be led by Mark Landon, MD, and Kartik Venkatesh, MD, PhD, of Ohio State University, will be the first large trial in the United States to both directly compare the ability of oral hypoglycemics and insulin to prevent GDM-associated pregnancy complications, and to follow children for 2 years, Dr. Saade said. “Prior research was either outside the United States, not randomized, not adequately powered, or had no long-term child follow-up,” he added after the meeting.
 

The State Of Knowledge About Oral Hypoglycemics

The trial was envisioned several years ago as a three-arm comparative trial including the sulfonylurea glyburide, but data published in recent years has increasingly “not favored” glyburide, and many providers “have stopped using it,” Dr. Saade said during and after the meeting. At this point, “it would not be useful to include it” in a pragmatic trial, he said.

Glyburide became the number one agent after a seminal trial published in 2000 (N Engl J Med. 2000;343:1134-8) showed equivalent glycemic control in about 400 women with GDM who were randomized to receive insulin or glyburide. While the trial was not powered to evaluate other outcomes, there were no significant differences in neonatal complications.

In 2015, a large retrospective population-based study (JAMA Pediatr. 2015;169[5]:452-8) of more than 9,000 women with GDM showed higher risks of neonatal intensive care admission, neonatal hypoglycemia, and large-for-gestational age with glyburide compared with insulin. “It prompted a pause in thinking,” Dr. Saade recalled at the DPSG meeting. After that, several meta-analyses/systematic reviews compared the two treatments, showing varying and sometimes conflicting degrees of difference in neonatal outcomes.

In 2018, a French noninferiority randomized controlled trial (JAMA 2018;319[17]:1773-80) did not show that glyburide is not inferior to insulin in the prevention of perinatal outcomes (macrosomia, neonatal hypoglycemia, and hyperbilirubinemia). “If you add this trial to the systematic reviews, it would probably would shift more in favor of insulin,” Dr. Saade said, noting that the trial’s supplementary data included a higher rate of maternal hypoglycemia with glyburide. “I feel personally now, with all the data, that glyburide is inferior to insulin.”

A 2021 network meta-analysis (BMC Endocr Disord. 2021;21:199) that looked at glycemic control and neonatal outcomes in GDM treated with glyburide, metformin, or insulin, also offers valuable insight, Dr. Saade said. The meta-analysis used a Bayesian framework and presents results as a ranking estimated probability of a treatment being the best or worst — or in between — for different outcomes (glycemic control and neonatal outcomes), which “is one of the best ways to look at data these days,” he said.

“It tells us how likely [it is for one agent] to be better than others. Will it work most of the time? More than 60% of the time?” Dr. Saade explained. For example, the analysis “tell us that for large for gestational age, glyburide has a 94% chance of being the worst, metformin has an 80% change of being the best, and insulin a 76% chance of being in between.”

Overall, the 2021 analysis suggests that “glyburide is the most likely to be worst in most outcomes and that there is equipoise between metformin and insulin,” he said.

Meta-analyses of pharmacologic treatment of GDM have been challenged, he said, by inconsistent reporting in trials of GDM diagnostic criteria, severity of hyperglycemia, and small sample sizes (and wide confidence intervals). Criteria for supplemental insulin are also often “unclear” in trials, Dr. Saade said, as is involvement of social determinants of health and the “care package” enveloping pharmacologic interventions.

Dr. Saade, Dr. Landon, and other researchers have also lamented over the years that there is limited long-term follow-up of exposed offspring.
 

The Challenge of Heterogeneity

In another presentation on GDM, Maisa Feghali, MD, MS, emphasized that GDM is a heterogeneous condition, with clinical hyperglycemia not capturing individual variation in underlying physiologic processes. A 2016 study (Diabetes Care. 2016;39[6]:1052-5) assessing insulin sensitivity and secretion in 800-plus women at 24-30 weeks’ gestation found that about 50% of those with GDM had predominant insulin resistance, 30% had predominant insulin secretion deficit, and 20% were mixed.

Those with predominant insulin resistance had higher BMI, higher fasting glucose, larger infants, and greater risk of GDM-associated adverse outcomes, “suggesting that the risk is not universal or equivalent,” said Dr. Feghali, assistant professor in the department of obstetrics, gynecology and reproductive sciences at the University of Pittsburgh and the UPCM Magee-Women’s Hospital.

A 2019 multicenter European study (Diabetologia. 2019;62[11]:2118-28) found an even higher proportion of GDM involving predominant insulin resistance and, similarly, a greater risk of adverse pregnancy outcomes in these women than in insulin-sensitive women with GDM, “again suggesting that there’s probably some benefit to looking deeper at physiology to understand individual risk,” she said.

Research published decades ago showed that insulin sensitivity decreases by over 50% during pregnancy, and “what we’ve come to recognize is there [can be] insulin secretion deficiency that’s not able to surmount or overcome the insulin resistance that develops during advanced gestation,” she said. “We need to think not at the population level but at the individual level.”

Dr. Feghali is leading the MATCh-GDM (Metabolic Analysis for Treatment Choice in GDM) study, which has been randomizing women to receive either usual, unmatched treatment or treatment matched to GDM mechanism — metformin for predominant insulin resistance, glyburide, or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. Data are not available yet.

There is still more to be learned about the pharmacologic effects of oral hypoglycemics, she noted, pointing to a 2020 study (Clin Pharmacol Ther. 2020;107[6]:1362-72) that randomized women to glyburide, metformin, or glyburide/metformin combination therapy and measured insulin sensitivity, beta-cell responsivity, and disposition index. (The latter describes the overall metabolic state and is a product of insulin sensitivity and total beta-cell responsivity.)

“Somewhat surprisingly, they found metformin performed better than glyburide,” shifting the overall disposition index closer to normal, Dr. Feghali said. “But not surprisingly, they found the combination worked best.”

Total beta-cell responsivity occurred in 56% of the glyburide group and 74% of the combination group. Improvements in insulin sensitivity occurred in 84% of the metformin group and 74% of the combination group. Surprisingly, there was “a decrease in first-phase insulin secretion” with glyburide, noted Dr. Feghali — a finding that means “the glyburide story has turned out to be a little more complicated.” With metformin, there was a positive change in insulin secretion as well as insulin sensitivity.

The authors’ conclusion, she noted, “is that there’s potential in thinking about metformin first, as the primary treatment, and then adding glyburide after that.”
 

Future Use Of Incretin Mimetics, and Intensive Targets in Overweight/Obesity

Dr. Feghali wonders whether incretin hormone mimetics — such as glucagonlike peptide–1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) — could play a future role in GDM treatment, helping to increase insulin secretion.

She is currently recruiting for a pilot study on the pharmacokinetics and pharmacodynamics in GDM of exenatide, a FDA-approved GLP-1 agonist that has been shown not to cross the placenta and that should, research suggests, lower the risk of maternal hypoglycemia and limit the risk of excessive fetal growth, “overcoming some of the concerns we have with glyburide,” Dr. Feghali said.

A recent study of the gut-generated incretin response during an oral glucose tolerance test in pregnant women with and without GDM showed that post-load GLP-1 and GIP were higher in women with GDM, and that the GLP-1 secretion was associated with insulin secretion only in those with GDM (J Clin Endocrinol Metab. 2022;107(6):e2425-30). “In those with normal OGTT, insulin secretion was independent of GLP-1,” she said. “This study suggests there’s a potential role for incretin mimetics in GDM.”

Also regarding the individualization of GDM treatment, patients who are overweight or obese in the prepregnancy setting and have gestational diabetes represent a different phenotype, she noted, with higher fasting and postprandial blood glucose compared to normal-weight counterparts despite higher doses of medication.

“After controlling for gestational weight gain and glycemic control, we see there’s an independent effect of prepregnancy obesity specifically for an increased risk of macrosomia, preterm birth, and hypertensive disorders of pregnancy,” said Dr. Feghali, referring to a 2015 retrospective study of GDM and obesity (Obstet Gynecol. 2015;126:316-25). “It suggests that we might think about redrawing the line, not on diagnosis and screening but on treatment.”

The randomized, controlled Intensive Glycemic Targets in Overweight and Obese Women with Gestational Diabetes Mellitus (iGDM) trial, is now recruiting at multiple centers, including at Dr. Feghali’s University of Pittsburgh, and will investigate the effect of intensive glycemic targets (fasting < 90 mg/dL, 1-hour postprandial < 120 mg/dL) versus standard glycemic targets (fasting < 95 mg/dL, 1-hour postprandial < 140 mg/dL), she said.

In another presentation on GDM, Monica Longo, MD, PhD, of the Inova Health System in Fairfax, Va., said researchers are also looking at whether nutritional supplements such as myo-inositol can reduce the risk of adverse pregnancy outcomes in GDM, and whether probiotics can improve insulin sensitivity in some patients.

Data on newer insulin analogs in pregnancy are lacking, she noted. “Preliminary data has shown no malformations in infants, but there is some increase in hypoglycemia-related admissions to the NICU,” she said. “It’s worth it [to research more].”

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.

Medication people with type 2 diabetes use to manage their blood sugar also appears to protect their hearts and kidneys, according to a study in JAMA Network Open. 

These pills, known as sodium-glucose cotransport protein 2 (SGLT2) inhibitors, reduce the amount of blood sugar in a kidney by causing more glucose to be excreted in urine.

Chronic kidney disease (CKD) cannot be cured and often leads to renal failure. SGLT2 inhibitor drugs can help stave off this possibility. Acute kidney disease (AKD), on the other hand, is potentially reversible. It typically occurs after an acute kidney injury, lasts for up to 90 days, and can progress to CKD if left unchecked. 

“There has been a notable absence of targeted pharmacotherapy to offer protection to these patients,” said Vin-Cent Wu, MD, PhD, a nephrologist at National Taiwan University Hospital in Taipei, and an author of the study. 

For the retrospective analysis, Dr. Wu and his colleagues looked at data from more than 230,000 adults with type 2 diabetes whose health records were gathered into a research tool called the TriNetX, a global research database. Patients had been treated for AKD between 2002 and 2022. Major adverse kidney events were noted for 5 years after discharge, which were defined as events which required regular dialysis, major adverse cardiovascular events such as a heart attack or stroke, or death. 

To determine the effects of SGLT2 inhibitors, Dr. Wu and colleagues compared outcomes among 5317 patients with AKD who received the drugs with 5317 similar patients who did not. Members of both groups had lived for at least 90 days after being discharged from the hospital and did not require dialysis during that period. 

After a median follow-up of 2.3 years, more patients who did not receive an SGLT2 inhibitor had died (994 compared with 481) or had endured major stress to their kidneys (1119 compared with 504) or heart (612 compared with 295). The relative reduction in mortality risk for people in the SGLT2-inhibitor arm was 31% (adjusted hazard ratio, 0.69; 95% CI, 0.62-0.77).

Only 2.3% of patients with AKD in the study were prescribed an SGLT2 inhibitor. 

In the United States, approximately 20% of people with type 2 diabetes and CKD receive a SGLT2 inhibitor, according to 2023 research.

“Our study reveals that the prescription rate of SGLT2 inhibitors remains relatively low in clinical practice among patients with type 2 diabetes and AKD,” Dr. Wu told this news organization. “This underscores the need for increased awareness and greater consideration of this critical issue in clinical decision-making.” 

Dr. Wu said that AKD management tends to be conservative and relies on symptom monitoring. He acknowledged that confounders may have influenced the results, and that the use of SGLT2 inhibitors might only be correlated with better results instead of producing a causation effect.

This point was raised by Ayodele Odutayo, MD, DPhil, a nephrologist at the University of Toronto, who was not involved in the study. But despite that caution, Dr. Odutayo said that he found the study to be encouraging overall and broadly in line with known benefits of SGLT2 inhibitors in CKD. 

“The findings are reassuring that the medications work even in people who’ve already had some kidney injury beforehand,” but who are not yet diagnosed with CKD, Dr. Odutayo said. 

“There is vast underuse of these medications in people for whom they are indicated,” perhaps due to clinician concern that the drugs will cause side effects such as low blood pressure or loss of salt and fluid, Dr. Odutayo said. Though those concerns are valid, the benefits of these drugs exceed the risks for most patients with CKD. 

Dr. Wu and Dr. Odutayo report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Medication people with type 2 diabetes use to manage their blood sugar also appears to protect their hearts and kidneys, according to a study in JAMA Network Open. 

These pills, known as sodium-glucose cotransport protein 2 (SGLT2) inhibitors, reduce the amount of blood sugar in a kidney by causing more glucose to be excreted in urine.

Chronic kidney disease (CKD) cannot be cured and often leads to renal failure. SGLT2 inhibitor drugs can help stave off this possibility. Acute kidney disease (AKD), on the other hand, is potentially reversible. It typically occurs after an acute kidney injury, lasts for up to 90 days, and can progress to CKD if left unchecked. 

“There has been a notable absence of targeted pharmacotherapy to offer protection to these patients,” said Vin-Cent Wu, MD, PhD, a nephrologist at National Taiwan University Hospital in Taipei, and an author of the study. 

For the retrospective analysis, Dr. Wu and his colleagues looked at data from more than 230,000 adults with type 2 diabetes whose health records were gathered into a research tool called the TriNetX, a global research database. Patients had been treated for AKD between 2002 and 2022. Major adverse kidney events were noted for 5 years after discharge, which were defined as events which required regular dialysis, major adverse cardiovascular events such as a heart attack or stroke, or death. 

To determine the effects of SGLT2 inhibitors, Dr. Wu and colleagues compared outcomes among 5317 patients with AKD who received the drugs with 5317 similar patients who did not. Members of both groups had lived for at least 90 days after being discharged from the hospital and did not require dialysis during that period. 

After a median follow-up of 2.3 years, more patients who did not receive an SGLT2 inhibitor had died (994 compared with 481) or had endured major stress to their kidneys (1119 compared with 504) or heart (612 compared with 295). The relative reduction in mortality risk for people in the SGLT2-inhibitor arm was 31% (adjusted hazard ratio, 0.69; 95% CI, 0.62-0.77).

Only 2.3% of patients with AKD in the study were prescribed an SGLT2 inhibitor. 

In the United States, approximately 20% of people with type 2 diabetes and CKD receive a SGLT2 inhibitor, according to 2023 research.

“Our study reveals that the prescription rate of SGLT2 inhibitors remains relatively low in clinical practice among patients with type 2 diabetes and AKD,” Dr. Wu told this news organization. “This underscores the need for increased awareness and greater consideration of this critical issue in clinical decision-making.” 

Dr. Wu said that AKD management tends to be conservative and relies on symptom monitoring. He acknowledged that confounders may have influenced the results, and that the use of SGLT2 inhibitors might only be correlated with better results instead of producing a causation effect.

This point was raised by Ayodele Odutayo, MD, DPhil, a nephrologist at the University of Toronto, who was not involved in the study. But despite that caution, Dr. Odutayo said that he found the study to be encouraging overall and broadly in line with known benefits of SGLT2 inhibitors in CKD. 

“The findings are reassuring that the medications work even in people who’ve already had some kidney injury beforehand,” but who are not yet diagnosed with CKD, Dr. Odutayo said. 

“There is vast underuse of these medications in people for whom they are indicated,” perhaps due to clinician concern that the drugs will cause side effects such as low blood pressure or loss of salt and fluid, Dr. Odutayo said. Though those concerns are valid, the benefits of these drugs exceed the risks for most patients with CKD. 

Dr. Wu and Dr. Odutayo report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Medication people with type 2 diabetes use to manage their blood sugar also appears to protect their hearts and kidneys, according to a study in JAMA Network Open. 

These pills, known as sodium-glucose cotransport protein 2 (SGLT2) inhibitors, reduce the amount of blood sugar in a kidney by causing more glucose to be excreted in urine.

Chronic kidney disease (CKD) cannot be cured and often leads to renal failure. SGLT2 inhibitor drugs can help stave off this possibility. Acute kidney disease (AKD), on the other hand, is potentially reversible. It typically occurs after an acute kidney injury, lasts for up to 90 days, and can progress to CKD if left unchecked. 

“There has been a notable absence of targeted pharmacotherapy to offer protection to these patients,” said Vin-Cent Wu, MD, PhD, a nephrologist at National Taiwan University Hospital in Taipei, and an author of the study. 

For the retrospective analysis, Dr. Wu and his colleagues looked at data from more than 230,000 adults with type 2 diabetes whose health records were gathered into a research tool called the TriNetX, a global research database. Patients had been treated for AKD between 2002 and 2022. Major adverse kidney events were noted for 5 years after discharge, which were defined as events which required regular dialysis, major adverse cardiovascular events such as a heart attack or stroke, or death. 

To determine the effects of SGLT2 inhibitors, Dr. Wu and colleagues compared outcomes among 5317 patients with AKD who received the drugs with 5317 similar patients who did not. Members of both groups had lived for at least 90 days after being discharged from the hospital and did not require dialysis during that period. 

After a median follow-up of 2.3 years, more patients who did not receive an SGLT2 inhibitor had died (994 compared with 481) or had endured major stress to their kidneys (1119 compared with 504) or heart (612 compared with 295). The relative reduction in mortality risk for people in the SGLT2-inhibitor arm was 31% (adjusted hazard ratio, 0.69; 95% CI, 0.62-0.77).

Only 2.3% of patients with AKD in the study were prescribed an SGLT2 inhibitor. 

In the United States, approximately 20% of people with type 2 diabetes and CKD receive a SGLT2 inhibitor, according to 2023 research.

“Our study reveals that the prescription rate of SGLT2 inhibitors remains relatively low in clinical practice among patients with type 2 diabetes and AKD,” Dr. Wu told this news organization. “This underscores the need for increased awareness and greater consideration of this critical issue in clinical decision-making.” 

Dr. Wu said that AKD management tends to be conservative and relies on symptom monitoring. He acknowledged that confounders may have influenced the results, and that the use of SGLT2 inhibitors might only be correlated with better results instead of producing a causation effect.

This point was raised by Ayodele Odutayo, MD, DPhil, a nephrologist at the University of Toronto, who was not involved in the study. But despite that caution, Dr. Odutayo said that he found the study to be encouraging overall and broadly in line with known benefits of SGLT2 inhibitors in CKD. 

“The findings are reassuring that the medications work even in people who’ve already had some kidney injury beforehand,” but who are not yet diagnosed with CKD, Dr. Odutayo said. 

“There is vast underuse of these medications in people for whom they are indicated,” perhaps due to clinician concern that the drugs will cause side effects such as low blood pressure or loss of salt and fluid, Dr. Odutayo said. Though those concerns are valid, the benefits of these drugs exceed the risks for most patients with CKD. 

Dr. Wu and Dr. Odutayo report no relevant financial relationships.

A version of this article appeared on Medscape.com.

Eli Lilly, maker of the anti-obesity drug Zepbound, announced this week the launch of LillyDirect, a direct-to-patient portal, allowing some patients to obtain its drug for as little as $25 a month.

The move is seen as a major shift in the way these popular medications can reach patients. 

For many of the 42 million Americans with obesity, weight loss medications such as Wegovy, Saxenda, and the brand-new Zepbound can be a godsend, helping them lose the excess pounds they’ve struggled with for decades or a lifetime.

But getting these medications has been a struggle for many who are eligible. Shortages of the drugs have been one barrier, and costs of up to $1,300 monthly — the price tag without insurance coverage — are another hurdle.

But 2024 may be a much brighter year, thanks to Lilly’s new portal as well as other developments:

Insurance coverage on private health plans, while still spotty, may be improving. Federal legislators are fighting a 2003 law that forbids Medicare from paying for the medications when prescribed for obesity.

New research found that semaglutide (Wegovy) can reduce the risk of recurrent strokes and heart attacks as well as deaths from cardiovascular events in those with obesity and preexisting cardiovascular disease (or diseases of the heart and blood vessels), a finding experts said should get the attention of health insurers.

The medications, also referred to as GLP-1 agonists, work by activating the receptors of hormones (called glucagon-like peptide 1 and others) that are naturally released after eating. That, in turn, makes you feel more full, leading to weight loss of up to 22% for some. The medications are approved for those with a body mass index (BMI) of 30 or a BMI of 27 with at least one other weight-related health condition such as high blood pressure or high cholesterol. The medicines, injected weekly or more often, are prescribed along with advice about a reduced-calorie diet and increased physical activity.

LillyDirect

Eli Lilly launched its direct-to-patient portal on Thursday, providing its obesity medicine (as well as diabetes and migraine drugs) direct to the consumer. Patients can access the obesity medicines through the telehealth platform FORM. Patients reach independent telehealth providers, according to Lilly, who can complement a patient’s current doctor or be an alternative to in-patient care in some cases. 

Eli Lilly officials did not respond to requests for comment. 

Some obesity experts welcomed the new service. “Any program that improves availability and affordability of these ground-breaking medications is welcome news for our long-suffering patients,” said Louis Aronne, MD, director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City, a long-time obesity researcher.

“It’s a great move for Lilly to do,” agreed Caroline Apovian, MD, a professor of medicine at Harvard Medical School and co-director of the Center for Weight Management and Wellness at Brigham & Women’s Hospital in Boston, who is also a veteran obesity specialist. “It is trying to help the accessibility issue and do it responsibly.” 

“The bottom line is, there is an overwhelming amount of consumer need and desire for these medications and not enough channels [to provide them],” said Zeev Neuwirth, MD, a former executive at Atrium Health who writes about health care trends. “Eli Lilly is responding to a market need that is out there and quite honestly continuing to grow.” 

There are still concerns and questions, Dr. Neuwirth said, “especially since this is to my knowledge the first of its kind in terms of a pharmaceutical manufacturer directly dispensing medication in this nontraditional way.”

He called for transparency between telehealth providers and the pharmaceutical company to rule out any conflicts of interest. 

The American College of Physicians, an organization of internal medicine doctors and others, issued a statement expressing concern. Omar T. Atiq, MD, group’s president, said his organization is “concerned by the development of websites that enable patients to order prescription medications directly from the drugmakers. While information on in-person care is available, this direct-to-consumer approach is primarily oriented around the use of telehealth services to prescribe a drug maker’s products.”

The group urged that an established patient-doctor relationship be present, or that care should happen in consultation with a doctor who does have an established relationship (the latter an option offered by Lilly). “These direct-to-consumer services have the potential to leave patients confused and misinformed about medications.”

Heart Attack, Stroke Reduction Benefits

Previous research has found that the GLP-1 medicines such as Ozempic (semaglutide), which the FDA approved to treat diabetes, also reduce the risk of cardiovascular issues such as strokes and heart attacks. Now, new research finds that semaglutide at the Wegovy dose (usually slightly higher than the Ozempic dose for diabetes) also has those benefits in those who don›t have a diabetes diagnosis but do have obesity and cardiovascular disease.

In a clinical trial sponsored by Novo Nordisk, the maker of Wegovy, half of more than 17,000 people with obesity were given semaglutide (Wegovy); the other half got a placebo. Compared to those on the placebo, those who took the Wegovy had a 20% reduction in strokes, heart attacks, and deaths from cardiovascular causes over a 33-month period. 

The study results are a “big deal,” Dr. Aronne said. The results make it clear that those with obesity but not diabetes will get the cardiovascular benefits from the treatment as well. While more analysis is necessary, he said the important point is that the study showed that reducing body weight is linked to improvement in critical health outcomes.

As the research evolves, he said, it’s going to be difficult for insurers to deny medications in the face of those findings, which promise reductions in long-term health care costs.

Insurance Coverage

In November, the American Medical Association voted to adopt a policy to urge insurance coverage for evidence-based treatment for obesity, including the new obesity medications.

“No single organization is going to be able to convince insurers and employers to cover this,” Dr. Aronne said. “But I think a prominent organization like the AMA adding their voice to the rising chorus is going to help.”

Coverage of GLP-1 medications could nearly double in 2024, according to a survey of 500 human resources decision-makers released in October by Accolade, a personalized health care advocacy and delivery company. While 25% of respondents said they currently offered coverage when the survey was done in August and September, 43% said they intend to offer coverage in 2024.

In an email, David Allen, a spokesperson for America’s Health Insurance Plans, a health care industry association, said: “Every American deserves affordable coverage and high-quality care, and that includes coverage and care for evidence-based obesity treatments and therapies.”

He said “clinical leaders and other experts at health insurance providers routinely review the evidence for all types of treatments, including treatments for obesity, and offer multiple options to patients — ranging from lifestyle changes and nutrition counseling, to surgical interventions, to prescription drugs.” 

Mr. Allen said the evidence that obesity drugs help with weight loss “is still evolving.”

“And some patients are experiencing bad effects related to these drugs such as vomiting and nausea, for example, and the likelihood of gaining the weight back when discontinuing the drugs,” he said. 

Others are fighting for Medicare coverage, while some experts contend the costs of that coverage would be overwhelming. A bipartisan bill, the Treat and Reduce Obesity Act of 2023, would allow coverage under Medicare›s prescription drug benefit for drugs used for the treatment of obesity or for weigh loss management for people who are overweight. Some say it›s an uphill climb, citing a Vanderbilt University analysis that found giving just 10% of Medicare-eligible patients the drugs would cost $13.6 billion to more than $26 billion.

However, a white paper from the University of Southern California concluded that the value to society of covering the drugs for Medicare recipients would equal nearly $1 trillion over 10 years, citing savings in hospitalizations and other health care costs.

Comprehensive insurance coverage is needed, Dr. Apovian said. Private insurance plans, Medicare, and Medicaid must all realize the importance of covering what has been now shown to be life-saving drugs, she said. 

Broader coverage might also reduce the number of patients getting obesity drugs from unreliable sources, in an effort to save money, and having adverse effects. The FDA warned against counterfeit semaglutide in December.

Long-Term Picture

Research suggests the obesity medications must be taken continuously, at least for most people, to maintain the weight loss. In a study of patients on Zepbound, Dr. Aronne and colleagues found that withdrawing the medication led people to regain weight, while continuing it led to maintaining and even increasing the initial weight loss. While some may be able to use the medications only from time to time, “the majority will have to take these on a chronic basis,” Dr. Aronne said.

Obesity, like high blood pressure and other chronic conditions, needs continuous treatment, Dr. Apovian said. No one would suggest withdrawing blood pressure medications that stabilize blood pressure; the same should be true for the obesity drugs, she said.

Dr. Apovian consults for FORM, the telehealth platform Lilly uses for LillyDirect, and consults for Novo Nordisk, which makes Saxenda and Wegovy. Dr. Aronne is a consultant and investigator for Novo Nordisk, Eli Lilly, and other companies.

A version of this article appeared on WebMD.com.

Eli Lilly, maker of the anti-obesity drug Zepbound, announced this week the launch of LillyDirect, a direct-to-patient portal, allowing some patients to obtain its drug for as little as $25 a month.

The move is seen as a major shift in the way these popular medications can reach patients. 

For many of the 42 million Americans with obesity, weight loss medications such as Wegovy, Saxenda, and the brand-new Zepbound can be a godsend, helping them lose the excess pounds they’ve struggled with for decades or a lifetime.

But getting these medications has been a struggle for many who are eligible. Shortages of the drugs have been one barrier, and costs of up to $1,300 monthly — the price tag without insurance coverage — are another hurdle.

But 2024 may be a much brighter year, thanks to Lilly’s new portal as well as other developments:

Insurance coverage on private health plans, while still spotty, may be improving. Federal legislators are fighting a 2003 law that forbids Medicare from paying for the medications when prescribed for obesity.

New research found that semaglutide (Wegovy) can reduce the risk of recurrent strokes and heart attacks as well as deaths from cardiovascular events in those with obesity and preexisting cardiovascular disease (or diseases of the heart and blood vessels), a finding experts said should get the attention of health insurers.

The medications, also referred to as GLP-1 agonists, work by activating the receptors of hormones (called glucagon-like peptide 1 and others) that are naturally released after eating. That, in turn, makes you feel more full, leading to weight loss of up to 22% for some. The medications are approved for those with a body mass index (BMI) of 30 or a BMI of 27 with at least one other weight-related health condition such as high blood pressure or high cholesterol. The medicines, injected weekly or more often, are prescribed along with advice about a reduced-calorie diet and increased physical activity.

LillyDirect

Eli Lilly launched its direct-to-patient portal on Thursday, providing its obesity medicine (as well as diabetes and migraine drugs) direct to the consumer. Patients can access the obesity medicines through the telehealth platform FORM. Patients reach independent telehealth providers, according to Lilly, who can complement a patient’s current doctor or be an alternative to in-patient care in some cases. 

Eli Lilly officials did not respond to requests for comment. 

Some obesity experts welcomed the new service. “Any program that improves availability and affordability of these ground-breaking medications is welcome news for our long-suffering patients,” said Louis Aronne, MD, director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City, a long-time obesity researcher.

“It’s a great move for Lilly to do,” agreed Caroline Apovian, MD, a professor of medicine at Harvard Medical School and co-director of the Center for Weight Management and Wellness at Brigham & Women’s Hospital in Boston, who is also a veteran obesity specialist. “It is trying to help the accessibility issue and do it responsibly.” 

“The bottom line is, there is an overwhelming amount of consumer need and desire for these medications and not enough channels [to provide them],” said Zeev Neuwirth, MD, a former executive at Atrium Health who writes about health care trends. “Eli Lilly is responding to a market need that is out there and quite honestly continuing to grow.” 

There are still concerns and questions, Dr. Neuwirth said, “especially since this is to my knowledge the first of its kind in terms of a pharmaceutical manufacturer directly dispensing medication in this nontraditional way.”

He called for transparency between telehealth providers and the pharmaceutical company to rule out any conflicts of interest. 

The American College of Physicians, an organization of internal medicine doctors and others, issued a statement expressing concern. Omar T. Atiq, MD, group’s president, said his organization is “concerned by the development of websites that enable patients to order prescription medications directly from the drugmakers. While information on in-person care is available, this direct-to-consumer approach is primarily oriented around the use of telehealth services to prescribe a drug maker’s products.”

The group urged that an established patient-doctor relationship be present, or that care should happen in consultation with a doctor who does have an established relationship (the latter an option offered by Lilly). “These direct-to-consumer services have the potential to leave patients confused and misinformed about medications.”

Heart Attack, Stroke Reduction Benefits

Previous research has found that the GLP-1 medicines such as Ozempic (semaglutide), which the FDA approved to treat diabetes, also reduce the risk of cardiovascular issues such as strokes and heart attacks. Now, new research finds that semaglutide at the Wegovy dose (usually slightly higher than the Ozempic dose for diabetes) also has those benefits in those who don›t have a diabetes diagnosis but do have obesity and cardiovascular disease.

In a clinical trial sponsored by Novo Nordisk, the maker of Wegovy, half of more than 17,000 people with obesity were given semaglutide (Wegovy); the other half got a placebo. Compared to those on the placebo, those who took the Wegovy had a 20% reduction in strokes, heart attacks, and deaths from cardiovascular causes over a 33-month period. 

The study results are a “big deal,” Dr. Aronne said. The results make it clear that those with obesity but not diabetes will get the cardiovascular benefits from the treatment as well. While more analysis is necessary, he said the important point is that the study showed that reducing body weight is linked to improvement in critical health outcomes.

As the research evolves, he said, it’s going to be difficult for insurers to deny medications in the face of those findings, which promise reductions in long-term health care costs.

Insurance Coverage

In November, the American Medical Association voted to adopt a policy to urge insurance coverage for evidence-based treatment for obesity, including the new obesity medications.

“No single organization is going to be able to convince insurers and employers to cover this,” Dr. Aronne said. “But I think a prominent organization like the AMA adding their voice to the rising chorus is going to help.”

Coverage of GLP-1 medications could nearly double in 2024, according to a survey of 500 human resources decision-makers released in October by Accolade, a personalized health care advocacy and delivery company. While 25% of respondents said they currently offered coverage when the survey was done in August and September, 43% said they intend to offer coverage in 2024.

In an email, David Allen, a spokesperson for America’s Health Insurance Plans, a health care industry association, said: “Every American deserves affordable coverage and high-quality care, and that includes coverage and care for evidence-based obesity treatments and therapies.”

He said “clinical leaders and other experts at health insurance providers routinely review the evidence for all types of treatments, including treatments for obesity, and offer multiple options to patients — ranging from lifestyle changes and nutrition counseling, to surgical interventions, to prescription drugs.” 

Mr. Allen said the evidence that obesity drugs help with weight loss “is still evolving.”

“And some patients are experiencing bad effects related to these drugs such as vomiting and nausea, for example, and the likelihood of gaining the weight back when discontinuing the drugs,” he said. 

Others are fighting for Medicare coverage, while some experts contend the costs of that coverage would be overwhelming. A bipartisan bill, the Treat and Reduce Obesity Act of 2023, would allow coverage under Medicare›s prescription drug benefit for drugs used for the treatment of obesity or for weigh loss management for people who are overweight. Some say it›s an uphill climb, citing a Vanderbilt University analysis that found giving just 10% of Medicare-eligible patients the drugs would cost $13.6 billion to more than $26 billion.

However, a white paper from the University of Southern California concluded that the value to society of covering the drugs for Medicare recipients would equal nearly $1 trillion over 10 years, citing savings in hospitalizations and other health care costs.

Comprehensive insurance coverage is needed, Dr. Apovian said. Private insurance plans, Medicare, and Medicaid must all realize the importance of covering what has been now shown to be life-saving drugs, she said. 

Broader coverage might also reduce the number of patients getting obesity drugs from unreliable sources, in an effort to save money, and having adverse effects. The FDA warned against counterfeit semaglutide in December.

Long-Term Picture

Research suggests the obesity medications must be taken continuously, at least for most people, to maintain the weight loss. In a study of patients on Zepbound, Dr. Aronne and colleagues found that withdrawing the medication led people to regain weight, while continuing it led to maintaining and even increasing the initial weight loss. While some may be able to use the medications only from time to time, “the majority will have to take these on a chronic basis,” Dr. Aronne said.

Obesity, like high blood pressure and other chronic conditions, needs continuous treatment, Dr. Apovian said. No one would suggest withdrawing blood pressure medications that stabilize blood pressure; the same should be true for the obesity drugs, she said.

Dr. Apovian consults for FORM, the telehealth platform Lilly uses for LillyDirect, and consults for Novo Nordisk, which makes Saxenda and Wegovy. Dr. Aronne is a consultant and investigator for Novo Nordisk, Eli Lilly, and other companies.

A version of this article appeared on WebMD.com.

Eli Lilly, maker of the anti-obesity drug Zepbound, announced this week the launch of LillyDirect, a direct-to-patient portal, allowing some patients to obtain its drug for as little as $25 a month.

The move is seen as a major shift in the way these popular medications can reach patients. 

For many of the 42 million Americans with obesity, weight loss medications such as Wegovy, Saxenda, and the brand-new Zepbound can be a godsend, helping them lose the excess pounds they’ve struggled with for decades or a lifetime.

But getting these medications has been a struggle for many who are eligible. Shortages of the drugs have been one barrier, and costs of up to $1,300 monthly — the price tag without insurance coverage — are another hurdle.

But 2024 may be a much brighter year, thanks to Lilly’s new portal as well as other developments:

Insurance coverage on private health plans, while still spotty, may be improving. Federal legislators are fighting a 2003 law that forbids Medicare from paying for the medications when prescribed for obesity.

New research found that semaglutide (Wegovy) can reduce the risk of recurrent strokes and heart attacks as well as deaths from cardiovascular events in those with obesity and preexisting cardiovascular disease (or diseases of the heart and blood vessels), a finding experts said should get the attention of health insurers.

The medications, also referred to as GLP-1 agonists, work by activating the receptors of hormones (called glucagon-like peptide 1 and others) that are naturally released after eating. That, in turn, makes you feel more full, leading to weight loss of up to 22% for some. The medications are approved for those with a body mass index (BMI) of 30 or a BMI of 27 with at least one other weight-related health condition such as high blood pressure or high cholesterol. The medicines, injected weekly or more often, are prescribed along with advice about a reduced-calorie diet and increased physical activity.

LillyDirect

Eli Lilly launched its direct-to-patient portal on Thursday, providing its obesity medicine (as well as diabetes and migraine drugs) direct to the consumer. Patients can access the obesity medicines through the telehealth platform FORM. Patients reach independent telehealth providers, according to Lilly, who can complement a patient’s current doctor or be an alternative to in-patient care in some cases. 

Eli Lilly officials did not respond to requests for comment. 

Some obesity experts welcomed the new service. “Any program that improves availability and affordability of these ground-breaking medications is welcome news for our long-suffering patients,” said Louis Aronne, MD, director of the Comprehensive Weight Control Center at Weill Cornell Medicine in New York City, a long-time obesity researcher.

“It’s a great move for Lilly to do,” agreed Caroline Apovian, MD, a professor of medicine at Harvard Medical School and co-director of the Center for Weight Management and Wellness at Brigham & Women’s Hospital in Boston, who is also a veteran obesity specialist. “It is trying to help the accessibility issue and do it responsibly.” 

“The bottom line is, there is an overwhelming amount of consumer need and desire for these medications and not enough channels [to provide them],” said Zeev Neuwirth, MD, a former executive at Atrium Health who writes about health care trends. “Eli Lilly is responding to a market need that is out there and quite honestly continuing to grow.” 

There are still concerns and questions, Dr. Neuwirth said, “especially since this is to my knowledge the first of its kind in terms of a pharmaceutical manufacturer directly dispensing medication in this nontraditional way.”

He called for transparency between telehealth providers and the pharmaceutical company to rule out any conflicts of interest. 

The American College of Physicians, an organization of internal medicine doctors and others, issued a statement expressing concern. Omar T. Atiq, MD, group’s president, said his organization is “concerned by the development of websites that enable patients to order prescription medications directly from the drugmakers. While information on in-person care is available, this direct-to-consumer approach is primarily oriented around the use of telehealth services to prescribe a drug maker’s products.”

The group urged that an established patient-doctor relationship be present, or that care should happen in consultation with a doctor who does have an established relationship (the latter an option offered by Lilly). “These direct-to-consumer services have the potential to leave patients confused and misinformed about medications.”

Heart Attack, Stroke Reduction Benefits

Previous research has found that the GLP-1 medicines such as Ozempic (semaglutide), which the FDA approved to treat diabetes, also reduce the risk of cardiovascular issues such as strokes and heart attacks. Now, new research finds that semaglutide at the Wegovy dose (usually slightly higher than the Ozempic dose for diabetes) also has those benefits in those who don›t have a diabetes diagnosis but do have obesity and cardiovascular disease.

In a clinical trial sponsored by Novo Nordisk, the maker of Wegovy, half of more than 17,000 people with obesity were given semaglutide (Wegovy); the other half got a placebo. Compared to those on the placebo, those who took the Wegovy had a 20% reduction in strokes, heart attacks, and deaths from cardiovascular causes over a 33-month period. 

The study results are a “big deal,” Dr. Aronne said. The results make it clear that those with obesity but not diabetes will get the cardiovascular benefits from the treatment as well. While more analysis is necessary, he said the important point is that the study showed that reducing body weight is linked to improvement in critical health outcomes.

As the research evolves, he said, it’s going to be difficult for insurers to deny medications in the face of those findings, which promise reductions in long-term health care costs.

Insurance Coverage

In November, the American Medical Association voted to adopt a policy to urge insurance coverage for evidence-based treatment for obesity, including the new obesity medications.

“No single organization is going to be able to convince insurers and employers to cover this,” Dr. Aronne said. “But I think a prominent organization like the AMA adding their voice to the rising chorus is going to help.”

Coverage of GLP-1 medications could nearly double in 2024, according to a survey of 500 human resources decision-makers released in October by Accolade, a personalized health care advocacy and delivery company. While 25% of respondents said they currently offered coverage when the survey was done in August and September, 43% said they intend to offer coverage in 2024.

In an email, David Allen, a spokesperson for America’s Health Insurance Plans, a health care industry association, said: “Every American deserves affordable coverage and high-quality care, and that includes coverage and care for evidence-based obesity treatments and therapies.”

He said “clinical leaders and other experts at health insurance providers routinely review the evidence for all types of treatments, including treatments for obesity, and offer multiple options to patients — ranging from lifestyle changes and nutrition counseling, to surgical interventions, to prescription drugs.” 

Mr. Allen said the evidence that obesity drugs help with weight loss “is still evolving.”

“And some patients are experiencing bad effects related to these drugs such as vomiting and nausea, for example, and the likelihood of gaining the weight back when discontinuing the drugs,” he said. 

Others are fighting for Medicare coverage, while some experts contend the costs of that coverage would be overwhelming. A bipartisan bill, the Treat and Reduce Obesity Act of 2023, would allow coverage under Medicare›s prescription drug benefit for drugs used for the treatment of obesity or for weigh loss management for people who are overweight. Some say it›s an uphill climb, citing a Vanderbilt University analysis that found giving just 10% of Medicare-eligible patients the drugs would cost $13.6 billion to more than $26 billion.

However, a white paper from the University of Southern California concluded that the value to society of covering the drugs for Medicare recipients would equal nearly $1 trillion over 10 years, citing savings in hospitalizations and other health care costs.

Comprehensive insurance coverage is needed, Dr. Apovian said. Private insurance plans, Medicare, and Medicaid must all realize the importance of covering what has been now shown to be life-saving drugs, she said. 

Broader coverage might also reduce the number of patients getting obesity drugs from unreliable sources, in an effort to save money, and having adverse effects. The FDA warned against counterfeit semaglutide in December.

Long-Term Picture

Research suggests the obesity medications must be taken continuously, at least for most people, to maintain the weight loss. In a study of patients on Zepbound, Dr. Aronne and colleagues found that withdrawing the medication led people to regain weight, while continuing it led to maintaining and even increasing the initial weight loss. While some may be able to use the medications only from time to time, “the majority will have to take these on a chronic basis,” Dr. Aronne said.

Obesity, like high blood pressure and other chronic conditions, needs continuous treatment, Dr. Apovian said. No one would suggest withdrawing blood pressure medications that stabilize blood pressure; the same should be true for the obesity drugs, she said.

Dr. Apovian consults for FORM, the telehealth platform Lilly uses for LillyDirect, and consults for Novo Nordisk, which makes Saxenda and Wegovy. Dr. Aronne is a consultant and investigator for Novo Nordisk, Eli Lilly, and other companies.

A version of this article appeared on WebMD.com.

Rapid surges in insulin following a meal are associated with favorable long-term cardiometabolic benefits, including improvements in beta cell function and a lower risk for the development of prediabetes or diabetes, contrary to some concerns of the surges being indicative of more negative effects.

“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal,” said first author Ravi Retnakaran, MD, an endocrinologist and Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital, Toronto, Ontario, in a press statement.

“But it’s not that simple,” he said. “We observed that a robust post-challenge insulin secretory response, once adjusted for glucose levels, is only associated with beneficial metabolic effects.”

The findings were published on December 13, 2023, in eClinicalMedicine, part of The Lancet Discovery Science.

Insulin levels increase after food consumption in the normal management of blood glucose; however, some research has suggested that more rapid spikes in insulin, especially after a high-carbohydrate meal, are linked to an anabolic state contributing to weight gain and insulin resistance.

As public awareness of those reports has grown, “patients are coming in concerned about the possibility of their insulin levels being high, and there is confusion about the physiology of these effects,” Dr. Retnakaran told this news organization. 

However, other studies have shown that the effects of insulin surges are important relative to baseline factors, including ambient glycemia and, specifically, baseline glucose levels prior to a meal.

Therefore, a more appropriate assessment is to use a corrected insulin response, measuring insulin secretion at 30 minutes after an oral glucose challenge, in relation to baseline glucose levels, research has suggested.

To investigate the issue in a longitudinal context, Dr. Retnakaran and colleagues conducted a prospective cohort study of 306 pregnant women representing a full range of glucose tolerance, who were enrolled at a hospital in Toronto between October 2003 and March 2014.

The women received comprehensive cardiometabolic testing, including oral glucose tolerance tests at 1-year, 3-year, and 5-year postpartum, and their baseline post-challenge insulinemia was established using corrected insulin response at 1 year.

Over 4 years of follow-up, a progressive worsening of cardiometabolic factors was associated with higher tertiles of corrected insulin responses at baseline, including waist circumference (P = .016), high-density lipoprotein (P = .018), C-reactive protein (CRP; P = .006), and insulin sensitivity (P < .001).

However, those trends were also associated with progressively improved beta cell function (P < .001).

After adjustment in the longitudinal analysis for the clinical risk factors for diabetes, including age, ethnicity, family history of diabetes, and body mass index (BMI) at 1 year, a higher corrected insulin response tertile at baseline was independently associated with improved Insulin Secretion-Sensitivity Index-2 and insulinogenic index/insulin resistance index (IGI/HOMA-IR), as well as lower glycemia, as observed on fasting and 2-hour glucose at 3 years and 5 years (all P < .001).

The insulin response was meanwhile not associated with BMI, waist, lipids, CRP, or insulin sensitivity or resistance.

Importantly, the highest corrected insulin response tertile at 1-year postpartum was also significantly associated with a lower risk for prediabetes or diabetes than the lowest tertile at 3 years (adjusted OR [aOR], 0.19) as well as 5 years (aOR, 0.18).

“The real question in my mind was whether we had the statistical power to be able to demonstrate a longitudinal beneficial effect on glucose regulation, but we did,” Dr. Retnakaran told this news organization. “The results show lower prediabetes and diabetes among people who had the most robust postprandial insulin excursion at 1-year postpartum.”

While the unadjusted analyses at baseline showed adverse as well as favorable outcomes, “adjusted longitudinal analyses revealed consistent independent associations of higher complete insulin response with better beta cell function, lower glycemia, and lower risk of prediabetes or diabetes in the years thereafter,” the authors reported.

“This evidence should help push back concern around the postprandial insulin spike,” Dr. Retnakaran said.

Commenting on the study, James D. Johnson, PhD, a professor of cellular and physiological sciences and director of the Life Sciences Institute at the University of British Columbia, Canada, noted that “it is already well-known that the loss of postprandial first phase insulin secretion can be a key and early defect in the transition to prediabetes and type 2 diabetes. That is not new, but the confirmatory data are welcome,” he told this news organization.

However, with other data linking high insulin with adiposity and insulin resistance, “the nuance and subtleties are critical for us to understand the directions of the causality,” he said.

“It is quite possible that both of these models are true at different life stages and/or in different people. There may be more than one pathway to diabetes. This is the nature of science and progress.”

A key caveat is that with a specific cohort of pregnant women, the question remains of the generalizability to men and to those younger or older than childbearing age.

Nevertheless, “I think this is an interesting and important study,” Dr. Johnson said. “More data on this topic is always welcome, but I am not sure this will be the final say in this debate.”

The authors and Dr. Johnson had no disclosures to report.

A version of this article appeared on Medscape.com.

Rapid surges in insulin following a meal are associated with favorable long-term cardiometabolic benefits, including improvements in beta cell function and a lower risk for the development of prediabetes or diabetes, contrary to some concerns of the surges being indicative of more negative effects.

“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal,” said first author Ravi Retnakaran, MD, an endocrinologist and Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital, Toronto, Ontario, in a press statement.

“But it’s not that simple,” he said. “We observed that a robust post-challenge insulin secretory response, once adjusted for glucose levels, is only associated with beneficial metabolic effects.”

The findings were published on December 13, 2023, in eClinicalMedicine, part of The Lancet Discovery Science.

Insulin levels increase after food consumption in the normal management of blood glucose; however, some research has suggested that more rapid spikes in insulin, especially after a high-carbohydrate meal, are linked to an anabolic state contributing to weight gain and insulin resistance.

As public awareness of those reports has grown, “patients are coming in concerned about the possibility of their insulin levels being high, and there is confusion about the physiology of these effects,” Dr. Retnakaran told this news organization. 

However, other studies have shown that the effects of insulin surges are important relative to baseline factors, including ambient glycemia and, specifically, baseline glucose levels prior to a meal.

Therefore, a more appropriate assessment is to use a corrected insulin response, measuring insulin secretion at 30 minutes after an oral glucose challenge, in relation to baseline glucose levels, research has suggested.

To investigate the issue in a longitudinal context, Dr. Retnakaran and colleagues conducted a prospective cohort study of 306 pregnant women representing a full range of glucose tolerance, who were enrolled at a hospital in Toronto between October 2003 and March 2014.

The women received comprehensive cardiometabolic testing, including oral glucose tolerance tests at 1-year, 3-year, and 5-year postpartum, and their baseline post-challenge insulinemia was established using corrected insulin response at 1 year.

Over 4 years of follow-up, a progressive worsening of cardiometabolic factors was associated with higher tertiles of corrected insulin responses at baseline, including waist circumference (P = .016), high-density lipoprotein (P = .018), C-reactive protein (CRP; P = .006), and insulin sensitivity (P < .001).

However, those trends were also associated with progressively improved beta cell function (P < .001).

After adjustment in the longitudinal analysis for the clinical risk factors for diabetes, including age, ethnicity, family history of diabetes, and body mass index (BMI) at 1 year, a higher corrected insulin response tertile at baseline was independently associated with improved Insulin Secretion-Sensitivity Index-2 and insulinogenic index/insulin resistance index (IGI/HOMA-IR), as well as lower glycemia, as observed on fasting and 2-hour glucose at 3 years and 5 years (all P < .001).

The insulin response was meanwhile not associated with BMI, waist, lipids, CRP, or insulin sensitivity or resistance.

Importantly, the highest corrected insulin response tertile at 1-year postpartum was also significantly associated with a lower risk for prediabetes or diabetes than the lowest tertile at 3 years (adjusted OR [aOR], 0.19) as well as 5 years (aOR, 0.18).

“The real question in my mind was whether we had the statistical power to be able to demonstrate a longitudinal beneficial effect on glucose regulation, but we did,” Dr. Retnakaran told this news organization. “The results show lower prediabetes and diabetes among people who had the most robust postprandial insulin excursion at 1-year postpartum.”

While the unadjusted analyses at baseline showed adverse as well as favorable outcomes, “adjusted longitudinal analyses revealed consistent independent associations of higher complete insulin response with better beta cell function, lower glycemia, and lower risk of prediabetes or diabetes in the years thereafter,” the authors reported.

“This evidence should help push back concern around the postprandial insulin spike,” Dr. Retnakaran said.

Commenting on the study, James D. Johnson, PhD, a professor of cellular and physiological sciences and director of the Life Sciences Institute at the University of British Columbia, Canada, noted that “it is already well-known that the loss of postprandial first phase insulin secretion can be a key and early defect in the transition to prediabetes and type 2 diabetes. That is not new, but the confirmatory data are welcome,” he told this news organization.

However, with other data linking high insulin with adiposity and insulin resistance, “the nuance and subtleties are critical for us to understand the directions of the causality,” he said.

“It is quite possible that both of these models are true at different life stages and/or in different people. There may be more than one pathway to diabetes. This is the nature of science and progress.”

A key caveat is that with a specific cohort of pregnant women, the question remains of the generalizability to men and to those younger or older than childbearing age.

Nevertheless, “I think this is an interesting and important study,” Dr. Johnson said. “More data on this topic is always welcome, but I am not sure this will be the final say in this debate.”

The authors and Dr. Johnson had no disclosures to report.

A version of this article appeared on Medscape.com.

Rapid surges in insulin following a meal are associated with favorable long-term cardiometabolic benefits, including improvements in beta cell function and a lower risk for the development of prediabetes or diabetes, contrary to some concerns of the surges being indicative of more negative effects.

“There are practitioners who subscribe to this notion of higher insulin levels being a bad thing, and sometimes are making recommendations to patients to limit their insulin fluctuations after the meal,” said first author Ravi Retnakaran, MD, an endocrinologist and Boehringer Ingelheim Chair in Beta-cell Preservation, Function and Regeneration at the Leadership Sinai Centre for Diabetes at Mount Sinai Hospital, Toronto, Ontario, in a press statement.

“But it’s not that simple,” he said. “We observed that a robust post-challenge insulin secretory response, once adjusted for glucose levels, is only associated with beneficial metabolic effects.”

The findings were published on December 13, 2023, in eClinicalMedicine, part of The Lancet Discovery Science.

Insulin levels increase after food consumption in the normal management of blood glucose; however, some research has suggested that more rapid spikes in insulin, especially after a high-carbohydrate meal, are linked to an anabolic state contributing to weight gain and insulin resistance.

As public awareness of those reports has grown, “patients are coming in concerned about the possibility of their insulin levels being high, and there is confusion about the physiology of these effects,” Dr. Retnakaran told this news organization. 

However, other studies have shown that the effects of insulin surges are important relative to baseline factors, including ambient glycemia and, specifically, baseline glucose levels prior to a meal.

Therefore, a more appropriate assessment is to use a corrected insulin response, measuring insulin secretion at 30 minutes after an oral glucose challenge, in relation to baseline glucose levels, research has suggested.

To investigate the issue in a longitudinal context, Dr. Retnakaran and colleagues conducted a prospective cohort study of 306 pregnant women representing a full range of glucose tolerance, who were enrolled at a hospital in Toronto between October 2003 and March 2014.

The women received comprehensive cardiometabolic testing, including oral glucose tolerance tests at 1-year, 3-year, and 5-year postpartum, and their baseline post-challenge insulinemia was established using corrected insulin response at 1 year.

Over 4 years of follow-up, a progressive worsening of cardiometabolic factors was associated with higher tertiles of corrected insulin responses at baseline, including waist circumference (P = .016), high-density lipoprotein (P = .018), C-reactive protein (CRP; P = .006), and insulin sensitivity (P < .001).

However, those trends were also associated with progressively improved beta cell function (P < .001).

After adjustment in the longitudinal analysis for the clinical risk factors for diabetes, including age, ethnicity, family history of diabetes, and body mass index (BMI) at 1 year, a higher corrected insulin response tertile at baseline was independently associated with improved Insulin Secretion-Sensitivity Index-2 and insulinogenic index/insulin resistance index (IGI/HOMA-IR), as well as lower glycemia, as observed on fasting and 2-hour glucose at 3 years and 5 years (all P < .001).

The insulin response was meanwhile not associated with BMI, waist, lipids, CRP, or insulin sensitivity or resistance.

Importantly, the highest corrected insulin response tertile at 1-year postpartum was also significantly associated with a lower risk for prediabetes or diabetes than the lowest tertile at 3 years (adjusted OR [aOR], 0.19) as well as 5 years (aOR, 0.18).

“The real question in my mind was whether we had the statistical power to be able to demonstrate a longitudinal beneficial effect on glucose regulation, but we did,” Dr. Retnakaran told this news organization. “The results show lower prediabetes and diabetes among people who had the most robust postprandial insulin excursion at 1-year postpartum.”

While the unadjusted analyses at baseline showed adverse as well as favorable outcomes, “adjusted longitudinal analyses revealed consistent independent associations of higher complete insulin response with better beta cell function, lower glycemia, and lower risk of prediabetes or diabetes in the years thereafter,” the authors reported.

“This evidence should help push back concern around the postprandial insulin spike,” Dr. Retnakaran said.

Commenting on the study, James D. Johnson, PhD, a professor of cellular and physiological sciences and director of the Life Sciences Institute at the University of British Columbia, Canada, noted that “it is already well-known that the loss of postprandial first phase insulin secretion can be a key and early defect in the transition to prediabetes and type 2 diabetes. That is not new, but the confirmatory data are welcome,” he told this news organization.

However, with other data linking high insulin with adiposity and insulin resistance, “the nuance and subtleties are critical for us to understand the directions of the causality,” he said.

“It is quite possible that both of these models are true at different life stages and/or in different people. There may be more than one pathway to diabetes. This is the nature of science and progress.”

A key caveat is that with a specific cohort of pregnant women, the question remains of the generalizability to men and to those younger or older than childbearing age.

Nevertheless, “I think this is an interesting and important study,” Dr. Johnson said. “More data on this topic is always welcome, but I am not sure this will be the final say in this debate.”

The authors and Dr. Johnson had no disclosures to report.

A version of this article appeared on Medscape.com.

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.

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].”

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.

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].”

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.

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].”

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.