Becky McCall

HAMBURG, Germany – Use of some antibiotic and antipsychotic drugs increases the risk of sudden cardiac arrest (SCA) among people with type 2 diabetes who do not have a history of cardiovascular disease (CVD), shows the first such analysis of real-world, primary care data.

People with type 2 diabetes who do not have a history of CVD have almost three times the risk of SCA if they take antipsychotic medications and nearly double the risk if they take certain antibiotics that prolong the QT interval, notably, macrolides and fluoroquinolones.

“These data show that commonly prescribed drugs - antipsychotic medications, used by about 3% of people with type 2 diabetes, and antibiotics, taken by 5% to 10%, convey an increased risk of sudden cardiac arrest in those without a history of cardiovascular disease,” said Peter Harms, MSc, who presented the study at the annual meeting of the European Association for the Study of Diabetes. Another drug associated with an increase in SCA among patients with diabetes was domperidone, an antinausea medication.

“Perhaps these drugs could be avoided in some cases, and GPs should be more aware of the possible consequences of their use,” he added. “If the patient has type 2 diabetes, then maybe it’s better to avoid some of these medications and try and cope without them, or at least find an alternative antibiotic.”

Mr. Harms, an epidemiologist from Amsterdam University Medical Centers, highlighted that their study was unique because the investigators drew upon primary care data. “These data are extensive, and we find a lot of associations which are very real.”

SCA is associated with 50% of all cardiac deaths and accounts for 20% of all mortality in high-income countries. Of those people who experience SCA, 80% of cases prove fatal.

“As the name suggests, it is difficult to predict because it is sudden, especially in people without a cardiovascular disease history,” Mr. Harms pointed out in an interview with this news organization. He highlighted that “around half of those who experience SCA, often between the ages of 40 and 60 years, have never seen a cardiologist, but many do have type 2 diabetes.

“We need to better understand how to recognize people at risk of SCA, know who to watch and how to prevent these events,” he emphasized.

Vladimira Fejfarova, MD, comoderated the session and commented on the study. “From the clinical point of view, it’s necessary to evaluate risk factors that can contribute to sudden cardiac arrest.”

Overall, the researchers found that, among people with type 2 diabetes who do not have a history of CVD, hypoglycemia, severe hypertension, dyslipidemia, and use of QTc-prolonging medications are associated with SCA risk. Among people with type 2 diabetes and CVD, albuminuria and heart failure are associated with SCA risk.

Dr. Fejfarova added: “With type 2 diabetes and also type 1, we need to look more at adverse events, especially when treating infections with macrolides, but also mycotic infections, because antimycotic drugs are known to influence QT intervals that could contribute to sudden cardiac arrest.

“We need to be more cautious with prescribing certain antibiotics that have these side effects in our patients with diabetes,” asserted Dr. Fejfarova, from the Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague.
 

Type 2 diabetes doubles the risk of SCA

The researcher decided to investigate the population of people with type 2 diabetes because their risk of SCD is around twice that of those without type 2 diabetes. Because these patients have relatively frequent checkups with general practitioners, Mr. Harms turned to primary care databases that contained comprehensive and relatively routine information on risk indicators.

Longitudinal associations between clinical characteristics of 3,919 patients with type 2 diabetes – both those with and those without a history of CVD – and SCA (a total of 689 patients) were determined.

Cases were found in the AmsteRdam REsuscitation STtudies (ARREST) registry of out-of-hospital resuscitation attempts by emergency medical services in the Dutch region of Noord-Holland from 2010 to 2019. Case patients were matched with up to five control patients. The control group comprised people with type 2 diabetes who had not experienced an SCA. Control patients were sourced from the same primary care practices who were of similar age and sex. Clinical measurements, including blood pressure and blood glucose readings, medication use, and medical history for the 5 years leading up to an SCA, were obtained from general practice records. A multivariable analysis was performed, and results were stratified for people with and for those without a history of CVD.

Of particular interest were drugs that interfere with cardiac function, including some prokinetic, antibiotic, and antipsychotic medications. All of the drugs are known to be associated with a change in QTc prolongation. Examples include domperidone (QTc-prolonging prokinetic), macrolides and fluoroquinolones (QTc-prolonging antibiotics), and haloperidol (a QTc-prolonging antipsychotic).
 

Antibiotic and antipsychotic use might contribute to SCA in T2D

Case patients and control patients were similar in age, hemoglobin A1c level, and other characteristics with the exception that more patients with SCA had a history of CVD (40.0% vs. 29.4%).

“Looking at the associations in the overall population, insulin use was strongly associated with SCA risk [hazard ratio, 2.38] and perhaps this was an indicator of severity of type 2 diabetes,” remarked Mr. Harms. “Also, unsurprisingly, a history of arrhythmia [HR, 1.68] and, more surprisingly, prokinetic drug use [HR, 1.66; 95% confidence interval, 1.20-2.31], specifically those known for QTc-prolongation, were associated with SCA.”

Among people who had experienced an SCA and who did not have a history of CVD (337 case patients/2,023 control patients), QTc-prolonging antipsychotic medication use was associated with SCA at an HR of 2.87, and antibiotic medication use was associated with SCA at an HR of 1.66. A low fasting glucose level (< 4.5 mmol/mol) was associated with SCA at an HR of 2.5; severely high systolic blood pressure (> 180 mm Hg) was associated with SCA at an HR of 2.21; low HDL cholesterol level, with an HR of 1.35; and high LDL cholesterol level (> 2.6 mmol/L), with an HR of 1.64.

Among people with a history of CVD (352 case patients/1,207 control patients), associations between albuminuria and SCA were moderate (HR, 1.54) and severe (HR, 1.55); heart failure was associated with SCA at an HR of 1.85 (95% CI, 1.50-2.29).

Comoderator Dr. Fejfarova added that, in addition to the findings from Dr. Harms’ study, other research presented in the same session highlighted the importance of checking patients for the presence of arrhythmias that could lead to the development of atrioventricular blocks, sinus node diseases, and SCA.

Mr. Harms and Dr. Fejfarova have disclosed no relevant financial relationships.

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

HAMBURG, Germany – Use of some antibiotic and antipsychotic drugs increases the risk of sudden cardiac arrest (SCA) among people with type 2 diabetes who do not have a history of cardiovascular disease (CVD), shows the first such analysis of real-world, primary care data.

People with type 2 diabetes who do not have a history of CVD have almost three times the risk of SCA if they take antipsychotic medications and nearly double the risk if they take certain antibiotics that prolong the QT interval, notably, macrolides and fluoroquinolones.

“These data show that commonly prescribed drugs - antipsychotic medications, used by about 3% of people with type 2 diabetes, and antibiotics, taken by 5% to 10%, convey an increased risk of sudden cardiac arrest in those without a history of cardiovascular disease,” said Peter Harms, MSc, who presented the study at the annual meeting of the European Association for the Study of Diabetes. Another drug associated with an increase in SCA among patients with diabetes was domperidone, an antinausea medication.

“Perhaps these drugs could be avoided in some cases, and GPs should be more aware of the possible consequences of their use,” he added. “If the patient has type 2 diabetes, then maybe it’s better to avoid some of these medications and try and cope without them, or at least find an alternative antibiotic.”

Mr. Harms, an epidemiologist from Amsterdam University Medical Centers, highlighted that their study was unique because the investigators drew upon primary care data. “These data are extensive, and we find a lot of associations which are very real.”

SCA is associated with 50% of all cardiac deaths and accounts for 20% of all mortality in high-income countries. Of those people who experience SCA, 80% of cases prove fatal.

“As the name suggests, it is difficult to predict because it is sudden, especially in people without a cardiovascular disease history,” Mr. Harms pointed out in an interview with this news organization. He highlighted that “around half of those who experience SCA, often between the ages of 40 and 60 years, have never seen a cardiologist, but many do have type 2 diabetes.

“We need to better understand how to recognize people at risk of SCA, know who to watch and how to prevent these events,” he emphasized.

Vladimira Fejfarova, MD, comoderated the session and commented on the study. “From the clinical point of view, it’s necessary to evaluate risk factors that can contribute to sudden cardiac arrest.”

Overall, the researchers found that, among people with type 2 diabetes who do not have a history of CVD, hypoglycemia, severe hypertension, dyslipidemia, and use of QTc-prolonging medications are associated with SCA risk. Among people with type 2 diabetes and CVD, albuminuria and heart failure are associated with SCA risk.

Dr. Fejfarova added: “With type 2 diabetes and also type 1, we need to look more at adverse events, especially when treating infections with macrolides, but also mycotic infections, because antimycotic drugs are known to influence QT intervals that could contribute to sudden cardiac arrest.

“We need to be more cautious with prescribing certain antibiotics that have these side effects in our patients with diabetes,” asserted Dr. Fejfarova, from the Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague.
 

Type 2 diabetes doubles the risk of SCA

The researcher decided to investigate the population of people with type 2 diabetes because their risk of SCD is around twice that of those without type 2 diabetes. Because these patients have relatively frequent checkups with general practitioners, Mr. Harms turned to primary care databases that contained comprehensive and relatively routine information on risk indicators.

Longitudinal associations between clinical characteristics of 3,919 patients with type 2 diabetes – both those with and those without a history of CVD – and SCA (a total of 689 patients) were determined.

Cases were found in the AmsteRdam REsuscitation STtudies (ARREST) registry of out-of-hospital resuscitation attempts by emergency medical services in the Dutch region of Noord-Holland from 2010 to 2019. Case patients were matched with up to five control patients. The control group comprised people with type 2 diabetes who had not experienced an SCA. Control patients were sourced from the same primary care practices who were of similar age and sex. Clinical measurements, including blood pressure and blood glucose readings, medication use, and medical history for the 5 years leading up to an SCA, were obtained from general practice records. A multivariable analysis was performed, and results were stratified for people with and for those without a history of CVD.

Of particular interest were drugs that interfere with cardiac function, including some prokinetic, antibiotic, and antipsychotic medications. All of the drugs are known to be associated with a change in QTc prolongation. Examples include domperidone (QTc-prolonging prokinetic), macrolides and fluoroquinolones (QTc-prolonging antibiotics), and haloperidol (a QTc-prolonging antipsychotic).
 

Antibiotic and antipsychotic use might contribute to SCA in T2D

Case patients and control patients were similar in age, hemoglobin A1c level, and other characteristics with the exception that more patients with SCA had a history of CVD (40.0% vs. 29.4%).

“Looking at the associations in the overall population, insulin use was strongly associated with SCA risk [hazard ratio, 2.38] and perhaps this was an indicator of severity of type 2 diabetes,” remarked Mr. Harms. “Also, unsurprisingly, a history of arrhythmia [HR, 1.68] and, more surprisingly, prokinetic drug use [HR, 1.66; 95% confidence interval, 1.20-2.31], specifically those known for QTc-prolongation, were associated with SCA.”

Among people who had experienced an SCA and who did not have a history of CVD (337 case patients/2,023 control patients), QTc-prolonging antipsychotic medication use was associated with SCA at an HR of 2.87, and antibiotic medication use was associated with SCA at an HR of 1.66. A low fasting glucose level (< 4.5 mmol/mol) was associated with SCA at an HR of 2.5; severely high systolic blood pressure (> 180 mm Hg) was associated with SCA at an HR of 2.21; low HDL cholesterol level, with an HR of 1.35; and high LDL cholesterol level (> 2.6 mmol/L), with an HR of 1.64.

Among people with a history of CVD (352 case patients/1,207 control patients), associations between albuminuria and SCA were moderate (HR, 1.54) and severe (HR, 1.55); heart failure was associated with SCA at an HR of 1.85 (95% CI, 1.50-2.29).

Comoderator Dr. Fejfarova added that, in addition to the findings from Dr. Harms’ study, other research presented in the same session highlighted the importance of checking patients for the presence of arrhythmias that could lead to the development of atrioventricular blocks, sinus node diseases, and SCA.

Mr. Harms and Dr. Fejfarova have disclosed no relevant financial relationships.

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

HAMBURG, Germany – Use of some antibiotic and antipsychotic drugs increases the risk of sudden cardiac arrest (SCA) among people with type 2 diabetes who do not have a history of cardiovascular disease (CVD), shows the first such analysis of real-world, primary care data.

People with type 2 diabetes who do not have a history of CVD have almost three times the risk of SCA if they take antipsychotic medications and nearly double the risk if they take certain antibiotics that prolong the QT interval, notably, macrolides and fluoroquinolones.

“These data show that commonly prescribed drugs - antipsychotic medications, used by about 3% of people with type 2 diabetes, and antibiotics, taken by 5% to 10%, convey an increased risk of sudden cardiac arrest in those without a history of cardiovascular disease,” said Peter Harms, MSc, who presented the study at the annual meeting of the European Association for the Study of Diabetes. Another drug associated with an increase in SCA among patients with diabetes was domperidone, an antinausea medication.

“Perhaps these drugs could be avoided in some cases, and GPs should be more aware of the possible consequences of their use,” he added. “If the patient has type 2 diabetes, then maybe it’s better to avoid some of these medications and try and cope without them, or at least find an alternative antibiotic.”

Mr. Harms, an epidemiologist from Amsterdam University Medical Centers, highlighted that their study was unique because the investigators drew upon primary care data. “These data are extensive, and we find a lot of associations which are very real.”

SCA is associated with 50% of all cardiac deaths and accounts for 20% of all mortality in high-income countries. Of those people who experience SCA, 80% of cases prove fatal.

“As the name suggests, it is difficult to predict because it is sudden, especially in people without a cardiovascular disease history,” Mr. Harms pointed out in an interview with this news organization. He highlighted that “around half of those who experience SCA, often between the ages of 40 and 60 years, have never seen a cardiologist, but many do have type 2 diabetes.

“We need to better understand how to recognize people at risk of SCA, know who to watch and how to prevent these events,” he emphasized.

Vladimira Fejfarova, MD, comoderated the session and commented on the study. “From the clinical point of view, it’s necessary to evaluate risk factors that can contribute to sudden cardiac arrest.”

Overall, the researchers found that, among people with type 2 diabetes who do not have a history of CVD, hypoglycemia, severe hypertension, dyslipidemia, and use of QTc-prolonging medications are associated with SCA risk. Among people with type 2 diabetes and CVD, albuminuria and heart failure are associated with SCA risk.

Dr. Fejfarova added: “With type 2 diabetes and also type 1, we need to look more at adverse events, especially when treating infections with macrolides, but also mycotic infections, because antimycotic drugs are known to influence QT intervals that could contribute to sudden cardiac arrest.

“We need to be more cautious with prescribing certain antibiotics that have these side effects in our patients with diabetes,” asserted Dr. Fejfarova, from the Diabetes Centre, Institute for Clinical and Experimental Medicine, Prague.
 

Type 2 diabetes doubles the risk of SCA

The researcher decided to investigate the population of people with type 2 diabetes because their risk of SCD is around twice that of those without type 2 diabetes. Because these patients have relatively frequent checkups with general practitioners, Mr. Harms turned to primary care databases that contained comprehensive and relatively routine information on risk indicators.

Longitudinal associations between clinical characteristics of 3,919 patients with type 2 diabetes – both those with and those without a history of CVD – and SCA (a total of 689 patients) were determined.

Cases were found in the AmsteRdam REsuscitation STtudies (ARREST) registry of out-of-hospital resuscitation attempts by emergency medical services in the Dutch region of Noord-Holland from 2010 to 2019. Case patients were matched with up to five control patients. The control group comprised people with type 2 diabetes who had not experienced an SCA. Control patients were sourced from the same primary care practices who were of similar age and sex. Clinical measurements, including blood pressure and blood glucose readings, medication use, and medical history for the 5 years leading up to an SCA, were obtained from general practice records. A multivariable analysis was performed, and results were stratified for people with and for those without a history of CVD.

Of particular interest were drugs that interfere with cardiac function, including some prokinetic, antibiotic, and antipsychotic medications. All of the drugs are known to be associated with a change in QTc prolongation. Examples include domperidone (QTc-prolonging prokinetic), macrolides and fluoroquinolones (QTc-prolonging antibiotics), and haloperidol (a QTc-prolonging antipsychotic).
 

Antibiotic and antipsychotic use might contribute to SCA in T2D

Case patients and control patients were similar in age, hemoglobin A1c level, and other characteristics with the exception that more patients with SCA had a history of CVD (40.0% vs. 29.4%).

“Looking at the associations in the overall population, insulin use was strongly associated with SCA risk [hazard ratio, 2.38] and perhaps this was an indicator of severity of type 2 diabetes,” remarked Mr. Harms. “Also, unsurprisingly, a history of arrhythmia [HR, 1.68] and, more surprisingly, prokinetic drug use [HR, 1.66; 95% confidence interval, 1.20-2.31], specifically those known for QTc-prolongation, were associated with SCA.”

Among people who had experienced an SCA and who did not have a history of CVD (337 case patients/2,023 control patients), QTc-prolonging antipsychotic medication use was associated with SCA at an HR of 2.87, and antibiotic medication use was associated with SCA at an HR of 1.66. A low fasting glucose level (< 4.5 mmol/mol) was associated with SCA at an HR of 2.5; severely high systolic blood pressure (> 180 mm Hg) was associated with SCA at an HR of 2.21; low HDL cholesterol level, with an HR of 1.35; and high LDL cholesterol level (> 2.6 mmol/L), with an HR of 1.64.

Among people with a history of CVD (352 case patients/1,207 control patients), associations between albuminuria and SCA were moderate (HR, 1.54) and severe (HR, 1.55); heart failure was associated with SCA at an HR of 1.85 (95% CI, 1.50-2.29).

Comoderator Dr. Fejfarova added that, in addition to the findings from Dr. Harms’ study, other research presented in the same session highlighted the importance of checking patients for the presence of arrhythmias that could lead to the development of atrioventricular blocks, sinus node diseases, and SCA.

Mr. Harms and Dr. Fejfarova have disclosed no relevant financial relationships.

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

GLASGOW – ChatGPT failed to pass the U.K.’s National Primary Care examinations in a new study, highlighting how artificial intelligence (AI) does not necessarily match human perceptions of medical complexity.

ChatGPT also provided novel explanations – it frequently “hallucinates” – by describing inaccurate information as if they were facts, according to Shathar Mahmood, BA, a fifth-year medical student at the University of Cambridge, England, who presented the findings at the annual meeting of the Royal College of General Practitioners. The study was published in JMIR Medical Education earlier this year.

“Artificial intelligence has generated impressive results across medicine, and with the release of ChatGPT there is now discussion about these large language models taking over clinicians’ jobs,” Arun James Thirunavukarasu, MB BChir, of the University of Oxford, England, and Oxford University Hospitals NHS Foundation Trust, who is the lead author of the study, told this news organization.

Performance of AI on medical school examinations has prompted much of this discussion, often because performance does not reflect real-world clinical practice, he said. “We used the Applied Knowledge Test instead, and this allowed us to explore the potential and pitfalls of deploying large language models in primary care and to explore what further development of medical large language model applications is required.”

The researchers investigated the strengths and weaknesses of ChatGPT in primary care using the Membership of the Royal College of General Practitioners Applied Knowledge Test. The computer-based, multiple-choice assessment is part of the U.K.’s specialty training to become a general practitioner (GP). It tests knowledge behind general practice within the context of the United Kingdom’s National Health Service.

The researchers entered a series of 674 questions into ChatGPT on two occasions, or “runs.” “By putting the questions into two separate dialogues, we hoped to avoid the influence of one dialogue on the other,” Ms. Mahmood said. To validate that the answers were correct, the ChatGPT responses were compared with the answers provided by the GP self-test and past articles.
 

Docs 1, AI 0

Overall performance of the algorithm was good across both runs (59.94% and 60.39%); 83.23% of questions produced the same answer on both runs.

But 17% of the answers didn’t match, Ms. Mahmood reported, a statistically significant difference. “And the overall performance of ChatGPT was 10% lower than the average RCGP pass mark in the last few years, which informs one of our conclusions about it not being very precise at expert level recall and decision-making,” she said.

Also, a small percentage of questions (1.48% and 2.25% in each run) produced an uncertain answer or there was no answer.
 

Say what?

Novel explanations were generated upon running a question through ChatGPT that then provided an extended answer, Ms. Mahmood said. When the accuracy of the extended answers was checked against the correct answers, no correlation was found. “ChatGPT can hallucinate answers, and there’s no way a nonexpert reading this could know it is incorrect,” she said.

Regarding the application of ChatGPT and similar algorithms to clinical practice, Ms. Mahmood was clear. “As they stand, [AI systems] will not be able to replace the health care professional workforce, in primary care at least,” she said. “I think larger and more medically specific datasets are required to improve their outputs in this field.”

Sandip Pramanik, MBcHB, a GP in Watford, Hertfordshire, England, said the study “clearly showed ChatGPT’s struggle to deal with the complexity of the exam questions that is based on the primary care system. In essence, this in indicative of the human factors involved in decision-making in primary care.”

The applied knowledge test is designed to test the knowledge required to be a generalist in the primary care setting, and as such, there are lots of nuances reflecting this within the questions, Dr. Pramanik said.

“ChatGPT may look at these in a more black and white way, whereas the generalist needs to be reflective of the complexities involved and the different possibilities that can present rather than take a binary ‘yes’ or ‘no’ stance,” he said. “In fact, this highlights a lot about the nature of general practice in managing uncertainty, and this is reflected in the questions asked in the exam,” he remarked. He noted, “Being a generalist is about factoring in human emotion and human perception as well as knowledge.”

Ms. Mahmood, Dr. Thirunavukarasu, and Dr. Pramanik have disclosed no relevant financial relationships.

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

GLASGOW – ChatGPT failed to pass the U.K.’s National Primary Care examinations in a new study, highlighting how artificial intelligence (AI) does not necessarily match human perceptions of medical complexity.

ChatGPT also provided novel explanations – it frequently “hallucinates” – by describing inaccurate information as if they were facts, according to Shathar Mahmood, BA, a fifth-year medical student at the University of Cambridge, England, who presented the findings at the annual meeting of the Royal College of General Practitioners. The study was published in JMIR Medical Education earlier this year.

“Artificial intelligence has generated impressive results across medicine, and with the release of ChatGPT there is now discussion about these large language models taking over clinicians’ jobs,” Arun James Thirunavukarasu, MB BChir, of the University of Oxford, England, and Oxford University Hospitals NHS Foundation Trust, who is the lead author of the study, told this news organization.

Performance of AI on medical school examinations has prompted much of this discussion, often because performance does not reflect real-world clinical practice, he said. “We used the Applied Knowledge Test instead, and this allowed us to explore the potential and pitfalls of deploying large language models in primary care and to explore what further development of medical large language model applications is required.”

The researchers investigated the strengths and weaknesses of ChatGPT in primary care using the Membership of the Royal College of General Practitioners Applied Knowledge Test. The computer-based, multiple-choice assessment is part of the U.K.’s specialty training to become a general practitioner (GP). It tests knowledge behind general practice within the context of the United Kingdom’s National Health Service.

The researchers entered a series of 674 questions into ChatGPT on two occasions, or “runs.” “By putting the questions into two separate dialogues, we hoped to avoid the influence of one dialogue on the other,” Ms. Mahmood said. To validate that the answers were correct, the ChatGPT responses were compared with the answers provided by the GP self-test and past articles.
 

Docs 1, AI 0

Overall performance of the algorithm was good across both runs (59.94% and 60.39%); 83.23% of questions produced the same answer on both runs.

But 17% of the answers didn’t match, Ms. Mahmood reported, a statistically significant difference. “And the overall performance of ChatGPT was 10% lower than the average RCGP pass mark in the last few years, which informs one of our conclusions about it not being very precise at expert level recall and decision-making,” she said.

Also, a small percentage of questions (1.48% and 2.25% in each run) produced an uncertain answer or there was no answer.
 

Say what?

Novel explanations were generated upon running a question through ChatGPT that then provided an extended answer, Ms. Mahmood said. When the accuracy of the extended answers was checked against the correct answers, no correlation was found. “ChatGPT can hallucinate answers, and there’s no way a nonexpert reading this could know it is incorrect,” she said.

Regarding the application of ChatGPT and similar algorithms to clinical practice, Ms. Mahmood was clear. “As they stand, [AI systems] will not be able to replace the health care professional workforce, in primary care at least,” she said. “I think larger and more medically specific datasets are required to improve their outputs in this field.”

Sandip Pramanik, MBcHB, a GP in Watford, Hertfordshire, England, said the study “clearly showed ChatGPT’s struggle to deal with the complexity of the exam questions that is based on the primary care system. In essence, this in indicative of the human factors involved in decision-making in primary care.”

The applied knowledge test is designed to test the knowledge required to be a generalist in the primary care setting, and as such, there are lots of nuances reflecting this within the questions, Dr. Pramanik said.

“ChatGPT may look at these in a more black and white way, whereas the generalist needs to be reflective of the complexities involved and the different possibilities that can present rather than take a binary ‘yes’ or ‘no’ stance,” he said. “In fact, this highlights a lot about the nature of general practice in managing uncertainty, and this is reflected in the questions asked in the exam,” he remarked. He noted, “Being a generalist is about factoring in human emotion and human perception as well as knowledge.”

Ms. Mahmood, Dr. Thirunavukarasu, and Dr. Pramanik have disclosed no relevant financial relationships.

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

GLASGOW – ChatGPT failed to pass the U.K.’s National Primary Care examinations in a new study, highlighting how artificial intelligence (AI) does not necessarily match human perceptions of medical complexity.

ChatGPT also provided novel explanations – it frequently “hallucinates” – by describing inaccurate information as if they were facts, according to Shathar Mahmood, BA, a fifth-year medical student at the University of Cambridge, England, who presented the findings at the annual meeting of the Royal College of General Practitioners. The study was published in JMIR Medical Education earlier this year.

“Artificial intelligence has generated impressive results across medicine, and with the release of ChatGPT there is now discussion about these large language models taking over clinicians’ jobs,” Arun James Thirunavukarasu, MB BChir, of the University of Oxford, England, and Oxford University Hospitals NHS Foundation Trust, who is the lead author of the study, told this news organization.

Performance of AI on medical school examinations has prompted much of this discussion, often because performance does not reflect real-world clinical practice, he said. “We used the Applied Knowledge Test instead, and this allowed us to explore the potential and pitfalls of deploying large language models in primary care and to explore what further development of medical large language model applications is required.”

The researchers investigated the strengths and weaknesses of ChatGPT in primary care using the Membership of the Royal College of General Practitioners Applied Knowledge Test. The computer-based, multiple-choice assessment is part of the U.K.’s specialty training to become a general practitioner (GP). It tests knowledge behind general practice within the context of the United Kingdom’s National Health Service.

The researchers entered a series of 674 questions into ChatGPT on two occasions, or “runs.” “By putting the questions into two separate dialogues, we hoped to avoid the influence of one dialogue on the other,” Ms. Mahmood said. To validate that the answers were correct, the ChatGPT responses were compared with the answers provided by the GP self-test and past articles.
 

Docs 1, AI 0

Overall performance of the algorithm was good across both runs (59.94% and 60.39%); 83.23% of questions produced the same answer on both runs.

But 17% of the answers didn’t match, Ms. Mahmood reported, a statistically significant difference. “And the overall performance of ChatGPT was 10% lower than the average RCGP pass mark in the last few years, which informs one of our conclusions about it not being very precise at expert level recall and decision-making,” she said.

Also, a small percentage of questions (1.48% and 2.25% in each run) produced an uncertain answer or there was no answer.
 

Say what?

Novel explanations were generated upon running a question through ChatGPT that then provided an extended answer, Ms. Mahmood said. When the accuracy of the extended answers was checked against the correct answers, no correlation was found. “ChatGPT can hallucinate answers, and there’s no way a nonexpert reading this could know it is incorrect,” she said.

Regarding the application of ChatGPT and similar algorithms to clinical practice, Ms. Mahmood was clear. “As they stand, [AI systems] will not be able to replace the health care professional workforce, in primary care at least,” she said. “I think larger and more medically specific datasets are required to improve their outputs in this field.”

Sandip Pramanik, MBcHB, a GP in Watford, Hertfordshire, England, said the study “clearly showed ChatGPT’s struggle to deal with the complexity of the exam questions that is based on the primary care system. In essence, this in indicative of the human factors involved in decision-making in primary care.”

The applied knowledge test is designed to test the knowledge required to be a generalist in the primary care setting, and as such, there are lots of nuances reflecting this within the questions, Dr. Pramanik said.

“ChatGPT may look at these in a more black and white way, whereas the generalist needs to be reflective of the complexities involved and the different possibilities that can present rather than take a binary ‘yes’ or ‘no’ stance,” he said. “In fact, this highlights a lot about the nature of general practice in managing uncertainty, and this is reflected in the questions asked in the exam,” he remarked. He noted, “Being a generalist is about factoring in human emotion and human perception as well as knowledge.”

Ms. Mahmood, Dr. Thirunavukarasu, and Dr. Pramanik have disclosed no relevant financial relationships.

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

GLASGOW – Amitriptyline, titrated at low dose, was superior to placebo as a second-line treatment for irritable bowel syndrome (IBS) across multiple outcomes in what the researchers call the largest randomized controlled trial (RCT) of a tricyclic antidepressant in the condition.

Patients who took low-dose amitriptyline were almost twice as likely to report an overall improvement in symptoms as those taking placebo, according to investigators of the Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment (ATLANTIS) trial. Low-dose amitriptyline appeared safe and well tolerated, they reported.

Hazel Everitt, PhD, professor of primary care research at the University of Southampton, England, presented the findings at the annual conference of the Royal College of General Practitioners.

The data were also published in The Lancet and were presented at the recent United European Gastroenterology Week 2023.

Clinicians “should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration,” the researchers wrote in the journal article.

Despite first-line treatments such as diet, fiber, and antispasmodics, many patients with IBS continue to have troublesome symptoms, Dr. Everitt said in an interview. “GPs haven’t often prescribed amitriptyline for IBS – probably because of the lack of research evidence for its use in primary care.”

Dr. Everitt added that primary care physicians and patients interviewed for the study welcomed low-dose amitriptyline as a potential additional option, especially with increased patient-led care. “The dose titration document that was developed with patients specifically for the trial enables patients to be more empowered to manage their IBS by helping them to titrate their dose up or down depending on their symptoms and side effects.”

Judith Danby, MBBS, a retired GP who moderated the session at which the ATLANTIS results were presented, said, “Self-titration of the dose equals patient empowerment, and if patients can be helped to manage their own medication, then they will also be more empowered to think about lifestyle change, too.”
 

RCT across 55 practices

The U.K.’s National Institute for Health and Care Excellence guidance for the management of IBS in primary care says clinicians should “consider” using low-dose tricyclic antidepressants as a second-line treatment but highlight the need for an RCT of these drugs carried out solely in primary care.

The ATLANTIS trial was conducted across 55 general practices in England and included adults with Rome IV IBS of any subtype and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥ 75 points) despite dietary changes and first-line therapies. Participants had normal full blood counts and C-reactive protein measures, negative celiac serology, and no evidence of suicidal ideation. The mean age was 48.5 years, and 68% were female. The mean IBS-SSS score in all participants was 272.8 at baseline.

Patients were randomly assigned in a 1:1 ratio to receive either low-dose oral amitriptyline (10 mg once daily; n = 232) with dose titration over 3 weeks (up to a maximum dose of 30 mg once daily) as determined by a participant’s symptoms and tolerability; or placebo (n = 231). Both groups participated for 6 months. The primary outcome was the IBS-SSS score at 6 months.
 

Amitriptyline

Three-quarters of participants adhered to the therapy over the 6 months, which was particularly notable given that the trial was conducted during the COVID-19 pandemic, according to the researchers.

An intent-to-treat analysis found that at 6 months, amitriptyline was superior to placebo, with a significant mean difference in IBS-SSS score between groups of –27.0 (95% confidence interval, –46.9 to –7.1; P = .0079; mean IBS-SSS, 170.4 vs. 200.1 with amitriptyline and placebo). A secondary outcome showed an increased likelihood of relief of IBS symptoms by subjective global assessment (odds ratio, 1.78; 95% CI. 1.19-2.66; P = .0050).

At 3 months, the difference in mean change in IBS-SSS score between groups was also significant, at –23.3 (95% CI, –42.0 to –4.6; P = .014), the researchers reported.

People who took the drug were 70% more likely to report relief of symptoms on SGA than those who took placebo (P = .08), according to the researchers.

The researchers reported no effect of low-dose amitriptyline on psychiatric symptoms, such as distressing thoughts, anxiety, and depression, during the 6-month follow-up, nor was there any effect on ability to work or go about social activities.

“This was a pragmatic trial performed in a large number of participants with IBS, with an average duration of symptoms of 10 years and with 80% having moderate to severe symptoms at baseline,” Alexander Ford, MD, professor of gastroenterology at the University of Leeds, England, and a coinvestigator on the study, told this news organization. “The fact that amitriptyline showed such a strong effect over placebo in this group of patients, with a mean decrease in IBS-SSS of almost 100 points at both 3 and 6 months, is therefore all the more impressive.”

Mild adverse events, such as dry mouth and drowsiness, were more frequent with low-dose amitriptyline than with placebo,

Dr. Everitt said the ATLANTIS findings could change practice. Previous trials of low-dose amitriptyline for IBS had mostly been small and were conducted in secondary care settings such as gastroenterology clinics with relatively short follow-up times.

“This is a problem for a long-term condition that fluctuates over time and is diagnosed and managed mostly in primary care,” she said. “The ATLANTIS trial is the largest trial of low-dose amitriptyline for IBS undertaken worldwide and was rigorously conducted with 6 months follow-up, providing reliable results that can help inform GPs and patients’ treatment decision-making in usual clinical practice.”

On a pragmatic level, the research group developed a dose titration document for use by patients and GPs. “Both the GPs and participants found the ATLANTIS dose titration document acceptable and helpful,” Dr. Everitt pointed out. She noted, “We’ve made the dose titration document freely available to support patients and clinicians to try low-dose amitriptyline for IBS.”

Dr. Ford and Dr. Everitt received grant funding (institutional) from the National Institute for Health and Care Research.

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

GLASGOW – Amitriptyline, titrated at low dose, was superior to placebo as a second-line treatment for irritable bowel syndrome (IBS) across multiple outcomes in what the researchers call the largest randomized controlled trial (RCT) of a tricyclic antidepressant in the condition.

Patients who took low-dose amitriptyline were almost twice as likely to report an overall improvement in symptoms as those taking placebo, according to investigators of the Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment (ATLANTIS) trial. Low-dose amitriptyline appeared safe and well tolerated, they reported.

Hazel Everitt, PhD, professor of primary care research at the University of Southampton, England, presented the findings at the annual conference of the Royal College of General Practitioners.

The data were also published in The Lancet and were presented at the recent United European Gastroenterology Week 2023.

Clinicians “should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration,” the researchers wrote in the journal article.

Despite first-line treatments such as diet, fiber, and antispasmodics, many patients with IBS continue to have troublesome symptoms, Dr. Everitt said in an interview. “GPs haven’t often prescribed amitriptyline for IBS – probably because of the lack of research evidence for its use in primary care.”

Dr. Everitt added that primary care physicians and patients interviewed for the study welcomed low-dose amitriptyline as a potential additional option, especially with increased patient-led care. “The dose titration document that was developed with patients specifically for the trial enables patients to be more empowered to manage their IBS by helping them to titrate their dose up or down depending on their symptoms and side effects.”

Judith Danby, MBBS, a retired GP who moderated the session at which the ATLANTIS results were presented, said, “Self-titration of the dose equals patient empowerment, and if patients can be helped to manage their own medication, then they will also be more empowered to think about lifestyle change, too.”
 

RCT across 55 practices

The U.K.’s National Institute for Health and Care Excellence guidance for the management of IBS in primary care says clinicians should “consider” using low-dose tricyclic antidepressants as a second-line treatment but highlight the need for an RCT of these drugs carried out solely in primary care.

The ATLANTIS trial was conducted across 55 general practices in England and included adults with Rome IV IBS of any subtype and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥ 75 points) despite dietary changes and first-line therapies. Participants had normal full blood counts and C-reactive protein measures, negative celiac serology, and no evidence of suicidal ideation. The mean age was 48.5 years, and 68% were female. The mean IBS-SSS score in all participants was 272.8 at baseline.

Patients were randomly assigned in a 1:1 ratio to receive either low-dose oral amitriptyline (10 mg once daily; n = 232) with dose titration over 3 weeks (up to a maximum dose of 30 mg once daily) as determined by a participant’s symptoms and tolerability; or placebo (n = 231). Both groups participated for 6 months. The primary outcome was the IBS-SSS score at 6 months.
 

Amitriptyline

Three-quarters of participants adhered to the therapy over the 6 months, which was particularly notable given that the trial was conducted during the COVID-19 pandemic, according to the researchers.

An intent-to-treat analysis found that at 6 months, amitriptyline was superior to placebo, with a significant mean difference in IBS-SSS score between groups of –27.0 (95% confidence interval, –46.9 to –7.1; P = .0079; mean IBS-SSS, 170.4 vs. 200.1 with amitriptyline and placebo). A secondary outcome showed an increased likelihood of relief of IBS symptoms by subjective global assessment (odds ratio, 1.78; 95% CI. 1.19-2.66; P = .0050).

At 3 months, the difference in mean change in IBS-SSS score between groups was also significant, at –23.3 (95% CI, –42.0 to –4.6; P = .014), the researchers reported.

People who took the drug were 70% more likely to report relief of symptoms on SGA than those who took placebo (P = .08), according to the researchers.

The researchers reported no effect of low-dose amitriptyline on psychiatric symptoms, such as distressing thoughts, anxiety, and depression, during the 6-month follow-up, nor was there any effect on ability to work or go about social activities.

“This was a pragmatic trial performed in a large number of participants with IBS, with an average duration of symptoms of 10 years and with 80% having moderate to severe symptoms at baseline,” Alexander Ford, MD, professor of gastroenterology at the University of Leeds, England, and a coinvestigator on the study, told this news organization. “The fact that amitriptyline showed such a strong effect over placebo in this group of patients, with a mean decrease in IBS-SSS of almost 100 points at both 3 and 6 months, is therefore all the more impressive.”

Mild adverse events, such as dry mouth and drowsiness, were more frequent with low-dose amitriptyline than with placebo,

Dr. Everitt said the ATLANTIS findings could change practice. Previous trials of low-dose amitriptyline for IBS had mostly been small and were conducted in secondary care settings such as gastroenterology clinics with relatively short follow-up times.

“This is a problem for a long-term condition that fluctuates over time and is diagnosed and managed mostly in primary care,” she said. “The ATLANTIS trial is the largest trial of low-dose amitriptyline for IBS undertaken worldwide and was rigorously conducted with 6 months follow-up, providing reliable results that can help inform GPs and patients’ treatment decision-making in usual clinical practice.”

On a pragmatic level, the research group developed a dose titration document for use by patients and GPs. “Both the GPs and participants found the ATLANTIS dose titration document acceptable and helpful,” Dr. Everitt pointed out. She noted, “We’ve made the dose titration document freely available to support patients and clinicians to try low-dose amitriptyline for IBS.”

Dr. Ford and Dr. Everitt received grant funding (institutional) from the National Institute for Health and Care Research.

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

GLASGOW – Amitriptyline, titrated at low dose, was superior to placebo as a second-line treatment for irritable bowel syndrome (IBS) across multiple outcomes in what the researchers call the largest randomized controlled trial (RCT) of a tricyclic antidepressant in the condition.

Patients who took low-dose amitriptyline were almost twice as likely to report an overall improvement in symptoms as those taking placebo, according to investigators of the Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment (ATLANTIS) trial. Low-dose amitriptyline appeared safe and well tolerated, they reported.

Hazel Everitt, PhD, professor of primary care research at the University of Southampton, England, presented the findings at the annual conference of the Royal College of General Practitioners.

The data were also published in The Lancet and were presented at the recent United European Gastroenterology Week 2023.

Clinicians “should offer low-dose amitriptyline to patients with IBS whose symptoms do not improve with first-line therapies, with appropriate support to guide patient-led dose titration,” the researchers wrote in the journal article.

Despite first-line treatments such as diet, fiber, and antispasmodics, many patients with IBS continue to have troublesome symptoms, Dr. Everitt said in an interview. “GPs haven’t often prescribed amitriptyline for IBS – probably because of the lack of research evidence for its use in primary care.”

Dr. Everitt added that primary care physicians and patients interviewed for the study welcomed low-dose amitriptyline as a potential additional option, especially with increased patient-led care. “The dose titration document that was developed with patients specifically for the trial enables patients to be more empowered to manage their IBS by helping them to titrate their dose up or down depending on their symptoms and side effects.”

Judith Danby, MBBS, a retired GP who moderated the session at which the ATLANTIS results were presented, said, “Self-titration of the dose equals patient empowerment, and if patients can be helped to manage their own medication, then they will also be more empowered to think about lifestyle change, too.”
 

RCT across 55 practices

The U.K.’s National Institute for Health and Care Excellence guidance for the management of IBS in primary care says clinicians should “consider” using low-dose tricyclic antidepressants as a second-line treatment but highlight the need for an RCT of these drugs carried out solely in primary care.

The ATLANTIS trial was conducted across 55 general practices in England and included adults with Rome IV IBS of any subtype and ongoing symptoms (IBS Severity Scoring System [IBS-SSS] score ≥ 75 points) despite dietary changes and first-line therapies. Participants had normal full blood counts and C-reactive protein measures, negative celiac serology, and no evidence of suicidal ideation. The mean age was 48.5 years, and 68% were female. The mean IBS-SSS score in all participants was 272.8 at baseline.

Patients were randomly assigned in a 1:1 ratio to receive either low-dose oral amitriptyline (10 mg once daily; n = 232) with dose titration over 3 weeks (up to a maximum dose of 30 mg once daily) as determined by a participant’s symptoms and tolerability; or placebo (n = 231). Both groups participated for 6 months. The primary outcome was the IBS-SSS score at 6 months.
 

Amitriptyline

Three-quarters of participants adhered to the therapy over the 6 months, which was particularly notable given that the trial was conducted during the COVID-19 pandemic, according to the researchers.

An intent-to-treat analysis found that at 6 months, amitriptyline was superior to placebo, with a significant mean difference in IBS-SSS score between groups of –27.0 (95% confidence interval, –46.9 to –7.1; P = .0079; mean IBS-SSS, 170.4 vs. 200.1 with amitriptyline and placebo). A secondary outcome showed an increased likelihood of relief of IBS symptoms by subjective global assessment (odds ratio, 1.78; 95% CI. 1.19-2.66; P = .0050).

At 3 months, the difference in mean change in IBS-SSS score between groups was also significant, at –23.3 (95% CI, –42.0 to –4.6; P = .014), the researchers reported.

People who took the drug were 70% more likely to report relief of symptoms on SGA than those who took placebo (P = .08), according to the researchers.

The researchers reported no effect of low-dose amitriptyline on psychiatric symptoms, such as distressing thoughts, anxiety, and depression, during the 6-month follow-up, nor was there any effect on ability to work or go about social activities.

“This was a pragmatic trial performed in a large number of participants with IBS, with an average duration of symptoms of 10 years and with 80% having moderate to severe symptoms at baseline,” Alexander Ford, MD, professor of gastroenterology at the University of Leeds, England, and a coinvestigator on the study, told this news organization. “The fact that amitriptyline showed such a strong effect over placebo in this group of patients, with a mean decrease in IBS-SSS of almost 100 points at both 3 and 6 months, is therefore all the more impressive.”

Mild adverse events, such as dry mouth and drowsiness, were more frequent with low-dose amitriptyline than with placebo,

Dr. Everitt said the ATLANTIS findings could change practice. Previous trials of low-dose amitriptyline for IBS had mostly been small and were conducted in secondary care settings such as gastroenterology clinics with relatively short follow-up times.

“This is a problem for a long-term condition that fluctuates over time and is diagnosed and managed mostly in primary care,” she said. “The ATLANTIS trial is the largest trial of low-dose amitriptyline for IBS undertaken worldwide and was rigorously conducted with 6 months follow-up, providing reliable results that can help inform GPs and patients’ treatment decision-making in usual clinical practice.”

On a pragmatic level, the research group developed a dose titration document for use by patients and GPs. “Both the GPs and participants found the ATLANTIS dose titration document acceptable and helpful,” Dr. Everitt pointed out. She noted, “We’ve made the dose titration document freely available to support patients and clinicians to try low-dose amitriptyline for IBS.”

Dr. Ford and Dr. Everitt received grant funding (institutional) from the National Institute for Health and Care Research.

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

COPENHAGEN – A real-time, blood-sensing capsule that detects upper gastrointestinal bleeding (UGIB) is safe and effective for patients before undergoing upper endoscopy, according to results from the first U.S.-based open-label, single-arm comparative clinical trial of a novel bleeding sensor for patients with suspected UGIB. It is also the largest such trial.

The capsule (PillSense, EnteraSense) is rapidly deployed, safe to use, and easy to interpret, study researchers say. In under 7 minutes, it correctly detected the presence of blood in 26 of 28 patients and its absence in 87 of 96 patients, as confirmed afterward by esophagogastroduodenoscopy (EGD).

“The use of the PillSense system will positively impact patient outcomes by providing early diagnosis, triaging, and directing care for UGIB,” said Karl Akiki, MD, study lead, who is in the division of gastroenterology and hepatology at the Mayo Clinic, Rochester, Minn. He presented the results at the annual United European Gastroenterology Week.

“Due to its ability to rapidly diagnose UGIB, it helps us, as doctors, expedite accurate clinical decision-making while also optimizing services to ensure the maximum number of patients obtain the best outcome,” he told this news organization.

“There are some pre-endoscopic assessment scores, like the Rockell or the Glasgow-Blatchford score, but they have limited clinical utility in predicting and confirming bleeding in suspected patients,” explained Dr. Akiki. He highlighted the need for a novel device that is rapid, accurate, and safe to use. He also pointed out that despite being the gold standard for diagnosis, EGD remains challenging in terms of time, personnel, and resources.

“The results of our study show the PillSense is a good diagnostic tool that will aid triage,” he said. He noted that PillSense and EGD supplement each other in patient care.

It’s not a device to replace the EGD itself,” he explained, but given the results from the capsule, it will act “as a kind of a bridge that helps us to determine which patients should undergo EGD.”

Optical sensing technology

The researchers aimed to assess the safety and efficacy of the PillSense system for patients with suspected UGIB. They enrolled 131 patients (mean age, 62 years), 60% of whom were men. The most common presenting symptoms for UGIB were melena (52%), anemia (41%), and hematemesis (15%). Five participants withdrew consent before capsule ingestion, and for two patients, primary endpoint data were missing. This left an intent-to-treat population of 124 patients; 110 completed the study.

Patients were asked to swallow the capsule and to lay on their left side. The PillSense is based on optical sensing technology that uses an optical signature of blood in the gut. The device differentiates blood from any other liquids that may be present. After 5-7 minutes, the device gathers and transmits data wirelessly to an external, handheld receiver that processes binary data and indicates either “blood detected” or “no blood detected” in the upper GI tract, explained Dr. Akiki.

Following the capsule reading, patients underwent EGD within 4 hours. This enabled the researchers to compare data between the two modalities. Follow-up visits were conducted on days 7, 14, and 21 to ensure the capsule had passed from the body. Endoscopists were blinded to the capsule result when reading the EGD.

Primary endpoints were the sensitivity and specificity of the device; secondary endpoints were positive predictive value, negative predictive value, successful passage of the capsule, and safety.
 

Rapid and accurate

The researchers determined the efficiency of the capsule in correctly detecting a UGIB. The capsule’s positive and negative predictive values were 74.3% and 97.8%, respectively.

“We achieved a sensitivity of around 93% (92.9%; P = 0.024) with the PillSense capsule and a specificity of 91% (90.6%; P < .001]), which were pretty good. We also detected a range from minimal bleeding – so, speckles of blood to large amounts of active bleeding covering the entire stomach,” reported Dr. Akiki.

There were no differences in terms of patient demographics, laboratory results, or concomitant use of medications. PillSense recording time was a mean of 6.71 minutes, the time from capsule ingestion to EGD was a mean of 55 minutes, and the time to capsule passage through the GI tract was 3.6 days. Most bleeds were found to be in the stomach (18/30; 60%), followed by the duodenum (5/30; 16.6%).

Various capsules for detecting UGIB are under development or are already available, but unlike some of the others, “[the PillSense] is not a video capsule,” said Dr. Akiki. “It does not take pictures at all but is more of a photo sensor capsule that measures the absorption of wavelengths.”

This explains why the PillSense was so rapid – results were available in around 7 minutes and did not require an interpretation by a physician, he explained. “Trained non-physician personnel can use it, and this is where it differs from other devices, such as video capsules that require someone highly trained to interpret the output. It’s an easy procedure and process to follow.”

The PillSense has value in improving workflow, Dr. Akiki said. “If we had someone come in during the night with a suspected upper GI bleed, we could give them the capsule, determine if they need an EGD or not, and potentially postpone it to a time – say, the morning, when more resources are available – freeing up the night for emergency cases. It helps me, as a physician, to determine which patients to send to EGD immediately or which to wait.”

He added that more studies are needed in the postmarketing phase to understand optimal use of the device and to define the exact clinical pathway for optimal implementation.

The device was approved by the U.S. Food and Drug Administration in February. Dr. Akiki noted that there were no adverse events or deaths related to the capsule.

Co-moderator, Philip Chiu, MD, a gastroenterologist from the Chinese University of Hong Kong, said, “It’s an interesting study, because sometimes we can’t differentiate by clinical symptoms as to whether this is a problem of continuous bleeding or something else. The capsule might help us in our decision-making in this respect and help determine whether we should scope the patients or just manage conservatively.”

Dr. Akiki and Dr. Chiu have disclosed no relevant financial relationships.

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

COPENHAGEN – A real-time, blood-sensing capsule that detects upper gastrointestinal bleeding (UGIB) is safe and effective for patients before undergoing upper endoscopy, according to results from the first U.S.-based open-label, single-arm comparative clinical trial of a novel bleeding sensor for patients with suspected UGIB. It is also the largest such trial.

The capsule (PillSense, EnteraSense) is rapidly deployed, safe to use, and easy to interpret, study researchers say. In under 7 minutes, it correctly detected the presence of blood in 26 of 28 patients and its absence in 87 of 96 patients, as confirmed afterward by esophagogastroduodenoscopy (EGD).

“The use of the PillSense system will positively impact patient outcomes by providing early diagnosis, triaging, and directing care for UGIB,” said Karl Akiki, MD, study lead, who is in the division of gastroenterology and hepatology at the Mayo Clinic, Rochester, Minn. He presented the results at the annual United European Gastroenterology Week.

“Due to its ability to rapidly diagnose UGIB, it helps us, as doctors, expedite accurate clinical decision-making while also optimizing services to ensure the maximum number of patients obtain the best outcome,” he told this news organization.

“There are some pre-endoscopic assessment scores, like the Rockell or the Glasgow-Blatchford score, but they have limited clinical utility in predicting and confirming bleeding in suspected patients,” explained Dr. Akiki. He highlighted the need for a novel device that is rapid, accurate, and safe to use. He also pointed out that despite being the gold standard for diagnosis, EGD remains challenging in terms of time, personnel, and resources.

“The results of our study show the PillSense is a good diagnostic tool that will aid triage,” he said. He noted that PillSense and EGD supplement each other in patient care.

It’s not a device to replace the EGD itself,” he explained, but given the results from the capsule, it will act “as a kind of a bridge that helps us to determine which patients should undergo EGD.”

Optical sensing technology

The researchers aimed to assess the safety and efficacy of the PillSense system for patients with suspected UGIB. They enrolled 131 patients (mean age, 62 years), 60% of whom were men. The most common presenting symptoms for UGIB were melena (52%), anemia (41%), and hematemesis (15%). Five participants withdrew consent before capsule ingestion, and for two patients, primary endpoint data were missing. This left an intent-to-treat population of 124 patients; 110 completed the study.

Patients were asked to swallow the capsule and to lay on their left side. The PillSense is based on optical sensing technology that uses an optical signature of blood in the gut. The device differentiates blood from any other liquids that may be present. After 5-7 minutes, the device gathers and transmits data wirelessly to an external, handheld receiver that processes binary data and indicates either “blood detected” or “no blood detected” in the upper GI tract, explained Dr. Akiki.

Following the capsule reading, patients underwent EGD within 4 hours. This enabled the researchers to compare data between the two modalities. Follow-up visits were conducted on days 7, 14, and 21 to ensure the capsule had passed from the body. Endoscopists were blinded to the capsule result when reading the EGD.

Primary endpoints were the sensitivity and specificity of the device; secondary endpoints were positive predictive value, negative predictive value, successful passage of the capsule, and safety.
 

Rapid and accurate

The researchers determined the efficiency of the capsule in correctly detecting a UGIB. The capsule’s positive and negative predictive values were 74.3% and 97.8%, respectively.

“We achieved a sensitivity of around 93% (92.9%; P = 0.024) with the PillSense capsule and a specificity of 91% (90.6%; P < .001]), which were pretty good. We also detected a range from minimal bleeding – so, speckles of blood to large amounts of active bleeding covering the entire stomach,” reported Dr. Akiki.

There were no differences in terms of patient demographics, laboratory results, or concomitant use of medications. PillSense recording time was a mean of 6.71 minutes, the time from capsule ingestion to EGD was a mean of 55 minutes, and the time to capsule passage through the GI tract was 3.6 days. Most bleeds were found to be in the stomach (18/30; 60%), followed by the duodenum (5/30; 16.6%).

Various capsules for detecting UGIB are under development or are already available, but unlike some of the others, “[the PillSense] is not a video capsule,” said Dr. Akiki. “It does not take pictures at all but is more of a photo sensor capsule that measures the absorption of wavelengths.”

This explains why the PillSense was so rapid – results were available in around 7 minutes and did not require an interpretation by a physician, he explained. “Trained non-physician personnel can use it, and this is where it differs from other devices, such as video capsules that require someone highly trained to interpret the output. It’s an easy procedure and process to follow.”

The PillSense has value in improving workflow, Dr. Akiki said. “If we had someone come in during the night with a suspected upper GI bleed, we could give them the capsule, determine if they need an EGD or not, and potentially postpone it to a time – say, the morning, when more resources are available – freeing up the night for emergency cases. It helps me, as a physician, to determine which patients to send to EGD immediately or which to wait.”

He added that more studies are needed in the postmarketing phase to understand optimal use of the device and to define the exact clinical pathway for optimal implementation.

The device was approved by the U.S. Food and Drug Administration in February. Dr. Akiki noted that there were no adverse events or deaths related to the capsule.

Co-moderator, Philip Chiu, MD, a gastroenterologist from the Chinese University of Hong Kong, said, “It’s an interesting study, because sometimes we can’t differentiate by clinical symptoms as to whether this is a problem of continuous bleeding or something else. The capsule might help us in our decision-making in this respect and help determine whether we should scope the patients or just manage conservatively.”

Dr. Akiki and Dr. Chiu have disclosed no relevant financial relationships.

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

COPENHAGEN – A real-time, blood-sensing capsule that detects upper gastrointestinal bleeding (UGIB) is safe and effective for patients before undergoing upper endoscopy, according to results from the first U.S.-based open-label, single-arm comparative clinical trial of a novel bleeding sensor for patients with suspected UGIB. It is also the largest such trial.

The capsule (PillSense, EnteraSense) is rapidly deployed, safe to use, and easy to interpret, study researchers say. In under 7 minutes, it correctly detected the presence of blood in 26 of 28 patients and its absence in 87 of 96 patients, as confirmed afterward by esophagogastroduodenoscopy (EGD).

“The use of the PillSense system will positively impact patient outcomes by providing early diagnosis, triaging, and directing care for UGIB,” said Karl Akiki, MD, study lead, who is in the division of gastroenterology and hepatology at the Mayo Clinic, Rochester, Minn. He presented the results at the annual United European Gastroenterology Week.

“Due to its ability to rapidly diagnose UGIB, it helps us, as doctors, expedite accurate clinical decision-making while also optimizing services to ensure the maximum number of patients obtain the best outcome,” he told this news organization.

“There are some pre-endoscopic assessment scores, like the Rockell or the Glasgow-Blatchford score, but they have limited clinical utility in predicting and confirming bleeding in suspected patients,” explained Dr. Akiki. He highlighted the need for a novel device that is rapid, accurate, and safe to use. He also pointed out that despite being the gold standard for diagnosis, EGD remains challenging in terms of time, personnel, and resources.

“The results of our study show the PillSense is a good diagnostic tool that will aid triage,” he said. He noted that PillSense and EGD supplement each other in patient care.

It’s not a device to replace the EGD itself,” he explained, but given the results from the capsule, it will act “as a kind of a bridge that helps us to determine which patients should undergo EGD.”

Optical sensing technology

The researchers aimed to assess the safety and efficacy of the PillSense system for patients with suspected UGIB. They enrolled 131 patients (mean age, 62 years), 60% of whom were men. The most common presenting symptoms for UGIB were melena (52%), anemia (41%), and hematemesis (15%). Five participants withdrew consent before capsule ingestion, and for two patients, primary endpoint data were missing. This left an intent-to-treat population of 124 patients; 110 completed the study.

Patients were asked to swallow the capsule and to lay on their left side. The PillSense is based on optical sensing technology that uses an optical signature of blood in the gut. The device differentiates blood from any other liquids that may be present. After 5-7 minutes, the device gathers and transmits data wirelessly to an external, handheld receiver that processes binary data and indicates either “blood detected” or “no blood detected” in the upper GI tract, explained Dr. Akiki.

Following the capsule reading, patients underwent EGD within 4 hours. This enabled the researchers to compare data between the two modalities. Follow-up visits were conducted on days 7, 14, and 21 to ensure the capsule had passed from the body. Endoscopists were blinded to the capsule result when reading the EGD.

Primary endpoints were the sensitivity and specificity of the device; secondary endpoints were positive predictive value, negative predictive value, successful passage of the capsule, and safety.
 

Rapid and accurate

The researchers determined the efficiency of the capsule in correctly detecting a UGIB. The capsule’s positive and negative predictive values were 74.3% and 97.8%, respectively.

“We achieved a sensitivity of around 93% (92.9%; P = 0.024) with the PillSense capsule and a specificity of 91% (90.6%; P < .001]), which were pretty good. We also detected a range from minimal bleeding – so, speckles of blood to large amounts of active bleeding covering the entire stomach,” reported Dr. Akiki.

There were no differences in terms of patient demographics, laboratory results, or concomitant use of medications. PillSense recording time was a mean of 6.71 minutes, the time from capsule ingestion to EGD was a mean of 55 minutes, and the time to capsule passage through the GI tract was 3.6 days. Most bleeds were found to be in the stomach (18/30; 60%), followed by the duodenum (5/30; 16.6%).

Various capsules for detecting UGIB are under development or are already available, but unlike some of the others, “[the PillSense] is not a video capsule,” said Dr. Akiki. “It does not take pictures at all but is more of a photo sensor capsule that measures the absorption of wavelengths.”

This explains why the PillSense was so rapid – results were available in around 7 minutes and did not require an interpretation by a physician, he explained. “Trained non-physician personnel can use it, and this is where it differs from other devices, such as video capsules that require someone highly trained to interpret the output. It’s an easy procedure and process to follow.”

The PillSense has value in improving workflow, Dr. Akiki said. “If we had someone come in during the night with a suspected upper GI bleed, we could give them the capsule, determine if they need an EGD or not, and potentially postpone it to a time – say, the morning, when more resources are available – freeing up the night for emergency cases. It helps me, as a physician, to determine which patients to send to EGD immediately or which to wait.”

He added that more studies are needed in the postmarketing phase to understand optimal use of the device and to define the exact clinical pathway for optimal implementation.

The device was approved by the U.S. Food and Drug Administration in February. Dr. Akiki noted that there were no adverse events or deaths related to the capsule.

Co-moderator, Philip Chiu, MD, a gastroenterologist from the Chinese University of Hong Kong, said, “It’s an interesting study, because sometimes we can’t differentiate by clinical symptoms as to whether this is a problem of continuous bleeding or something else. The capsule might help us in our decision-making in this respect and help determine whether we should scope the patients or just manage conservatively.”

Dr. Akiki and Dr. Chiu have disclosed no relevant financial relationships.

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

AT UEG WEEK 2023

COPENHAGEN – Risankizumab shows noninferiority for clinical remission at week 24, and superiority of endoscopic remission at week 48 when compared with ustekinumab in patients with moderately to severely active Crohn’s disease (CD) who have failed one or more anti–tumor necrosis factor (anti-TNF) therapies, according to the results of the phase 3 SEQUENCE trial.

Secondary endpoints – presented for the first time at the United European Gastroenterology Week 2023 – also showed superiority of risankizumab (Skyrizi, AbbVie), an interleulin-23 inhibitor, over ustekinumab (Stelara), an IL-12 and IL-23 inhibitor, for clinical remission at week 48 (60.8% vs. 40.8%) and a statistically significant endoscopic response also favoring risankizumab at weeks 24 and 48.

“With endoscopic remission we see that with a single agent we have doubled the endoscopic remission rate by moving from 16% to 31% with risankizumab [at week 48],” said Laurent Peyrin-Biroulet, MD, PhD, a gastroenterologist specializing in inflammatory bowel disease at Nancy University Hospital, France. “Superiority for sure was met.”

“This sort of thing happens once in your career,” noted Dr. Peyrin-Biroulet, who presented the results of the study at the meeting. “It’s totally amazing that everything you see here was in favor of risankizumab.

“Already we see the efficacy signal in the proportion of premature discontinuations at 2% vs. 13% due to lack of efficacy [in risankizumab and ustekinumab, respectively],” he said. “This is due to drug failure.”

Risankizumab is an IL-23 inhibitor that selectively blocks the cytokine IL-23, thought to be linked to a number of chronic immune-mediated diseases, by binding to its p19 subunit. It is the first IL-23 inhibitor to receive approval from the U.S. Food and Drug Administration in June 2022 for moderately to severely active CD based on data from the ADVANCE, MOTIVATE, and FORTIFY trials.

Risankizumab and ustekinumab head-to-head

The phase 3, open-label, multicenter, randomized, clinical trial evaluated risankizumab vs. ustekinumab through week 48 in patients with moderately to severely active CD.

Participants were required to have a CD Activity Index (CDAI) score of 220 to 450 at baseline, a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 6 or more for ileocolonic or colonic disease (and of 4 or more for isolated ileal disease), excluding the presence of a narrowing component, plus an average daily stool frequency of four or more and/or average daily abdominal pain score of 2 or more. They were also required to have previously failed one or more anti-TNF therapies.

Randomization was stratified by the number of anti-TNF therapies failed (one or more than one), and steroid use at baseline; steroids were then tapered from week 2. Two primary endpoints comprised clinical remission at week 24 (defined as CDAI < 150, noninferiority margin within 10% of risankizumab vs ustekinumab in 50% of participants), and also endoscopic remission (SES-CD of 4 or less, and at least a 2-point reduction vs. baseline and no subscore greater than 1 in any individual component) at week 48 demonstrating superiority of risankizumab vs ustekinumab.

Secondary endpoints included clinical remission at week 48, endoscopic response at weeks 48 and 24, steroid-free endoscopic remission at week 48, and steroid-free clinical remission at week 48 (all tested for superiority of risankizumab vs ustekinumab).

Intravenous risankizumab at 600 mg was given at weeks 0, 4 , and 8 followed by subcutaneous risankizumab at a 360-mg maintenance dose every 8 weeks through week 48 (n = 255). Participants who completed the week-48 visit continued on subcutaneous risankizumab for up to an additional 220 weeks. Ustekinumab was given as a weight-based, intravenous induction dose at week 0 followed by a 90-mg subcutaneous dose every 8 weeks, starting at week 8 through week 48 (n = 265). Participants received open-label drug administration but efficacy assessment was blinded.

Superiority of risankizumab

Both primary endpoints were met. For clinical remission at week 24, in half of the patients enrolled, rates were 58.6% (75/128) for risankizumab and 39.5% (54/137) for ustekinumab, for a difference of 18.4% [95% confidence interval, 6.6-30.3], meaning that noninferiority was met within the predefined margin of 10%. The second primary endpoint of endoscopic remission at week 48 showed rates of 31.8% (81/255) for risankizumab and 16.2% (43/265) for ustekinumab (P < .0001 for superiority).

Risankizumab was found to be superior to ustekinumab for all secondary endpoints (all with P < .0001). Steroid-free endoscopic remission at week 48 showed a 16% difference, and steroid-free clinical remission at week 48 showed a 20% difference – both in favor of risankizumab.

In addition, more participants on risankizumab completed the study (89.4%) than those on ustekinumab (74.0%), Dr. Peyrin-Biroulet reported.

Adverse event rates (events per 100 person-years) were comparable between the two drugs at 341.2 for risankizumab and 282.7 for ustekinumab. For risankizumab, no new safety risks were observed, and those recorded were consistent with the known safety profile. Serious adverse events occurred in 10% of risankizumab-treated patients, and 17% of ustekinumab-treated patients.

“We know the safety of IL-23 inhibitors is good,” said Dr. Peyrin-Biroulet. “If we look at all adverse events there was no difference across arms, and in terms of serious adverse events, it was in favor of risankizumab because a CD flare is considered a serious adverse event.”

Session comoderator, Alessandro Armuzzi, MD, head of the Inflammatory Bowel Disease Center at the IRCCS Humanitas Research Hospital in Milan, commented on the findings. “The results look in favor of risankizumab – all the endpoints were met, not only the co-endpoints but also the secondary endpoints too,” he said.

These results, showing a preference for risankizumab, have value in helping clinicians with the sequence of therapies when patients with Crohn’s disease have failed one or more TNF inhibitor, said Dr. Armuzzi.

No funding for this study was disclosed. Dr. Peyrin-Biroulet has disclosed receiving fees from Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index, Sandoz, Celgene, Biogen, SamsungBioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSEImmunotherapeutics, Enthera, Theravance, Pandion, Gossamer, Viatris, ThermoFisher, ONOPharma, Mopac, Cytoki, Morphic, Prometheus, and Applied MolecularTransport. Dr. Armuzzi disclosed consulting/advisory board fees from AbbVie, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, and Tillots Pharma; speaker’s fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, and Takeda; and research grants from MSD, Takeda, Pfizer, and Biogen.

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

AT UEG WEEK 2023

COPENHAGEN – Risankizumab shows noninferiority for clinical remission at week 24, and superiority of endoscopic remission at week 48 when compared with ustekinumab in patients with moderately to severely active Crohn’s disease (CD) who have failed one or more anti–tumor necrosis factor (anti-TNF) therapies, according to the results of the phase 3 SEQUENCE trial.

Secondary endpoints – presented for the first time at the United European Gastroenterology Week 2023 – also showed superiority of risankizumab (Skyrizi, AbbVie), an interleulin-23 inhibitor, over ustekinumab (Stelara), an IL-12 and IL-23 inhibitor, for clinical remission at week 48 (60.8% vs. 40.8%) and a statistically significant endoscopic response also favoring risankizumab at weeks 24 and 48.

“With endoscopic remission we see that with a single agent we have doubled the endoscopic remission rate by moving from 16% to 31% with risankizumab [at week 48],” said Laurent Peyrin-Biroulet, MD, PhD, a gastroenterologist specializing in inflammatory bowel disease at Nancy University Hospital, France. “Superiority for sure was met.”

“This sort of thing happens once in your career,” noted Dr. Peyrin-Biroulet, who presented the results of the study at the meeting. “It’s totally amazing that everything you see here was in favor of risankizumab.

“Already we see the efficacy signal in the proportion of premature discontinuations at 2% vs. 13% due to lack of efficacy [in risankizumab and ustekinumab, respectively],” he said. “This is due to drug failure.”

Risankizumab is an IL-23 inhibitor that selectively blocks the cytokine IL-23, thought to be linked to a number of chronic immune-mediated diseases, by binding to its p19 subunit. It is the first IL-23 inhibitor to receive approval from the U.S. Food and Drug Administration in June 2022 for moderately to severely active CD based on data from the ADVANCE, MOTIVATE, and FORTIFY trials.

Risankizumab and ustekinumab head-to-head

The phase 3, open-label, multicenter, randomized, clinical trial evaluated risankizumab vs. ustekinumab through week 48 in patients with moderately to severely active CD.

Participants were required to have a CD Activity Index (CDAI) score of 220 to 450 at baseline, a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 6 or more for ileocolonic or colonic disease (and of 4 or more for isolated ileal disease), excluding the presence of a narrowing component, plus an average daily stool frequency of four or more and/or average daily abdominal pain score of 2 or more. They were also required to have previously failed one or more anti-TNF therapies.

Randomization was stratified by the number of anti-TNF therapies failed (one or more than one), and steroid use at baseline; steroids were then tapered from week 2. Two primary endpoints comprised clinical remission at week 24 (defined as CDAI < 150, noninferiority margin within 10% of risankizumab vs ustekinumab in 50% of participants), and also endoscopic remission (SES-CD of 4 or less, and at least a 2-point reduction vs. baseline and no subscore greater than 1 in any individual component) at week 48 demonstrating superiority of risankizumab vs ustekinumab.

Secondary endpoints included clinical remission at week 48, endoscopic response at weeks 48 and 24, steroid-free endoscopic remission at week 48, and steroid-free clinical remission at week 48 (all tested for superiority of risankizumab vs ustekinumab).

Intravenous risankizumab at 600 mg was given at weeks 0, 4 , and 8 followed by subcutaneous risankizumab at a 360-mg maintenance dose every 8 weeks through week 48 (n = 255). Participants who completed the week-48 visit continued on subcutaneous risankizumab for up to an additional 220 weeks. Ustekinumab was given as a weight-based, intravenous induction dose at week 0 followed by a 90-mg subcutaneous dose every 8 weeks, starting at week 8 through week 48 (n = 265). Participants received open-label drug administration but efficacy assessment was blinded.

Superiority of risankizumab

Both primary endpoints were met. For clinical remission at week 24, in half of the patients enrolled, rates were 58.6% (75/128) for risankizumab and 39.5% (54/137) for ustekinumab, for a difference of 18.4% [95% confidence interval, 6.6-30.3], meaning that noninferiority was met within the predefined margin of 10%. The second primary endpoint of endoscopic remission at week 48 showed rates of 31.8% (81/255) for risankizumab and 16.2% (43/265) for ustekinumab (P < .0001 for superiority).

Risankizumab was found to be superior to ustekinumab for all secondary endpoints (all with P < .0001). Steroid-free endoscopic remission at week 48 showed a 16% difference, and steroid-free clinical remission at week 48 showed a 20% difference – both in favor of risankizumab.

In addition, more participants on risankizumab completed the study (89.4%) than those on ustekinumab (74.0%), Dr. Peyrin-Biroulet reported.

Adverse event rates (events per 100 person-years) were comparable between the two drugs at 341.2 for risankizumab and 282.7 for ustekinumab. For risankizumab, no new safety risks were observed, and those recorded were consistent with the known safety profile. Serious adverse events occurred in 10% of risankizumab-treated patients, and 17% of ustekinumab-treated patients.

“We know the safety of IL-23 inhibitors is good,” said Dr. Peyrin-Biroulet. “If we look at all adverse events there was no difference across arms, and in terms of serious adverse events, it was in favor of risankizumab because a CD flare is considered a serious adverse event.”

Session comoderator, Alessandro Armuzzi, MD, head of the Inflammatory Bowel Disease Center at the IRCCS Humanitas Research Hospital in Milan, commented on the findings. “The results look in favor of risankizumab – all the endpoints were met, not only the co-endpoints but also the secondary endpoints too,” he said.

These results, showing a preference for risankizumab, have value in helping clinicians with the sequence of therapies when patients with Crohn’s disease have failed one or more TNF inhibitor, said Dr. Armuzzi.

No funding for this study was disclosed. Dr. Peyrin-Biroulet has disclosed receiving fees from Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index, Sandoz, Celgene, Biogen, SamsungBioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSEImmunotherapeutics, Enthera, Theravance, Pandion, Gossamer, Viatris, ThermoFisher, ONOPharma, Mopac, Cytoki, Morphic, Prometheus, and Applied MolecularTransport. Dr. Armuzzi disclosed consulting/advisory board fees from AbbVie, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, and Tillots Pharma; speaker’s fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, and Takeda; and research grants from MSD, Takeda, Pfizer, and Biogen.

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

AT UEG WEEK 2023

COPENHAGEN – Risankizumab shows noninferiority for clinical remission at week 24, and superiority of endoscopic remission at week 48 when compared with ustekinumab in patients with moderately to severely active Crohn’s disease (CD) who have failed one or more anti–tumor necrosis factor (anti-TNF) therapies, according to the results of the phase 3 SEQUENCE trial.

Secondary endpoints – presented for the first time at the United European Gastroenterology Week 2023 – also showed superiority of risankizumab (Skyrizi, AbbVie), an interleulin-23 inhibitor, over ustekinumab (Stelara), an IL-12 and IL-23 inhibitor, for clinical remission at week 48 (60.8% vs. 40.8%) and a statistically significant endoscopic response also favoring risankizumab at weeks 24 and 48.

“With endoscopic remission we see that with a single agent we have doubled the endoscopic remission rate by moving from 16% to 31% with risankizumab [at week 48],” said Laurent Peyrin-Biroulet, MD, PhD, a gastroenterologist specializing in inflammatory bowel disease at Nancy University Hospital, France. “Superiority for sure was met.”

“This sort of thing happens once in your career,” noted Dr. Peyrin-Biroulet, who presented the results of the study at the meeting. “It’s totally amazing that everything you see here was in favor of risankizumab.

“Already we see the efficacy signal in the proportion of premature discontinuations at 2% vs. 13% due to lack of efficacy [in risankizumab and ustekinumab, respectively],” he said. “This is due to drug failure.”

Risankizumab is an IL-23 inhibitor that selectively blocks the cytokine IL-23, thought to be linked to a number of chronic immune-mediated diseases, by binding to its p19 subunit. It is the first IL-23 inhibitor to receive approval from the U.S. Food and Drug Administration in June 2022 for moderately to severely active CD based on data from the ADVANCE, MOTIVATE, and FORTIFY trials.

Risankizumab and ustekinumab head-to-head

The phase 3, open-label, multicenter, randomized, clinical trial evaluated risankizumab vs. ustekinumab through week 48 in patients with moderately to severely active CD.

Participants were required to have a CD Activity Index (CDAI) score of 220 to 450 at baseline, a Simple Endoscopic Score for Crohn’s Disease (SES-CD) of 6 or more for ileocolonic or colonic disease (and of 4 or more for isolated ileal disease), excluding the presence of a narrowing component, plus an average daily stool frequency of four or more and/or average daily abdominal pain score of 2 or more. They were also required to have previously failed one or more anti-TNF therapies.

Randomization was stratified by the number of anti-TNF therapies failed (one or more than one), and steroid use at baseline; steroids were then tapered from week 2. Two primary endpoints comprised clinical remission at week 24 (defined as CDAI < 150, noninferiority margin within 10% of risankizumab vs ustekinumab in 50% of participants), and also endoscopic remission (SES-CD of 4 or less, and at least a 2-point reduction vs. baseline and no subscore greater than 1 in any individual component) at week 48 demonstrating superiority of risankizumab vs ustekinumab.

Secondary endpoints included clinical remission at week 48, endoscopic response at weeks 48 and 24, steroid-free endoscopic remission at week 48, and steroid-free clinical remission at week 48 (all tested for superiority of risankizumab vs ustekinumab).

Intravenous risankizumab at 600 mg was given at weeks 0, 4 , and 8 followed by subcutaneous risankizumab at a 360-mg maintenance dose every 8 weeks through week 48 (n = 255). Participants who completed the week-48 visit continued on subcutaneous risankizumab for up to an additional 220 weeks. Ustekinumab was given as a weight-based, intravenous induction dose at week 0 followed by a 90-mg subcutaneous dose every 8 weeks, starting at week 8 through week 48 (n = 265). Participants received open-label drug administration but efficacy assessment was blinded.

Superiority of risankizumab

Both primary endpoints were met. For clinical remission at week 24, in half of the patients enrolled, rates were 58.6% (75/128) for risankizumab and 39.5% (54/137) for ustekinumab, for a difference of 18.4% [95% confidence interval, 6.6-30.3], meaning that noninferiority was met within the predefined margin of 10%. The second primary endpoint of endoscopic remission at week 48 showed rates of 31.8% (81/255) for risankizumab and 16.2% (43/265) for ustekinumab (P < .0001 for superiority).

Risankizumab was found to be superior to ustekinumab for all secondary endpoints (all with P < .0001). Steroid-free endoscopic remission at week 48 showed a 16% difference, and steroid-free clinical remission at week 48 showed a 20% difference – both in favor of risankizumab.

In addition, more participants on risankizumab completed the study (89.4%) than those on ustekinumab (74.0%), Dr. Peyrin-Biroulet reported.

Adverse event rates (events per 100 person-years) were comparable between the two drugs at 341.2 for risankizumab and 282.7 for ustekinumab. For risankizumab, no new safety risks were observed, and those recorded were consistent with the known safety profile. Serious adverse events occurred in 10% of risankizumab-treated patients, and 17% of ustekinumab-treated patients.

“We know the safety of IL-23 inhibitors is good,” said Dr. Peyrin-Biroulet. “If we look at all adverse events there was no difference across arms, and in terms of serious adverse events, it was in favor of risankizumab because a CD flare is considered a serious adverse event.”

Session comoderator, Alessandro Armuzzi, MD, head of the Inflammatory Bowel Disease Center at the IRCCS Humanitas Research Hospital in Milan, commented on the findings. “The results look in favor of risankizumab – all the endpoints were met, not only the co-endpoints but also the secondary endpoints too,” he said.

These results, showing a preference for risankizumab, have value in helping clinicians with the sequence of therapies when patients with Crohn’s disease have failed one or more TNF inhibitor, said Dr. Armuzzi.

No funding for this study was disclosed. Dr. Peyrin-Biroulet has disclosed receiving fees from Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index, Sandoz, Celgene, Biogen, SamsungBioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSEImmunotherapeutics, Enthera, Theravance, Pandion, Gossamer, Viatris, ThermoFisher, ONOPharma, Mopac, Cytoki, Morphic, Prometheus, and Applied MolecularTransport. Dr. Armuzzi disclosed consulting/advisory board fees from AbbVie, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Nestlé, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, and Tillots Pharma; speaker’s fees from AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, Lionhealth, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, and Takeda; and research grants from MSD, Takeda, Pfizer, and Biogen.

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

HAMBURG, GERMANY – Respiratory tract infections and asthma are 10 times more prevalent at type 2 diabetes diagnosis, compared with matched controls without a diagnosis, shows a longitudinal study looking at comorbidities both 25 years before and 25 years after a type 2 diabetes diagnosis.

About 40% of people had respiratory tract infections at the time of diagnosis with type 2 diabetes, compared with 4% who were not diagnosed. Likewise, ear, nose, and throat infections were present in 20% of people at type 2 diabetes diagnosis, compared with around 2% who were not diagnosed. A similar pattern was seen with asthma.

Taken together, the data suggest that subacute inflammation manifesting in asthma as well as the onset of asthma or an acute infection may be a precursor to a type 2 diabetes diagnosis.

“We have also found that in the years prior to diagnosis, there are associations with infections and inflammatory disorders to a much greater degree than in those people who do not get a diabetes diagnosis but who have very similar demographics,” Adrian Heald, MD, study lead and diabetes consultant from Salford (England) Royal Hospital, said in an interview.

Five years prior to diagnosis, respiratory tract infections were documented in around 23% of patients who were later diagnosed with type 2 diabetes versus 2.5% in those not diagnosed, and a similar pattern was seen for ear, nose, and throat infections and asthma. The findings suggest that patients reporting infections, in addition to other known risk factors for type 2 diabetes, might benefit from diabetes tests and early interventions, if needed.

“These novel insights offer a fascinating and fresh perspective on the onset and natural progression to type 2 diabetes and beyond, suggesting an early phase of inflammation-related disease activity long before any clinical diagnosis of type 2 diabetes is made.”

Dr. Heald points out that clinicians may intervene to stave off progression to a type 2 diabetes diagnosis in at risk patients. “At this point, an intervention could relate to lifestyle changes and involve highlighting to the patient that the morbidity they have already accumulated is suggestive of diabetes risk,” he said, adding that, “they may have dyslipidemia, hypertension, and most often excess weight so annual checks of their HbA1c, weight management, and blood pressure would need checking,” he explained.

Moderator Coen Stehouwer, MD, professor of internal medicine at Maastricht University, the Netherlands, commented, “Before clinical diagnosis of type 2 diabetes there is often a lengthy period of undiagnosed disease and before that, prediabetes, because glucose can be abnormal up to 10 years prior to clinical diagnosis.”

But he added that, “It’s not entirely clear whether the rise seen before clinical diagnosis in this study correlates with undiagnosed diabetes or prediabetes or even if it precedes type 2 diabetes – it might be because inflammation is a common origin for type 2 diabetes and various comorbidities. This might explain how they go together.”
 

Longitudinal study 25 years before and 25 years after type 2 diagnosis

Dr. Heald presented the findings at a session on inflammation in diabetes at the annual meeting of the European Association for the Study of Diabetes. The work was also published in Diabetes Therapy.

The researchers wanted to investigate the pattern of comorbidities in the years and decades prior to a diagnosis of type 2 diabetes as well as after: “With the database we used, called DARE [Diabetes Alliance for Research in England], we are able to explore phenomena longitudinally going right back to the beginning of their digital health records, looking at phenotypes over time.”

By mapping significant health issues in people who went on to develop type 2 diabetes alongside those that did not, Dr. Heald managed to develop a continuum spanning 25 years prior and 25 years after diagnosis of type 2 diabetes. The researchers also examined relationships between sociodemographic factors and longitudinal health outcomes of relevance to cardiac conditions and lower respiratory tract infections. His talk in Hamburg primarily addressed clinical phenotypes before the point of diagnosis.

Data were drawn from 1,932 people with (1,196) and without (736) type 2 diabetes. Participants in both groups were aged 66-67 years, 43%-46% were women, age at diagnosis was 50-52 years, and participants lived in Greater Manchester, United Kingdom.

In the years leading up to type 2 diagnosis, individuals consistently exhibited a considerable increase in several clinical phenotypes, reported Dr. Heald. Of note, he added, “immediately prior to type 2 diagnosis, there was a significantly greater proportion of hypertension at 35%, respiratory tract infection at 34%, heart disease at 17%, ear, nose, and throat infection at 19%, and asthma at 12%. And by comparison, the corresponding disease trajectory in matched controls was much less dramatic.”

“There is a huge difference in people who went on to receive a diagnosis of type 2 diabetes and those who did not, and not just what we’d expect – so hypertension for example or manifestations of renal disease, but importantly inflammatory disorders are more common,” he emphasized.

In addition, a larger signal for ischemic heart disease was seen just before type 2 diabetes diagnosis.

These data suggest that longitudinal clinical histories prior to a diagnosis of type 2 diabetes might offer new information, both genetic and nongenetic, about development of type 2 diabetes in relation to comorbidities.

After type 2 diabetes diagnosis, the proportion of people exhibiting coronary artery disease, hypertension, chronic kidney disease, retinopathy, and infections climbed rapidly before plateauing, reported Dr. Heald. “We also know that individuals with coronary artery disease are more highly represented in socially disadvantaged groups, and this is borne out in the data at 25 years prior and after type 2 diagnosis.”

Dr. Heald has received speaker fees or contributed to advisory boards from Lilly, AstraZeneca, Janssen, Bristol-Myers Squibb, Besins, Bayer, Sanofi, and Recordati. Research grants from Novo Nordisk, Pfizer, and Besins. Professor Stehouwer has declared no relevant conflicts.

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

HAMBURG, GERMANY – Respiratory tract infections and asthma are 10 times more prevalent at type 2 diabetes diagnosis, compared with matched controls without a diagnosis, shows a longitudinal study looking at comorbidities both 25 years before and 25 years after a type 2 diabetes diagnosis.

About 40% of people had respiratory tract infections at the time of diagnosis with type 2 diabetes, compared with 4% who were not diagnosed. Likewise, ear, nose, and throat infections were present in 20% of people at type 2 diabetes diagnosis, compared with around 2% who were not diagnosed. A similar pattern was seen with asthma.

Taken together, the data suggest that subacute inflammation manifesting in asthma as well as the onset of asthma or an acute infection may be a precursor to a type 2 diabetes diagnosis.

“We have also found that in the years prior to diagnosis, there are associations with infections and inflammatory disorders to a much greater degree than in those people who do not get a diabetes diagnosis but who have very similar demographics,” Adrian Heald, MD, study lead and diabetes consultant from Salford (England) Royal Hospital, said in an interview.

Five years prior to diagnosis, respiratory tract infections were documented in around 23% of patients who were later diagnosed with type 2 diabetes versus 2.5% in those not diagnosed, and a similar pattern was seen for ear, nose, and throat infections and asthma. The findings suggest that patients reporting infections, in addition to other known risk factors for type 2 diabetes, might benefit from diabetes tests and early interventions, if needed.

“These novel insights offer a fascinating and fresh perspective on the onset and natural progression to type 2 diabetes and beyond, suggesting an early phase of inflammation-related disease activity long before any clinical diagnosis of type 2 diabetes is made.”

Dr. Heald points out that clinicians may intervene to stave off progression to a type 2 diabetes diagnosis in at risk patients. “At this point, an intervention could relate to lifestyle changes and involve highlighting to the patient that the morbidity they have already accumulated is suggestive of diabetes risk,” he said, adding that, “they may have dyslipidemia, hypertension, and most often excess weight so annual checks of their HbA1c, weight management, and blood pressure would need checking,” he explained.

Moderator Coen Stehouwer, MD, professor of internal medicine at Maastricht University, the Netherlands, commented, “Before clinical diagnosis of type 2 diabetes there is often a lengthy period of undiagnosed disease and before that, prediabetes, because glucose can be abnormal up to 10 years prior to clinical diagnosis.”

But he added that, “It’s not entirely clear whether the rise seen before clinical diagnosis in this study correlates with undiagnosed diabetes or prediabetes or even if it precedes type 2 diabetes – it might be because inflammation is a common origin for type 2 diabetes and various comorbidities. This might explain how they go together.”
 

Longitudinal study 25 years before and 25 years after type 2 diagnosis

Dr. Heald presented the findings at a session on inflammation in diabetes at the annual meeting of the European Association for the Study of Diabetes. The work was also published in Diabetes Therapy.

The researchers wanted to investigate the pattern of comorbidities in the years and decades prior to a diagnosis of type 2 diabetes as well as after: “With the database we used, called DARE [Diabetes Alliance for Research in England], we are able to explore phenomena longitudinally going right back to the beginning of their digital health records, looking at phenotypes over time.”

By mapping significant health issues in people who went on to develop type 2 diabetes alongside those that did not, Dr. Heald managed to develop a continuum spanning 25 years prior and 25 years after diagnosis of type 2 diabetes. The researchers also examined relationships between sociodemographic factors and longitudinal health outcomes of relevance to cardiac conditions and lower respiratory tract infections. His talk in Hamburg primarily addressed clinical phenotypes before the point of diagnosis.

Data were drawn from 1,932 people with (1,196) and without (736) type 2 diabetes. Participants in both groups were aged 66-67 years, 43%-46% were women, age at diagnosis was 50-52 years, and participants lived in Greater Manchester, United Kingdom.

In the years leading up to type 2 diagnosis, individuals consistently exhibited a considerable increase in several clinical phenotypes, reported Dr. Heald. Of note, he added, “immediately prior to type 2 diagnosis, there was a significantly greater proportion of hypertension at 35%, respiratory tract infection at 34%, heart disease at 17%, ear, nose, and throat infection at 19%, and asthma at 12%. And by comparison, the corresponding disease trajectory in matched controls was much less dramatic.”

“There is a huge difference in people who went on to receive a diagnosis of type 2 diabetes and those who did not, and not just what we’d expect – so hypertension for example or manifestations of renal disease, but importantly inflammatory disorders are more common,” he emphasized.

In addition, a larger signal for ischemic heart disease was seen just before type 2 diabetes diagnosis.

These data suggest that longitudinal clinical histories prior to a diagnosis of type 2 diabetes might offer new information, both genetic and nongenetic, about development of type 2 diabetes in relation to comorbidities.

After type 2 diabetes diagnosis, the proportion of people exhibiting coronary artery disease, hypertension, chronic kidney disease, retinopathy, and infections climbed rapidly before plateauing, reported Dr. Heald. “We also know that individuals with coronary artery disease are more highly represented in socially disadvantaged groups, and this is borne out in the data at 25 years prior and after type 2 diagnosis.”

Dr. Heald has received speaker fees or contributed to advisory boards from Lilly, AstraZeneca, Janssen, Bristol-Myers Squibb, Besins, Bayer, Sanofi, and Recordati. Research grants from Novo Nordisk, Pfizer, and Besins. Professor Stehouwer has declared no relevant conflicts.

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

HAMBURG, GERMANY – Respiratory tract infections and asthma are 10 times more prevalent at type 2 diabetes diagnosis, compared with matched controls without a diagnosis, shows a longitudinal study looking at comorbidities both 25 years before and 25 years after a type 2 diabetes diagnosis.

About 40% of people had respiratory tract infections at the time of diagnosis with type 2 diabetes, compared with 4% who were not diagnosed. Likewise, ear, nose, and throat infections were present in 20% of people at type 2 diabetes diagnosis, compared with around 2% who were not diagnosed. A similar pattern was seen with asthma.

Taken together, the data suggest that subacute inflammation manifesting in asthma as well as the onset of asthma or an acute infection may be a precursor to a type 2 diabetes diagnosis.

“We have also found that in the years prior to diagnosis, there are associations with infections and inflammatory disorders to a much greater degree than in those people who do not get a diabetes diagnosis but who have very similar demographics,” Adrian Heald, MD, study lead and diabetes consultant from Salford (England) Royal Hospital, said in an interview.

Five years prior to diagnosis, respiratory tract infections were documented in around 23% of patients who were later diagnosed with type 2 diabetes versus 2.5% in those not diagnosed, and a similar pattern was seen for ear, nose, and throat infections and asthma. The findings suggest that patients reporting infections, in addition to other known risk factors for type 2 diabetes, might benefit from diabetes tests and early interventions, if needed.

“These novel insights offer a fascinating and fresh perspective on the onset and natural progression to type 2 diabetes and beyond, suggesting an early phase of inflammation-related disease activity long before any clinical diagnosis of type 2 diabetes is made.”

Dr. Heald points out that clinicians may intervene to stave off progression to a type 2 diabetes diagnosis in at risk patients. “At this point, an intervention could relate to lifestyle changes and involve highlighting to the patient that the morbidity they have already accumulated is suggestive of diabetes risk,” he said, adding that, “they may have dyslipidemia, hypertension, and most often excess weight so annual checks of their HbA1c, weight management, and blood pressure would need checking,” he explained.

Moderator Coen Stehouwer, MD, professor of internal medicine at Maastricht University, the Netherlands, commented, “Before clinical diagnosis of type 2 diabetes there is often a lengthy period of undiagnosed disease and before that, prediabetes, because glucose can be abnormal up to 10 years prior to clinical diagnosis.”

But he added that, “It’s not entirely clear whether the rise seen before clinical diagnosis in this study correlates with undiagnosed diabetes or prediabetes or even if it precedes type 2 diabetes – it might be because inflammation is a common origin for type 2 diabetes and various comorbidities. This might explain how they go together.”
 

Longitudinal study 25 years before and 25 years after type 2 diagnosis

Dr. Heald presented the findings at a session on inflammation in diabetes at the annual meeting of the European Association for the Study of Diabetes. The work was also published in Diabetes Therapy.

The researchers wanted to investigate the pattern of comorbidities in the years and decades prior to a diagnosis of type 2 diabetes as well as after: “With the database we used, called DARE [Diabetes Alliance for Research in England], we are able to explore phenomena longitudinally going right back to the beginning of their digital health records, looking at phenotypes over time.”

By mapping significant health issues in people who went on to develop type 2 diabetes alongside those that did not, Dr. Heald managed to develop a continuum spanning 25 years prior and 25 years after diagnosis of type 2 diabetes. The researchers also examined relationships between sociodemographic factors and longitudinal health outcomes of relevance to cardiac conditions and lower respiratory tract infections. His talk in Hamburg primarily addressed clinical phenotypes before the point of diagnosis.

Data were drawn from 1,932 people with (1,196) and without (736) type 2 diabetes. Participants in both groups were aged 66-67 years, 43%-46% were women, age at diagnosis was 50-52 years, and participants lived in Greater Manchester, United Kingdom.

In the years leading up to type 2 diagnosis, individuals consistently exhibited a considerable increase in several clinical phenotypes, reported Dr. Heald. Of note, he added, “immediately prior to type 2 diagnosis, there was a significantly greater proportion of hypertension at 35%, respiratory tract infection at 34%, heart disease at 17%, ear, nose, and throat infection at 19%, and asthma at 12%. And by comparison, the corresponding disease trajectory in matched controls was much less dramatic.”

“There is a huge difference in people who went on to receive a diagnosis of type 2 diabetes and those who did not, and not just what we’d expect – so hypertension for example or manifestations of renal disease, but importantly inflammatory disorders are more common,” he emphasized.

In addition, a larger signal for ischemic heart disease was seen just before type 2 diabetes diagnosis.

These data suggest that longitudinal clinical histories prior to a diagnosis of type 2 diabetes might offer new information, both genetic and nongenetic, about development of type 2 diabetes in relation to comorbidities.

After type 2 diabetes diagnosis, the proportion of people exhibiting coronary artery disease, hypertension, chronic kidney disease, retinopathy, and infections climbed rapidly before plateauing, reported Dr. Heald. “We also know that individuals with coronary artery disease are more highly represented in socially disadvantaged groups, and this is borne out in the data at 25 years prior and after type 2 diagnosis.”

Dr. Heald has received speaker fees or contributed to advisory boards from Lilly, AstraZeneca, Janssen, Bristol-Myers Squibb, Besins, Bayer, Sanofi, and Recordati. Research grants from Novo Nordisk, Pfizer, and Besins. Professor Stehouwer has declared no relevant conflicts.

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

Once weekly glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide (Ozempic, Novo Nordisk) significantly improved hemoglobin A1c level and body weight for up to 3 years in a large cohort of adults with type 2 diabetes, show real-world data from Israel.

Treatment with semaglutide was associated with reductions in both A1c (–0.77%; P < .001) and body weight (–4.7 kg; P < .001) at 6 months of treatment. These reductions were maintained for up to 3 years and, in particular, in those patients with higher adherence to the therapy.

Avraham Karasik, MD, from the Institute of Research and Innovation at Maccabi Health Services, Tel Aviv, led the study and presented the work as a poster at this year’s annual meeting of the European Association for the Study of Diabetes.

“We found a clinically relevant improvement in blood sugar control and weight loss after 6 months of treatment, comparable with that seen in randomized trials,” said Dr. Karasik during an interview. “Importantly, these effects were sustained for up to 3 years, supporting the use of once weekly semaglutide for the long-term management of type 2 diabetes.”

Esther Walden, RN, deputy head of care at Diabetes UK, appreciated that the real-world findings reflected those seen in the randomized controlled trials. “This study suggests that improvements in blood sugars and weight loss can potentially be sustained in the longer term for adults with type 2 diabetes taking semaglutide as prescribed.”
 

Large scale, long term, and real world

Dr. Karasik explained that in Israel, there are many early adopters of once weekly semaglutide, and as such, it made for a large sample size, with a significant use duration for the retrospective study. “It’s a popular drug and there are lots of questions about durability of effect,” he pointed out.

Though evidence from randomized controlled trials support the effectiveness of once weekly semaglutide to treat type 2 diabetes, these studies are mostly of relatively short follow-up, explained Dr. Karasik, pointing out that long-term, large-scale, real-world data are needed. “In real life, people are acting differently to the trial setting and some adhere while others don’t, so it was interesting to see the durability as well as what happens when people discontinue treatment or adhere less.”

“Unsurprisingly, people who had a higher proportion of days covered ([PDC]; the total days of semaglutide use as a proportion of the total number of days followed up) had a higher effect,” explained Dr. Karasik, adding that, “if you don’t take it, it doesn’t work.”

A total of 23,442 patients were included in the study, with 6,049 followed up for 2 years or more. Mean baseline A1c was 7.6%-7.9%; body mass index (BMI) was 33.7-33.8 kg/m²; metformin was taken by 84%-88% of participants; insulin was taken by 30%; and 31% were treated with another GLP-1 RA prior to receiving semaglutide.

For study inclusion, participants were required to have had redeemed at least one prescription for subcutaneous semaglutide (0.25, 0.5, or 1 mg), and had at least one A1c measurement 12 months before and around 6 months after the start of semaglutide.

The primary outcome was change in A1c from baseline to the end of the follow-up at 6, 12, 18, 24, 30, and 36 months. Key secondary outcomes included change in body weight from baseline to the end of the follow-up (36 months); change in A1c and body weight in subgroups of patients who were persistently on therapy (at 12, 24, 36 months); and change in A1c and body weight in subgroups stratified by baseline characteristics. There was also an exploratory outcome, which was change in A1c and weight after treatment discontinuation. Dr. Karasik presented some of these results in his poster.

Median follow-up was 17.6 months in the total population and was 29.9 months in those who persisted with therapy for 2 years or more. “We have over 23,000 participants so it’s a large group, and these are not selected patients so the generalizability is better.”
 

Three-year sustained effect

Results from the total population showed that A1c lowered by a mean of 0.77% (from 7.6% to 6.8%) and body weight reduced by 4.7 kg (from 94.1 kg to 89.7 kg) after 6 months of treatment. These reductions were maintained during 3 years of follow-up in around 1,000 patients.

A significant 75% of participants adhered to once weekly semaglutide (PDC of more than 60%) within the first 6 months. In patients who used semaglutide for at least 2 years, those with high adherence (PDC of at least 80%) showed an A1c reduction of 0.76% after 24 months and of 0.43% after 36 months. Body weight was reduced by 6.0 kg after 24 months and 5.8 kg after 36 months.

Reductions in both A1c and weight were lower in patients with PDC of below 60%, compared with those with PDC of 60%-79% or 80% or over (statistically significant difference of P < .05 for between-groups differences for both outcomes across maximum follow-up time).

As expected, among patients who were GLP-1 RA–naive, reductions in A1c level and body weight were more pronounced, compared with GLP-1 RA–experienced patients (A1c reduction, –0.87% vs. –0.54%; weight loss, –5.5 kg vs. –3.0 kg, respectively; P < .001 for between-groups difference for both outcomes).

Dr. Karasik reported that some patients who stopped taking semaglutide did not regain weight immediately and that this potential residual effect after treatment discontinuation merits additional investigation. “This is not like in the randomized controlled trials. I don’t know how to interpret it, but that’s the observation. A1c did increase a little when they stopped therapy, compared to those with PDC [of 60%-79% or 80% or over] (P < .05 for between-groups difference for both outcomes in most follow-up time).”

He also highlighted that in regard to the long-term outcomes, “unlike many drugs where the effect fades out with time, here we don’t see that happening. This is another encouraging point.”

Dr. Karasik declares speaker fees and grants from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. The study was supported by Novo Nordisk.

A version of this article appeared on Medscape.com.

Once weekly glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide (Ozempic, Novo Nordisk) significantly improved hemoglobin A1c level and body weight for up to 3 years in a large cohort of adults with type 2 diabetes, show real-world data from Israel.

Treatment with semaglutide was associated with reductions in both A1c (–0.77%; P < .001) and body weight (–4.7 kg; P < .001) at 6 months of treatment. These reductions were maintained for up to 3 years and, in particular, in those patients with higher adherence to the therapy.

Avraham Karasik, MD, from the Institute of Research and Innovation at Maccabi Health Services, Tel Aviv, led the study and presented the work as a poster at this year’s annual meeting of the European Association for the Study of Diabetes.

“We found a clinically relevant improvement in blood sugar control and weight loss after 6 months of treatment, comparable with that seen in randomized trials,” said Dr. Karasik during an interview. “Importantly, these effects were sustained for up to 3 years, supporting the use of once weekly semaglutide for the long-term management of type 2 diabetes.”

Esther Walden, RN, deputy head of care at Diabetes UK, appreciated that the real-world findings reflected those seen in the randomized controlled trials. “This study suggests that improvements in blood sugars and weight loss can potentially be sustained in the longer term for adults with type 2 diabetes taking semaglutide as prescribed.”
 

Large scale, long term, and real world

Dr. Karasik explained that in Israel, there are many early adopters of once weekly semaglutide, and as such, it made for a large sample size, with a significant use duration for the retrospective study. “It’s a popular drug and there are lots of questions about durability of effect,” he pointed out.

Though evidence from randomized controlled trials support the effectiveness of once weekly semaglutide to treat type 2 diabetes, these studies are mostly of relatively short follow-up, explained Dr. Karasik, pointing out that long-term, large-scale, real-world data are needed. “In real life, people are acting differently to the trial setting and some adhere while others don’t, so it was interesting to see the durability as well as what happens when people discontinue treatment or adhere less.”

“Unsurprisingly, people who had a higher proportion of days covered ([PDC]; the total days of semaglutide use as a proportion of the total number of days followed up) had a higher effect,” explained Dr. Karasik, adding that, “if you don’t take it, it doesn’t work.”

A total of 23,442 patients were included in the study, with 6,049 followed up for 2 years or more. Mean baseline A1c was 7.6%-7.9%; body mass index (BMI) was 33.7-33.8 kg/m²; metformin was taken by 84%-88% of participants; insulin was taken by 30%; and 31% were treated with another GLP-1 RA prior to receiving semaglutide.

For study inclusion, participants were required to have had redeemed at least one prescription for subcutaneous semaglutide (0.25, 0.5, or 1 mg), and had at least one A1c measurement 12 months before and around 6 months after the start of semaglutide.

The primary outcome was change in A1c from baseline to the end of the follow-up at 6, 12, 18, 24, 30, and 36 months. Key secondary outcomes included change in body weight from baseline to the end of the follow-up (36 months); change in A1c and body weight in subgroups of patients who were persistently on therapy (at 12, 24, 36 months); and change in A1c and body weight in subgroups stratified by baseline characteristics. There was also an exploratory outcome, which was change in A1c and weight after treatment discontinuation. Dr. Karasik presented some of these results in his poster.

Median follow-up was 17.6 months in the total population and was 29.9 months in those who persisted with therapy for 2 years or more. “We have over 23,000 participants so it’s a large group, and these are not selected patients so the generalizability is better.”
 

Three-year sustained effect

Results from the total population showed that A1c lowered by a mean of 0.77% (from 7.6% to 6.8%) and body weight reduced by 4.7 kg (from 94.1 kg to 89.7 kg) after 6 months of treatment. These reductions were maintained during 3 years of follow-up in around 1,000 patients.

A significant 75% of participants adhered to once weekly semaglutide (PDC of more than 60%) within the first 6 months. In patients who used semaglutide for at least 2 years, those with high adherence (PDC of at least 80%) showed an A1c reduction of 0.76% after 24 months and of 0.43% after 36 months. Body weight was reduced by 6.0 kg after 24 months and 5.8 kg after 36 months.

Reductions in both A1c and weight were lower in patients with PDC of below 60%, compared with those with PDC of 60%-79% or 80% or over (statistically significant difference of P < .05 for between-groups differences for both outcomes across maximum follow-up time).

As expected, among patients who were GLP-1 RA–naive, reductions in A1c level and body weight were more pronounced, compared with GLP-1 RA–experienced patients (A1c reduction, –0.87% vs. –0.54%; weight loss, –5.5 kg vs. –3.0 kg, respectively; P < .001 for between-groups difference for both outcomes).

Dr. Karasik reported that some patients who stopped taking semaglutide did not regain weight immediately and that this potential residual effect after treatment discontinuation merits additional investigation. “This is not like in the randomized controlled trials. I don’t know how to interpret it, but that’s the observation. A1c did increase a little when they stopped therapy, compared to those with PDC [of 60%-79% or 80% or over] (P < .05 for between-groups difference for both outcomes in most follow-up time).”

He also highlighted that in regard to the long-term outcomes, “unlike many drugs where the effect fades out with time, here we don’t see that happening. This is another encouraging point.”

Dr. Karasik declares speaker fees and grants from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. The study was supported by Novo Nordisk.

A version of this article appeared on Medscape.com.

Once weekly glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide (Ozempic, Novo Nordisk) significantly improved hemoglobin A1c level and body weight for up to 3 years in a large cohort of adults with type 2 diabetes, show real-world data from Israel.

Treatment with semaglutide was associated with reductions in both A1c (–0.77%; P < .001) and body weight (–4.7 kg; P < .001) at 6 months of treatment. These reductions were maintained for up to 3 years and, in particular, in those patients with higher adherence to the therapy.

Avraham Karasik, MD, from the Institute of Research and Innovation at Maccabi Health Services, Tel Aviv, led the study and presented the work as a poster at this year’s annual meeting of the European Association for the Study of Diabetes.

“We found a clinically relevant improvement in blood sugar control and weight loss after 6 months of treatment, comparable with that seen in randomized trials,” said Dr. Karasik during an interview. “Importantly, these effects were sustained for up to 3 years, supporting the use of once weekly semaglutide for the long-term management of type 2 diabetes.”

Esther Walden, RN, deputy head of care at Diabetes UK, appreciated that the real-world findings reflected those seen in the randomized controlled trials. “This study suggests that improvements in blood sugars and weight loss can potentially be sustained in the longer term for adults with type 2 diabetes taking semaglutide as prescribed.”
 

Large scale, long term, and real world

Dr. Karasik explained that in Israel, there are many early adopters of once weekly semaglutide, and as such, it made for a large sample size, with a significant use duration for the retrospective study. “It’s a popular drug and there are lots of questions about durability of effect,” he pointed out.

Though evidence from randomized controlled trials support the effectiveness of once weekly semaglutide to treat type 2 diabetes, these studies are mostly of relatively short follow-up, explained Dr. Karasik, pointing out that long-term, large-scale, real-world data are needed. “In real life, people are acting differently to the trial setting and some adhere while others don’t, so it was interesting to see the durability as well as what happens when people discontinue treatment or adhere less.”

“Unsurprisingly, people who had a higher proportion of days covered ([PDC]; the total days of semaglutide use as a proportion of the total number of days followed up) had a higher effect,” explained Dr. Karasik, adding that, “if you don’t take it, it doesn’t work.”

A total of 23,442 patients were included in the study, with 6,049 followed up for 2 years or more. Mean baseline A1c was 7.6%-7.9%; body mass index (BMI) was 33.7-33.8 kg/m²; metformin was taken by 84%-88% of participants; insulin was taken by 30%; and 31% were treated with another GLP-1 RA prior to receiving semaglutide.

For study inclusion, participants were required to have had redeemed at least one prescription for subcutaneous semaglutide (0.25, 0.5, or 1 mg), and had at least one A1c measurement 12 months before and around 6 months after the start of semaglutide.

The primary outcome was change in A1c from baseline to the end of the follow-up at 6, 12, 18, 24, 30, and 36 months. Key secondary outcomes included change in body weight from baseline to the end of the follow-up (36 months); change in A1c and body weight in subgroups of patients who were persistently on therapy (at 12, 24, 36 months); and change in A1c and body weight in subgroups stratified by baseline characteristics. There was also an exploratory outcome, which was change in A1c and weight after treatment discontinuation. Dr. Karasik presented some of these results in his poster.

Median follow-up was 17.6 months in the total population and was 29.9 months in those who persisted with therapy for 2 years or more. “We have over 23,000 participants so it’s a large group, and these are not selected patients so the generalizability is better.”
 

Three-year sustained effect

Results from the total population showed that A1c lowered by a mean of 0.77% (from 7.6% to 6.8%) and body weight reduced by 4.7 kg (from 94.1 kg to 89.7 kg) after 6 months of treatment. These reductions were maintained during 3 years of follow-up in around 1,000 patients.

A significant 75% of participants adhered to once weekly semaglutide (PDC of more than 60%) within the first 6 months. In patients who used semaglutide for at least 2 years, those with high adherence (PDC of at least 80%) showed an A1c reduction of 0.76% after 24 months and of 0.43% after 36 months. Body weight was reduced by 6.0 kg after 24 months and 5.8 kg after 36 months.

Reductions in both A1c and weight were lower in patients with PDC of below 60%, compared with those with PDC of 60%-79% or 80% or over (statistically significant difference of P < .05 for between-groups differences for both outcomes across maximum follow-up time).

As expected, among patients who were GLP-1 RA–naive, reductions in A1c level and body weight were more pronounced, compared with GLP-1 RA–experienced patients (A1c reduction, –0.87% vs. –0.54%; weight loss, –5.5 kg vs. –3.0 kg, respectively; P < .001 for between-groups difference for both outcomes).

Dr. Karasik reported that some patients who stopped taking semaglutide did not regain weight immediately and that this potential residual effect after treatment discontinuation merits additional investigation. “This is not like in the randomized controlled trials. I don’t know how to interpret it, but that’s the observation. A1c did increase a little when they stopped therapy, compared to those with PDC [of 60%-79% or 80% or over] (P < .05 for between-groups difference for both outcomes in most follow-up time).”

He also highlighted that in regard to the long-term outcomes, “unlike many drugs where the effect fades out with time, here we don’t see that happening. This is another encouraging point.”

Dr. Karasik declares speaker fees and grants from Novo Nordisk, Boehringer Ingelheim, and AstraZeneca. The study was supported by Novo Nordisk.

A version of this article appeared on Medscape.com.

HAMBURG, GERMANY – Once-weekly tirzepatide (Mounjaro, Lilly) added to insulin glargine resulted in greater reductions in hemoglobin A1c along with more weight loss and less hypoglycemia, compared with prandial insulin lispro (Humalog, Sanofi), for patients with inadequately controlled type 2 diabetes, show data from the SURPASS-6 randomized clinical trial.

Tirzepatide led to a statistically and clinically significant reduction in mean A1c, at −2.1%, compared with insulin lispro, at −1.1%, by week 52. It also resulted in a higher percentage of participants meeting an A1c target of less than 7.0%, wrote the researchers, whose study was presented at the annual meeting of the European Association for the Study of Diabetes and was published simultaneously in JAMA.

Also, daily insulin glargine use was substantially lower among participants who received tirzepatide, compared with insulin lispro. Insulin glargine was administered at a dosage 13 IU/day; insulin lispro was administered at a dosage of 62 IU/day. “At the highest dose, some patients stopped their insulin [glargine] in the tirzepatide arm,” said Juan Pablo Frias, MD, medical director and principal investigator of Velocity Clinical Research, Los Angeles, who presented the findings. “We demonstrated clinically meaningful and superior glycemic and body weight control with tirzepatide compared with insulin lispro, while tirzepatide was also associated with less clinically significant hypoglycemia.”

Weight improved for participants who received tirzepatide compared with those who received insulin lispro, at –10 kg and +4 kg respectively. The rate of clinically significant hypoglycemia (blood glucose < 54 mg/dL) or severe hypoglycemia was tenfold lower with tirzepatide, compared with insulin lispro.

The session dedicated to tirzepatide was comoderated by Apostolos Tsapas, MD, professor of medicine and diabetes, Aristotle University, Thessaloniki, Greece, and Konstantinos Toulis, MD, consultant in endocrinology and diabetes, General Military Hospital, Thessaloniki, Greece. Dr. Toulis remarked that, in the chronic disease setting, management and treatment intensification are challenging to integrate, and there are barriers to adoption in routine practice. “This is particularly true when it adds complexity, as in the case of multiple prandial insulin injections on top of basal insulin in suboptimally treated individuals with type 2 diabetes.

“Demonstrating superiority over insulin lispro in terms of the so-called trio of A1c, weight loss, and hypoglycemic events, tirzepatide offers both a simpler to adhere to and a more efficacious treatment intensification option.” He noted that, while long-term safety data are awaited, “this seems to be a definite step forward from any viewpoint, with the possible exception of the taxpayer’s perspective.”

Dr. Tsapas added: “These data further support the very high dual glucose and weight efficacy of tirzepatide and the primary role of incretin-related therapies amongst the injectables for the treatment of type 2 diabetes.”
 

Tirzepatide 5, 10, 15 mg vs. insulin lispro in addition to insulin glargine

The researchers aimed to assess the efficacy and safety of adding once-weekly tirzepatide, compared with thrice-daily prandial insulin lispro, as an adjunctive therapy to insulin glargine for patients with type 2 diabetes that was inadequately controlled with basal insulin.

Tirzepatide activates the body’s receptors for glucose-dependent insulinotropic polypeptide and glucagonlike peptide–1 (GLP-1). The study authors noted that “recent guidelines support adding an injectable incretin-related therapy such as GLP-1 receptor agonist for glycemic control, rather than basal insulin, when oral medications are inadequate.”

The open-label, phase 3b clinical trial drew data from 135 sites across 15 countries and included 1,428 adults with type 2 diabetes who were taking basal insulin. Participants were randomly assigned in a 1:1:1:3 ratio to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708).

Both arms were well matched. The average age was 60 years, and 60% of participants were women. The average amount of time patients had type 2 diabetes was 14 years; 85% of participants continued taking metformin. The average A1c level was 8.8% at baseline. Patients were categorized as having obesity (average body mass index, 33 kg/m²). The average insulin glargine dose was 46 units, or 0.5 units/kg.

Outcomes included noninferiority of tirzepatide (pooled cohort) compared with insulin lispro, both in addition to insulin glargine; and A1c change from baseline to week 52 (noninferiority margin, 0.3%). Key secondary endpoints included change in body weight and percentage of participants who achieved an A1c target of less than 7.0%.

About 90% of participants who received the study drug completed the study, said Dr. Frias. “Only 0.5% of tirzepatide patients needed rescue therapy, while only 2% of the insulin lispro did.”

Prior to optimization, the average insulin glargine dose was 42 IU/kg; during optimization, it rose to an average of 46 IU/kg. “At 52 weeks, those on basal-bolus insulin found their insulin glargine dose stayed flat while insulin lispro was 62 units,” reported Dr. Frias. “The three tirzepatide doses show a reduction in insulin glargine, such that the pooled dose reached an average of 11 units, while 20% actually came off their basal insulin altogether [pooled tirzepatide].”

Tirzepatide (pooled) led to the recommended A1c target of less than 7.0% for 68% of patients versus 36% of patients in the insulin lispro group.

About 68% of the patients who received tirzepatide (pooled) achieved the recommended A1c target of less than 7.0% versus 36% of patients in the insulin lispro group.

“Individual tirzepatide doses and pooled doses showed significant reduction in A1c and up to a 2.5% reduction,” Dr. Frias added. “Normoglycemia was obtained by a greater proportion of patients on tirzepatide doses versus basal-bolus insulin – one-third in the 15-mg tirzepatide dose.”
 

Body weight reduction of 10% or more with tirzepatide

Further, at week 52, weight loss of 5% or more was achieved by 75.4% of participants in the pooled tirzepatide group, compared with 6.3% in the prandial lispro group. The weight loss was accompanied by clinically relevant improvements in cardiometabolic parameters.

In an exploratory analysis, weight loss of 10% or more was achieved by a mean of 48.9% of pooled tirzepatide-treated participants at week 52, compared with 2% of those taking insulin lispro, said Dr. Frias.

“It is possible that the body weight loss induced by tirzepatide therapy and its reported effect in reducing liver fat content may have led to an improvement in insulin sensitivity and decreased insulin requirements,” wrote the researchers in their article.

Hypoglycemia risk and the weight gain observed with complex insulin regimens that include prandial insulin have been main limitations to optimally up-titrate insulin therapy in clinical practice, wrote the authors.

Dr. Frias noted that, in this study, 48% of patients who received insulin lispro experienced clinically significant hypoglycemia, while only 10% of patients in the tirzepatide arms did. “This was 0.4 episodes per patient-year versus 4.4 in tirzepatide and insulin lispro respectively.”

There were more reports of adverse events among the tirzepatide groups than the insulin lispro group. “Typically, with tirzepatide, the commonest adverse events were GI in origin and were mild to moderate.” Rates were 14%-26% for nausea, 11%-15% for diarrhea, and 5%-13% for vomiting.

The study was sponsored by Eli Lilly. Dr. Frias has received grants from Eli Lilly paid to his institution during the conduct of the study and grants, personal fees, or nonfinancial support from Boehringer Ingelheim, Pfizer, Merck, Altimmune, 89BIO, Akero, Carmot Therapeutics, Intercept, Janssen, Madrigal, Novartis, Eli Lilly, Sanofi, and Novo Nordisk outside the submitted work. Dr. Toulis and Dr. Tsapas declared no relevant disclosures.

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

HAMBURG, GERMANY – Once-weekly tirzepatide (Mounjaro, Lilly) added to insulin glargine resulted in greater reductions in hemoglobin A1c along with more weight loss and less hypoglycemia, compared with prandial insulin lispro (Humalog, Sanofi), for patients with inadequately controlled type 2 diabetes, show data from the SURPASS-6 randomized clinical trial.

Tirzepatide led to a statistically and clinically significant reduction in mean A1c, at −2.1%, compared with insulin lispro, at −1.1%, by week 52. It also resulted in a higher percentage of participants meeting an A1c target of less than 7.0%, wrote the researchers, whose study was presented at the annual meeting of the European Association for the Study of Diabetes and was published simultaneously in JAMA.

Also, daily insulin glargine use was substantially lower among participants who received tirzepatide, compared with insulin lispro. Insulin glargine was administered at a dosage 13 IU/day; insulin lispro was administered at a dosage of 62 IU/day. “At the highest dose, some patients stopped their insulin [glargine] in the tirzepatide arm,” said Juan Pablo Frias, MD, medical director and principal investigator of Velocity Clinical Research, Los Angeles, who presented the findings. “We demonstrated clinically meaningful and superior glycemic and body weight control with tirzepatide compared with insulin lispro, while tirzepatide was also associated with less clinically significant hypoglycemia.”

Weight improved for participants who received tirzepatide compared with those who received insulin lispro, at –10 kg and +4 kg respectively. The rate of clinically significant hypoglycemia (blood glucose < 54 mg/dL) or severe hypoglycemia was tenfold lower with tirzepatide, compared with insulin lispro.

The session dedicated to tirzepatide was comoderated by Apostolos Tsapas, MD, professor of medicine and diabetes, Aristotle University, Thessaloniki, Greece, and Konstantinos Toulis, MD, consultant in endocrinology and diabetes, General Military Hospital, Thessaloniki, Greece. Dr. Toulis remarked that, in the chronic disease setting, management and treatment intensification are challenging to integrate, and there are barriers to adoption in routine practice. “This is particularly true when it adds complexity, as in the case of multiple prandial insulin injections on top of basal insulin in suboptimally treated individuals with type 2 diabetes.

“Demonstrating superiority over insulin lispro in terms of the so-called trio of A1c, weight loss, and hypoglycemic events, tirzepatide offers both a simpler to adhere to and a more efficacious treatment intensification option.” He noted that, while long-term safety data are awaited, “this seems to be a definite step forward from any viewpoint, with the possible exception of the taxpayer’s perspective.”

Dr. Tsapas added: “These data further support the very high dual glucose and weight efficacy of tirzepatide and the primary role of incretin-related therapies amongst the injectables for the treatment of type 2 diabetes.”
 

Tirzepatide 5, 10, 15 mg vs. insulin lispro in addition to insulin glargine

The researchers aimed to assess the efficacy and safety of adding once-weekly tirzepatide, compared with thrice-daily prandial insulin lispro, as an adjunctive therapy to insulin glargine for patients with type 2 diabetes that was inadequately controlled with basal insulin.

Tirzepatide activates the body’s receptors for glucose-dependent insulinotropic polypeptide and glucagonlike peptide–1 (GLP-1). The study authors noted that “recent guidelines support adding an injectable incretin-related therapy such as GLP-1 receptor agonist for glycemic control, rather than basal insulin, when oral medications are inadequate.”

The open-label, phase 3b clinical trial drew data from 135 sites across 15 countries and included 1,428 adults with type 2 diabetes who were taking basal insulin. Participants were randomly assigned in a 1:1:1:3 ratio to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708).

Both arms were well matched. The average age was 60 years, and 60% of participants were women. The average amount of time patients had type 2 diabetes was 14 years; 85% of participants continued taking metformin. The average A1c level was 8.8% at baseline. Patients were categorized as having obesity (average body mass index, 33 kg/m²). The average insulin glargine dose was 46 units, or 0.5 units/kg.

Outcomes included noninferiority of tirzepatide (pooled cohort) compared with insulin lispro, both in addition to insulin glargine; and A1c change from baseline to week 52 (noninferiority margin, 0.3%). Key secondary endpoints included change in body weight and percentage of participants who achieved an A1c target of less than 7.0%.

About 90% of participants who received the study drug completed the study, said Dr. Frias. “Only 0.5% of tirzepatide patients needed rescue therapy, while only 2% of the insulin lispro did.”

Prior to optimization, the average insulin glargine dose was 42 IU/kg; during optimization, it rose to an average of 46 IU/kg. “At 52 weeks, those on basal-bolus insulin found their insulin glargine dose stayed flat while insulin lispro was 62 units,” reported Dr. Frias. “The three tirzepatide doses show a reduction in insulin glargine, such that the pooled dose reached an average of 11 units, while 20% actually came off their basal insulin altogether [pooled tirzepatide].”

Tirzepatide (pooled) led to the recommended A1c target of less than 7.0% for 68% of patients versus 36% of patients in the insulin lispro group.

About 68% of the patients who received tirzepatide (pooled) achieved the recommended A1c target of less than 7.0% versus 36% of patients in the insulin lispro group.

“Individual tirzepatide doses and pooled doses showed significant reduction in A1c and up to a 2.5% reduction,” Dr. Frias added. “Normoglycemia was obtained by a greater proportion of patients on tirzepatide doses versus basal-bolus insulin – one-third in the 15-mg tirzepatide dose.”
 

Body weight reduction of 10% or more with tirzepatide

Further, at week 52, weight loss of 5% or more was achieved by 75.4% of participants in the pooled tirzepatide group, compared with 6.3% in the prandial lispro group. The weight loss was accompanied by clinically relevant improvements in cardiometabolic parameters.

In an exploratory analysis, weight loss of 10% or more was achieved by a mean of 48.9% of pooled tirzepatide-treated participants at week 52, compared with 2% of those taking insulin lispro, said Dr. Frias.

“It is possible that the body weight loss induced by tirzepatide therapy and its reported effect in reducing liver fat content may have led to an improvement in insulin sensitivity and decreased insulin requirements,” wrote the researchers in their article.

Hypoglycemia risk and the weight gain observed with complex insulin regimens that include prandial insulin have been main limitations to optimally up-titrate insulin therapy in clinical practice, wrote the authors.

Dr. Frias noted that, in this study, 48% of patients who received insulin lispro experienced clinically significant hypoglycemia, while only 10% of patients in the tirzepatide arms did. “This was 0.4 episodes per patient-year versus 4.4 in tirzepatide and insulin lispro respectively.”

There were more reports of adverse events among the tirzepatide groups than the insulin lispro group. “Typically, with tirzepatide, the commonest adverse events were GI in origin and were mild to moderate.” Rates were 14%-26% for nausea, 11%-15% for diarrhea, and 5%-13% for vomiting.

The study was sponsored by Eli Lilly. Dr. Frias has received grants from Eli Lilly paid to his institution during the conduct of the study and grants, personal fees, or nonfinancial support from Boehringer Ingelheim, Pfizer, Merck, Altimmune, 89BIO, Akero, Carmot Therapeutics, Intercept, Janssen, Madrigal, Novartis, Eli Lilly, Sanofi, and Novo Nordisk outside the submitted work. Dr. Toulis and Dr. Tsapas declared no relevant disclosures.

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

HAMBURG, GERMANY – Once-weekly tirzepatide (Mounjaro, Lilly) added to insulin glargine resulted in greater reductions in hemoglobin A1c along with more weight loss and less hypoglycemia, compared with prandial insulin lispro (Humalog, Sanofi), for patients with inadequately controlled type 2 diabetes, show data from the SURPASS-6 randomized clinical trial.

Tirzepatide led to a statistically and clinically significant reduction in mean A1c, at −2.1%, compared with insulin lispro, at −1.1%, by week 52. It also resulted in a higher percentage of participants meeting an A1c target of less than 7.0%, wrote the researchers, whose study was presented at the annual meeting of the European Association for the Study of Diabetes and was published simultaneously in JAMA.

Also, daily insulin glargine use was substantially lower among participants who received tirzepatide, compared with insulin lispro. Insulin glargine was administered at a dosage 13 IU/day; insulin lispro was administered at a dosage of 62 IU/day. “At the highest dose, some patients stopped their insulin [glargine] in the tirzepatide arm,” said Juan Pablo Frias, MD, medical director and principal investigator of Velocity Clinical Research, Los Angeles, who presented the findings. “We demonstrated clinically meaningful and superior glycemic and body weight control with tirzepatide compared with insulin lispro, while tirzepatide was also associated with less clinically significant hypoglycemia.”

Weight improved for participants who received tirzepatide compared with those who received insulin lispro, at –10 kg and +4 kg respectively. The rate of clinically significant hypoglycemia (blood glucose < 54 mg/dL) or severe hypoglycemia was tenfold lower with tirzepatide, compared with insulin lispro.

The session dedicated to tirzepatide was comoderated by Apostolos Tsapas, MD, professor of medicine and diabetes, Aristotle University, Thessaloniki, Greece, and Konstantinos Toulis, MD, consultant in endocrinology and diabetes, General Military Hospital, Thessaloniki, Greece. Dr. Toulis remarked that, in the chronic disease setting, management and treatment intensification are challenging to integrate, and there are barriers to adoption in routine practice. “This is particularly true when it adds complexity, as in the case of multiple prandial insulin injections on top of basal insulin in suboptimally treated individuals with type 2 diabetes.

“Demonstrating superiority over insulin lispro in terms of the so-called trio of A1c, weight loss, and hypoglycemic events, tirzepatide offers both a simpler to adhere to and a more efficacious treatment intensification option.” He noted that, while long-term safety data are awaited, “this seems to be a definite step forward from any viewpoint, with the possible exception of the taxpayer’s perspective.”

Dr. Tsapas added: “These data further support the very high dual glucose and weight efficacy of tirzepatide and the primary role of incretin-related therapies amongst the injectables for the treatment of type 2 diabetes.”
 

Tirzepatide 5, 10, 15 mg vs. insulin lispro in addition to insulin glargine

The researchers aimed to assess the efficacy and safety of adding once-weekly tirzepatide, compared with thrice-daily prandial insulin lispro, as an adjunctive therapy to insulin glargine for patients with type 2 diabetes that was inadequately controlled with basal insulin.

Tirzepatide activates the body’s receptors for glucose-dependent insulinotropic polypeptide and glucagonlike peptide–1 (GLP-1). The study authors noted that “recent guidelines support adding an injectable incretin-related therapy such as GLP-1 receptor agonist for glycemic control, rather than basal insulin, when oral medications are inadequate.”

The open-label, phase 3b clinical trial drew data from 135 sites across 15 countries and included 1,428 adults with type 2 diabetes who were taking basal insulin. Participants were randomly assigned in a 1:1:1:3 ratio to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708).

Both arms were well matched. The average age was 60 years, and 60% of participants were women. The average amount of time patients had type 2 diabetes was 14 years; 85% of participants continued taking metformin. The average A1c level was 8.8% at baseline. Patients were categorized as having obesity (average body mass index, 33 kg/m²). The average insulin glargine dose was 46 units, or 0.5 units/kg.

Outcomes included noninferiority of tirzepatide (pooled cohort) compared with insulin lispro, both in addition to insulin glargine; and A1c change from baseline to week 52 (noninferiority margin, 0.3%). Key secondary endpoints included change in body weight and percentage of participants who achieved an A1c target of less than 7.0%.

About 90% of participants who received the study drug completed the study, said Dr. Frias. “Only 0.5% of tirzepatide patients needed rescue therapy, while only 2% of the insulin lispro did.”

Prior to optimization, the average insulin glargine dose was 42 IU/kg; during optimization, it rose to an average of 46 IU/kg. “At 52 weeks, those on basal-bolus insulin found their insulin glargine dose stayed flat while insulin lispro was 62 units,” reported Dr. Frias. “The three tirzepatide doses show a reduction in insulin glargine, such that the pooled dose reached an average of 11 units, while 20% actually came off their basal insulin altogether [pooled tirzepatide].”

Tirzepatide (pooled) led to the recommended A1c target of less than 7.0% for 68% of patients versus 36% of patients in the insulin lispro group.

About 68% of the patients who received tirzepatide (pooled) achieved the recommended A1c target of less than 7.0% versus 36% of patients in the insulin lispro group.

“Individual tirzepatide doses and pooled doses showed significant reduction in A1c and up to a 2.5% reduction,” Dr. Frias added. “Normoglycemia was obtained by a greater proportion of patients on tirzepatide doses versus basal-bolus insulin – one-third in the 15-mg tirzepatide dose.”
 

Body weight reduction of 10% or more with tirzepatide

Further, at week 52, weight loss of 5% or more was achieved by 75.4% of participants in the pooled tirzepatide group, compared with 6.3% in the prandial lispro group. The weight loss was accompanied by clinically relevant improvements in cardiometabolic parameters.

In an exploratory analysis, weight loss of 10% or more was achieved by a mean of 48.9% of pooled tirzepatide-treated participants at week 52, compared with 2% of those taking insulin lispro, said Dr. Frias.

“It is possible that the body weight loss induced by tirzepatide therapy and its reported effect in reducing liver fat content may have led to an improvement in insulin sensitivity and decreased insulin requirements,” wrote the researchers in their article.

Hypoglycemia risk and the weight gain observed with complex insulin regimens that include prandial insulin have been main limitations to optimally up-titrate insulin therapy in clinical practice, wrote the authors.

Dr. Frias noted that, in this study, 48% of patients who received insulin lispro experienced clinically significant hypoglycemia, while only 10% of patients in the tirzepatide arms did. “This was 0.4 episodes per patient-year versus 4.4 in tirzepatide and insulin lispro respectively.”

There were more reports of adverse events among the tirzepatide groups than the insulin lispro group. “Typically, with tirzepatide, the commonest adverse events were GI in origin and were mild to moderate.” Rates were 14%-26% for nausea, 11%-15% for diarrhea, and 5%-13% for vomiting.

The study was sponsored by Eli Lilly. Dr. Frias has received grants from Eli Lilly paid to his institution during the conduct of the study and grants, personal fees, or nonfinancial support from Boehringer Ingelheim, Pfizer, Merck, Altimmune, 89BIO, Akero, Carmot Therapeutics, Intercept, Janssen, Madrigal, Novartis, Eli Lilly, Sanofi, and Novo Nordisk outside the submitted work. Dr. Toulis and Dr. Tsapas declared no relevant disclosures.

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

Use of A1c levels for the diagnosis of type 2 diabetes (T2D) in women younger than 50 years may lead to underdiagnosis, owing to the effects of menstrual blood loss on A1c readings, shows the first study of its kind.

The analysis estimates that an additional 17% of undiagnosed women younger than 50 years could be reclassified as having T2D, and that women under 50 had an A1c distribution that was markedly lower than that of men under 50, by a mean of 1.6 mmol/mol.

In a study that will be presented at this year’s annual meeting of the European Association for the Study of Diabetes (EASD), the researchers wanted to investigate whether a contributing factor to late diagnosis of T2D in women under 50 may be the difference in A1c levels due to hemoglobin replacement linked to menstrual blood loss.

The study was published online in Diabetes Therapy. “If the threshold for diagnosis of diabetes ... was lowered by 2 mmol/mol in women under the age of 50, an additional 17% of these women (approximately equivalent to 35,000 women in England and Wales) would be diagnosed with diabetes ... which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years,” the researchers noted.

They added that A1c levels in women under 50 years were found to be consistently lower than those in men, and with A1c levels in women reaching the equivalent of those in men up to 10 years later, this “may result in delayed diagnosis of diabetes mellitus in premenopausal women.”

Noting that the study was observational, senior author Adrian Heald, MD, consultant endocrinologist, Salford (England) Royal NHS Foundation Trust, said that it “may be the case that prediabetes and type 2 diabetes in women are not being spotted because the set point needs to be slightly lower, but a systematic study sampling from the population of at-risk individuals is needed further to our findings.

“We also need to refer back to use of the glucose tolerance test, because A1c has been used for the past 15 years but it is not the gold standard,” added Dr. Heald. “Clinicians have often wondered if patients might be missed with A1c measurement, or even overdiagnosed.”

Lucy Chambers, PhD, from Diabetes UK, acknowledged that the research was valuable but added: “More research on sex differences in thresholds for a type 2 diagnosis is needed to inform any changes to clinical practice. In the meantime, we encourage clinicians to follow the current guidance of not ruling out type 2 diabetes based on a one-off A1c below the diagnostic threshold.”

But in support of greater understanding around the sex differences in A1c diagnostic thresholds, Dr. Chambers added: “Receiving an accurate and timely diagnosis ensures that women get the treatment and support needed to manage their type 2 diabetes and avoid long-term complications, including heart disease, where sex-based inequalities in care already contribute to poorer outcomes for women.” 
 

Effect of A1c reference range on T2D diagnosis and associated CVD

Compared with men, women with T2D have poorer glycemic control; a higher risk for cardiovascular (CV) complications; reduced life expectancy (5.3 years shorter vs. 4.5 years shorter); and a higher risk factor burden, such as obesity and hypertension at diagnosis.

In addition, T2D is a stronger risk factor for CV disease (CVD) in women than in men, and those aged 35-59 years who receive a diagnosis have the highest relative CV death risk across all age and sex groups.

The researchers pointed out that previous studies have observed differences in A1c relative to menopause, and they too found that “A1c levels rose after the age of 50 in women.”

However, they noted that the implication of differing A1c reference ranges on delayed diabetes diagnosis with worsening CV risk profile had not been previously recognized and that their study “[h]ighlights for the first time that, while 1.6 mmol/mol may appear only a small difference in terms of laboratory measurement, at population level this has implications for significant number of premenopausal women.”

The researchers initially observed the trend in local data in Salford, in the northwest of England. “These ... data highlighted that women seemed to be diagnosed with type 2 diabetes at an older age, so we wanted to examine what the source of that might be,” study author Mike Stedman, BSc, director, Res Consortium, Andover, England, said in an interview.

Dr. Stedman and his colleagues assessed the sex and age differences of A1c in individuals who had not been diagnosed with diabetes (A1c ≤ 48 mmol/mol [≤ 6.5%]). “We looked at data from other labs [in addition to those in Salford, totaling 938,678 people] to see if this was a local phenomenon. They could only provide more recent data, but these also showed a similar pattern,” he added.

Finally, Dr. Stedman, Dr. Heald, and their colleagues estimated the possible national impact by extrapolating findings based on population data from the UK Office of National Statistics and on National Diabetes Audit data for type 2 diabetes prevalence and related excess mortality. This brought them to the conclusion that T2D would be diagnosed in an additional 17% of women if the threshold were lowered by 2 mmol/mol, to 46 mmol/mol, in women under 50 years.
 

Lower A1c in women under 50 may delay T2D diagnosis by up to 10 years

The analysis found that the median A1c increased with age, with values in women younger than 50 years consistently being 1 mmol/mol lower than values in men. In contrast, A1c values in women over 50 years were equivalent to those in men.

However, at age 50 years, compared with men, A1c in women was found to lag by approximately 5 years. Women under 50 had an A1c distribution that was lower than that of men by an average of 1.6 mmol/mol (4.7% of mean; P < .0001), whereas this difference in individuals aged 50 years or older was less pronounced (P < .0001).

The authors wrote that “an undermeasurement of approximately 1.6 mmol/mol A1c in women may delay their diabetes ... diagnosis by up to 10 years.”

Further analysis showed that, at an A1c of 48 mmol/mol, 50% fewer women than men under the age of 50 could be diagnosed with T2D, whereas only 20% fewer women than men aged 50 years or older could be diagnosed with T2D.

Lowering the A1c threshold for diagnosis of T2D from 48 mmol/mol to 46 mmol/mol in women under 50 led to an estimate that an additional 35,345 undiagnosed women in England could be reclassified as having a T2D diagnosis.

The authors pointed out that “gender difference in adverse cardiovascular risk factors are known to be present prior to the development of [type 2] diabetes” and that “once diagnosed, atherosclerotic CVD prevalence is twice as high in patients with diabetes ... compared to those without a diagnosis.”

Dr. Heald added that there is always the possibility that other factors might be at play and that the work posed questions rather than presented answers.

Taking a pragmatic view, the researchers suggested that “one alternative approach may be to offer further assessment using fasting plasma glucose or oral glucose tolerance testing in those with A1c values of 46 or 47 mmol/mol.”

“In anyone with an early diagnosis of type 2 diabetes, in addition to dietary modification and especially if there is cardiovascular risk, then one might start them on metformin due to the cardiovascular benefits as well as the sugar-lowering effects,” said Dr. Heald, adding that “we certainly don’t want women missing out on metformin that could have huge benefits in the longer term.”

Dr. Stedman and Dr. Heald declared no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. Dr. Chambers has declared no conflicts.

A version of this article appeared on Medscape.com.

Use of A1c levels for the diagnosis of type 2 diabetes (T2D) in women younger than 50 years may lead to underdiagnosis, owing to the effects of menstrual blood loss on A1c readings, shows the first study of its kind.

The analysis estimates that an additional 17% of undiagnosed women younger than 50 years could be reclassified as having T2D, and that women under 50 had an A1c distribution that was markedly lower than that of men under 50, by a mean of 1.6 mmol/mol.

In a study that will be presented at this year’s annual meeting of the European Association for the Study of Diabetes (EASD), the researchers wanted to investigate whether a contributing factor to late diagnosis of T2D in women under 50 may be the difference in A1c levels due to hemoglobin replacement linked to menstrual blood loss.

The study was published online in Diabetes Therapy. “If the threshold for diagnosis of diabetes ... was lowered by 2 mmol/mol in women under the age of 50, an additional 17% of these women (approximately equivalent to 35,000 women in England and Wales) would be diagnosed with diabetes ... which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years,” the researchers noted.

They added that A1c levels in women under 50 years were found to be consistently lower than those in men, and with A1c levels in women reaching the equivalent of those in men up to 10 years later, this “may result in delayed diagnosis of diabetes mellitus in premenopausal women.”

Noting that the study was observational, senior author Adrian Heald, MD, consultant endocrinologist, Salford (England) Royal NHS Foundation Trust, said that it “may be the case that prediabetes and type 2 diabetes in women are not being spotted because the set point needs to be slightly lower, but a systematic study sampling from the population of at-risk individuals is needed further to our findings.

“We also need to refer back to use of the glucose tolerance test, because A1c has been used for the past 15 years but it is not the gold standard,” added Dr. Heald. “Clinicians have often wondered if patients might be missed with A1c measurement, or even overdiagnosed.”

Lucy Chambers, PhD, from Diabetes UK, acknowledged that the research was valuable but added: “More research on sex differences in thresholds for a type 2 diagnosis is needed to inform any changes to clinical practice. In the meantime, we encourage clinicians to follow the current guidance of not ruling out type 2 diabetes based on a one-off A1c below the diagnostic threshold.”

But in support of greater understanding around the sex differences in A1c diagnostic thresholds, Dr. Chambers added: “Receiving an accurate and timely diagnosis ensures that women get the treatment and support needed to manage their type 2 diabetes and avoid long-term complications, including heart disease, where sex-based inequalities in care already contribute to poorer outcomes for women.” 
 

Effect of A1c reference range on T2D diagnosis and associated CVD

Compared with men, women with T2D have poorer glycemic control; a higher risk for cardiovascular (CV) complications; reduced life expectancy (5.3 years shorter vs. 4.5 years shorter); and a higher risk factor burden, such as obesity and hypertension at diagnosis.

In addition, T2D is a stronger risk factor for CV disease (CVD) in women than in men, and those aged 35-59 years who receive a diagnosis have the highest relative CV death risk across all age and sex groups.

The researchers pointed out that previous studies have observed differences in A1c relative to menopause, and they too found that “A1c levels rose after the age of 50 in women.”

However, they noted that the implication of differing A1c reference ranges on delayed diabetes diagnosis with worsening CV risk profile had not been previously recognized and that their study “[h]ighlights for the first time that, while 1.6 mmol/mol may appear only a small difference in terms of laboratory measurement, at population level this has implications for significant number of premenopausal women.”

The researchers initially observed the trend in local data in Salford, in the northwest of England. “These ... data highlighted that women seemed to be diagnosed with type 2 diabetes at an older age, so we wanted to examine what the source of that might be,” study author Mike Stedman, BSc, director, Res Consortium, Andover, England, said in an interview.

Dr. Stedman and his colleagues assessed the sex and age differences of A1c in individuals who had not been diagnosed with diabetes (A1c ≤ 48 mmol/mol [≤ 6.5%]). “We looked at data from other labs [in addition to those in Salford, totaling 938,678 people] to see if this was a local phenomenon. They could only provide more recent data, but these also showed a similar pattern,” he added.

Finally, Dr. Stedman, Dr. Heald, and their colleagues estimated the possible national impact by extrapolating findings based on population data from the UK Office of National Statistics and on National Diabetes Audit data for type 2 diabetes prevalence and related excess mortality. This brought them to the conclusion that T2D would be diagnosed in an additional 17% of women if the threshold were lowered by 2 mmol/mol, to 46 mmol/mol, in women under 50 years.
 

Lower A1c in women under 50 may delay T2D diagnosis by up to 10 years

The analysis found that the median A1c increased with age, with values in women younger than 50 years consistently being 1 mmol/mol lower than values in men. In contrast, A1c values in women over 50 years were equivalent to those in men.

However, at age 50 years, compared with men, A1c in women was found to lag by approximately 5 years. Women under 50 had an A1c distribution that was lower than that of men by an average of 1.6 mmol/mol (4.7% of mean; P < .0001), whereas this difference in individuals aged 50 years or older was less pronounced (P < .0001).

The authors wrote that “an undermeasurement of approximately 1.6 mmol/mol A1c in women may delay their diabetes ... diagnosis by up to 10 years.”

Further analysis showed that, at an A1c of 48 mmol/mol, 50% fewer women than men under the age of 50 could be diagnosed with T2D, whereas only 20% fewer women than men aged 50 years or older could be diagnosed with T2D.

Lowering the A1c threshold for diagnosis of T2D from 48 mmol/mol to 46 mmol/mol in women under 50 led to an estimate that an additional 35,345 undiagnosed women in England could be reclassified as having a T2D diagnosis.

The authors pointed out that “gender difference in adverse cardiovascular risk factors are known to be present prior to the development of [type 2] diabetes” and that “once diagnosed, atherosclerotic CVD prevalence is twice as high in patients with diabetes ... compared to those without a diagnosis.”

Dr. Heald added that there is always the possibility that other factors might be at play and that the work posed questions rather than presented answers.

Taking a pragmatic view, the researchers suggested that “one alternative approach may be to offer further assessment using fasting plasma glucose or oral glucose tolerance testing in those with A1c values of 46 or 47 mmol/mol.”

“In anyone with an early diagnosis of type 2 diabetes, in addition to dietary modification and especially if there is cardiovascular risk, then one might start them on metformin due to the cardiovascular benefits as well as the sugar-lowering effects,” said Dr. Heald, adding that “we certainly don’t want women missing out on metformin that could have huge benefits in the longer term.”

Dr. Stedman and Dr. Heald declared no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. Dr. Chambers has declared no conflicts.

A version of this article appeared on Medscape.com.

Use of A1c levels for the diagnosis of type 2 diabetes (T2D) in women younger than 50 years may lead to underdiagnosis, owing to the effects of menstrual blood loss on A1c readings, shows the first study of its kind.

The analysis estimates that an additional 17% of undiagnosed women younger than 50 years could be reclassified as having T2D, and that women under 50 had an A1c distribution that was markedly lower than that of men under 50, by a mean of 1.6 mmol/mol.

In a study that will be presented at this year’s annual meeting of the European Association for the Study of Diabetes (EASD), the researchers wanted to investigate whether a contributing factor to late diagnosis of T2D in women under 50 may be the difference in A1c levels due to hemoglobin replacement linked to menstrual blood loss.

The study was published online in Diabetes Therapy. “If the threshold for diagnosis of diabetes ... was lowered by 2 mmol/mol in women under the age of 50, an additional 17% of these women (approximately equivalent to 35,000 women in England and Wales) would be diagnosed with diabetes ... which may contribute to up to 64% of the difference in mortality rates between men/women with diabetes mellitus aged 16-50 years,” the researchers noted.

They added that A1c levels in women under 50 years were found to be consistently lower than those in men, and with A1c levels in women reaching the equivalent of those in men up to 10 years later, this “may result in delayed diagnosis of diabetes mellitus in premenopausal women.”

Noting that the study was observational, senior author Adrian Heald, MD, consultant endocrinologist, Salford (England) Royal NHS Foundation Trust, said that it “may be the case that prediabetes and type 2 diabetes in women are not being spotted because the set point needs to be slightly lower, but a systematic study sampling from the population of at-risk individuals is needed further to our findings.

“We also need to refer back to use of the glucose tolerance test, because A1c has been used for the past 15 years but it is not the gold standard,” added Dr. Heald. “Clinicians have often wondered if patients might be missed with A1c measurement, or even overdiagnosed.”

Lucy Chambers, PhD, from Diabetes UK, acknowledged that the research was valuable but added: “More research on sex differences in thresholds for a type 2 diagnosis is needed to inform any changes to clinical practice. In the meantime, we encourage clinicians to follow the current guidance of not ruling out type 2 diabetes based on a one-off A1c below the diagnostic threshold.”

But in support of greater understanding around the sex differences in A1c diagnostic thresholds, Dr. Chambers added: “Receiving an accurate and timely diagnosis ensures that women get the treatment and support needed to manage their type 2 diabetes and avoid long-term complications, including heart disease, where sex-based inequalities in care already contribute to poorer outcomes for women.” 
 

Effect of A1c reference range on T2D diagnosis and associated CVD

Compared with men, women with T2D have poorer glycemic control; a higher risk for cardiovascular (CV) complications; reduced life expectancy (5.3 years shorter vs. 4.5 years shorter); and a higher risk factor burden, such as obesity and hypertension at diagnosis.

In addition, T2D is a stronger risk factor for CV disease (CVD) in women than in men, and those aged 35-59 years who receive a diagnosis have the highest relative CV death risk across all age and sex groups.

The researchers pointed out that previous studies have observed differences in A1c relative to menopause, and they too found that “A1c levels rose after the age of 50 in women.”

However, they noted that the implication of differing A1c reference ranges on delayed diabetes diagnosis with worsening CV risk profile had not been previously recognized and that their study “[h]ighlights for the first time that, while 1.6 mmol/mol may appear only a small difference in terms of laboratory measurement, at population level this has implications for significant number of premenopausal women.”

The researchers initially observed the trend in local data in Salford, in the northwest of England. “These ... data highlighted that women seemed to be diagnosed with type 2 diabetes at an older age, so we wanted to examine what the source of that might be,” study author Mike Stedman, BSc, director, Res Consortium, Andover, England, said in an interview.

Dr. Stedman and his colleagues assessed the sex and age differences of A1c in individuals who had not been diagnosed with diabetes (A1c ≤ 48 mmol/mol [≤ 6.5%]). “We looked at data from other labs [in addition to those in Salford, totaling 938,678 people] to see if this was a local phenomenon. They could only provide more recent data, but these also showed a similar pattern,” he added.

Finally, Dr. Stedman, Dr. Heald, and their colleagues estimated the possible national impact by extrapolating findings based on population data from the UK Office of National Statistics and on National Diabetes Audit data for type 2 diabetes prevalence and related excess mortality. This brought them to the conclusion that T2D would be diagnosed in an additional 17% of women if the threshold were lowered by 2 mmol/mol, to 46 mmol/mol, in women under 50 years.
 

Lower A1c in women under 50 may delay T2D diagnosis by up to 10 years

The analysis found that the median A1c increased with age, with values in women younger than 50 years consistently being 1 mmol/mol lower than values in men. In contrast, A1c values in women over 50 years were equivalent to those in men.

However, at age 50 years, compared with men, A1c in women was found to lag by approximately 5 years. Women under 50 had an A1c distribution that was lower than that of men by an average of 1.6 mmol/mol (4.7% of mean; P < .0001), whereas this difference in individuals aged 50 years or older was less pronounced (P < .0001).

The authors wrote that “an undermeasurement of approximately 1.6 mmol/mol A1c in women may delay their diabetes ... diagnosis by up to 10 years.”

Further analysis showed that, at an A1c of 48 mmol/mol, 50% fewer women than men under the age of 50 could be diagnosed with T2D, whereas only 20% fewer women than men aged 50 years or older could be diagnosed with T2D.

Lowering the A1c threshold for diagnosis of T2D from 48 mmol/mol to 46 mmol/mol in women under 50 led to an estimate that an additional 35,345 undiagnosed women in England could be reclassified as having a T2D diagnosis.

The authors pointed out that “gender difference in adverse cardiovascular risk factors are known to be present prior to the development of [type 2] diabetes” and that “once diagnosed, atherosclerotic CVD prevalence is twice as high in patients with diabetes ... compared to those without a diagnosis.”

Dr. Heald added that there is always the possibility that other factors might be at play and that the work posed questions rather than presented answers.

Taking a pragmatic view, the researchers suggested that “one alternative approach may be to offer further assessment using fasting plasma glucose or oral glucose tolerance testing in those with A1c values of 46 or 47 mmol/mol.”

“In anyone with an early diagnosis of type 2 diabetes, in addition to dietary modification and especially if there is cardiovascular risk, then one might start them on metformin due to the cardiovascular benefits as well as the sugar-lowering effects,” said Dr. Heald, adding that “we certainly don’t want women missing out on metformin that could have huge benefits in the longer term.”

Dr. Stedman and Dr. Heald declared no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; and no other relationships or activities that could appear to have influenced the submitted work. Dr. Chambers has declared no conflicts.

A version of this article appeared on Medscape.com.

Public perception of disease is everything. “Diabetics” are now referred to as “people living with diabetes,” and an “obese person” is now an “individual living with obesity.”

But what is the definition of obesity? Does it refer to a disease or a risk factor? And is the term so tainted in negativity, blame, and bias that the only solution is to scrap it and completely rename it? Society (and medicine) have changed significantly since the Latin word obesitas was adopted back in the 1600s.

Despite so much hinging on the word “obesity,” it’s remarkable that the label persists while the concepts underpinning it have evolved significantly. So perhaps it is more about finding the least-worst option rather than pursuing the impossibility of a solution that suits all?

This is precisely the challenge faced by a Lancet Diabetes & Endocrinology Commission on the Definition and Diagnosis of Clinical Obesity, which is due to publish its initial findings this coming fall. The global task force has 60 leaders in the clinical management of obesity, including representatives with lived experiences of obesity. Leading the project is Francesco Rubino, MD, chair of metabolic and bariatric surgery at King’s College London.

“Renaming ‘obesity’ is very important,” states Dr. Rubino. “The word is so stigmatized, with so much misunderstanding and misperception, some might say the only solution is to change the name.”

One possibility for a new name, introduced by the American Association of Clinical Endocrinologists (now –Endocrinology) and the American College of Endocrinology back in 2016, was based on framing the disease on the central characteristic of adiposity and was termed ABCD, for adiposity-based chronic disease.

Dr. Rubino welcomes “ABCD” but has some reservations. “It is good from a physiological point of view, but the problem is it speaks to scientists and medical professionals. I don’t know how much it would appeal to the general public. ‘ABCD’ still falls short of telling us what the illness is.”

He adds that the Lancet Commission’s approach is rather to call it “clinical obesity.” “ ‘Obesity’ itself doesn’t necessarily convey the message that you have a disease or an illness,” he observes. “It is similar to the difference in meaning between depression and clinical depression, which communicate two different things.”

But underpinning any renaming is greater clarification of the definition and diagnosis of obesity. In 1997, the World Health Organization recognized obesity as a chronic disease; in 2013, the American Medical Association did likewise, adding that it warranted medical attention; while it took until 2021 for the European Commission to define obesity as a “chronic relapsing disease, which in turn acts as a gateway to a range of other non-communicable diseases.”

Yet, 25 years after the initial recognition of obesity as a disease, the concept is still riddled with negativity, whether openly or unconsciously. Such stigma denigrates overweight people and those with obesity as “lazy, sloppy, unintelligent, and unattractive.”

Dr. Rubino explains that first, it’s important to establish and define the essential components and characteristics of the disease of obesity. This is key to improving access to clinical care, reducing personal blame, and nurturing a more supportive research environment to help inform both clinical and policy decision-making.

“This is the question that is at the core of our commission. We have a problem with the current definition of obesity, and the way we measure it does not allow us to accurately define a state of illness with obesity,” he explains.
 

Labels shape public perceptions of disease; ‘obesity’ epitomizes this

Another expert championing the need for a name that better reflects the definition – whatever that turns out to be – is Margaret Steele, PhD, School of Public Health, University College Cork (Ireland), who, according to her university webpage, has a special interest in “ ‘fatness’ as a cultural, social and political phenomenon.”

She believes that labels, including “obesity,” have a pivotal role in shaping public perceptions. In our digital, information-rich age, the boundaries of medicine and society overlap, with public perception shaping decisions of a medical nature as never before. But with this comes controversy and division – obesity management being a case in point.

Specifically, the word “obesity” is too widely associated with negative connotations, she says, and therefore she welcomes the dialogue around redefining and renaming it. Despite wide general support for a name and definition that reflects adiposity, due to its central physiologic role in the complications of obesity, Dr. Steele believes that the “effects on adipose tissue are downstream of brain issues and the food environment,” and she wants to see more attention brought to this.

Referring to most Westernized societies, she describes how people who grew up in times of food scarcity, before processed foods became widely available, have a different taste profile from those who grew up afterwards. “Growing up in 1940s and ‘50s Ireland, people recall how they remember getting an orange as a treat at Christmas, because the idea that you could have food all year-round – any fruit and veg that you want, when you want it – just wasn’t there.”

By comparison, societal changes leading to more financial and time pressure in later decades meant that fast, high-fat, high-sugar, and processed foods became more desirable, she points out. “Most young children now recognize the company name, and even the specific fast-food brand [they like], before they know their alphabet.”

The current environment has cultivated “a very different physical reaction to foods, maybe a different kind of emotional response,” she believes, highlighting the tightly woven relationship between obesity, society, mental health, and food options.

Dr. Steele wants to stimulate a conversation about the term used to describe individuals, conventionally described as ‘”obese” or using the word “obesity.” “We’re thinking in terms of maybe chronic appetite, chronic food intake, or dietary intake dysregulation.”

Changing medical terminology when it has become useless or harmful is not new, she argues, with co-author, Francis Finucane, MD, consultant endocrinologist at Galway University Hospitals, Ireland, in a recent paper on the subject.

“In the 20th century, the terms ‘feeble-minded’ and ‘moron’ had become used in a pejorative way in the wider culture and were dropped from medical usage,” Dr. Steele points out. She adds that changing the term “obesity” can facilitate pursuit of the strategic goals of clinical medicine “without causing needless controversy with those who, given their own goals and contexts, understand body mass index or body weight in a radically different way.”
 

Obesity: Disease, risk factor, or both?

Dr. Rubino stresses that prior to any renaming, there is a need to establish and define the essential components and characteristics of the disease of obesity. “This question is at the core of our Commission, and it is not an easy conversation to have.” He further explains that the struggle with the current definition of obesity, and the way it is conceived, is largely centered on it still being considered a risk factor for something else.

Disease is characterized by three things, says Dr. Rubino. These comprise the phenomenon of having a pathogenic cause, leading to pathophysiologic alterations (of the organs), causing clinical manifestations.

He adds that obesity is currently described by what it can cause – for example, type 2 diabetes, cancer, or hypertension. “Each of these things have their own clinical manifestations but obesity doesn’t. [As a disease], we don’t have a definition of the clinical manifestations of obesity other than excess adiposity.”

“If we use BMI, this does not predict excess adiposity, nor does it determine a disease here and now. There is no disease without an illness, which is the clinical manifestation, and the perception by the patient of it being an illness,” explains Dr. Rubino, pointing out that the Lancet Commission is filling this gap in knowledge by asking, “If obesity is an illness, then what does it look like?”

He adds that waist circumference probably provides a better measure than BMI in directly indicating the abnormal distribution of adiposity, known to be associated with poor cardiometabolic outcomes, “but it doesn’t tell you if you have an illness here and now – only that someone is at risk of developing cardiovascular disease in the future. Most people with some excess fat around the waist are perfectly functional and don’t feel ill.”

He also explains that confusion persists around whether obesity – or excess adiposity – is a risk factor for or a symptom of another disease. “The picture is blurred, and we do not know how to discriminate between these. We only have one name, and it applies to all those things, and we have one criterion – BMI – to diagnose it!”

Dr. Rubino adds, “So, what defines it? Is it diabetes? No, because that is another disease. You don’t define a disease by another. It has to stand on its own.”

Recently, the American Medical Association advised that BMI now be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.

Aayush Visaria, MD, an internal medicine resident at Rutgers University, New Brunswick, New Jersey, agrees that a new name might help change public perception of obesity for the better. A study he presented at the 2023 Endocrine Society Meeting found that BMI “vastly underestimates” obesity.

He agrees with Dr. Rubino that the challenge lies in the lack of precise understanding of the mechanisms driving obesity: “It’s multifactorial, so not just appetite or food intake. Putting this into one phrase is difficult.”

However, if a new term can incorporate the many facets of the disease, “overall, it’ll reduce stigma because we’ll start to think about obesity as a disease process, not a personal thing with blame attached,” says Dr. Visaria.

But simultaneously, he expresses caution around possible negative connotations associated with the classification of obesity as a disease. Dr. Steele also reflects on this risk, highlighting that medicalizing body size can be counterproductive in feeding into weight stigma and fatphobia.

“Medicalizing obesity can be discouraging rather than empowering, but by specifying more clearly that we’re talking about a specific set of interrelated metabolic conditions, it would make it much clearer, and that ... this isn’t about making people skinny, it isn’t about an aesthetic thing,” Dr. Steele observes.
 

The word ‘obesity’ hinders disease explanations

Dr. Steele explains that her goal is to overcome the ambiguity around the word “obesity” that hinders explanations of the disease of obesity to the wider public.

“Much confusion and controversy might be avoided if we were to clarify that when doctors say that obesity is a disease, they do not mean that being ‘fat’ is a disease.”

Nevertheless, adipose tissue is an active endocrine organ, producing hormones that function less well in people with obesity, she notes. “This new knowledge has led to better treatments, including drugs like semaglutide and tirzepatide. These drugs, like bariatric surgery, typically lead to significant weight loss and to improvements in overall metabolic health.”

Dr. Rubino also expresses concerns around medicalization, as determined by definition and diagnosis and the availability of drug treatment that could potentially lead to overtreatment. “Currently, when everyone with a BMI of greater than 30 gets access to every obesity treatment out there, we see drugs are running out of stock. We should prioritize that treatment.”

Ultimately, the diagnosis of obesity as a disease needs an anthropometric biomarker that provides, on an individual level, the confidence that a person has a disease today, or at least close to a 100% likelihood of developing this disease and illness, asserts Dr. Rubino.

“If we use BMI, or even waist circumference, these might diagnose the disease; but if the person lives to 90 years, what’s the point of labeling somebody as having an illness?” he points out.

“As doctors, we have to be cautious. We say this is a disease, but you must think about the implications for the person on the receiving end of that diagnosis of a chronic disease that is substantially incurable. When we say it, we need to be certain.”

Dr. Steele and Dr. Visaria have disclosed no relevant financial relationships. Dr. Rubino disclosed that he has received research grants from Novo Nordisk, Medtronic, and Johnson & Johnson. He has undertaken paid consultancy work for GI Dynamics and received honoraria for lectures from Medtronic, Novo Nordisk, and Johnson & Johnson. He is a member of the data safety monitoring board for GT Metabolic Solutions and has provided scientific advice to Keyron, Metadeq, GHP Scientific, and ViBo Health for no remuneration.

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

Public perception of disease is everything. “Diabetics” are now referred to as “people living with diabetes,” and an “obese person” is now an “individual living with obesity.”

But what is the definition of obesity? Does it refer to a disease or a risk factor? And is the term so tainted in negativity, blame, and bias that the only solution is to scrap it and completely rename it? Society (and medicine) have changed significantly since the Latin word obesitas was adopted back in the 1600s.

Despite so much hinging on the word “obesity,” it’s remarkable that the label persists while the concepts underpinning it have evolved significantly. So perhaps it is more about finding the least-worst option rather than pursuing the impossibility of a solution that suits all?

This is precisely the challenge faced by a Lancet Diabetes & Endocrinology Commission on the Definition and Diagnosis of Clinical Obesity, which is due to publish its initial findings this coming fall. The global task force has 60 leaders in the clinical management of obesity, including representatives with lived experiences of obesity. Leading the project is Francesco Rubino, MD, chair of metabolic and bariatric surgery at King’s College London.

“Renaming ‘obesity’ is very important,” states Dr. Rubino. “The word is so stigmatized, with so much misunderstanding and misperception, some might say the only solution is to change the name.”

One possibility for a new name, introduced by the American Association of Clinical Endocrinologists (now –Endocrinology) and the American College of Endocrinology back in 2016, was based on framing the disease on the central characteristic of adiposity and was termed ABCD, for adiposity-based chronic disease.

Dr. Rubino welcomes “ABCD” but has some reservations. “It is good from a physiological point of view, but the problem is it speaks to scientists and medical professionals. I don’t know how much it would appeal to the general public. ‘ABCD’ still falls short of telling us what the illness is.”

He adds that the Lancet Commission’s approach is rather to call it “clinical obesity.” “ ‘Obesity’ itself doesn’t necessarily convey the message that you have a disease or an illness,” he observes. “It is similar to the difference in meaning between depression and clinical depression, which communicate two different things.”

But underpinning any renaming is greater clarification of the definition and diagnosis of obesity. In 1997, the World Health Organization recognized obesity as a chronic disease; in 2013, the American Medical Association did likewise, adding that it warranted medical attention; while it took until 2021 for the European Commission to define obesity as a “chronic relapsing disease, which in turn acts as a gateway to a range of other non-communicable diseases.”

Yet, 25 years after the initial recognition of obesity as a disease, the concept is still riddled with negativity, whether openly or unconsciously. Such stigma denigrates overweight people and those with obesity as “lazy, sloppy, unintelligent, and unattractive.”

Dr. Rubino explains that first, it’s important to establish and define the essential components and characteristics of the disease of obesity. This is key to improving access to clinical care, reducing personal blame, and nurturing a more supportive research environment to help inform both clinical and policy decision-making.

“This is the question that is at the core of our commission. We have a problem with the current definition of obesity, and the way we measure it does not allow us to accurately define a state of illness with obesity,” he explains.
 

Labels shape public perceptions of disease; ‘obesity’ epitomizes this

Another expert championing the need for a name that better reflects the definition – whatever that turns out to be – is Margaret Steele, PhD, School of Public Health, University College Cork (Ireland), who, according to her university webpage, has a special interest in “ ‘fatness’ as a cultural, social and political phenomenon.”

She believes that labels, including “obesity,” have a pivotal role in shaping public perceptions. In our digital, information-rich age, the boundaries of medicine and society overlap, with public perception shaping decisions of a medical nature as never before. But with this comes controversy and division – obesity management being a case in point.

Specifically, the word “obesity” is too widely associated with negative connotations, she says, and therefore she welcomes the dialogue around redefining and renaming it. Despite wide general support for a name and definition that reflects adiposity, due to its central physiologic role in the complications of obesity, Dr. Steele believes that the “effects on adipose tissue are downstream of brain issues and the food environment,” and she wants to see more attention brought to this.

Referring to most Westernized societies, she describes how people who grew up in times of food scarcity, before processed foods became widely available, have a different taste profile from those who grew up afterwards. “Growing up in 1940s and ‘50s Ireland, people recall how they remember getting an orange as a treat at Christmas, because the idea that you could have food all year-round – any fruit and veg that you want, when you want it – just wasn’t there.”

By comparison, societal changes leading to more financial and time pressure in later decades meant that fast, high-fat, high-sugar, and processed foods became more desirable, she points out. “Most young children now recognize the company name, and even the specific fast-food brand [they like], before they know their alphabet.”

The current environment has cultivated “a very different physical reaction to foods, maybe a different kind of emotional response,” she believes, highlighting the tightly woven relationship between obesity, society, mental health, and food options.

Dr. Steele wants to stimulate a conversation about the term used to describe individuals, conventionally described as ‘”obese” or using the word “obesity.” “We’re thinking in terms of maybe chronic appetite, chronic food intake, or dietary intake dysregulation.”

Changing medical terminology when it has become useless or harmful is not new, she argues, with co-author, Francis Finucane, MD, consultant endocrinologist at Galway University Hospitals, Ireland, in a recent paper on the subject.

“In the 20th century, the terms ‘feeble-minded’ and ‘moron’ had become used in a pejorative way in the wider culture and were dropped from medical usage,” Dr. Steele points out. She adds that changing the term “obesity” can facilitate pursuit of the strategic goals of clinical medicine “without causing needless controversy with those who, given their own goals and contexts, understand body mass index or body weight in a radically different way.”
 

Obesity: Disease, risk factor, or both?

Dr. Rubino stresses that prior to any renaming, there is a need to establish and define the essential components and characteristics of the disease of obesity. “This question is at the core of our Commission, and it is not an easy conversation to have.” He further explains that the struggle with the current definition of obesity, and the way it is conceived, is largely centered on it still being considered a risk factor for something else.

Disease is characterized by three things, says Dr. Rubino. These comprise the phenomenon of having a pathogenic cause, leading to pathophysiologic alterations (of the organs), causing clinical manifestations.

He adds that obesity is currently described by what it can cause – for example, type 2 diabetes, cancer, or hypertension. “Each of these things have their own clinical manifestations but obesity doesn’t. [As a disease], we don’t have a definition of the clinical manifestations of obesity other than excess adiposity.”

“If we use BMI, this does not predict excess adiposity, nor does it determine a disease here and now. There is no disease without an illness, which is the clinical manifestation, and the perception by the patient of it being an illness,” explains Dr. Rubino, pointing out that the Lancet Commission is filling this gap in knowledge by asking, “If obesity is an illness, then what does it look like?”

He adds that waist circumference probably provides a better measure than BMI in directly indicating the abnormal distribution of adiposity, known to be associated with poor cardiometabolic outcomes, “but it doesn’t tell you if you have an illness here and now – only that someone is at risk of developing cardiovascular disease in the future. Most people with some excess fat around the waist are perfectly functional and don’t feel ill.”

He also explains that confusion persists around whether obesity – or excess adiposity – is a risk factor for or a symptom of another disease. “The picture is blurred, and we do not know how to discriminate between these. We only have one name, and it applies to all those things, and we have one criterion – BMI – to diagnose it!”

Dr. Rubino adds, “So, what defines it? Is it diabetes? No, because that is another disease. You don’t define a disease by another. It has to stand on its own.”

Recently, the American Medical Association advised that BMI now be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.

Aayush Visaria, MD, an internal medicine resident at Rutgers University, New Brunswick, New Jersey, agrees that a new name might help change public perception of obesity for the better. A study he presented at the 2023 Endocrine Society Meeting found that BMI “vastly underestimates” obesity.

He agrees with Dr. Rubino that the challenge lies in the lack of precise understanding of the mechanisms driving obesity: “It’s multifactorial, so not just appetite or food intake. Putting this into one phrase is difficult.”

However, if a new term can incorporate the many facets of the disease, “overall, it’ll reduce stigma because we’ll start to think about obesity as a disease process, not a personal thing with blame attached,” says Dr. Visaria.

But simultaneously, he expresses caution around possible negative connotations associated with the classification of obesity as a disease. Dr. Steele also reflects on this risk, highlighting that medicalizing body size can be counterproductive in feeding into weight stigma and fatphobia.

“Medicalizing obesity can be discouraging rather than empowering, but by specifying more clearly that we’re talking about a specific set of interrelated metabolic conditions, it would make it much clearer, and that ... this isn’t about making people skinny, it isn’t about an aesthetic thing,” Dr. Steele observes.
 

The word ‘obesity’ hinders disease explanations

Dr. Steele explains that her goal is to overcome the ambiguity around the word “obesity” that hinders explanations of the disease of obesity to the wider public.

“Much confusion and controversy might be avoided if we were to clarify that when doctors say that obesity is a disease, they do not mean that being ‘fat’ is a disease.”

Nevertheless, adipose tissue is an active endocrine organ, producing hormones that function less well in people with obesity, she notes. “This new knowledge has led to better treatments, including drugs like semaglutide and tirzepatide. These drugs, like bariatric surgery, typically lead to significant weight loss and to improvements in overall metabolic health.”

Dr. Rubino also expresses concerns around medicalization, as determined by definition and diagnosis and the availability of drug treatment that could potentially lead to overtreatment. “Currently, when everyone with a BMI of greater than 30 gets access to every obesity treatment out there, we see drugs are running out of stock. We should prioritize that treatment.”

Ultimately, the diagnosis of obesity as a disease needs an anthropometric biomarker that provides, on an individual level, the confidence that a person has a disease today, or at least close to a 100% likelihood of developing this disease and illness, asserts Dr. Rubino.

“If we use BMI, or even waist circumference, these might diagnose the disease; but if the person lives to 90 years, what’s the point of labeling somebody as having an illness?” he points out.

“As doctors, we have to be cautious. We say this is a disease, but you must think about the implications for the person on the receiving end of that diagnosis of a chronic disease that is substantially incurable. When we say it, we need to be certain.”

Dr. Steele and Dr. Visaria have disclosed no relevant financial relationships. Dr. Rubino disclosed that he has received research grants from Novo Nordisk, Medtronic, and Johnson & Johnson. He has undertaken paid consultancy work for GI Dynamics and received honoraria for lectures from Medtronic, Novo Nordisk, and Johnson & Johnson. He is a member of the data safety monitoring board for GT Metabolic Solutions and has provided scientific advice to Keyron, Metadeq, GHP Scientific, and ViBo Health for no remuneration.

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

Public perception of disease is everything. “Diabetics” are now referred to as “people living with diabetes,” and an “obese person” is now an “individual living with obesity.”

But what is the definition of obesity? Does it refer to a disease or a risk factor? And is the term so tainted in negativity, blame, and bias that the only solution is to scrap it and completely rename it? Society (and medicine) have changed significantly since the Latin word obesitas was adopted back in the 1600s.

Despite so much hinging on the word “obesity,” it’s remarkable that the label persists while the concepts underpinning it have evolved significantly. So perhaps it is more about finding the least-worst option rather than pursuing the impossibility of a solution that suits all?

This is precisely the challenge faced by a Lancet Diabetes & Endocrinology Commission on the Definition and Diagnosis of Clinical Obesity, which is due to publish its initial findings this coming fall. The global task force has 60 leaders in the clinical management of obesity, including representatives with lived experiences of obesity. Leading the project is Francesco Rubino, MD, chair of metabolic and bariatric surgery at King’s College London.

“Renaming ‘obesity’ is very important,” states Dr. Rubino. “The word is so stigmatized, with so much misunderstanding and misperception, some might say the only solution is to change the name.”

One possibility for a new name, introduced by the American Association of Clinical Endocrinologists (now –Endocrinology) and the American College of Endocrinology back in 2016, was based on framing the disease on the central characteristic of adiposity and was termed ABCD, for adiposity-based chronic disease.

Dr. Rubino welcomes “ABCD” but has some reservations. “It is good from a physiological point of view, but the problem is it speaks to scientists and medical professionals. I don’t know how much it would appeal to the general public. ‘ABCD’ still falls short of telling us what the illness is.”

He adds that the Lancet Commission’s approach is rather to call it “clinical obesity.” “ ‘Obesity’ itself doesn’t necessarily convey the message that you have a disease or an illness,” he observes. “It is similar to the difference in meaning between depression and clinical depression, which communicate two different things.”

But underpinning any renaming is greater clarification of the definition and diagnosis of obesity. In 1997, the World Health Organization recognized obesity as a chronic disease; in 2013, the American Medical Association did likewise, adding that it warranted medical attention; while it took until 2021 for the European Commission to define obesity as a “chronic relapsing disease, which in turn acts as a gateway to a range of other non-communicable diseases.”

Yet, 25 years after the initial recognition of obesity as a disease, the concept is still riddled with negativity, whether openly or unconsciously. Such stigma denigrates overweight people and those with obesity as “lazy, sloppy, unintelligent, and unattractive.”

Dr. Rubino explains that first, it’s important to establish and define the essential components and characteristics of the disease of obesity. This is key to improving access to clinical care, reducing personal blame, and nurturing a more supportive research environment to help inform both clinical and policy decision-making.

“This is the question that is at the core of our commission. We have a problem with the current definition of obesity, and the way we measure it does not allow us to accurately define a state of illness with obesity,” he explains.
 

Labels shape public perceptions of disease; ‘obesity’ epitomizes this

Another expert championing the need for a name that better reflects the definition – whatever that turns out to be – is Margaret Steele, PhD, School of Public Health, University College Cork (Ireland), who, according to her university webpage, has a special interest in “ ‘fatness’ as a cultural, social and political phenomenon.”

She believes that labels, including “obesity,” have a pivotal role in shaping public perceptions. In our digital, information-rich age, the boundaries of medicine and society overlap, with public perception shaping decisions of a medical nature as never before. But with this comes controversy and division – obesity management being a case in point.

Specifically, the word “obesity” is too widely associated with negative connotations, she says, and therefore she welcomes the dialogue around redefining and renaming it. Despite wide general support for a name and definition that reflects adiposity, due to its central physiologic role in the complications of obesity, Dr. Steele believes that the “effects on adipose tissue are downstream of brain issues and the food environment,” and she wants to see more attention brought to this.

Referring to most Westernized societies, she describes how people who grew up in times of food scarcity, before processed foods became widely available, have a different taste profile from those who grew up afterwards. “Growing up in 1940s and ‘50s Ireland, people recall how they remember getting an orange as a treat at Christmas, because the idea that you could have food all year-round – any fruit and veg that you want, when you want it – just wasn’t there.”

By comparison, societal changes leading to more financial and time pressure in later decades meant that fast, high-fat, high-sugar, and processed foods became more desirable, she points out. “Most young children now recognize the company name, and even the specific fast-food brand [they like], before they know their alphabet.”

The current environment has cultivated “a very different physical reaction to foods, maybe a different kind of emotional response,” she believes, highlighting the tightly woven relationship between obesity, society, mental health, and food options.

Dr. Steele wants to stimulate a conversation about the term used to describe individuals, conventionally described as ‘”obese” or using the word “obesity.” “We’re thinking in terms of maybe chronic appetite, chronic food intake, or dietary intake dysregulation.”

Changing medical terminology when it has become useless or harmful is not new, she argues, with co-author, Francis Finucane, MD, consultant endocrinologist at Galway University Hospitals, Ireland, in a recent paper on the subject.

“In the 20th century, the terms ‘feeble-minded’ and ‘moron’ had become used in a pejorative way in the wider culture and were dropped from medical usage,” Dr. Steele points out. She adds that changing the term “obesity” can facilitate pursuit of the strategic goals of clinical medicine “without causing needless controversy with those who, given their own goals and contexts, understand body mass index or body weight in a radically different way.”
 

Obesity: Disease, risk factor, or both?

Dr. Rubino stresses that prior to any renaming, there is a need to establish and define the essential components and characteristics of the disease of obesity. “This question is at the core of our Commission, and it is not an easy conversation to have.” He further explains that the struggle with the current definition of obesity, and the way it is conceived, is largely centered on it still being considered a risk factor for something else.

Disease is characterized by three things, says Dr. Rubino. These comprise the phenomenon of having a pathogenic cause, leading to pathophysiologic alterations (of the organs), causing clinical manifestations.

He adds that obesity is currently described by what it can cause – for example, type 2 diabetes, cancer, or hypertension. “Each of these things have their own clinical manifestations but obesity doesn’t. [As a disease], we don’t have a definition of the clinical manifestations of obesity other than excess adiposity.”

“If we use BMI, this does not predict excess adiposity, nor does it determine a disease here and now. There is no disease without an illness, which is the clinical manifestation, and the perception by the patient of it being an illness,” explains Dr. Rubino, pointing out that the Lancet Commission is filling this gap in knowledge by asking, “If obesity is an illness, then what does it look like?”

He adds that waist circumference probably provides a better measure than BMI in directly indicating the abnormal distribution of adiposity, known to be associated with poor cardiometabolic outcomes, “but it doesn’t tell you if you have an illness here and now – only that someone is at risk of developing cardiovascular disease in the future. Most people with some excess fat around the waist are perfectly functional and don’t feel ill.”

He also explains that confusion persists around whether obesity – or excess adiposity – is a risk factor for or a symptom of another disease. “The picture is blurred, and we do not know how to discriminate between these. We only have one name, and it applies to all those things, and we have one criterion – BMI – to diagnose it!”

Dr. Rubino adds, “So, what defines it? Is it diabetes? No, because that is another disease. You don’t define a disease by another. It has to stand on its own.”

Recently, the American Medical Association advised that BMI now be used in conjunction with other valid measures of risk such as, but not limited to, measurements of visceral fat, body adiposity index, body composition, relative fat mass, waist circumference, and genetic/metabolic factors.

Aayush Visaria, MD, an internal medicine resident at Rutgers University, New Brunswick, New Jersey, agrees that a new name might help change public perception of obesity for the better. A study he presented at the 2023 Endocrine Society Meeting found that BMI “vastly underestimates” obesity.

He agrees with Dr. Rubino that the challenge lies in the lack of precise understanding of the mechanisms driving obesity: “It’s multifactorial, so not just appetite or food intake. Putting this into one phrase is difficult.”

However, if a new term can incorporate the many facets of the disease, “overall, it’ll reduce stigma because we’ll start to think about obesity as a disease process, not a personal thing with blame attached,” says Dr. Visaria.

But simultaneously, he expresses caution around possible negative connotations associated with the classification of obesity as a disease. Dr. Steele also reflects on this risk, highlighting that medicalizing body size can be counterproductive in feeding into weight stigma and fatphobia.

“Medicalizing obesity can be discouraging rather than empowering, but by specifying more clearly that we’re talking about a specific set of interrelated metabolic conditions, it would make it much clearer, and that ... this isn’t about making people skinny, it isn’t about an aesthetic thing,” Dr. Steele observes.
 

The word ‘obesity’ hinders disease explanations

Dr. Steele explains that her goal is to overcome the ambiguity around the word “obesity” that hinders explanations of the disease of obesity to the wider public.

“Much confusion and controversy might be avoided if we were to clarify that when doctors say that obesity is a disease, they do not mean that being ‘fat’ is a disease.”

Nevertheless, adipose tissue is an active endocrine organ, producing hormones that function less well in people with obesity, she notes. “This new knowledge has led to better treatments, including drugs like semaglutide and tirzepatide. These drugs, like bariatric surgery, typically lead to significant weight loss and to improvements in overall metabolic health.”

Dr. Rubino also expresses concerns around medicalization, as determined by definition and diagnosis and the availability of drug treatment that could potentially lead to overtreatment. “Currently, when everyone with a BMI of greater than 30 gets access to every obesity treatment out there, we see drugs are running out of stock. We should prioritize that treatment.”

Ultimately, the diagnosis of obesity as a disease needs an anthropometric biomarker that provides, on an individual level, the confidence that a person has a disease today, or at least close to a 100% likelihood of developing this disease and illness, asserts Dr. Rubino.

“If we use BMI, or even waist circumference, these might diagnose the disease; but if the person lives to 90 years, what’s the point of labeling somebody as having an illness?” he points out.

“As doctors, we have to be cautious. We say this is a disease, but you must think about the implications for the person on the receiving end of that diagnosis of a chronic disease that is substantially incurable. When we say it, we need to be certain.”

Dr. Steele and Dr. Visaria have disclosed no relevant financial relationships. Dr. Rubino disclosed that he has received research grants from Novo Nordisk, Medtronic, and Johnson & Johnson. He has undertaken paid consultancy work for GI Dynamics and received honoraria for lectures from Medtronic, Novo Nordisk, and Johnson & Johnson. He is a member of the data safety monitoring board for GT Metabolic Solutions and has provided scientific advice to Keyron, Metadeq, GHP Scientific, and ViBo Health for no remuneration.

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