Marlene Busko

The Food and Drug Administration has approved a supplemental indication for setmelanotide (Imcivree, Rhythm Pharmaceuticals) injection for chronic weight management in adults and pediatric patients age 6 and older with obesity due to Bardet-Biedl Syndrome (BBS).

Olivier Le Moal/Getty Images

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for BBS, a rare genetic disorder that impairs a hunger signal along the melanocortin-4 receptor (MC4R) pathway.

BBS affects an estimated 1,500-2,500 people in the United States.

Individuals with BBS typically have obesity that starts at age 1 along with insatiable hunger (hyperphagia). Available weight management options are generally unsuccessful.

Other symptoms may include retinal degeneration, reduced kidney function, or extra digits of the hands or feet.

Setmelanotide received priority review, orphan drug designation, and breakthrough designation for this new indication.

As previously reported, in November 2020, the FDA approved setmelanotide for weight management in adults and children as young as 6 years with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing – who also have impaired hunger signaling from the brain.

These individuals have a normal weight at birth but develop persistent, severe obesity within months due to hyperphagia.

The FDA approval of Imcivree for BBS “represents a significant milestone for Rhythm [Pharmaceuticals], validating our strategy of developing Imcivree for people with hyperphagia and severe obesity caused by rare MC4R-pathway diseases and allowing us to provide our precision therapy to an established community of patients living with BBS and their families who are eagerly awaiting a new treatment option,” said David Meeker, MD, chair, president and CEO of Rhythm, in a press release.
 

Safety, effectiveness in 66-week trial in 44 patients

The safety and effectiveness of setmelanotidewas evaluated in a 66-week phase 3 clinical trial that enrolled 44 patients age 6 and older who had a diagnosis of BBS and obesity – defined as a body mass index greater than or equal to 30 kg/m2 or greater than or equal to 97th percentile for pediatric patients.

After an initial 14-week, randomized, double-blind, placebo-controlled treatment period, patients entered a 52-week, open-label period.

The trial met its primary endpoint and all key secondary endpoints, with statistically significant reductions in weight and hunger at 52 weeks on therapy.

• After 52 weeks of treatment, patients taking setmelanotide lost, on average, 7.9% of their initial BMI.
• 61% of patients lost 5% or more of their initial BMI, and 39% lost 10% or more of their initial BMI.
• In the 14-week, placebo-controlled treatment, on average, BMI dropped by 4.6% in the 22 patients treated with the study drug and dropped 0.1% in the 22 patients treated with placebo.
• At 52 weeks, the 14 patients aged 12 and older who were able to self-report their hunger had a significant –2.1 mean change in hunger score.

Setmelanotide is associated with the following warnings and precautions:

• Spontaneous penile erections in males and sexual adverse reactions in females. Instruct males with erection lasting longer than 4 hours to seek emergency medical attention.
• Depression and suicidal ideation. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing the drug if patients have suicidal thoughts or behaviors or clinically significant or persistent depression symptoms.
• Skin pigmentation and darkening of preexisting nevi (moles). Examine skin before and during treatment.
• Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs.

The most common adverse reactions (with an incidence greater than or equal to 20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.

The FDA did not approve the company’s supplemental new drug application for setmelanotide in Alström syndrome.

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

The Food and Drug Administration has approved a supplemental indication for setmelanotide (Imcivree, Rhythm Pharmaceuticals) injection for chronic weight management in adults and pediatric patients age 6 and older with obesity due to Bardet-Biedl Syndrome (BBS).

Olivier Le Moal/Getty Images

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for BBS, a rare genetic disorder that impairs a hunger signal along the melanocortin-4 receptor (MC4R) pathway.

BBS affects an estimated 1,500-2,500 people in the United States.

Individuals with BBS typically have obesity that starts at age 1 along with insatiable hunger (hyperphagia). Available weight management options are generally unsuccessful.

Other symptoms may include retinal degeneration, reduced kidney function, or extra digits of the hands or feet.

Setmelanotide received priority review, orphan drug designation, and breakthrough designation for this new indication.

As previously reported, in November 2020, the FDA approved setmelanotide for weight management in adults and children as young as 6 years with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing – who also have impaired hunger signaling from the brain.

These individuals have a normal weight at birth but develop persistent, severe obesity within months due to hyperphagia.

The FDA approval of Imcivree for BBS “represents a significant milestone for Rhythm [Pharmaceuticals], validating our strategy of developing Imcivree for people with hyperphagia and severe obesity caused by rare MC4R-pathway diseases and allowing us to provide our precision therapy to an established community of patients living with BBS and their families who are eagerly awaiting a new treatment option,” said David Meeker, MD, chair, president and CEO of Rhythm, in a press release.
 

Safety, effectiveness in 66-week trial in 44 patients

The safety and effectiveness of setmelanotidewas evaluated in a 66-week phase 3 clinical trial that enrolled 44 patients age 6 and older who had a diagnosis of BBS and obesity – defined as a body mass index greater than or equal to 30 kg/m2 or greater than or equal to 97th percentile for pediatric patients.

After an initial 14-week, randomized, double-blind, placebo-controlled treatment period, patients entered a 52-week, open-label period.

The trial met its primary endpoint and all key secondary endpoints, with statistically significant reductions in weight and hunger at 52 weeks on therapy.

• After 52 weeks of treatment, patients taking setmelanotide lost, on average, 7.9% of their initial BMI.
• 61% of patients lost 5% or more of their initial BMI, and 39% lost 10% or more of their initial BMI.
• In the 14-week, placebo-controlled treatment, on average, BMI dropped by 4.6% in the 22 patients treated with the study drug and dropped 0.1% in the 22 patients treated with placebo.
• At 52 weeks, the 14 patients aged 12 and older who were able to self-report their hunger had a significant –2.1 mean change in hunger score.

Setmelanotide is associated with the following warnings and precautions:

• Spontaneous penile erections in males and sexual adverse reactions in females. Instruct males with erection lasting longer than 4 hours to seek emergency medical attention.
• Depression and suicidal ideation. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing the drug if patients have suicidal thoughts or behaviors or clinically significant or persistent depression symptoms.
• Skin pigmentation and darkening of preexisting nevi (moles). Examine skin before and during treatment.
• Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs.

The most common adverse reactions (with an incidence greater than or equal to 20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.

The FDA did not approve the company’s supplemental new drug application for setmelanotide in Alström syndrome.

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

The Food and Drug Administration has approved a supplemental indication for setmelanotide (Imcivree, Rhythm Pharmaceuticals) injection for chronic weight management in adults and pediatric patients age 6 and older with obesity due to Bardet-Biedl Syndrome (BBS).

Olivier Le Moal/Getty Images

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, is the first FDA-approved therapy for BBS, a rare genetic disorder that impairs a hunger signal along the melanocortin-4 receptor (MC4R) pathway.

BBS affects an estimated 1,500-2,500 people in the United States.

Individuals with BBS typically have obesity that starts at age 1 along with insatiable hunger (hyperphagia). Available weight management options are generally unsuccessful.

Other symptoms may include retinal degeneration, reduced kidney function, or extra digits of the hands or feet.

Setmelanotide received priority review, orphan drug designation, and breakthrough designation for this new indication.

As previously reported, in November 2020, the FDA approved setmelanotide for weight management in adults and children as young as 6 years with obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency confirmed by genetic testing – who also have impaired hunger signaling from the brain.

These individuals have a normal weight at birth but develop persistent, severe obesity within months due to hyperphagia.

The FDA approval of Imcivree for BBS “represents a significant milestone for Rhythm [Pharmaceuticals], validating our strategy of developing Imcivree for people with hyperphagia and severe obesity caused by rare MC4R-pathway diseases and allowing us to provide our precision therapy to an established community of patients living with BBS and their families who are eagerly awaiting a new treatment option,” said David Meeker, MD, chair, president and CEO of Rhythm, in a press release.
 

Safety, effectiveness in 66-week trial in 44 patients

The safety and effectiveness of setmelanotidewas evaluated in a 66-week phase 3 clinical trial that enrolled 44 patients age 6 and older who had a diagnosis of BBS and obesity – defined as a body mass index greater than or equal to 30 kg/m2 or greater than or equal to 97th percentile for pediatric patients.

After an initial 14-week, randomized, double-blind, placebo-controlled treatment period, patients entered a 52-week, open-label period.

The trial met its primary endpoint and all key secondary endpoints, with statistically significant reductions in weight and hunger at 52 weeks on therapy.

• After 52 weeks of treatment, patients taking setmelanotide lost, on average, 7.9% of their initial BMI.
• 61% of patients lost 5% or more of their initial BMI, and 39% lost 10% or more of their initial BMI.
• In the 14-week, placebo-controlled treatment, on average, BMI dropped by 4.6% in the 22 patients treated with the study drug and dropped 0.1% in the 22 patients treated with placebo.
• At 52 weeks, the 14 patients aged 12 and older who were able to self-report their hunger had a significant –2.1 mean change in hunger score.

Setmelanotide is associated with the following warnings and precautions:

• Spontaneous penile erections in males and sexual adverse reactions in females. Instruct males with erection lasting longer than 4 hours to seek emergency medical attention.
• Depression and suicidal ideation. Monitor patients for new onset or worsening depression or suicidal thoughts or behaviors. Consider discontinuing the drug if patients have suicidal thoughts or behaviors or clinically significant or persistent depression symptoms.
• Skin pigmentation and darkening of preexisting nevi (moles). Examine skin before and during treatment.
• Setmelanotide is not approved for use in neonates or infants. Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and low-birth-weight infants treated with benzyl alcohol-preserved drugs.

The most common adverse reactions (with an incidence greater than or equal to 20%) included skin hyperpigmentation, injection site reactions, nausea, headache, diarrhea, abdominal pain, vomiting, depression, and spontaneous penile erection.

The FDA did not approve the company’s supplemental new drug application for setmelanotide in Alström syndrome.

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

Goal-directed glycemic management – which may include new technologies for glucose monitoring – for non–critically ill hospitalized patients who have diabetes or newly recognized hyperglycemia can improve outcomes, according to a new practice guideline from the Endocrine Society.  

Even though roughly 35% of hospitalized patients have diabetes or newly discovered hyperglycemia, there is “wide variability in glycemic management in clinical practice,” writing panel chair Mary Korytkowski, MD, from the University of Pittsburgh, said at the annual meeting of the Endocrine Society. “These patients get admitted to every patient service in the hospital, meaning that every clinical service will encounter this group of patients, and their glycemic management can have a major effect on their outcomes. Both short term and long term.”

This guideline provides strategies “to achieve previously recommended glycemic goals while also reducing the risk for hypoglycemia, and this includes inpatient use of insulin pump therapy or continuous glucose monitoring [CGM] devices, among others,” she said.

It also includes “recommendations for preoperative glycemic goals as well as when the use of correctional insulin – well known as sliding scale insulin – may be appropriate” and when it is not.

The document, which replaces a 2012 guideline, was published online in the Journal of Clinical Endocrinology & Metabolism.

A multidisciplinary panel developed the document over the last 3 years to answer 10 clinical practice questions related to management of non–critically ill hospitalized patients with diabetes or newly discovered hyperglycemia.
 

Use of CGM devices in hospital

The first recommendation is: “In adults with insulin-treated diabetes hospitalized for noncritical illness who are at high risk of hypoglycemia, we suggest the use of real-time [CGM] with confirmatory bedside point-of-care blood glucose monitoring for adjustments in insulin dosing rather than point-of-care blood glucose rather than testing alone in hospital settings where resources and training are available.” (Conditional recommendation. Low certainty of evidence).

“We were actually very careful in terms of looking at the data” for use of CGMs, Dr. Korytkowski said in an interview.

Although CGMs are approved by the Food and Drug Administration in the outpatient setting, and that’s becoming the standard of care there, they are not yet approved for in-hospital use.

However, the FDA granted an emergency allowance for use of CGMs in hospitals during the COVID-19 pandemic.

That was “when everyone was scrambling for what to do,” Dr. Korytkowski noted. “There was a shortage of personal protective equipment and a real interest in trying to limit the amount of exposure of healthcare personnel in some of these really critically ill patients for whom intravenous insulin therapy was used to control their glucose level.”

On March 1, the FDA granted Breakthrough Devices Designation for Dexcom CGM use in the hospital setting.

The new guideline suggests CGM be used to detect trends in glycemic management, with insulin dosing decisions made with point-of-care glucose measure (the standard of care).

To implement CGM for glycemic management in hospitals, Dr. Korytkowski said, would require “extensive staff and nursing education to have people with expertise available to provide support to nursing personnel who are both placing these devices, changing these devices, looking at trends, and then knowing when to remove them for certain procedures such as MRI or radiologic procedures.”

“We know that not all hospitals may be readily available to use these devices,” she said. “It is an area of active research. But the use of these devices during the pandemic, in both critical care and non–critical care setting has really provided us with a lot of information that was used to formulate this suggestion in the guideline.”

The document addresses the following areas: CGM, continuous subcutaneous insulin infusion pump therapy, inpatient diabetes education, prespecified preoperative glycemic targets, use of neutral protamine Hagedorn insulin for glucocorticoid or enteral nutrition-associated hyperglycemia, noninsulin therapies, preoperative carbohydrate-containing oral fluids, carbohydrate counting for prandial (mealtime) insulin dosing, and correctional and scheduled (basal or basal bolus) insulin therapies.

Nine key recommendations

Dr. Korytkowski identified nine key recommendations:

• CGM systems can help guide glycemic management with reduced risk for hypoglycemia.
• Patients experiencing glucocorticoid- or enteral nutrition–associated hyperglycemia require scheduled insulin therapy to address anticipated glucose excursions.
• Selected patients using insulin pump therapy prior to a hospital admission can continue to use these devices in the hospital if they have the mental and physical capacity to do so with knowledgeable hospital personnel.
• Diabetes self-management education provided to hospitalized patients can promote improved glycemic control following discharge with reductions in the risk for hospital readmission. “We know that is recommended for patients in the outpatient setting but often they do not get this,” she said. “We were able to observe that this can also impact long-term outcomes “
• Patients with diabetes scheduled for elective surgery may have improved postoperative outcomes when preoperative hemoglobin A1c is 8% or less and preoperative blood glucose is less than 180 mg/dL. “This recommendation answers the question: ‘Where should glycemic goals be for people who are undergoing surgery?’ ”
• Providing preoperative carbohydrate-containing beverages to patients with known diabetes is not recommended.
• Patients with newly recognized hyperglycemia or well-managed diabetes on noninsulin therapy may be treated with correctional insulin alone as initial therapy at hospital admission.
• Some noninsulin diabetes therapies can be used in combination with correction insulin for patients with type 2 diabetes who have mild hyperglycemia.
• Correctional insulin – “otherwise known as sliding-scale insulin” –  can be used as initial therapy for patients with newly recognized hyperglycemia or type 2 diabetes treated with noninsulin therapy prior to hospital admission.
• Scheduled insulin therapy is preferred for patients experiencing persistent blood glucose values greater than 180 mg/dL and is recommended for patients using insulin therapy prior to admission. 

The guideline writers’ hopes

“We hope that this guideline will resolve debates” about appropriate preoperative glycemic management and when sliding-scale insulin can be used and should not be used, said Dr. Korytkowski.

The authors also hope that “it will stimulate research funding for this very important aspect of diabetes care, and that hospitals will recognize the importance of having access to knowledgeable diabetes care and education specialists who can provide staff education regarding inpatient glycemic management, provide oversight for patients using insulin pump therapy or CGM devices, and empower hospital nurses to provide diabetes [self-management] education prior to patient discharge.”

Claire Pegg, the patient representative on the panel, hopes “that this guideline serves as the beginning of a conversation that will allow inpatient caregivers to provide individualized care to patients – some of whom may be self-sufficient with their glycemic management and others who need additional assistance.” 

Development of the guideline was funded by the Endocrine Society. Dr. Korytkowski has reported no relevant financial disclosures.

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

Goal-directed glycemic management – which may include new technologies for glucose monitoring – for non–critically ill hospitalized patients who have diabetes or newly recognized hyperglycemia can improve outcomes, according to a new practice guideline from the Endocrine Society.  

Even though roughly 35% of hospitalized patients have diabetes or newly discovered hyperglycemia, there is “wide variability in glycemic management in clinical practice,” writing panel chair Mary Korytkowski, MD, from the University of Pittsburgh, said at the annual meeting of the Endocrine Society. “These patients get admitted to every patient service in the hospital, meaning that every clinical service will encounter this group of patients, and their glycemic management can have a major effect on their outcomes. Both short term and long term.”

This guideline provides strategies “to achieve previously recommended glycemic goals while also reducing the risk for hypoglycemia, and this includes inpatient use of insulin pump therapy or continuous glucose monitoring [CGM] devices, among others,” she said.

It also includes “recommendations for preoperative glycemic goals as well as when the use of correctional insulin – well known as sliding scale insulin – may be appropriate” and when it is not.

The document, which replaces a 2012 guideline, was published online in the Journal of Clinical Endocrinology & Metabolism.

A multidisciplinary panel developed the document over the last 3 years to answer 10 clinical practice questions related to management of non–critically ill hospitalized patients with diabetes or newly discovered hyperglycemia.
 

Use of CGM devices in hospital

The first recommendation is: “In adults with insulin-treated diabetes hospitalized for noncritical illness who are at high risk of hypoglycemia, we suggest the use of real-time [CGM] with confirmatory bedside point-of-care blood glucose monitoring for adjustments in insulin dosing rather than point-of-care blood glucose rather than testing alone in hospital settings where resources and training are available.” (Conditional recommendation. Low certainty of evidence).

“We were actually very careful in terms of looking at the data” for use of CGMs, Dr. Korytkowski said in an interview.

Although CGMs are approved by the Food and Drug Administration in the outpatient setting, and that’s becoming the standard of care there, they are not yet approved for in-hospital use.

However, the FDA granted an emergency allowance for use of CGMs in hospitals during the COVID-19 pandemic.

That was “when everyone was scrambling for what to do,” Dr. Korytkowski noted. “There was a shortage of personal protective equipment and a real interest in trying to limit the amount of exposure of healthcare personnel in some of these really critically ill patients for whom intravenous insulin therapy was used to control their glucose level.”

On March 1, the FDA granted Breakthrough Devices Designation for Dexcom CGM use in the hospital setting.

The new guideline suggests CGM be used to detect trends in glycemic management, with insulin dosing decisions made with point-of-care glucose measure (the standard of care).

To implement CGM for glycemic management in hospitals, Dr. Korytkowski said, would require “extensive staff and nursing education to have people with expertise available to provide support to nursing personnel who are both placing these devices, changing these devices, looking at trends, and then knowing when to remove them for certain procedures such as MRI or radiologic procedures.”

“We know that not all hospitals may be readily available to use these devices,” she said. “It is an area of active research. But the use of these devices during the pandemic, in both critical care and non–critical care setting has really provided us with a lot of information that was used to formulate this suggestion in the guideline.”

The document addresses the following areas: CGM, continuous subcutaneous insulin infusion pump therapy, inpatient diabetes education, prespecified preoperative glycemic targets, use of neutral protamine Hagedorn insulin for glucocorticoid or enteral nutrition-associated hyperglycemia, noninsulin therapies, preoperative carbohydrate-containing oral fluids, carbohydrate counting for prandial (mealtime) insulin dosing, and correctional and scheduled (basal or basal bolus) insulin therapies.

Nine key recommendations

Dr. Korytkowski identified nine key recommendations:

• CGM systems can help guide glycemic management with reduced risk for hypoglycemia.
• Patients experiencing glucocorticoid- or enteral nutrition–associated hyperglycemia require scheduled insulin therapy to address anticipated glucose excursions.
• Selected patients using insulin pump therapy prior to a hospital admission can continue to use these devices in the hospital if they have the mental and physical capacity to do so with knowledgeable hospital personnel.
• Diabetes self-management education provided to hospitalized patients can promote improved glycemic control following discharge with reductions in the risk for hospital readmission. “We know that is recommended for patients in the outpatient setting but often they do not get this,” she said. “We were able to observe that this can also impact long-term outcomes “
• Patients with diabetes scheduled for elective surgery may have improved postoperative outcomes when preoperative hemoglobin A1c is 8% or less and preoperative blood glucose is less than 180 mg/dL. “This recommendation answers the question: ‘Where should glycemic goals be for people who are undergoing surgery?’ ”
• Providing preoperative carbohydrate-containing beverages to patients with known diabetes is not recommended.
• Patients with newly recognized hyperglycemia or well-managed diabetes on noninsulin therapy may be treated with correctional insulin alone as initial therapy at hospital admission.
• Some noninsulin diabetes therapies can be used in combination with correction insulin for patients with type 2 diabetes who have mild hyperglycemia.
• Correctional insulin – “otherwise known as sliding-scale insulin” –  can be used as initial therapy for patients with newly recognized hyperglycemia or type 2 diabetes treated with noninsulin therapy prior to hospital admission.
• Scheduled insulin therapy is preferred for patients experiencing persistent blood glucose values greater than 180 mg/dL and is recommended for patients using insulin therapy prior to admission. 

The guideline writers’ hopes

“We hope that this guideline will resolve debates” about appropriate preoperative glycemic management and when sliding-scale insulin can be used and should not be used, said Dr. Korytkowski.

The authors also hope that “it will stimulate research funding for this very important aspect of diabetes care, and that hospitals will recognize the importance of having access to knowledgeable diabetes care and education specialists who can provide staff education regarding inpatient glycemic management, provide oversight for patients using insulin pump therapy or CGM devices, and empower hospital nurses to provide diabetes [self-management] education prior to patient discharge.”

Claire Pegg, the patient representative on the panel, hopes “that this guideline serves as the beginning of a conversation that will allow inpatient caregivers to provide individualized care to patients – some of whom may be self-sufficient with their glycemic management and others who need additional assistance.” 

Development of the guideline was funded by the Endocrine Society. Dr. Korytkowski has reported no relevant financial disclosures.

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

Goal-directed glycemic management – which may include new technologies for glucose monitoring – for non–critically ill hospitalized patients who have diabetes or newly recognized hyperglycemia can improve outcomes, according to a new practice guideline from the Endocrine Society.  

Even though roughly 35% of hospitalized patients have diabetes or newly discovered hyperglycemia, there is “wide variability in glycemic management in clinical practice,” writing panel chair Mary Korytkowski, MD, from the University of Pittsburgh, said at the annual meeting of the Endocrine Society. “These patients get admitted to every patient service in the hospital, meaning that every clinical service will encounter this group of patients, and their glycemic management can have a major effect on their outcomes. Both short term and long term.”

This guideline provides strategies “to achieve previously recommended glycemic goals while also reducing the risk for hypoglycemia, and this includes inpatient use of insulin pump therapy or continuous glucose monitoring [CGM] devices, among others,” she said.

It also includes “recommendations for preoperative glycemic goals as well as when the use of correctional insulin – well known as sliding scale insulin – may be appropriate” and when it is not.

The document, which replaces a 2012 guideline, was published online in the Journal of Clinical Endocrinology & Metabolism.

A multidisciplinary panel developed the document over the last 3 years to answer 10 clinical practice questions related to management of non–critically ill hospitalized patients with diabetes or newly discovered hyperglycemia.
 

Use of CGM devices in hospital

The first recommendation is: “In adults with insulin-treated diabetes hospitalized for noncritical illness who are at high risk of hypoglycemia, we suggest the use of real-time [CGM] with confirmatory bedside point-of-care blood glucose monitoring for adjustments in insulin dosing rather than point-of-care blood glucose rather than testing alone in hospital settings where resources and training are available.” (Conditional recommendation. Low certainty of evidence).

“We were actually very careful in terms of looking at the data” for use of CGMs, Dr. Korytkowski said in an interview.

Although CGMs are approved by the Food and Drug Administration in the outpatient setting, and that’s becoming the standard of care there, they are not yet approved for in-hospital use.

However, the FDA granted an emergency allowance for use of CGMs in hospitals during the COVID-19 pandemic.

That was “when everyone was scrambling for what to do,” Dr. Korytkowski noted. “There was a shortage of personal protective equipment and a real interest in trying to limit the amount of exposure of healthcare personnel in some of these really critically ill patients for whom intravenous insulin therapy was used to control their glucose level.”

On March 1, the FDA granted Breakthrough Devices Designation for Dexcom CGM use in the hospital setting.

The new guideline suggests CGM be used to detect trends in glycemic management, with insulin dosing decisions made with point-of-care glucose measure (the standard of care).

To implement CGM for glycemic management in hospitals, Dr. Korytkowski said, would require “extensive staff and nursing education to have people with expertise available to provide support to nursing personnel who are both placing these devices, changing these devices, looking at trends, and then knowing when to remove them for certain procedures such as MRI or radiologic procedures.”

“We know that not all hospitals may be readily available to use these devices,” she said. “It is an area of active research. But the use of these devices during the pandemic, in both critical care and non–critical care setting has really provided us with a lot of information that was used to formulate this suggestion in the guideline.”

The document addresses the following areas: CGM, continuous subcutaneous insulin infusion pump therapy, inpatient diabetes education, prespecified preoperative glycemic targets, use of neutral protamine Hagedorn insulin for glucocorticoid or enteral nutrition-associated hyperglycemia, noninsulin therapies, preoperative carbohydrate-containing oral fluids, carbohydrate counting for prandial (mealtime) insulin dosing, and correctional and scheduled (basal or basal bolus) insulin therapies.

Nine key recommendations

Dr. Korytkowski identified nine key recommendations:

• CGM systems can help guide glycemic management with reduced risk for hypoglycemia.
• Patients experiencing glucocorticoid- or enteral nutrition–associated hyperglycemia require scheduled insulin therapy to address anticipated glucose excursions.
• Selected patients using insulin pump therapy prior to a hospital admission can continue to use these devices in the hospital if they have the mental and physical capacity to do so with knowledgeable hospital personnel.
• Diabetes self-management education provided to hospitalized patients can promote improved glycemic control following discharge with reductions in the risk for hospital readmission. “We know that is recommended for patients in the outpatient setting but often they do not get this,” she said. “We were able to observe that this can also impact long-term outcomes “
• Patients with diabetes scheduled for elective surgery may have improved postoperative outcomes when preoperative hemoglobin A1c is 8% or less and preoperative blood glucose is less than 180 mg/dL. “This recommendation answers the question: ‘Where should glycemic goals be for people who are undergoing surgery?’ ”
• Providing preoperative carbohydrate-containing beverages to patients with known diabetes is not recommended.
• Patients with newly recognized hyperglycemia or well-managed diabetes on noninsulin therapy may be treated with correctional insulin alone as initial therapy at hospital admission.
• Some noninsulin diabetes therapies can be used in combination with correction insulin for patients with type 2 diabetes who have mild hyperglycemia.
• Correctional insulin – “otherwise known as sliding-scale insulin” –  can be used as initial therapy for patients with newly recognized hyperglycemia or type 2 diabetes treated with noninsulin therapy prior to hospital admission.
• Scheduled insulin therapy is preferred for patients experiencing persistent blood glucose values greater than 180 mg/dL and is recommended for patients using insulin therapy prior to admission. 

The guideline writers’ hopes

“We hope that this guideline will resolve debates” about appropriate preoperative glycemic management and when sliding-scale insulin can be used and should not be used, said Dr. Korytkowski.

The authors also hope that “it will stimulate research funding for this very important aspect of diabetes care, and that hospitals will recognize the importance of having access to knowledgeable diabetes care and education specialists who can provide staff education regarding inpatient glycemic management, provide oversight for patients using insulin pump therapy or CGM devices, and empower hospital nurses to provide diabetes [self-management] education prior to patient discharge.”

Claire Pegg, the patient representative on the panel, hopes “that this guideline serves as the beginning of a conversation that will allow inpatient caregivers to provide individualized care to patients – some of whom may be self-sufficient with their glycemic management and others who need additional assistance.” 

Development of the guideline was funded by the Endocrine Society. Dr. Korytkowski has reported no relevant financial disclosures.

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

Depression, self-harm, and suicide among people with type 1 and type 2 diabetes are “underappreciated” among health care practitioners, according to Katharine Barnard-Kelly, PhD, who founded the Reducing Suicide Rates Among Individuals With Diabetes (RESCUE) advocacy group in 2021.

“We have the most advanced technology to achieve glycemic control, but the mental burden remains underappreciated,” she said at a symposium with other speakers from RESCUE during the annual scientific sessions of the American Diabetes Association.

Notably, suicide and self-harm are “all too common” among young adults with type 1 diabetes who are receiving insulin, said Dr. Barnard-Kelly, a psychologist and visiting professor at Southern Health NHS Foundation Trust, Southampton, United Kingdom. And insulin under- or overdosing is the most common method of self-harm.  

However, “with a multipronged approach to awareness, education, and identification, we have the opportunity to intervene on the link between suicide and diabetes,” she said, noting that the aim is to “raise awareness and arm [doctors and others] with messages that can ultimately save a young person’s life if adopted in clinical practice and through mental health screenings.”

The rationale behind the RESCUE initiative is also described in a brief report published in Diabetes Technology & Therapeutics.
 

Six key messages

RESCUE now has “approximately 30 members across academia, clinical practice, industry, advocacy, government, regulatory bodies [including the U.S. Food and Drug Administration], and people with diabetes from several countries,” Dr. Barnard-Kelly told this news organization.

She identified six key messages from the symposium:

• “Suicide prevalence is considerably higher among people with diabetes than the general population.
• Talking about suicide does not increase an individual’s risk of suicide.
• Current screening tools for depression and suicide are not sufficiently sensitive to be effective among people with diabetes.
• Identification of suicidal acts among people with diabetes is extremely difficult.
• For every suicide, the World Health Organization reports there are 20 suicide attempts.
• Health care providers often underestimate the prevalence of suicidality among their patient population and feel ill-equipped to initiate conversations with their patients about suicide.”

Dr. Barnard-Kelly also presented some sobering statistics that highlight the need for increased awareness.

A study  reported that, of 160 cases of insulin overdose, 90% were suicides.

Adolescents and young adults with type 2 diabetes are 61% more likely to report suicidal thoughts than those without diabetes.

The risk of depression is two- to three-times higher in people with diabetes. According to another study, 7% of deaths in individuals with type 1 diabetes are estimated to be from suicide.

Survey about screening for depression, suicide risk in diabetes

During the symposium, Daniel R. Chernavvsky, MD, reported results from a small online survey of health care professionals who treat patients with type 1 or type 2 diabetes, which identified their concerns about screening for depression and assessing suicide risk in patients with diabetes.

Respondents were mainly from the United States (103) but were also from the United Kingdom (18), Slovenia, and the Netherlands (5), said Dr. Chernavvsky, who is senior director of medical affairs at Dexcom, Charlottesville, Va.

They included 59 doctors, 21 nurses,17 diabetes educators, 15 psychologists, seven dieticians, four social workers, and six “other” health care professionals, with a mean age of 46 (range, 25-72 years old) who had been working on average 14 years (range, 0.5-45 years).

Close to three-quarters (72%) reported that at least one of their patients had attempted suicide. The most common self-harm behaviors in their patients were insulin omission or a too large insulin bolus, and less often, binge eating.

Almost all respondents (95%) believed that routine visits to the diabetes clinic were appropriate times to discuss depression, self-injury, and suicidal ideation – at every visit (42% of respondents) or some visits (52%).

Only 30% were comfortable asking patients about self-harm or suicide.

Psychologists and social workers were very comfortable, but others were less comfortable or not comfortable at all.  

Many respondents expressed concerns such as, “What do I do?” “Would I make the problem worse?” “Would I give the patient the idea?” Some reported they had “limited resources” or it “feels invasive.”

They identified a need for “a better understanding of what [they could] do to support and care for patients,” and “more knowledge about how to deal with [patients’] answers” to screening questionnaires.
 

Screening for psychological morbidities in diabetes

Guidelines from the ADA and the International Society for Pediatric and Adolescent Diabetes recommend routine screening of patients with diabetes for psychological morbidities, including depression, said Shideh Majidi, MD.  

Depression is associated with higher A1c, noted Dr. Majidi, who is associate director, childhood and adolescent diabetes program at Children’s National Hospital, Washington, D.C.

She identified the following topics that need to be addressed when considering implementing a program for depression screening and suicide risk assessment in a diabetes clinic:

• Conducting screening: Which screening questionnaire will you use? Who will do it? Where? How often?
• Scoring screening questionnaires: Who will do it?
• Depression screening discussion: Who will do it? How will the person be notified of the score?
• Suicide risk assessment: Who will conduct it? What is the process to get someone to the emergency department?
• Resources/referral: Who will initiate and follow-up? 

Next steps

The RESCUE advocacy group is preparing educational and support materials for health care professionals who treat patients with diabetes, as well as other materials for patients themselves.

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

Depression, self-harm, and suicide among people with type 1 and type 2 diabetes are “underappreciated” among health care practitioners, according to Katharine Barnard-Kelly, PhD, who founded the Reducing Suicide Rates Among Individuals With Diabetes (RESCUE) advocacy group in 2021.

“We have the most advanced technology to achieve glycemic control, but the mental burden remains underappreciated,” she said at a symposium with other speakers from RESCUE during the annual scientific sessions of the American Diabetes Association.

Notably, suicide and self-harm are “all too common” among young adults with type 1 diabetes who are receiving insulin, said Dr. Barnard-Kelly, a psychologist and visiting professor at Southern Health NHS Foundation Trust, Southampton, United Kingdom. And insulin under- or overdosing is the most common method of self-harm.  

However, “with a multipronged approach to awareness, education, and identification, we have the opportunity to intervene on the link between suicide and diabetes,” she said, noting that the aim is to “raise awareness and arm [doctors and others] with messages that can ultimately save a young person’s life if adopted in clinical practice and through mental health screenings.”

The rationale behind the RESCUE initiative is also described in a brief report published in Diabetes Technology & Therapeutics.
 

Six key messages

RESCUE now has “approximately 30 members across academia, clinical practice, industry, advocacy, government, regulatory bodies [including the U.S. Food and Drug Administration], and people with diabetes from several countries,” Dr. Barnard-Kelly told this news organization.

She identified six key messages from the symposium:

• “Suicide prevalence is considerably higher among people with diabetes than the general population.
• Talking about suicide does not increase an individual’s risk of suicide.
• Current screening tools for depression and suicide are not sufficiently sensitive to be effective among people with diabetes.
• Identification of suicidal acts among people with diabetes is extremely difficult.
• For every suicide, the World Health Organization reports there are 20 suicide attempts.
• Health care providers often underestimate the prevalence of suicidality among their patient population and feel ill-equipped to initiate conversations with their patients about suicide.”

Dr. Barnard-Kelly also presented some sobering statistics that highlight the need for increased awareness.

A study  reported that, of 160 cases of insulin overdose, 90% were suicides.

Adolescents and young adults with type 2 diabetes are 61% more likely to report suicidal thoughts than those without diabetes.

The risk of depression is two- to three-times higher in people with diabetes. According to another study, 7% of deaths in individuals with type 1 diabetes are estimated to be from suicide.

Survey about screening for depression, suicide risk in diabetes

During the symposium, Daniel R. Chernavvsky, MD, reported results from a small online survey of health care professionals who treat patients with type 1 or type 2 diabetes, which identified their concerns about screening for depression and assessing suicide risk in patients with diabetes.

Respondents were mainly from the United States (103) but were also from the United Kingdom (18), Slovenia, and the Netherlands (5), said Dr. Chernavvsky, who is senior director of medical affairs at Dexcom, Charlottesville, Va.

They included 59 doctors, 21 nurses,17 diabetes educators, 15 psychologists, seven dieticians, four social workers, and six “other” health care professionals, with a mean age of 46 (range, 25-72 years old) who had been working on average 14 years (range, 0.5-45 years).

Close to three-quarters (72%) reported that at least one of their patients had attempted suicide. The most common self-harm behaviors in their patients were insulin omission or a too large insulin bolus, and less often, binge eating.

Almost all respondents (95%) believed that routine visits to the diabetes clinic were appropriate times to discuss depression, self-injury, and suicidal ideation – at every visit (42% of respondents) or some visits (52%).

Only 30% were comfortable asking patients about self-harm or suicide.

Psychologists and social workers were very comfortable, but others were less comfortable or not comfortable at all.  

Many respondents expressed concerns such as, “What do I do?” “Would I make the problem worse?” “Would I give the patient the idea?” Some reported they had “limited resources” or it “feels invasive.”

They identified a need for “a better understanding of what [they could] do to support and care for patients,” and “more knowledge about how to deal with [patients’] answers” to screening questionnaires.
 

Screening for psychological morbidities in diabetes

Guidelines from the ADA and the International Society for Pediatric and Adolescent Diabetes recommend routine screening of patients with diabetes for psychological morbidities, including depression, said Shideh Majidi, MD.  

Depression is associated with higher A1c, noted Dr. Majidi, who is associate director, childhood and adolescent diabetes program at Children’s National Hospital, Washington, D.C.

She identified the following topics that need to be addressed when considering implementing a program for depression screening and suicide risk assessment in a diabetes clinic:

• Conducting screening: Which screening questionnaire will you use? Who will do it? Where? How often?
• Scoring screening questionnaires: Who will do it?
• Depression screening discussion: Who will do it? How will the person be notified of the score?
• Suicide risk assessment: Who will conduct it? What is the process to get someone to the emergency department?
• Resources/referral: Who will initiate and follow-up? 

Next steps

The RESCUE advocacy group is preparing educational and support materials for health care professionals who treat patients with diabetes, as well as other materials for patients themselves.

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

Depression, self-harm, and suicide among people with type 1 and type 2 diabetes are “underappreciated” among health care practitioners, according to Katharine Barnard-Kelly, PhD, who founded the Reducing Suicide Rates Among Individuals With Diabetes (RESCUE) advocacy group in 2021.

“We have the most advanced technology to achieve glycemic control, but the mental burden remains underappreciated,” she said at a symposium with other speakers from RESCUE during the annual scientific sessions of the American Diabetes Association.

Notably, suicide and self-harm are “all too common” among young adults with type 1 diabetes who are receiving insulin, said Dr. Barnard-Kelly, a psychologist and visiting professor at Southern Health NHS Foundation Trust, Southampton, United Kingdom. And insulin under- or overdosing is the most common method of self-harm.  

However, “with a multipronged approach to awareness, education, and identification, we have the opportunity to intervene on the link between suicide and diabetes,” she said, noting that the aim is to “raise awareness and arm [doctors and others] with messages that can ultimately save a young person’s life if adopted in clinical practice and through mental health screenings.”

The rationale behind the RESCUE initiative is also described in a brief report published in Diabetes Technology & Therapeutics.
 

Six key messages

RESCUE now has “approximately 30 members across academia, clinical practice, industry, advocacy, government, regulatory bodies [including the U.S. Food and Drug Administration], and people with diabetes from several countries,” Dr. Barnard-Kelly told this news organization.

She identified six key messages from the symposium:

• “Suicide prevalence is considerably higher among people with diabetes than the general population.
• Talking about suicide does not increase an individual’s risk of suicide.
• Current screening tools for depression and suicide are not sufficiently sensitive to be effective among people with diabetes.
• Identification of suicidal acts among people with diabetes is extremely difficult.
• For every suicide, the World Health Organization reports there are 20 suicide attempts.
• Health care providers often underestimate the prevalence of suicidality among their patient population and feel ill-equipped to initiate conversations with their patients about suicide.”

Dr. Barnard-Kelly also presented some sobering statistics that highlight the need for increased awareness.

A study  reported that, of 160 cases of insulin overdose, 90% were suicides.

Adolescents and young adults with type 2 diabetes are 61% more likely to report suicidal thoughts than those without diabetes.

The risk of depression is two- to three-times higher in people with diabetes. According to another study, 7% of deaths in individuals with type 1 diabetes are estimated to be from suicide.

Survey about screening for depression, suicide risk in diabetes

During the symposium, Daniel R. Chernavvsky, MD, reported results from a small online survey of health care professionals who treat patients with type 1 or type 2 diabetes, which identified their concerns about screening for depression and assessing suicide risk in patients with diabetes.

Respondents were mainly from the United States (103) but were also from the United Kingdom (18), Slovenia, and the Netherlands (5), said Dr. Chernavvsky, who is senior director of medical affairs at Dexcom, Charlottesville, Va.

They included 59 doctors, 21 nurses,17 diabetes educators, 15 psychologists, seven dieticians, four social workers, and six “other” health care professionals, with a mean age of 46 (range, 25-72 years old) who had been working on average 14 years (range, 0.5-45 years).

Close to three-quarters (72%) reported that at least one of their patients had attempted suicide. The most common self-harm behaviors in their patients were insulin omission or a too large insulin bolus, and less often, binge eating.

Almost all respondents (95%) believed that routine visits to the diabetes clinic were appropriate times to discuss depression, self-injury, and suicidal ideation – at every visit (42% of respondents) or some visits (52%).

Only 30% were comfortable asking patients about self-harm or suicide.

Psychologists and social workers were very comfortable, but others were less comfortable or not comfortable at all.  

Many respondents expressed concerns such as, “What do I do?” “Would I make the problem worse?” “Would I give the patient the idea?” Some reported they had “limited resources” or it “feels invasive.”

They identified a need for “a better understanding of what [they could] do to support and care for patients,” and “more knowledge about how to deal with [patients’] answers” to screening questionnaires.
 

Screening for psychological morbidities in diabetes

Guidelines from the ADA and the International Society for Pediatric and Adolescent Diabetes recommend routine screening of patients with diabetes for psychological morbidities, including depression, said Shideh Majidi, MD.  

Depression is associated with higher A1c, noted Dr. Majidi, who is associate director, childhood and adolescent diabetes program at Children’s National Hospital, Washington, D.C.

She identified the following topics that need to be addressed when considering implementing a program for depression screening and suicide risk assessment in a diabetes clinic:

• Conducting screening: Which screening questionnaire will you use? Who will do it? Where? How often?
• Scoring screening questionnaires: Who will do it?
• Depression screening discussion: Who will do it? How will the person be notified of the score?
• Suicide risk assessment: Who will conduct it? What is the process to get someone to the emergency department?
• Resources/referral: Who will initiate and follow-up? 

Next steps

The RESCUE advocacy group is preparing educational and support materials for health care professionals who treat patients with diabetes, as well as other materials for patients themselves.

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

A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.

Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.

This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.

Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.

An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.

Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.

Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).

These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
 

Remission is not reversal or cure ...

“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission

Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.

However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.

“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”

This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”

The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”

“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
 

How the intervention works

The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.

The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.

The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.

The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.

The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.

The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.

The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.

U.S. clinical trial, health insurance coverage

The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.

The company has started a clinical trial in the United States, with 5-year results expected in 2027.

“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”

The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.

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

A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.

Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.

This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.

Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.

An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.

Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.

Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).

These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
 

Remission is not reversal or cure ...

“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission

Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.

However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.

“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”

This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”

The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”

“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
 

How the intervention works

The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.

The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.

The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.

The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.

The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.

The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.

The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.

U.S. clinical trial, health insurance coverage

The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.

The company has started a clinical trial in the United States, with 5-year results expected in 2027.

“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”

The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.

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

A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.

Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.

This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.

Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.

An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.

Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.

Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).

These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
 

Remission is not reversal or cure ...

“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission

Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.

However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.

“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”

This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”

The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”

“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
 

How the intervention works

The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.

The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.

The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.

The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.

The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.

The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.

The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.

U.S. clinical trial, health insurance coverage

The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.

The company has started a clinical trial in the United States, with 5-year results expected in 2027.

“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”

The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.

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

Another glucagonlike peptide-1 (GLP1) agonist, dulaglutide (Trulicity, Lilly), is poised to be a new option for glycemic control in youth aged 10-18 years with type 2 diabetes, given as a weekly injection, based on the AWARD-PEDS clinical trial.

The U.S. Food and Drug Administration has already approved daily injection liraglutide (Victoza, Novo Nordisk) in 2019 and weekly exenatide (Bydureon/Bydureon BCise, AstraZeneca) in 2021 for glycemic control in young patients with type 2 diabetes, both of which are also GLP-1 agonists.  

AWARD-PEDS showed that youth with type 2 diabetes and obesity treated with or without metformin or basal insulin who received weekly injections of 0.75 mg or 1.5 mg of dulaglutide had lower hemoglobin A1c at 26 weeks than patients who received placebo.

Eli Lilly is now submitting these trial results to the FDA for this indication.

Dulaglutide was cleared for use in adults with type 2 diabetes in the United States in 2014 and was additionally approved for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes at high risk of such events in 2020.

The most common adverse symptoms were gastrointestinal, and the safety profile was consistent with that in adults. However, the drug had no effect on body mass index.

The study was simultaneously published in the New England Journal of Medicine and presented as a late-breaking poster at the annual scientific sessions of the American Diabetes Association in New Orleans.

Might dulaglutide target pathophysiologic impairments in youth?

Dulaglutide would “offer a new treatment that targets the pathophysiologic impairments of type 2 diabetes in youth,” Silva A. Arslanian, MD, lead investigator, told this news organization.

Exenatide is also given as a weekly injection but is associated with a smaller decrease in A1c and does not improve fasting glucose concentrations, plus it requires more steps compared with the dulaglutide single-use pen, said Dr. Arslanian, who is scientific director at the Center for Pediatric Research in Obesity & Metabolism, UPMC Children’s Hospital of Pittsburgh.

“Liraglutide is a daily injection, and I believe most patients, particularly adolescents, would prefer a weekly injection,” she added.  

Invited to comment, Elvira Isganaitis, MD, MPH, said “the significance of this paper lies in the fact that options for treating type 2 diabetes in children are currently much more limited than in adults – which is a major problem given recent studies that show that type 2 diabetes in youth is much more aggressive and more likely to cause complications early in the disease course.”

Dr. Isganaitis was not involved with the trial but is an investigator for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

“With supply chain shortages and health insurance coverage issues that are common in the U.S., it would be helpful to have more than one FDA-approved option for a weekly GLP-1 receptor agonist in children [and] access to other classes of medications,” added Dr. Isganaitis, a pediatric endocrinologist at the Joslin Diabetes Center, Boston.

Phase 3 trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in youth with type 2 diabetes are also ongoing, Dr. Arslanian noted, “but as always, recruitment is slow with adolescents.”

“I am not optimistic that DPP4 inhibitors will have a place in the treatment of youth with type 2 diabetes,” she said. A recent study showed the addition of sitagliptin to metformin in youth with type 2 diabetes did not provide durable improvement in glycemic control.

Potentially promising therapy

In their published article, Dr. Arslanian and colleagues write that “considering the progressive increase in [A1c] over time that was observed in the TODAY trial, with 34% of youths having [an A1c] of at least 10% after up to 15 years of follow-up, we believe that the effects of dulaglutide therapy appear to be potentially promising.”

The TODAY trial showed that more than 50% of youth with type 2 diabetes taking metformin failed to maintain glycemic control within a median of 11.5 months, Dr. Arslanian elaborated, and over time their A1c escalated while their beta-cell function deteriorated rapidly, and complications progressed quickly.

“Therefore,” she noted, “considering that dulaglutide and the GLP-1 receptor agonist class of drugs improve A1c, improve beta-cell function, suppress glucagon concentrations, and improve insulin sensitivity, dulaglutide would provide a promising new treatment option for youth with type 2 diabetes.”

Phase 3 superiority trial

The AWARD-PEDS trial included 154 youth with type 2 diabetes and a BMI greater than the 85th percentile for their age and sex at 46 centers in nine countries. Researchers randomized participants 1:1:1 to the two doses of dulaglutide or placebo for 26 weeks, followed by a 26-week open-label study (during which the placebo group received 0.75 mg dulaglutide) and a 4-week safety extension. 

Participants were a mean age of 14.5 years and had a mean BMI of 34 kg/m².

In each of the dulaglutide groups, roughly 66% of patients were female and 58% were White, 18% were Black, and about 57% were Hispanic. They had a mean weight of 91 kg (200 lb) and a mean A1c of about 8%; 62% were taking metformin only, 27% were taking metformin plus basal insulin, 3% were taking basal insulin only, and 10% were on diet and exercise only.

At 26 weeks, mean A1c increased by 0.6% in the placebo group but decreased by 0.6% in the 0.75-mg dulaglutide group and by 0.9% in the 1.5-mg dulaglutide group (P < .001 for both comparisons versus placebo).

Also at 26 weeks, more participants in the pooled dulaglutide groups than in the placebo group had an A1c <7.0% (51% vs. 14%; P < .001).

Fasting glucose concentration increased in the placebo group (+17.1 mg/dL ) and decreased in the pooled dulaglutide groups (–18.9 mg/dL; P < .001).

There were no group differences in BMI or adiposity-related parameters even at 52 weeks.

“I believe adolescents may be somewhat resistant to the weight-reducing effects of GLP-1 agonists in diabetes trials (liraglutide and exenatide youth type 2 diabetes trials showed the same thing) and they may need higher doses,” Dr. Arslanian speculated.

“Only future studies will be able to address this issue,” she concluded.

The study was funded by Eli Lilly. Dr. Arslanian has disclosed being a consultant for Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals; participating in data safety monitoring for AstraZeneca and Eli Lilly trials; and receiving institutional research funding from Eli Lilly and Novo Nordisk. Dr. Isganaitis has disclosed receiving research funding (paid to her institution) from Dexcom and AstraZeneca.

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

Another glucagonlike peptide-1 (GLP1) agonist, dulaglutide (Trulicity, Lilly), is poised to be a new option for glycemic control in youth aged 10-18 years with type 2 diabetes, given as a weekly injection, based on the AWARD-PEDS clinical trial.

The U.S. Food and Drug Administration has already approved daily injection liraglutide (Victoza, Novo Nordisk) in 2019 and weekly exenatide (Bydureon/Bydureon BCise, AstraZeneca) in 2021 for glycemic control in young patients with type 2 diabetes, both of which are also GLP-1 agonists.  

AWARD-PEDS showed that youth with type 2 diabetes and obesity treated with or without metformin or basal insulin who received weekly injections of 0.75 mg or 1.5 mg of dulaglutide had lower hemoglobin A1c at 26 weeks than patients who received placebo.

Eli Lilly is now submitting these trial results to the FDA for this indication.

Dulaglutide was cleared for use in adults with type 2 diabetes in the United States in 2014 and was additionally approved for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes at high risk of such events in 2020.

The most common adverse symptoms were gastrointestinal, and the safety profile was consistent with that in adults. However, the drug had no effect on body mass index.

The study was simultaneously published in the New England Journal of Medicine and presented as a late-breaking poster at the annual scientific sessions of the American Diabetes Association in New Orleans.

Might dulaglutide target pathophysiologic impairments in youth?

Dulaglutide would “offer a new treatment that targets the pathophysiologic impairments of type 2 diabetes in youth,” Silva A. Arslanian, MD, lead investigator, told this news organization.

Exenatide is also given as a weekly injection but is associated with a smaller decrease in A1c and does not improve fasting glucose concentrations, plus it requires more steps compared with the dulaglutide single-use pen, said Dr. Arslanian, who is scientific director at the Center for Pediatric Research in Obesity & Metabolism, UPMC Children’s Hospital of Pittsburgh.

“Liraglutide is a daily injection, and I believe most patients, particularly adolescents, would prefer a weekly injection,” she added.  

Invited to comment, Elvira Isganaitis, MD, MPH, said “the significance of this paper lies in the fact that options for treating type 2 diabetes in children are currently much more limited than in adults – which is a major problem given recent studies that show that type 2 diabetes in youth is much more aggressive and more likely to cause complications early in the disease course.”

Dr. Isganaitis was not involved with the trial but is an investigator for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

“With supply chain shortages and health insurance coverage issues that are common in the U.S., it would be helpful to have more than one FDA-approved option for a weekly GLP-1 receptor agonist in children [and] access to other classes of medications,” added Dr. Isganaitis, a pediatric endocrinologist at the Joslin Diabetes Center, Boston.

Phase 3 trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in youth with type 2 diabetes are also ongoing, Dr. Arslanian noted, “but as always, recruitment is slow with adolescents.”

“I am not optimistic that DPP4 inhibitors will have a place in the treatment of youth with type 2 diabetes,” she said. A recent study showed the addition of sitagliptin to metformin in youth with type 2 diabetes did not provide durable improvement in glycemic control.

Potentially promising therapy

In their published article, Dr. Arslanian and colleagues write that “considering the progressive increase in [A1c] over time that was observed in the TODAY trial, with 34% of youths having [an A1c] of at least 10% after up to 15 years of follow-up, we believe that the effects of dulaglutide therapy appear to be potentially promising.”

The TODAY trial showed that more than 50% of youth with type 2 diabetes taking metformin failed to maintain glycemic control within a median of 11.5 months, Dr. Arslanian elaborated, and over time their A1c escalated while their beta-cell function deteriorated rapidly, and complications progressed quickly.

“Therefore,” she noted, “considering that dulaglutide and the GLP-1 receptor agonist class of drugs improve A1c, improve beta-cell function, suppress glucagon concentrations, and improve insulin sensitivity, dulaglutide would provide a promising new treatment option for youth with type 2 diabetes.”

Phase 3 superiority trial

The AWARD-PEDS trial included 154 youth with type 2 diabetes and a BMI greater than the 85th percentile for their age and sex at 46 centers in nine countries. Researchers randomized participants 1:1:1 to the two doses of dulaglutide or placebo for 26 weeks, followed by a 26-week open-label study (during which the placebo group received 0.75 mg dulaglutide) and a 4-week safety extension. 

Participants were a mean age of 14.5 years and had a mean BMI of 34 kg/m².

In each of the dulaglutide groups, roughly 66% of patients were female and 58% were White, 18% were Black, and about 57% were Hispanic. They had a mean weight of 91 kg (200 lb) and a mean A1c of about 8%; 62% were taking metformin only, 27% were taking metformin plus basal insulin, 3% were taking basal insulin only, and 10% were on diet and exercise only.

At 26 weeks, mean A1c increased by 0.6% in the placebo group but decreased by 0.6% in the 0.75-mg dulaglutide group and by 0.9% in the 1.5-mg dulaglutide group (P < .001 for both comparisons versus placebo).

Also at 26 weeks, more participants in the pooled dulaglutide groups than in the placebo group had an A1c <7.0% (51% vs. 14%; P < .001).

Fasting glucose concentration increased in the placebo group (+17.1 mg/dL ) and decreased in the pooled dulaglutide groups (–18.9 mg/dL; P < .001).

There were no group differences in BMI or adiposity-related parameters even at 52 weeks.

“I believe adolescents may be somewhat resistant to the weight-reducing effects of GLP-1 agonists in diabetes trials (liraglutide and exenatide youth type 2 diabetes trials showed the same thing) and they may need higher doses,” Dr. Arslanian speculated.

“Only future studies will be able to address this issue,” she concluded.

The study was funded by Eli Lilly. Dr. Arslanian has disclosed being a consultant for Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals; participating in data safety monitoring for AstraZeneca and Eli Lilly trials; and receiving institutional research funding from Eli Lilly and Novo Nordisk. Dr. Isganaitis has disclosed receiving research funding (paid to her institution) from Dexcom and AstraZeneca.

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

Another glucagonlike peptide-1 (GLP1) agonist, dulaglutide (Trulicity, Lilly), is poised to be a new option for glycemic control in youth aged 10-18 years with type 2 diabetes, given as a weekly injection, based on the AWARD-PEDS clinical trial.

The U.S. Food and Drug Administration has already approved daily injection liraglutide (Victoza, Novo Nordisk) in 2019 and weekly exenatide (Bydureon/Bydureon BCise, AstraZeneca) in 2021 for glycemic control in young patients with type 2 diabetes, both of which are also GLP-1 agonists.  

AWARD-PEDS showed that youth with type 2 diabetes and obesity treated with or without metformin or basal insulin who received weekly injections of 0.75 mg or 1.5 mg of dulaglutide had lower hemoglobin A1c at 26 weeks than patients who received placebo.

Eli Lilly is now submitting these trial results to the FDA for this indication.

Dulaglutide was cleared for use in adults with type 2 diabetes in the United States in 2014 and was additionally approved for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes at high risk of such events in 2020.

The most common adverse symptoms were gastrointestinal, and the safety profile was consistent with that in adults. However, the drug had no effect on body mass index.

The study was simultaneously published in the New England Journal of Medicine and presented as a late-breaking poster at the annual scientific sessions of the American Diabetes Association in New Orleans.

Might dulaglutide target pathophysiologic impairments in youth?

Dulaglutide would “offer a new treatment that targets the pathophysiologic impairments of type 2 diabetes in youth,” Silva A. Arslanian, MD, lead investigator, told this news organization.

Exenatide is also given as a weekly injection but is associated with a smaller decrease in A1c and does not improve fasting glucose concentrations, plus it requires more steps compared with the dulaglutide single-use pen, said Dr. Arslanian, who is scientific director at the Center for Pediatric Research in Obesity & Metabolism, UPMC Children’s Hospital of Pittsburgh.

“Liraglutide is a daily injection, and I believe most patients, particularly adolescents, would prefer a weekly injection,” she added.  

Invited to comment, Elvira Isganaitis, MD, MPH, said “the significance of this paper lies in the fact that options for treating type 2 diabetes in children are currently much more limited than in adults – which is a major problem given recent studies that show that type 2 diabetes in youth is much more aggressive and more likely to cause complications early in the disease course.”

Dr. Isganaitis was not involved with the trial but is an investigator for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.

“With supply chain shortages and health insurance coverage issues that are common in the U.S., it would be helpful to have more than one FDA-approved option for a weekly GLP-1 receptor agonist in children [and] access to other classes of medications,” added Dr. Isganaitis, a pediatric endocrinologist at the Joslin Diabetes Center, Boston.

Phase 3 trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in youth with type 2 diabetes are also ongoing, Dr. Arslanian noted, “but as always, recruitment is slow with adolescents.”

“I am not optimistic that DPP4 inhibitors will have a place in the treatment of youth with type 2 diabetes,” she said. A recent study showed the addition of sitagliptin to metformin in youth with type 2 diabetes did not provide durable improvement in glycemic control.

Potentially promising therapy

In their published article, Dr. Arslanian and colleagues write that “considering the progressive increase in [A1c] over time that was observed in the TODAY trial, with 34% of youths having [an A1c] of at least 10% after up to 15 years of follow-up, we believe that the effects of dulaglutide therapy appear to be potentially promising.”

The TODAY trial showed that more than 50% of youth with type 2 diabetes taking metformin failed to maintain glycemic control within a median of 11.5 months, Dr. Arslanian elaborated, and over time their A1c escalated while their beta-cell function deteriorated rapidly, and complications progressed quickly.

“Therefore,” she noted, “considering that dulaglutide and the GLP-1 receptor agonist class of drugs improve A1c, improve beta-cell function, suppress glucagon concentrations, and improve insulin sensitivity, dulaglutide would provide a promising new treatment option for youth with type 2 diabetes.”

Phase 3 superiority trial

The AWARD-PEDS trial included 154 youth with type 2 diabetes and a BMI greater than the 85th percentile for their age and sex at 46 centers in nine countries. Researchers randomized participants 1:1:1 to the two doses of dulaglutide or placebo for 26 weeks, followed by a 26-week open-label study (during which the placebo group received 0.75 mg dulaglutide) and a 4-week safety extension. 

Participants were a mean age of 14.5 years and had a mean BMI of 34 kg/m².

In each of the dulaglutide groups, roughly 66% of patients were female and 58% were White, 18% were Black, and about 57% were Hispanic. They had a mean weight of 91 kg (200 lb) and a mean A1c of about 8%; 62% were taking metformin only, 27% were taking metformin plus basal insulin, 3% were taking basal insulin only, and 10% were on diet and exercise only.

At 26 weeks, mean A1c increased by 0.6% in the placebo group but decreased by 0.6% in the 0.75-mg dulaglutide group and by 0.9% in the 1.5-mg dulaglutide group (P < .001 for both comparisons versus placebo).

Also at 26 weeks, more participants in the pooled dulaglutide groups than in the placebo group had an A1c <7.0% (51% vs. 14%; P < .001).

Fasting glucose concentration increased in the placebo group (+17.1 mg/dL ) and decreased in the pooled dulaglutide groups (–18.9 mg/dL; P < .001).

There were no group differences in BMI or adiposity-related parameters even at 52 weeks.

“I believe adolescents may be somewhat resistant to the weight-reducing effects of GLP-1 agonists in diabetes trials (liraglutide and exenatide youth type 2 diabetes trials showed the same thing) and they may need higher doses,” Dr. Arslanian speculated.

“Only future studies will be able to address this issue,” she concluded.

The study was funded by Eli Lilly. Dr. Arslanian has disclosed being a consultant for Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals; participating in data safety monitoring for AstraZeneca and Eli Lilly trials; and receiving institutional research funding from Eli Lilly and Novo Nordisk. Dr. Isganaitis has disclosed receiving research funding (paid to her institution) from Dexcom and AstraZeneca.

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

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.

“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.

The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.

Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.

40% reduced risk of kidney function decline

The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.

Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).

“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).

“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.

The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.

“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”

Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).

“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.

“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.

Strongest reduction seen in risk of new macroalbuminuria

One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.

The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.

The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.

Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m².

Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m²). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).

The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:

• Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
• Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.

During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.

In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.

Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.

Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”

The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.

Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.

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

Long-term use of a proton-pump inhibitor (PPI) was associated with an increased risk of being diagnosed with type 2 diabetes in a large, population-based case-control study in Italy.

The risk of diabetes increased from 19% to 56% as treatment duration increased from 8 weeks to more than 2 years, and prolonged treatment was associated with an even higher risk of diabetes in the youngest patients (age 40-65) and those with the most comorbidities.

The results suggest that “physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use,” say Stefano Ciardullo, MD, University of Milano-Bicocca, Italy, and colleagues, in their article recently published online in the Journal of Clinical Endocrinology & Metabolism.

“Nonetheless, epidemiologic evidence on the topic remains conflicting,” they acknowledge, adding that “future studies are still needed to validate our findings.”

If the results are confirmed, these “may have important implications for both public health and clinical practice, given the high number of patients being treated with PPIs and the influence of diabetes on morbidity and mortality related to its possible micro- and macrovascular complications,” Dr. Ciardullo and colleagues conclude.
 

Not enough data to support a change in practice

The current findings align with a recent analysis of three prospective cohort studies of U.S. health care workers that showed a progressively increased risk of diabetes with longer treatment with PPIs, David A. Leiman, MD, MSHP, who was not involved with the current study, told this news organization in an email. “But the effect size remains relatively small and may be explained by residual or unmeasured confounding,” he cautioned.

“Ultimately, there do not seem to be enough data to support a change in clinical practice from this study alone, and, as a result, clinicians should continue to inform patients of the best available evidence regarding the benefits and risks of PPIs,” said Dr. Leiman, assistant professor of medicine, Division of Gastroenterology, Duke University Medical Center, Durham, N.C.

“Recent best practice advice from the American Gastroenterological Association does not recommend screening for insulin resistance among PPI users [and recommends that the decision to discontinue PPIs] should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events,” he noted.

“Clinicians should be prepared to discuss the described risks associated with PPIs,” said Dr. Leiman, but they should “also feel comfortable affirming their safety profile and substantial efficacy in managing symptoms and preventing complications when prescribed for the appropriate indication.”

First-choice therapy for acid-related disorders

PPIs have become first-choice therapy for patients with acid-related disorders such as gastroesophageal reflux disease, Barrett esophagus, and peptic ulcer, and to prevent gastrointestinal bleeding while on nonsteroidal anti-inflammatory drugs (NSAIDs), Dr. Ciardullo and colleagues explain.

However, several studies have identified potential fractures, hypomagnesemia, gastric carcinoids, chronic kidney disease, dementia, and Clostridium difficile diarrhea with prolonged use of PPIs, and these agents can cause changes in the gut microbiome that may play a role in diabetes and other metabolic diseases.

To investigate a potential association between PPIs and type 2 diabetes, the researchers analyzed data from 777,420 patients age 40 and older who were newly treated with PPIs between 2010 and 2015 in Lombardy, Italy.

Of these, 50,540 patients were diagnosed with type 2 diabetes during follow-up until 2020 (a mean follow-up of 6.2 years and a diabetes incidence of 10.6 cases per 1,000 person-years).

The researchers matched 50,535 patients diagnosed with diabetes during follow-up with 50,535 control patients who had the same age, sex, and clinical status.

Patients were a mean age of 66 years and half were men. The most prescribed PPIs were pantoprazole and omeprazole, and the patients diagnosed with diabetes were more likely to use antihypertensives and lipid-lowering drugs.

Compared with patients who received PPIs for less than 8 weeks, those who received PPIs for 8 weeks to 6 months had a 19% increased risk of being diagnosed with diabetes during follow-up (odds ratio, 1.19; 95% confidence interval, 1.15-1.24), after adjusting for age, clinical profile, comorbidities, medical therapy, and PPI type.

Patients who received PPIs for 6 months to 2 years had a 43% increased risk of the outcome (OR, 1.43; 95% CI, 1.38-1.49), and those who received PPIs for more than 2 years had a 56% increased risk of the outcome (OR, 1.56; 95% CI, 1.49-1.64).

The researchers acknowledge limitations including that the study was not a randomized controlled trial, and it lacked information about over-the-counter medications and unmeasured confounders such as body mass index or family history of diabetes that may have affected the outcomes.

Dr. Leiman added that patients may have had prediabetes or undiagnosed diabetes and symptoms such as heartburn or dyspepsia arising from complications of insulin resistance, for which PPIs might have been prescribed.

The study was funded by a grant from the Italian Ministry of Education, University and Research. Dr. Ciardullo and Dr. Leiman have reported no relevant financial relationships.

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

Long-term use of a proton-pump inhibitor (PPI) was associated with an increased risk of being diagnosed with type 2 diabetes in a large, population-based case-control study in Italy.

The risk of diabetes increased from 19% to 56% as treatment duration increased from 8 weeks to more than 2 years, and prolonged treatment was associated with an even higher risk of diabetes in the youngest patients (age 40-65) and those with the most comorbidities.

The results suggest that “physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use,” say Stefano Ciardullo, MD, University of Milano-Bicocca, Italy, and colleagues, in their article recently published online in the Journal of Clinical Endocrinology & Metabolism.

“Nonetheless, epidemiologic evidence on the topic remains conflicting,” they acknowledge, adding that “future studies are still needed to validate our findings.”

If the results are confirmed, these “may have important implications for both public health and clinical practice, given the high number of patients being treated with PPIs and the influence of diabetes on morbidity and mortality related to its possible micro- and macrovascular complications,” Dr. Ciardullo and colleagues conclude.
 

Not enough data to support a change in practice

The current findings align with a recent analysis of three prospective cohort studies of U.S. health care workers that showed a progressively increased risk of diabetes with longer treatment with PPIs, David A. Leiman, MD, MSHP, who was not involved with the current study, told this news organization in an email. “But the effect size remains relatively small and may be explained by residual or unmeasured confounding,” he cautioned.

“Ultimately, there do not seem to be enough data to support a change in clinical practice from this study alone, and, as a result, clinicians should continue to inform patients of the best available evidence regarding the benefits and risks of PPIs,” said Dr. Leiman, assistant professor of medicine, Division of Gastroenterology, Duke University Medical Center, Durham, N.C.

“Recent best practice advice from the American Gastroenterological Association does not recommend screening for insulin resistance among PPI users [and recommends that the decision to discontinue PPIs] should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events,” he noted.

“Clinicians should be prepared to discuss the described risks associated with PPIs,” said Dr. Leiman, but they should “also feel comfortable affirming their safety profile and substantial efficacy in managing symptoms and preventing complications when prescribed for the appropriate indication.”

First-choice therapy for acid-related disorders

PPIs have become first-choice therapy for patients with acid-related disorders such as gastroesophageal reflux disease, Barrett esophagus, and peptic ulcer, and to prevent gastrointestinal bleeding while on nonsteroidal anti-inflammatory drugs (NSAIDs), Dr. Ciardullo and colleagues explain.

However, several studies have identified potential fractures, hypomagnesemia, gastric carcinoids, chronic kidney disease, dementia, and Clostridium difficile diarrhea with prolonged use of PPIs, and these agents can cause changes in the gut microbiome that may play a role in diabetes and other metabolic diseases.

To investigate a potential association between PPIs and type 2 diabetes, the researchers analyzed data from 777,420 patients age 40 and older who were newly treated with PPIs between 2010 and 2015 in Lombardy, Italy.

Of these, 50,540 patients were diagnosed with type 2 diabetes during follow-up until 2020 (a mean follow-up of 6.2 years and a diabetes incidence of 10.6 cases per 1,000 person-years).

The researchers matched 50,535 patients diagnosed with diabetes during follow-up with 50,535 control patients who had the same age, sex, and clinical status.

Patients were a mean age of 66 years and half were men. The most prescribed PPIs were pantoprazole and omeprazole, and the patients diagnosed with diabetes were more likely to use antihypertensives and lipid-lowering drugs.

Compared with patients who received PPIs for less than 8 weeks, those who received PPIs for 8 weeks to 6 months had a 19% increased risk of being diagnosed with diabetes during follow-up (odds ratio, 1.19; 95% confidence interval, 1.15-1.24), after adjusting for age, clinical profile, comorbidities, medical therapy, and PPI type.

Patients who received PPIs for 6 months to 2 years had a 43% increased risk of the outcome (OR, 1.43; 95% CI, 1.38-1.49), and those who received PPIs for more than 2 years had a 56% increased risk of the outcome (OR, 1.56; 95% CI, 1.49-1.64).

The researchers acknowledge limitations including that the study was not a randomized controlled trial, and it lacked information about over-the-counter medications and unmeasured confounders such as body mass index or family history of diabetes that may have affected the outcomes.

Dr. Leiman added that patients may have had prediabetes or undiagnosed diabetes and symptoms such as heartburn or dyspepsia arising from complications of insulin resistance, for which PPIs might have been prescribed.

The study was funded by a grant from the Italian Ministry of Education, University and Research. Dr. Ciardullo and Dr. Leiman have reported no relevant financial relationships.

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

Long-term use of a proton-pump inhibitor (PPI) was associated with an increased risk of being diagnosed with type 2 diabetes in a large, population-based case-control study in Italy.

The risk of diabetes increased from 19% to 56% as treatment duration increased from 8 weeks to more than 2 years, and prolonged treatment was associated with an even higher risk of diabetes in the youngest patients (age 40-65) and those with the most comorbidities.

The results suggest that “physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use,” say Stefano Ciardullo, MD, University of Milano-Bicocca, Italy, and colleagues, in their article recently published online in the Journal of Clinical Endocrinology & Metabolism.

“Nonetheless, epidemiologic evidence on the topic remains conflicting,” they acknowledge, adding that “future studies are still needed to validate our findings.”

If the results are confirmed, these “may have important implications for both public health and clinical practice, given the high number of patients being treated with PPIs and the influence of diabetes on morbidity and mortality related to its possible micro- and macrovascular complications,” Dr. Ciardullo and colleagues conclude.
 

Not enough data to support a change in practice

The current findings align with a recent analysis of three prospective cohort studies of U.S. health care workers that showed a progressively increased risk of diabetes with longer treatment with PPIs, David A. Leiman, MD, MSHP, who was not involved with the current study, told this news organization in an email. “But the effect size remains relatively small and may be explained by residual or unmeasured confounding,” he cautioned.

“Ultimately, there do not seem to be enough data to support a change in clinical practice from this study alone, and, as a result, clinicians should continue to inform patients of the best available evidence regarding the benefits and risks of PPIs,” said Dr. Leiman, assistant professor of medicine, Division of Gastroenterology, Duke University Medical Center, Durham, N.C.

“Recent best practice advice from the American Gastroenterological Association does not recommend screening for insulin resistance among PPI users [and recommends that the decision to discontinue PPIs] should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events,” he noted.

“Clinicians should be prepared to discuss the described risks associated with PPIs,” said Dr. Leiman, but they should “also feel comfortable affirming their safety profile and substantial efficacy in managing symptoms and preventing complications when prescribed for the appropriate indication.”

First-choice therapy for acid-related disorders

PPIs have become first-choice therapy for patients with acid-related disorders such as gastroesophageal reflux disease, Barrett esophagus, and peptic ulcer, and to prevent gastrointestinal bleeding while on nonsteroidal anti-inflammatory drugs (NSAIDs), Dr. Ciardullo and colleagues explain.

However, several studies have identified potential fractures, hypomagnesemia, gastric carcinoids, chronic kidney disease, dementia, and Clostridium difficile diarrhea with prolonged use of PPIs, and these agents can cause changes in the gut microbiome that may play a role in diabetes and other metabolic diseases.

To investigate a potential association between PPIs and type 2 diabetes, the researchers analyzed data from 777,420 patients age 40 and older who were newly treated with PPIs between 2010 and 2015 in Lombardy, Italy.

Of these, 50,540 patients were diagnosed with type 2 diabetes during follow-up until 2020 (a mean follow-up of 6.2 years and a diabetes incidence of 10.6 cases per 1,000 person-years).

The researchers matched 50,535 patients diagnosed with diabetes during follow-up with 50,535 control patients who had the same age, sex, and clinical status.

Patients were a mean age of 66 years and half were men. The most prescribed PPIs were pantoprazole and omeprazole, and the patients diagnosed with diabetes were more likely to use antihypertensives and lipid-lowering drugs.

Compared with patients who received PPIs for less than 8 weeks, those who received PPIs for 8 weeks to 6 months had a 19% increased risk of being diagnosed with diabetes during follow-up (odds ratio, 1.19; 95% confidence interval, 1.15-1.24), after adjusting for age, clinical profile, comorbidities, medical therapy, and PPI type.

Patients who received PPIs for 6 months to 2 years had a 43% increased risk of the outcome (OR, 1.43; 95% CI, 1.38-1.49), and those who received PPIs for more than 2 years had a 56% increased risk of the outcome (OR, 1.56; 95% CI, 1.49-1.64).

The researchers acknowledge limitations including that the study was not a randomized controlled trial, and it lacked information about over-the-counter medications and unmeasured confounders such as body mass index or family history of diabetes that may have affected the outcomes.

Dr. Leiman added that patients may have had prediabetes or undiagnosed diabetes and symptoms such as heartburn or dyspepsia arising from complications of insulin resistance, for which PPIs might have been prescribed.

The study was funded by a grant from the Italian Ministry of Education, University and Research. Dr. Ciardullo and Dr. Leiman have reported no relevant financial relationships.

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

Using the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline target of systolic blood pressure (BP) < 120 mm Hg, 66% of adults with chronic kidney disease (CKD) would be eligible for BP lowering, according to a study from Korea.

This represents an added > 10% of patients compared with two earlier guidelines, and these patients have a high risk of cardiovascular disease (CVD), Hyeok-Hee Lee, MD, Yonsei University College of Medicine, Seoul, South Korea, and colleagues reported.

London_England/Thinkstock

The study was published online  in the Journal of the American College of Cardiology.

“New candidates for BP-lowering treatment per the 2021 KDIGO guideline account for a substantial proportion of the total CKD population and bear significantly high CVD risk,” the researchers concluded.

“Undoubtedly, a multipronged approach will be required to address the swelling number of people needing more intense treatment, especially against a background of falling rates of BP control in the general community,” Alexander G. Logan, MD, of Mount Sinai Hospital, Toronto, and the University of Toronto, wrote in an accompanying editorial.

“Let’s not forget hypertension is the number one killer today,” Valentin Fuster, MD, of Icahn School of Medicine at Mount Sinai, New York, who is editor-in-chief of the Journal of the American College of Cardiology, stressed in a podcast that accompanied the article.

“Only 50% of individuals know of their blood pressure, and from this, less than half are properly treated,” he said.

“Today the details of knowing blood pressure levels appear to dominate over the huge ignorance of not knowing about blood pressure at all. Let’s think more and more about this reality,” he urged.
 

Three guidelines, two study objectives

The researchers compared three guidelines:

• The 2021 KDIGO guidelines, with a target systolic BP of < 120 mm Hg (largely based on the SPRINT trial).
• The 2012 KDIGO guidelines, with a target BP of ≤ 130/80 mm Hg for patients with albuminuria and ≤ 140/90 mm Hg for patients without albuminuria.
• The 2017 American College of Cardiology/American Heart Association (ACC/AHA) BP guideline target of < 130/80 mm Hg.

The study had two objectives:

• To examine the proportions of concordance and discordance between the three guidelines among adults with CKD based on cross-sectional data from the Korea National Health and Nutrition Examination Survey (KNHANES).
• To evaluate the association of each concordance/discordance group with cardiovascular outcomes of patients in the Korean National Health Insurance Service (NHIS) database.

For the first objective, the researchers identified 1,939 adults with CKD from the 2011-2014 survey cycles of KNHANES. Patients were a median age of 59 and 51% were men.

Comparison of the KDIGO 2021 versus 2012 BP targets showed that 50% of patients had BP above both targets; 16% had BP above the KDIGO 2021 target only; 4% had BP above the KDIGO 2012 target only; and 30% had BP control within both targets.

Comparison of the KDIGO 2021 versus 2017 ACC/AHA BP targets showed that 55% of patients had BP above both targets; 11% had BP above the KDIGO 2021 target only; 5% had BP above the 2017 ACC/AHA target only; and 29% had BP control within both targets.

For the second objective, using the NHIS database, researchers identified 412,167 adults with CKD who had routine health examinations during 2009 and 2010. The patients were a median age of 65 and 44% were men.

During a median follow-up of 10 years, the patients had 37,912 incident CVD events, defined as the first hospitalization for myocardial infarction, stroke, or heart failure, or death from CVD.

The adjusted risk of a composite CVD event was higher in patients with BP above the 2021 KDIGO target only (HR, 1.28) or above both the 2012 and 2021 KDIGO targets (HR, 1.52), compared to patients who had BP within both targets.

The adjusted risk of a composite CVD event was also higher in patients with BP above the 2021 KDIGO target only (HR, 1.18) or above both the 2021 KDIGO target and the 2017 ACC/AHA target (HR, 1.41), compared with patients who had BP within both targets.
 

Editorialist highlights three study aspects

Dr. Fuster noted three main points made by Dr. Logan.

First, the KDIGO 2021 guideline is based on office blood pressure, measured according to the procedure used in the 2017 ACC/AHA guideline. However, the SPRINT ambulatory BP ancillary study found that daytime ambulatory systolic BP was 6.8 mm Hg higher in the < 120 mm Hg group than clinic systolic BP that was measured with an automated BP device, mostly without study personnel.

Second, Dr. Logan noted that “not surprisingly, the investigators showed that the weighted proportion of adults with CKD eligible for BP lowering was highest (66.1%) according to 2021 KDIGO guideline,” compared with the two earlier guidelines.

The findings by Dr. Lee and colleagues align with those of a study that used data from the 2015-2018 U.S. NHANES to estimate the proportion of U.S. adults with CKD eligible for BP lowering according to the 2021 KDIGO guidelines, Dr. Logan added. The study found that 69% of U.S. adults (roughly 24.5 million) should correct their BP.

Third, the study in Korea showed a small percentage of patients (3%-5% of the total) had elevated diastolic BP but controlled systolic BP (< 120 mm Hg) with no increased risk of CVD compared to a reference group of patients with well-controlled BP.

“There is a paucity of evidence examining the relationship between diastolic hypertension and outcomes independently from systolic BP level in CKD patients,” Dr. Logan wrote. Similarly, Dr. Lee and colleagues identified this as an area for further research.

This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare, Republic of Korea. The authors and editorialist have reported no relevant financial relationships.

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

Using the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline target of systolic blood pressure (BP) < 120 mm Hg, 66% of adults with chronic kidney disease (CKD) would be eligible for BP lowering, according to a study from Korea.

This represents an added > 10% of patients compared with two earlier guidelines, and these patients have a high risk of cardiovascular disease (CVD), Hyeok-Hee Lee, MD, Yonsei University College of Medicine, Seoul, South Korea, and colleagues reported.

London_England/Thinkstock

The study was published online  in the Journal of the American College of Cardiology.

“New candidates for BP-lowering treatment per the 2021 KDIGO guideline account for a substantial proportion of the total CKD population and bear significantly high CVD risk,” the researchers concluded.

“Undoubtedly, a multipronged approach will be required to address the swelling number of people needing more intense treatment, especially against a background of falling rates of BP control in the general community,” Alexander G. Logan, MD, of Mount Sinai Hospital, Toronto, and the University of Toronto, wrote in an accompanying editorial.

“Let’s not forget hypertension is the number one killer today,” Valentin Fuster, MD, of Icahn School of Medicine at Mount Sinai, New York, who is editor-in-chief of the Journal of the American College of Cardiology, stressed in a podcast that accompanied the article.

“Only 50% of individuals know of their blood pressure, and from this, less than half are properly treated,” he said.

“Today the details of knowing blood pressure levels appear to dominate over the huge ignorance of not knowing about blood pressure at all. Let’s think more and more about this reality,” he urged.
 

Three guidelines, two study objectives

The researchers compared three guidelines:

• The 2021 KDIGO guidelines, with a target systolic BP of < 120 mm Hg (largely based on the SPRINT trial).
• The 2012 KDIGO guidelines, with a target BP of ≤ 130/80 mm Hg for patients with albuminuria and ≤ 140/90 mm Hg for patients without albuminuria.
• The 2017 American College of Cardiology/American Heart Association (ACC/AHA) BP guideline target of < 130/80 mm Hg.

The study had two objectives:

• To examine the proportions of concordance and discordance between the three guidelines among adults with CKD based on cross-sectional data from the Korea National Health and Nutrition Examination Survey (KNHANES).
• To evaluate the association of each concordance/discordance group with cardiovascular outcomes of patients in the Korean National Health Insurance Service (NHIS) database.

For the first objective, the researchers identified 1,939 adults with CKD from the 2011-2014 survey cycles of KNHANES. Patients were a median age of 59 and 51% were men.

Comparison of the KDIGO 2021 versus 2012 BP targets showed that 50% of patients had BP above both targets; 16% had BP above the KDIGO 2021 target only; 4% had BP above the KDIGO 2012 target only; and 30% had BP control within both targets.

Comparison of the KDIGO 2021 versus 2017 ACC/AHA BP targets showed that 55% of patients had BP above both targets; 11% had BP above the KDIGO 2021 target only; 5% had BP above the 2017 ACC/AHA target only; and 29% had BP control within both targets.

For the second objective, using the NHIS database, researchers identified 412,167 adults with CKD who had routine health examinations during 2009 and 2010. The patients were a median age of 65 and 44% were men.

During a median follow-up of 10 years, the patients had 37,912 incident CVD events, defined as the first hospitalization for myocardial infarction, stroke, or heart failure, or death from CVD.

The adjusted risk of a composite CVD event was higher in patients with BP above the 2021 KDIGO target only (HR, 1.28) or above both the 2012 and 2021 KDIGO targets (HR, 1.52), compared to patients who had BP within both targets.

The adjusted risk of a composite CVD event was also higher in patients with BP above the 2021 KDIGO target only (HR, 1.18) or above both the 2021 KDIGO target and the 2017 ACC/AHA target (HR, 1.41), compared with patients who had BP within both targets.
 

Editorialist highlights three study aspects

Dr. Fuster noted three main points made by Dr. Logan.

First, the KDIGO 2021 guideline is based on office blood pressure, measured according to the procedure used in the 2017 ACC/AHA guideline. However, the SPRINT ambulatory BP ancillary study found that daytime ambulatory systolic BP was 6.8 mm Hg higher in the < 120 mm Hg group than clinic systolic BP that was measured with an automated BP device, mostly without study personnel.

Second, Dr. Logan noted that “not surprisingly, the investigators showed that the weighted proportion of adults with CKD eligible for BP lowering was highest (66.1%) according to 2021 KDIGO guideline,” compared with the two earlier guidelines.

The findings by Dr. Lee and colleagues align with those of a study that used data from the 2015-2018 U.S. NHANES to estimate the proportion of U.S. adults with CKD eligible for BP lowering according to the 2021 KDIGO guidelines, Dr. Logan added. The study found that 69% of U.S. adults (roughly 24.5 million) should correct their BP.

Third, the study in Korea showed a small percentage of patients (3%-5% of the total) had elevated diastolic BP but controlled systolic BP (< 120 mm Hg) with no increased risk of CVD compared to a reference group of patients with well-controlled BP.

“There is a paucity of evidence examining the relationship between diastolic hypertension and outcomes independently from systolic BP level in CKD patients,” Dr. Logan wrote. Similarly, Dr. Lee and colleagues identified this as an area for further research.

This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare, Republic of Korea. The authors and editorialist have reported no relevant financial relationships.

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

Using the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline target of systolic blood pressure (BP) < 120 mm Hg, 66% of adults with chronic kidney disease (CKD) would be eligible for BP lowering, according to a study from Korea.

This represents an added > 10% of patients compared with two earlier guidelines, and these patients have a high risk of cardiovascular disease (CVD), Hyeok-Hee Lee, MD, Yonsei University College of Medicine, Seoul, South Korea, and colleagues reported.

London_England/Thinkstock

The study was published online  in the Journal of the American College of Cardiology.

“New candidates for BP-lowering treatment per the 2021 KDIGO guideline account for a substantial proportion of the total CKD population and bear significantly high CVD risk,” the researchers concluded.

“Undoubtedly, a multipronged approach will be required to address the swelling number of people needing more intense treatment, especially against a background of falling rates of BP control in the general community,” Alexander G. Logan, MD, of Mount Sinai Hospital, Toronto, and the University of Toronto, wrote in an accompanying editorial.

“Let’s not forget hypertension is the number one killer today,” Valentin Fuster, MD, of Icahn School of Medicine at Mount Sinai, New York, who is editor-in-chief of the Journal of the American College of Cardiology, stressed in a podcast that accompanied the article.

“Only 50% of individuals know of their blood pressure, and from this, less than half are properly treated,” he said.

“Today the details of knowing blood pressure levels appear to dominate over the huge ignorance of not knowing about blood pressure at all. Let’s think more and more about this reality,” he urged.
 

Three guidelines, two study objectives

The researchers compared three guidelines:

• The 2021 KDIGO guidelines, with a target systolic BP of < 120 mm Hg (largely based on the SPRINT trial).
• The 2012 KDIGO guidelines, with a target BP of ≤ 130/80 mm Hg for patients with albuminuria and ≤ 140/90 mm Hg for patients without albuminuria.
• The 2017 American College of Cardiology/American Heart Association (ACC/AHA) BP guideline target of < 130/80 mm Hg.

The study had two objectives:

• To examine the proportions of concordance and discordance between the three guidelines among adults with CKD based on cross-sectional data from the Korea National Health and Nutrition Examination Survey (KNHANES).
• To evaluate the association of each concordance/discordance group with cardiovascular outcomes of patients in the Korean National Health Insurance Service (NHIS) database.

For the first objective, the researchers identified 1,939 adults with CKD from the 2011-2014 survey cycles of KNHANES. Patients were a median age of 59 and 51% were men.

Comparison of the KDIGO 2021 versus 2012 BP targets showed that 50% of patients had BP above both targets; 16% had BP above the KDIGO 2021 target only; 4% had BP above the KDIGO 2012 target only; and 30% had BP control within both targets.

Comparison of the KDIGO 2021 versus 2017 ACC/AHA BP targets showed that 55% of patients had BP above both targets; 11% had BP above the KDIGO 2021 target only; 5% had BP above the 2017 ACC/AHA target only; and 29% had BP control within both targets.

For the second objective, using the NHIS database, researchers identified 412,167 adults with CKD who had routine health examinations during 2009 and 2010. The patients were a median age of 65 and 44% were men.

During a median follow-up of 10 years, the patients had 37,912 incident CVD events, defined as the first hospitalization for myocardial infarction, stroke, or heart failure, or death from CVD.

The adjusted risk of a composite CVD event was higher in patients with BP above the 2021 KDIGO target only (HR, 1.28) or above both the 2012 and 2021 KDIGO targets (HR, 1.52), compared to patients who had BP within both targets.

The adjusted risk of a composite CVD event was also higher in patients with BP above the 2021 KDIGO target only (HR, 1.18) or above both the 2021 KDIGO target and the 2017 ACC/AHA target (HR, 1.41), compared with patients who had BP within both targets.
 

Editorialist highlights three study aspects

Dr. Fuster noted three main points made by Dr. Logan.

First, the KDIGO 2021 guideline is based on office blood pressure, measured according to the procedure used in the 2017 ACC/AHA guideline. However, the SPRINT ambulatory BP ancillary study found that daytime ambulatory systolic BP was 6.8 mm Hg higher in the < 120 mm Hg group than clinic systolic BP that was measured with an automated BP device, mostly without study personnel.

Second, Dr. Logan noted that “not surprisingly, the investigators showed that the weighted proportion of adults with CKD eligible for BP lowering was highest (66.1%) according to 2021 KDIGO guideline,” compared with the two earlier guidelines.

The findings by Dr. Lee and colleagues align with those of a study that used data from the 2015-2018 U.S. NHANES to estimate the proportion of U.S. adults with CKD eligible for BP lowering according to the 2021 KDIGO guidelines, Dr. Logan added. The study found that 69% of U.S. adults (roughly 24.5 million) should correct their BP.

Third, the study in Korea showed a small percentage of patients (3%-5% of the total) had elevated diastolic BP but controlled systolic BP (< 120 mm Hg) with no increased risk of CVD compared to a reference group of patients with well-controlled BP.

“There is a paucity of evidence examining the relationship between diastolic hypertension and outcomes independently from systolic BP level in CKD patients,” Dr. Logan wrote. Similarly, Dr. Lee and colleagues identified this as an area for further research.

This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare, Republic of Korea. The authors and editorialist have reported no relevant financial relationships.

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

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

In a randomized trial of patients with angina and no obstructive coronary artery disease (ANOCA), 6 weeks of treatment with diltiazem did not improve coronary vasomotor dysfunction – apart from epicardial spasm – or angina symptoms and quality of life. 

The trial investigated whether this therapy would improve these outcomes in patients with two mutually exclusive subgroups, or endotypes, of coronary vasomotor dysfunction: coronary artery spasm (epicardial spasm, microvascular spasm) or coronary microvascular dysfunction indicated by coronary flow reserve (CFR) and index of microvascular resistance (IMR) values.

Treatment success, the primary study endpoint – defined as normalization of one of the abnormal endotypes and no normal endotype becoming abnormal – was similar after treatment with diltiazem, compared with placebo. Nor were there significant differences for secondary endpoints apart from improvements in epicardial spasm in the two groups.

Tijn Jansen, MD, presented these findings from the EDIT-CMD trial in a featured clinical research session at the annual scientific sessions of the American College of Cardiology. The study was simultaneously published online April 2, 2022, in JACC: Cardiovascular Imaging.

“This first study using repeated coronary function testing provides a platform for future research,” concluded Dr. Jansen, a PhD candidate in the department of cardiology, Radboud University, Nijmegen, the Netherlands.

“We were surprised indeed” that diltiazem did not meet its primary endpoint for successful treatment and did not reduce symptoms or improve quality of life, compared with placebo, unlike results of the CorMicA trial, he said in an interview.

“We did find a treatment success, however, of 21%, which was slightly lower than expected, but it was not better than just giving placebo. This was similar regarding symptoms and quality of life, where we did find an overall improvement with diltiazem, but again not higher than using placebo,” he added. “It seems that giving the diagnosis to these patients itself creates a reduction in symptoms,” that might be caused by a reduction in stress, Dr. Jansen suggested.

The clinical implication, he said, is that more randomized controlled trials in this patient population are needed to permit evidence-based patient-tailored treatment, based on the different endotypes. “It might even be imaginable to test effectiveness in each individual patient using coronary function testing,” he said.

These tests are more and more commonly used in clinical practice, Dr. Jansen noted. “In the Netherlands, we recently launched the NL-CFT registry, which enables the participating centers to perform the CFT with a standardized protocol, with the goal to collect data and increase knowledge in this patient population.”

Heterogeneous population?

“I think probably the reason this trial was negative is [that coronary vasomotor dysfunction is] just too heterogeneous,” assigned discussant, C. Noel Bairey Merz, MD, commented.

First RCT of diltiazem in patients with ANOCA

Up to 40% of patients undergoing coronary angiography for stable angina do not have obstructive coronary artery disease (CAD), and 60%-90% of these patients have coronary vasomotor dysfunction, Dr. Jansen noted.

The landmark CorMicA trial showed that diagnosing the specific endotype of coronary vasomotor dysfunction using coronary function testing allows for tailored medication that decreased angina and improved quality of life, the researchers noted.

A recent European Society of Cardiology position paper on ANOCA “recommends the use of various pharmacological treatments including calcium-channel blockers, beta-blockers, ACE inhibitors, statins, and nitric oxide modulators, of which CCBs have the most prominent role in both endotypes of coronary vasospasms” and coronary microvascular dysfunction, they wrote.

“However, evidence substantiating these recommendations is lacking,” the researchers added, “since it is based on studies in a different population, with small sample sizes, or not placebo controlled.”

To investigate this, between 2019 and 2021, EDIT-CMD enrolled 126 adults aged 18 years and older who had two or more chronic angina episodes per week and no signs of obstructive CAD, who were seen at three hospitals specializing in ANOCA in the Netherlands.

The participants underwent coronary function testing that consisted of an acetylcholine spasm provocation test to evaluate for epicardial spasm and microvascular spasm, and a bolus thermodilution test with adenosine, to assess CFR and IMR. Coronary microvascular dysfunction was defined as CFR less than 2.0 and IMR of 25 or greater.

Of 99 patients with vasospasm or microvascular dysfunction, 85 patients were randomly assigned to receive diltiazem (n = 41) or placebo (n = 44) for 6 weeks.

The patients in both groups had a mean age of 58 years, and 29% were male; 22% had previously undergone percutaneous coronary intervention, and 48% had severe angina (Canadian Cardiovascular Society grade III/IV).

At baseline, about 50% had epicardial spasm, 25% had microvascular spasm and 25% had no spasm, and 54% in the diltiazem group and 73% in the placebo group had microvascular dysfunction.

After 6 weeks, 73 patients (35 in the placebo group and 38 in the diltiazem group) were available for repeat coronary function testing.

For the primary outcome, after 6 weeks of treatment, the proportion of patients with normalization of one abnormal parameter of coronary vasomotor dysfunction, without any normal parameter becoming abnormal, occurred in 8 patients (21%) in the diltiazem group versus 10 patients (29%) in the placebo group (P = .46)

In secondary outcomes, after 6 weeks of treatment, there were no significant differences in the prevalence of microvascular dysfunction, in Seattle Angina Questionnaire scores for angina symptoms, or RAND-36 scores for quality of life between patients who received diltiazem vs those who received placebo.

However, more patients in the diltiazem group than in the placebo group progressed from epicardial spasm to microvascular or no spasm (47% vs. 6%; P = .006).

The EDIT-CMD trial was sponsored by Abbott. Dr. Jansen has no relevant financial disclosures. Dr. Bairey Merz discloses having a fiduciary role and shares in iRhythm and being on the advisory board for Sanofi.

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

Treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist was associated with a 37% increase in the relative risk of gallbladder or biliary disease, compared with controls – especially when used at high doses, for a longer time, and for weight loss rather than type 2 diabetes – a new meta-analysis has found.

The results “indicate that physicians and patients should be concerned about the risks of gallbladder or biliary diseases with using GLP-1 agonists,” study authors Liyun He and colleagues from Peking Union Medical College, Beijing, summarize.

However, “the overall absolute risk increase for gallbladder and biliary disease with use of GLP-1 receptor agonists was small (an additional 27 cases per 10,000 persons treated per year),” they note.

“This absolute risk increase should be weighed against the benefits of treatment with GLP-1 agonists,” which include glucose control, decreased cardiovascular risk, and weight loss, they add.

The findings are from a meta-analysis of 76 randomized controlled trials of GLP-1 agonists published online March 28 in JAMA Internal Medicine.

In an accompanying editorial, Shanzay Haider, MD, and Kasia J. Lipska, MD, also characterize the absolute risk of these complications as “modest.”

“The highest risk for these complications,” they add, “occurred among individuals in the weight loss, compared with the type 2 diabetes studies (119 vs. 13 more events per 10,000 persons per year).”

“Ultimately, the decision to start, continue, or change the dose of a GLP-1 agonist should be reached through a collaborative and individualized discussion between a clinician and a patient,” Dr. Haider and Dr. Lipska, from Yale School of Medicine, New Haven, Conn., summarize.

The study authors also note that few of the trials reported biliary-related events.

“Future trials [of drugs in this class] should prespecify gallbladder and biliary diseases as potential adverse events, and fully test for and report on these outcomes,” they urge.   

Certain drugs in this class are now approved by the U.S. Food and Drug Administration for weight loss at higher doses than for type 2 diabetes – subcutaneous liraglutide (3.0 mg) and subcutaneous semaglutide (2.4 mg) – “suggesting that GLP-1 agonist drugs will increasingly be used at high doses for weight control,” the authors note.

Controversial link

The association between GLP-1 agonists and gallbladder or biliary disease is controversial, the authors write.

Several randomized controlled trials reported higher rates of gallbladder disorders in patients who received a GLP-1 agonist versus placebo, but it is not clear if this is a class effect.

Liraglutide “has drawn the most attention” about this risk, and a post-hoc analysis of the LEADER trial found a significantly increased risk of acute biliary obstruction with liraglutide versus placebo.

To investigate this, the researchers identified 76 randomized controlled trials of GLP-1 agonists in 103,371 patients that had data for the following safety outcomes: cholelithiasis (gallstones, 61 trials), cholecystitis (inflamed gallbladder, 53 trials), biliary disease (21 trials), cholecystectomy (surgical removal of the gallbladder, seven trials), and biliary cancer (12 trials).

Sixty trials were for type 2 diabetes, 13 were for weight loss, and three were for nonalcoholic steatohepatitis, polycystic ovary syndrome, and schizophrenia. They were classed as short or long (≤ 26 weeks or > 26 weeks).

The GLP-1 agonists were liraglutide (21 trials), subcutaneous semaglutide (14), dulaglutide (11), exenatide (9), albiglutide (8), oral semaglutide (8), and lixisenatide (6). 

Participants were a mean age of 58 years and 41% were women. They had a mean BMI of 31.6 kg/m² and 36.9 kg/m² in trials of GLP-1 agonists for type 2 diabetes and weight loss, respectively.  

Patients who received a GLP-1 agonist versus controls had significantly increased rates of cholelithiasis (RR, 1.27; P = .001), cholecystitis (RR, 1.36; P < .001), biliary disease (RR, 1.55; P = .02), and cholecystectomy (RR, 1.70; P < .001) but a nonsignificant increased rate of biliary cancer (RR, 1.43; P = .22).

Use of GLP-1 agonists was associated with a greater increased risk of gallbladder or biliary diseases in trials for weight loss (RR, 2.29) than in trials for type 2 diabetes or other diseases (RR, 1.27; P < .001 for interaction).

Use of these drugs was also associated with higher risks of these complications at higher doses and when given for a longer duration.     

Limitations of the meta-analysis include that the individual studies were not designed to evaluate the risk of gallbladder or biliary diseases associated with GLP-1 agonists.

Also, biliary-related events may have been under-reported, because this was not a predefined safety outcome in most of the trials. The meta-analysis lacked patient-level data, and it may have been underpowered for subgroup analyses.       

The work was supported by grants from the National Natural Science Foundation of China, the Beijing Municipal Natural Science Foundation, the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences, the CAMS Innovation Fund for Medical Sciences, and the Training Program for Excellent Talents in Dongcheng District. The researchers have no relevant financial disclosures.

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

Treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist was associated with a 37% increase in the relative risk of gallbladder or biliary disease, compared with controls – especially when used at high doses, for a longer time, and for weight loss rather than type 2 diabetes – a new meta-analysis has found.

The results “indicate that physicians and patients should be concerned about the risks of gallbladder or biliary diseases with using GLP-1 agonists,” study authors Liyun He and colleagues from Peking Union Medical College, Beijing, summarize.

However, “the overall absolute risk increase for gallbladder and biliary disease with use of GLP-1 receptor agonists was small (an additional 27 cases per 10,000 persons treated per year),” they note.

“This absolute risk increase should be weighed against the benefits of treatment with GLP-1 agonists,” which include glucose control, decreased cardiovascular risk, and weight loss, they add.

The findings are from a meta-analysis of 76 randomized controlled trials of GLP-1 agonists published online March 28 in JAMA Internal Medicine.

In an accompanying editorial, Shanzay Haider, MD, and Kasia J. Lipska, MD, also characterize the absolute risk of these complications as “modest.”

“The highest risk for these complications,” they add, “occurred among individuals in the weight loss, compared with the type 2 diabetes studies (119 vs. 13 more events per 10,000 persons per year).”

“Ultimately, the decision to start, continue, or change the dose of a GLP-1 agonist should be reached through a collaborative and individualized discussion between a clinician and a patient,” Dr. Haider and Dr. Lipska, from Yale School of Medicine, New Haven, Conn., summarize.

The study authors also note that few of the trials reported biliary-related events.

“Future trials [of drugs in this class] should prespecify gallbladder and biliary diseases as potential adverse events, and fully test for and report on these outcomes,” they urge.   

Certain drugs in this class are now approved by the U.S. Food and Drug Administration for weight loss at higher doses than for type 2 diabetes – subcutaneous liraglutide (3.0 mg) and subcutaneous semaglutide (2.4 mg) – “suggesting that GLP-1 agonist drugs will increasingly be used at high doses for weight control,” the authors note.

Controversial link

The association between GLP-1 agonists and gallbladder or biliary disease is controversial, the authors write.

Several randomized controlled trials reported higher rates of gallbladder disorders in patients who received a GLP-1 agonist versus placebo, but it is not clear if this is a class effect.

Liraglutide “has drawn the most attention” about this risk, and a post-hoc analysis of the LEADER trial found a significantly increased risk of acute biliary obstruction with liraglutide versus placebo.

To investigate this, the researchers identified 76 randomized controlled trials of GLP-1 agonists in 103,371 patients that had data for the following safety outcomes: cholelithiasis (gallstones, 61 trials), cholecystitis (inflamed gallbladder, 53 trials), biliary disease (21 trials), cholecystectomy (surgical removal of the gallbladder, seven trials), and biliary cancer (12 trials).

Sixty trials were for type 2 diabetes, 13 were for weight loss, and three were for nonalcoholic steatohepatitis, polycystic ovary syndrome, and schizophrenia. They were classed as short or long (≤ 26 weeks or > 26 weeks).

The GLP-1 agonists were liraglutide (21 trials), subcutaneous semaglutide (14), dulaglutide (11), exenatide (9), albiglutide (8), oral semaglutide (8), and lixisenatide (6). 

Participants were a mean age of 58 years and 41% were women. They had a mean BMI of 31.6 kg/m² and 36.9 kg/m² in trials of GLP-1 agonists for type 2 diabetes and weight loss, respectively.  

Patients who received a GLP-1 agonist versus controls had significantly increased rates of cholelithiasis (RR, 1.27; P = .001), cholecystitis (RR, 1.36; P < .001), biliary disease (RR, 1.55; P = .02), and cholecystectomy (RR, 1.70; P < .001) but a nonsignificant increased rate of biliary cancer (RR, 1.43; P = .22).

Use of GLP-1 agonists was associated with a greater increased risk of gallbladder or biliary diseases in trials for weight loss (RR, 2.29) than in trials for type 2 diabetes or other diseases (RR, 1.27; P < .001 for interaction).

Use of these drugs was also associated with higher risks of these complications at higher doses and when given for a longer duration.     

Limitations of the meta-analysis include that the individual studies were not designed to evaluate the risk of gallbladder or biliary diseases associated with GLP-1 agonists.

Also, biliary-related events may have been under-reported, because this was not a predefined safety outcome in most of the trials. The meta-analysis lacked patient-level data, and it may have been underpowered for subgroup analyses.       

The work was supported by grants from the National Natural Science Foundation of China, the Beijing Municipal Natural Science Foundation, the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences, the CAMS Innovation Fund for Medical Sciences, and the Training Program for Excellent Talents in Dongcheng District. The researchers have no relevant financial disclosures.

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

Treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist was associated with a 37% increase in the relative risk of gallbladder or biliary disease, compared with controls – especially when used at high doses, for a longer time, and for weight loss rather than type 2 diabetes – a new meta-analysis has found.

The results “indicate that physicians and patients should be concerned about the risks of gallbladder or biliary diseases with using GLP-1 agonists,” study authors Liyun He and colleagues from Peking Union Medical College, Beijing, summarize.

However, “the overall absolute risk increase for gallbladder and biliary disease with use of GLP-1 receptor agonists was small (an additional 27 cases per 10,000 persons treated per year),” they note.

“This absolute risk increase should be weighed against the benefits of treatment with GLP-1 agonists,” which include glucose control, decreased cardiovascular risk, and weight loss, they add.

The findings are from a meta-analysis of 76 randomized controlled trials of GLP-1 agonists published online March 28 in JAMA Internal Medicine.

In an accompanying editorial, Shanzay Haider, MD, and Kasia J. Lipska, MD, also characterize the absolute risk of these complications as “modest.”

“The highest risk for these complications,” they add, “occurred among individuals in the weight loss, compared with the type 2 diabetes studies (119 vs. 13 more events per 10,000 persons per year).”

“Ultimately, the decision to start, continue, or change the dose of a GLP-1 agonist should be reached through a collaborative and individualized discussion between a clinician and a patient,” Dr. Haider and Dr. Lipska, from Yale School of Medicine, New Haven, Conn., summarize.

The study authors also note that few of the trials reported biliary-related events.

“Future trials [of drugs in this class] should prespecify gallbladder and biliary diseases as potential adverse events, and fully test for and report on these outcomes,” they urge.   

Certain drugs in this class are now approved by the U.S. Food and Drug Administration for weight loss at higher doses than for type 2 diabetes – subcutaneous liraglutide (3.0 mg) and subcutaneous semaglutide (2.4 mg) – “suggesting that GLP-1 agonist drugs will increasingly be used at high doses for weight control,” the authors note.

Controversial link

The association between GLP-1 agonists and gallbladder or biliary disease is controversial, the authors write.

Several randomized controlled trials reported higher rates of gallbladder disorders in patients who received a GLP-1 agonist versus placebo, but it is not clear if this is a class effect.

Liraglutide “has drawn the most attention” about this risk, and a post-hoc analysis of the LEADER trial found a significantly increased risk of acute biliary obstruction with liraglutide versus placebo.

To investigate this, the researchers identified 76 randomized controlled trials of GLP-1 agonists in 103,371 patients that had data for the following safety outcomes: cholelithiasis (gallstones, 61 trials), cholecystitis (inflamed gallbladder, 53 trials), biliary disease (21 trials), cholecystectomy (surgical removal of the gallbladder, seven trials), and biliary cancer (12 trials).

Sixty trials were for type 2 diabetes, 13 were for weight loss, and three were for nonalcoholic steatohepatitis, polycystic ovary syndrome, and schizophrenia. They were classed as short or long (≤ 26 weeks or > 26 weeks).

The GLP-1 agonists were liraglutide (21 trials), subcutaneous semaglutide (14), dulaglutide (11), exenatide (9), albiglutide (8), oral semaglutide (8), and lixisenatide (6). 

Participants were a mean age of 58 years and 41% were women. They had a mean BMI of 31.6 kg/m² and 36.9 kg/m² in trials of GLP-1 agonists for type 2 diabetes and weight loss, respectively.  

Patients who received a GLP-1 agonist versus controls had significantly increased rates of cholelithiasis (RR, 1.27; P = .001), cholecystitis (RR, 1.36; P < .001), biliary disease (RR, 1.55; P = .02), and cholecystectomy (RR, 1.70; P < .001) but a nonsignificant increased rate of biliary cancer (RR, 1.43; P = .22).

Use of GLP-1 agonists was associated with a greater increased risk of gallbladder or biliary diseases in trials for weight loss (RR, 2.29) than in trials for type 2 diabetes or other diseases (RR, 1.27; P < .001 for interaction).

Use of these drugs was also associated with higher risks of these complications at higher doses and when given for a longer duration.     

Limitations of the meta-analysis include that the individual studies were not designed to evaluate the risk of gallbladder or biliary diseases associated with GLP-1 agonists.

Also, biliary-related events may have been under-reported, because this was not a predefined safety outcome in most of the trials. The meta-analysis lacked patient-level data, and it may have been underpowered for subgroup analyses.       

The work was supported by grants from the National Natural Science Foundation of China, the Beijing Municipal Natural Science Foundation, the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences, the CAMS Innovation Fund for Medical Sciences, and the Training Program for Excellent Talents in Dongcheng District. The researchers have no relevant financial disclosures.

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