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GERD with bronchiectasis: New invasive interventions show benefit
NEW YORK – Newer invasive procedures for gastroesophageal reflux disease (GERD) are associated with lower risks of postprocedural complications when performed to improve control of bronchiectasis or other serious lung diseases, according to a surgeon who addressed the 6th World Bronchiectasis & NTM Conference.
“The options are not what they were 20 or 30 years ago,” according to Tanuja Damani, MD, surgical director of the Center for Esophageal and Foregut Health, NYU Langone Health, New York.
The more favorable benefit-to-risk ratio of the newer options might make them more attractive to consider earlier for control of GERD in worsening lung disease than interventions have in the past, Dr. Damani suggested.
The association between the presence of GERD and increased severity of bronchiectasis or many other lung diseases is well established, according to Dr. Damani. In the case of bronchiectasis, GERD not only impairs lung function and quality of life, but is strongly linked to greater symptom burden, more exacerbations, more hospitalizations, and even increased mortality.
Proton pump inhibitors (PPIs) are effective in reducing intragastric acid, a source of irritation and discomfort when the contents of the stomach are refluxed past the lower esophageal sphincter (LES), but Dr. Damani explained that this therapy is often inadequate. Control of intragastric acid is an oversimplification of a more complex pathophysiology.
“It is not just the lower esophageal sphincter,” she said, explaining that other factors, particularly hiatal hernias that often contribute to transient LES relaxations, can play an important role in postprandial transit of gastric contents into the esophagus.
“Any procedure aimed at reinforcing just the LES [without addressing other mechanisms of GERD] are destined to fail,” Dr. Damani said.
She backed up this assertion with examples. These include the many endoscopic procedures designed to strengthen the barrier function of the LES, such as the Stretta procedure or transoral incisionless fundoplication (TIF). Neither addresses the hiatal hernia. Both typically provide immediate symptom relief, but acid in the lower esophagus and symptoms return over time. This has been shown with pH testing, which Dr. Damani called the gold standard for monitoring GERD control.
In procedures that function only by supporting the barrier function of the LES, symptoms typically recur in 6-12 months, requiring resumption of PPIs, if they were ever discontinued, Dr. Damani said. They also include the return of the complications of GERD in lung disease, which includes the damage to lung tissue associated with aspiration of acid as well as the extraesophageal symptoms, including cough, laryngitis and chest pain.
Nissen fundoplication performed with hiatal hernia repair was long regarded as the gold standard for surgical management of GERD, but this is now changing, according to Dr. Damani. She said most centers, including her own, are moving from this to the related Toupet fundoplication, which differs primarily by its use of a 270-degree rather than a 360-degree fundoplication.
By incompletely wrapping the esophagus with the gastric fundus, “the benefit is the same, but the risk of adverse events is much lower,” said Dr. Damani, referring to the bloating, flatulence, and discomfort experienced by some patients following the Nissen procedure. “It is now our operation of choice.”
This Toupet fundoplication, like the Nissen, can be performed laparoscopically or robotically, according to Dr. Damani, who said that efficacy and safety are achieved at a very high rate of consistency in high-volume centers.
However, Dr. Damani also reported that there has been progress with endoscopic approaches and reversible interventions for GERD. These expand the array of options and might be particularly attractive in patients who are poor candidates for surgery or those seeking a reversible intervention.
Of these options, Dr. Damani paid particular attention to the Linx reflux management system. This device is composed of a chain of titanium beads with a magnetic cord that are looped around the lower esophagus to add a barrier function. The level of the magnetic force allows the chain of beads to expand when food descends or gas rises but prevents transient LES relaxations. As a result of its ability to expand and contract, the device is “very dynamic,” Dr. Damani said.
Prior to placement of the device, “the hiatal hernia is dissected and closed like other effective procedures. Then the Linx device is sized and placed,” Dr. Damani explained. Importantly, this procedure can be reversed simply by removing the device.
“There is no side-by-side comparison with a Nissen, but the results have been excellent so far,” Dr. Damani said. The most significant concern is foreign body reactions, but the erosion rates have been reported as less than 0.1%, according to Dr. Damani, who noted that erosion, if it occurs, can be managed endoscopically.
She did caution that candidates for the Linx device must have normal esophageal motility and be free of metal allergies, but she has been impressed with its durable function.
Perhaps the most difficult question in assessing and treating GERD in the context of bronchiectasis is to determine when it is needed. Dr. Damani warned that many patients with lung disease exacerbated by GERD are asymptomatic, requiring a workup to determine if GERD is present. Even if present, it can be challenging to confirm that GERD is a major treatable contributor to poor lung function.
Illustrative of that point, Doreen J. Addrizzo-Harris, MD, codirector of the NYU Langone Health bronchiectasis & NTM clinical and translational program, and President of American College of Chest Physicians, described a patient with advanced bronchiectasis whose poorly controlled lung function had not been considered to be GERD related even though the patent had been inadequately responsive to multiple aggressive treatment strategies. The decision to surgically correct GERD was taken on the basis of diminishing alternative options.
“The improvement in lung function was substantial and rapid,” she said.
Dr. Addrizzo-Harris, who served as a chair of the 2023 World Bronchiectasis & NTM Conference, recounted this case to support the major potential improvements in selected patients with advanced lung disease when GERD is treated. She indicated that even experts overlook this variable.
This still does not answer the question of when to consider an invasive procedure for GERD, but “there is no hard and fast answer,” according to David Kamelhar, MD, who is the other codirector of the NYU Langone Health bronchiectasis & NTM clinical and translational program.
Dr. Kamelhar admitted that he does not immediately think of GERD as a strategy to control lung disease treatable in patients without GERD-related symptoms, but he has pursued this comorbidity in cases when he has “nothing else to offer.” He suggested that multidisciplinary management is one way to consider GERD as treatment target before it becomes a last resort.
As pulmonologists, “we are not GERD experts, so we need to bring in a gastroenterologist or a surgeon who can help with this decision,” he said, referring to when and how to intervene.
From Dr. Damani’s talk, he suggested that the take-home message is that GERD treatment options have improved, and it might make more sense to consider GERD as a treatable comorbidity of lung disease in earlier rather than later stages of disease.
Dr. Damani, Dr. Addrizzo-Harris, and Dr. Kamelhar reported having no potential conflicts of interest relevant to this topic.
NEW YORK – Newer invasive procedures for gastroesophageal reflux disease (GERD) are associated with lower risks of postprocedural complications when performed to improve control of bronchiectasis or other serious lung diseases, according to a surgeon who addressed the 6th World Bronchiectasis & NTM Conference.
“The options are not what they were 20 or 30 years ago,” according to Tanuja Damani, MD, surgical director of the Center for Esophageal and Foregut Health, NYU Langone Health, New York.
The more favorable benefit-to-risk ratio of the newer options might make them more attractive to consider earlier for control of GERD in worsening lung disease than interventions have in the past, Dr. Damani suggested.
The association between the presence of GERD and increased severity of bronchiectasis or many other lung diseases is well established, according to Dr. Damani. In the case of bronchiectasis, GERD not only impairs lung function and quality of life, but is strongly linked to greater symptom burden, more exacerbations, more hospitalizations, and even increased mortality.
Proton pump inhibitors (PPIs) are effective in reducing intragastric acid, a source of irritation and discomfort when the contents of the stomach are refluxed past the lower esophageal sphincter (LES), but Dr. Damani explained that this therapy is often inadequate. Control of intragastric acid is an oversimplification of a more complex pathophysiology.
“It is not just the lower esophageal sphincter,” she said, explaining that other factors, particularly hiatal hernias that often contribute to transient LES relaxations, can play an important role in postprandial transit of gastric contents into the esophagus.
“Any procedure aimed at reinforcing just the LES [without addressing other mechanisms of GERD] are destined to fail,” Dr. Damani said.
She backed up this assertion with examples. These include the many endoscopic procedures designed to strengthen the barrier function of the LES, such as the Stretta procedure or transoral incisionless fundoplication (TIF). Neither addresses the hiatal hernia. Both typically provide immediate symptom relief, but acid in the lower esophagus and symptoms return over time. This has been shown with pH testing, which Dr. Damani called the gold standard for monitoring GERD control.
In procedures that function only by supporting the barrier function of the LES, symptoms typically recur in 6-12 months, requiring resumption of PPIs, if they were ever discontinued, Dr. Damani said. They also include the return of the complications of GERD in lung disease, which includes the damage to lung tissue associated with aspiration of acid as well as the extraesophageal symptoms, including cough, laryngitis and chest pain.
Nissen fundoplication performed with hiatal hernia repair was long regarded as the gold standard for surgical management of GERD, but this is now changing, according to Dr. Damani. She said most centers, including her own, are moving from this to the related Toupet fundoplication, which differs primarily by its use of a 270-degree rather than a 360-degree fundoplication.
By incompletely wrapping the esophagus with the gastric fundus, “the benefit is the same, but the risk of adverse events is much lower,” said Dr. Damani, referring to the bloating, flatulence, and discomfort experienced by some patients following the Nissen procedure. “It is now our operation of choice.”
This Toupet fundoplication, like the Nissen, can be performed laparoscopically or robotically, according to Dr. Damani, who said that efficacy and safety are achieved at a very high rate of consistency in high-volume centers.
However, Dr. Damani also reported that there has been progress with endoscopic approaches and reversible interventions for GERD. These expand the array of options and might be particularly attractive in patients who are poor candidates for surgery or those seeking a reversible intervention.
Of these options, Dr. Damani paid particular attention to the Linx reflux management system. This device is composed of a chain of titanium beads with a magnetic cord that are looped around the lower esophagus to add a barrier function. The level of the magnetic force allows the chain of beads to expand when food descends or gas rises but prevents transient LES relaxations. As a result of its ability to expand and contract, the device is “very dynamic,” Dr. Damani said.
Prior to placement of the device, “the hiatal hernia is dissected and closed like other effective procedures. Then the Linx device is sized and placed,” Dr. Damani explained. Importantly, this procedure can be reversed simply by removing the device.
“There is no side-by-side comparison with a Nissen, but the results have been excellent so far,” Dr. Damani said. The most significant concern is foreign body reactions, but the erosion rates have been reported as less than 0.1%, according to Dr. Damani, who noted that erosion, if it occurs, can be managed endoscopically.
She did caution that candidates for the Linx device must have normal esophageal motility and be free of metal allergies, but she has been impressed with its durable function.
Perhaps the most difficult question in assessing and treating GERD in the context of bronchiectasis is to determine when it is needed. Dr. Damani warned that many patients with lung disease exacerbated by GERD are asymptomatic, requiring a workup to determine if GERD is present. Even if present, it can be challenging to confirm that GERD is a major treatable contributor to poor lung function.
Illustrative of that point, Doreen J. Addrizzo-Harris, MD, codirector of the NYU Langone Health bronchiectasis & NTM clinical and translational program, and President of American College of Chest Physicians, described a patient with advanced bronchiectasis whose poorly controlled lung function had not been considered to be GERD related even though the patent had been inadequately responsive to multiple aggressive treatment strategies. The decision to surgically correct GERD was taken on the basis of diminishing alternative options.
“The improvement in lung function was substantial and rapid,” she said.
Dr. Addrizzo-Harris, who served as a chair of the 2023 World Bronchiectasis & NTM Conference, recounted this case to support the major potential improvements in selected patients with advanced lung disease when GERD is treated. She indicated that even experts overlook this variable.
This still does not answer the question of when to consider an invasive procedure for GERD, but “there is no hard and fast answer,” according to David Kamelhar, MD, who is the other codirector of the NYU Langone Health bronchiectasis & NTM clinical and translational program.
Dr. Kamelhar admitted that he does not immediately think of GERD as a strategy to control lung disease treatable in patients without GERD-related symptoms, but he has pursued this comorbidity in cases when he has “nothing else to offer.” He suggested that multidisciplinary management is one way to consider GERD as treatment target before it becomes a last resort.
As pulmonologists, “we are not GERD experts, so we need to bring in a gastroenterologist or a surgeon who can help with this decision,” he said, referring to when and how to intervene.
From Dr. Damani’s talk, he suggested that the take-home message is that GERD treatment options have improved, and it might make more sense to consider GERD as a treatable comorbidity of lung disease in earlier rather than later stages of disease.
Dr. Damani, Dr. Addrizzo-Harris, and Dr. Kamelhar reported having no potential conflicts of interest relevant to this topic.
NEW YORK – Newer invasive procedures for gastroesophageal reflux disease (GERD) are associated with lower risks of postprocedural complications when performed to improve control of bronchiectasis or other serious lung diseases, according to a surgeon who addressed the 6th World Bronchiectasis & NTM Conference.
“The options are not what they were 20 or 30 years ago,” according to Tanuja Damani, MD, surgical director of the Center for Esophageal and Foregut Health, NYU Langone Health, New York.
The more favorable benefit-to-risk ratio of the newer options might make them more attractive to consider earlier for control of GERD in worsening lung disease than interventions have in the past, Dr. Damani suggested.
The association between the presence of GERD and increased severity of bronchiectasis or many other lung diseases is well established, according to Dr. Damani. In the case of bronchiectasis, GERD not only impairs lung function and quality of life, but is strongly linked to greater symptom burden, more exacerbations, more hospitalizations, and even increased mortality.
Proton pump inhibitors (PPIs) are effective in reducing intragastric acid, a source of irritation and discomfort when the contents of the stomach are refluxed past the lower esophageal sphincter (LES), but Dr. Damani explained that this therapy is often inadequate. Control of intragastric acid is an oversimplification of a more complex pathophysiology.
“It is not just the lower esophageal sphincter,” she said, explaining that other factors, particularly hiatal hernias that often contribute to transient LES relaxations, can play an important role in postprandial transit of gastric contents into the esophagus.
“Any procedure aimed at reinforcing just the LES [without addressing other mechanisms of GERD] are destined to fail,” Dr. Damani said.
She backed up this assertion with examples. These include the many endoscopic procedures designed to strengthen the barrier function of the LES, such as the Stretta procedure or transoral incisionless fundoplication (TIF). Neither addresses the hiatal hernia. Both typically provide immediate symptom relief, but acid in the lower esophagus and symptoms return over time. This has been shown with pH testing, which Dr. Damani called the gold standard for monitoring GERD control.
In procedures that function only by supporting the barrier function of the LES, symptoms typically recur in 6-12 months, requiring resumption of PPIs, if they were ever discontinued, Dr. Damani said. They also include the return of the complications of GERD in lung disease, which includes the damage to lung tissue associated with aspiration of acid as well as the extraesophageal symptoms, including cough, laryngitis and chest pain.
Nissen fundoplication performed with hiatal hernia repair was long regarded as the gold standard for surgical management of GERD, but this is now changing, according to Dr. Damani. She said most centers, including her own, are moving from this to the related Toupet fundoplication, which differs primarily by its use of a 270-degree rather than a 360-degree fundoplication.
By incompletely wrapping the esophagus with the gastric fundus, “the benefit is the same, but the risk of adverse events is much lower,” said Dr. Damani, referring to the bloating, flatulence, and discomfort experienced by some patients following the Nissen procedure. “It is now our operation of choice.”
This Toupet fundoplication, like the Nissen, can be performed laparoscopically or robotically, according to Dr. Damani, who said that efficacy and safety are achieved at a very high rate of consistency in high-volume centers.
However, Dr. Damani also reported that there has been progress with endoscopic approaches and reversible interventions for GERD. These expand the array of options and might be particularly attractive in patients who are poor candidates for surgery or those seeking a reversible intervention.
Of these options, Dr. Damani paid particular attention to the Linx reflux management system. This device is composed of a chain of titanium beads with a magnetic cord that are looped around the lower esophagus to add a barrier function. The level of the magnetic force allows the chain of beads to expand when food descends or gas rises but prevents transient LES relaxations. As a result of its ability to expand and contract, the device is “very dynamic,” Dr. Damani said.
Prior to placement of the device, “the hiatal hernia is dissected and closed like other effective procedures. Then the Linx device is sized and placed,” Dr. Damani explained. Importantly, this procedure can be reversed simply by removing the device.
“There is no side-by-side comparison with a Nissen, but the results have been excellent so far,” Dr. Damani said. The most significant concern is foreign body reactions, but the erosion rates have been reported as less than 0.1%, according to Dr. Damani, who noted that erosion, if it occurs, can be managed endoscopically.
She did caution that candidates for the Linx device must have normal esophageal motility and be free of metal allergies, but she has been impressed with its durable function.
Perhaps the most difficult question in assessing and treating GERD in the context of bronchiectasis is to determine when it is needed. Dr. Damani warned that many patients with lung disease exacerbated by GERD are asymptomatic, requiring a workup to determine if GERD is present. Even if present, it can be challenging to confirm that GERD is a major treatable contributor to poor lung function.
Illustrative of that point, Doreen J. Addrizzo-Harris, MD, codirector of the NYU Langone Health bronchiectasis & NTM clinical and translational program, and President of American College of Chest Physicians, described a patient with advanced bronchiectasis whose poorly controlled lung function had not been considered to be GERD related even though the patent had been inadequately responsive to multiple aggressive treatment strategies. The decision to surgically correct GERD was taken on the basis of diminishing alternative options.
“The improvement in lung function was substantial and rapid,” she said.
Dr. Addrizzo-Harris, who served as a chair of the 2023 World Bronchiectasis & NTM Conference, recounted this case to support the major potential improvements in selected patients with advanced lung disease when GERD is treated. She indicated that even experts overlook this variable.
This still does not answer the question of when to consider an invasive procedure for GERD, but “there is no hard and fast answer,” according to David Kamelhar, MD, who is the other codirector of the NYU Langone Health bronchiectasis & NTM clinical and translational program.
Dr. Kamelhar admitted that he does not immediately think of GERD as a strategy to control lung disease treatable in patients without GERD-related symptoms, but he has pursued this comorbidity in cases when he has “nothing else to offer.” He suggested that multidisciplinary management is one way to consider GERD as treatment target before it becomes a last resort.
As pulmonologists, “we are not GERD experts, so we need to bring in a gastroenterologist or a surgeon who can help with this decision,” he said, referring to when and how to intervene.
From Dr. Damani’s talk, he suggested that the take-home message is that GERD treatment options have improved, and it might make more sense to consider GERD as a treatable comorbidity of lung disease in earlier rather than later stages of disease.
Dr. Damani, Dr. Addrizzo-Harris, and Dr. Kamelhar reported having no potential conflicts of interest relevant to this topic.
AT WBC 2023
Noteworthy advances in treatment and management of IBD
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).1 The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.2
The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.3
Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.4 In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.5
The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.6,7
There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.8 Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.9 Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.10
For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.11 Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.12
A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.13
We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.14 Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.15 We will see more studies combining therapies with diverse mechanisms of action.
In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.
DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).
Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.
References
1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.
2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.
3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.
4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.
5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.
6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.
7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.
8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.
9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.
10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.
11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30
12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.
13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.
14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.
15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.
AT DDW 2023
Genetic profiles affect smokers’ lung cancer risk
conducted by specialists from the Cancer Center at the University of Navarra Clinic (CUN). The results were presented at the annual meeting of the American Society for Clinical Oncology.
Ana Patiño García, PhD, director of the genomic medicine unit at the CUN and a coordinator of the research, explained in an interview the main reason why this study was conducted. “This study came straight out of the oncology clinic, where we are constantly encountering patients with lung cancer who have never smoked or who have smoked very little, while we also all know people who have smoked a lot throughout their lifetime and have never developed cancer. This observation has led us to ask whether there are genetic factors that increase or decrease the risk of cancer and protect people against this disease.”
José Luis Pérez Gracia, MD, PhD, oncologist, coordinator of the oncology trials department at the CUN and another of the individuals responsible for this research, said: “This is the first study to validate genetic factors associated with people who appear to be resistant to developing tobacco-related lung cancer or who, on the other hand, are at high risk of developing this disease.”
Pioneering approach
Earlier evidence showed that some smokers develop cancer, and others don’t. “This is a very well-known fact, since everyone knows about some elderly person who has been a heavy smoker and has never developed lung cancer,” said Dr. Pérez. “Unfortunately, we oncologists encounter young smokers who have been diagnosed with this disease. However, despite the importance of understanding the causes behind these phenotypes, it is a question that has never been studied from a genetic standpoint.”
The study was conducted using DNA from 133 heavy smokers who had not developed lung cancer at a mean age of 80 years, and from another 116 heavy smokers who had developed this type of cancer at a mean age of 50 years. This DNA was sequenced using next-generation techniques, and the results were analyzed using bioinformatics and artificial intelligence systems in collaboration with the University of Navarra Applied Medical Research Center and the University of Navarra School of Engineering.
When asked how this methodology could be applied to support other research conducted along these lines, Dr. Patiño said, “The most novel thing about this research is actually its approach. It’s based on groups at the extremes, defined by the patient’s age at the time of developing lung cancer and how much they had smoked. This type of comparative design is called extreme phenotypes, and its main distinguishing characteristic – which is also its most limiting characteristic – is choosing cases and controls well. Obviously, with today’s next-generation sequencing technologies, we achieve a quantity and quality of data that would have been unattainable in years gone by.”
Speaking to the role played by bioinformatics and artificial intelligence in this research, Dr. Patiño explained that they are fairly new techniques. “In fact, these technologies could be thought of as spearheading a lot of the biomedical research being done today. They’ve also somewhat set the stage for the paradigm shift where the investigator asks the data a question, and in the case of artificial intelligence, it’s the data that answer.”
Pinpointing genetic differences
In his analysis of the most noteworthy data and conclusions from this research, Dr. Pérez noted, “The most significant thing we’ve seen is that both populations have genetic differences. This suggests that our hypothesis is correct. Of course, more studies including a larger number of individuals will be needed to confirm these findings. For the first time, our work has laid the foundation for developing this line of research.”
“Many genetic variants that we have identified as differentials in cases and controls are found in genes relevant to the immune system (HLA system), in genes related to functional pathways that are often altered in tumor development, and in structural proteins and in genes related to cell mobility,” emphasized Dr. Patiño.
Many of the genetic characteristics that were discovered are located in genes with functions related to cancer development, such as immune response, repair of genetic material, regulation of inflammation, etc. This finding is highly significant, said Dr. Pérez. “However, we must remember that these phenotypes may be attributable to multiple causes, not just one cause.”
Furthermore, the specialist explained the next steps to be taken in the context of the line opened up by this research. “First, we must expand these studies, including more individuals with, if possible, even more extreme phenotypes: more smokers who are older and younger, respectively. Once the statistical evidence is stronger, we must also confirm that the alterations observed in lab-based studies truly impact gene function.”
Earlier diagnosis
The clinician also discussed the potential ways that the conclusions of this study could be applied to clinical practice now and in the future, and how the conclusions could benefit these patients. “The results of our line of research may help in early identification of those individuals at high risk of developing lung cancer if they smoke, so that they could be included in prevention programs to keep them from smoking or to help them stop smoking,” said Dr. Pérez. “It would also allow for early diagnosis of cancer at a time when there is a much higher chance of curing it.
“However, the most important thing is that our study may allow us to better understand the mechanisms by which cancer arises and especially why some people do not develop it. This [understanding] could lead to new diagnostic techniques and new treatments for this disease. The techniques needed to develop this line of research (bioinformatic mass sequencing and artificial intelligence) are available and becoming more reliable and more accessible every day. So, we believe our strategy is very realistic,” he added.
Although the line of research opened up by this study depicts a new scenario, the specialists still must face several challenges to discover why some smokers are more likely than others to develop lung cancer.
“There are many lines of research in this regard,” said Dr. Pérez. “But to name a few, I would draw attention to the need to increase the number of cases and controls to improve the comparison, study patients with other tumors related to tobacco use, ask new questions using the data we have already collected, and apply other genomic techniques that would allow us to perform additional studies of genetic variants that have not yet been studied. And, of course, we need to use functional studies to expand our understanding of the function and activity of the genes that have already been identified.”
Dr. Patiño and Dr. Pérez declared that they have no relevant financial conflicts of interest.
This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.
conducted by specialists from the Cancer Center at the University of Navarra Clinic (CUN). The results were presented at the annual meeting of the American Society for Clinical Oncology.
Ana Patiño García, PhD, director of the genomic medicine unit at the CUN and a coordinator of the research, explained in an interview the main reason why this study was conducted. “This study came straight out of the oncology clinic, where we are constantly encountering patients with lung cancer who have never smoked or who have smoked very little, while we also all know people who have smoked a lot throughout their lifetime and have never developed cancer. This observation has led us to ask whether there are genetic factors that increase or decrease the risk of cancer and protect people against this disease.”
José Luis Pérez Gracia, MD, PhD, oncologist, coordinator of the oncology trials department at the CUN and another of the individuals responsible for this research, said: “This is the first study to validate genetic factors associated with people who appear to be resistant to developing tobacco-related lung cancer or who, on the other hand, are at high risk of developing this disease.”
Pioneering approach
Earlier evidence showed that some smokers develop cancer, and others don’t. “This is a very well-known fact, since everyone knows about some elderly person who has been a heavy smoker and has never developed lung cancer,” said Dr. Pérez. “Unfortunately, we oncologists encounter young smokers who have been diagnosed with this disease. However, despite the importance of understanding the causes behind these phenotypes, it is a question that has never been studied from a genetic standpoint.”
The study was conducted using DNA from 133 heavy smokers who had not developed lung cancer at a mean age of 80 years, and from another 116 heavy smokers who had developed this type of cancer at a mean age of 50 years. This DNA was sequenced using next-generation techniques, and the results were analyzed using bioinformatics and artificial intelligence systems in collaboration with the University of Navarra Applied Medical Research Center and the University of Navarra School of Engineering.
When asked how this methodology could be applied to support other research conducted along these lines, Dr. Patiño said, “The most novel thing about this research is actually its approach. It’s based on groups at the extremes, defined by the patient’s age at the time of developing lung cancer and how much they had smoked. This type of comparative design is called extreme phenotypes, and its main distinguishing characteristic – which is also its most limiting characteristic – is choosing cases and controls well. Obviously, with today’s next-generation sequencing technologies, we achieve a quantity and quality of data that would have been unattainable in years gone by.”
Speaking to the role played by bioinformatics and artificial intelligence in this research, Dr. Patiño explained that they are fairly new techniques. “In fact, these technologies could be thought of as spearheading a lot of the biomedical research being done today. They’ve also somewhat set the stage for the paradigm shift where the investigator asks the data a question, and in the case of artificial intelligence, it’s the data that answer.”
Pinpointing genetic differences
In his analysis of the most noteworthy data and conclusions from this research, Dr. Pérez noted, “The most significant thing we’ve seen is that both populations have genetic differences. This suggests that our hypothesis is correct. Of course, more studies including a larger number of individuals will be needed to confirm these findings. For the first time, our work has laid the foundation for developing this line of research.”
“Many genetic variants that we have identified as differentials in cases and controls are found in genes relevant to the immune system (HLA system), in genes related to functional pathways that are often altered in tumor development, and in structural proteins and in genes related to cell mobility,” emphasized Dr. Patiño.
Many of the genetic characteristics that were discovered are located in genes with functions related to cancer development, such as immune response, repair of genetic material, regulation of inflammation, etc. This finding is highly significant, said Dr. Pérez. “However, we must remember that these phenotypes may be attributable to multiple causes, not just one cause.”
Furthermore, the specialist explained the next steps to be taken in the context of the line opened up by this research. “First, we must expand these studies, including more individuals with, if possible, even more extreme phenotypes: more smokers who are older and younger, respectively. Once the statistical evidence is stronger, we must also confirm that the alterations observed in lab-based studies truly impact gene function.”
Earlier diagnosis
The clinician also discussed the potential ways that the conclusions of this study could be applied to clinical practice now and in the future, and how the conclusions could benefit these patients. “The results of our line of research may help in early identification of those individuals at high risk of developing lung cancer if they smoke, so that they could be included in prevention programs to keep them from smoking or to help them stop smoking,” said Dr. Pérez. “It would also allow for early diagnosis of cancer at a time when there is a much higher chance of curing it.
“However, the most important thing is that our study may allow us to better understand the mechanisms by which cancer arises and especially why some people do not develop it. This [understanding] could lead to new diagnostic techniques and new treatments for this disease. The techniques needed to develop this line of research (bioinformatic mass sequencing and artificial intelligence) are available and becoming more reliable and more accessible every day. So, we believe our strategy is very realistic,” he added.
Although the line of research opened up by this study depicts a new scenario, the specialists still must face several challenges to discover why some smokers are more likely than others to develop lung cancer.
“There are many lines of research in this regard,” said Dr. Pérez. “But to name a few, I would draw attention to the need to increase the number of cases and controls to improve the comparison, study patients with other tumors related to tobacco use, ask new questions using the data we have already collected, and apply other genomic techniques that would allow us to perform additional studies of genetic variants that have not yet been studied. And, of course, we need to use functional studies to expand our understanding of the function and activity of the genes that have already been identified.”
Dr. Patiño and Dr. Pérez declared that they have no relevant financial conflicts of interest.
This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.
conducted by specialists from the Cancer Center at the University of Navarra Clinic (CUN). The results were presented at the annual meeting of the American Society for Clinical Oncology.
Ana Patiño García, PhD, director of the genomic medicine unit at the CUN and a coordinator of the research, explained in an interview the main reason why this study was conducted. “This study came straight out of the oncology clinic, where we are constantly encountering patients with lung cancer who have never smoked or who have smoked very little, while we also all know people who have smoked a lot throughout their lifetime and have never developed cancer. This observation has led us to ask whether there are genetic factors that increase or decrease the risk of cancer and protect people against this disease.”
José Luis Pérez Gracia, MD, PhD, oncologist, coordinator of the oncology trials department at the CUN and another of the individuals responsible for this research, said: “This is the first study to validate genetic factors associated with people who appear to be resistant to developing tobacco-related lung cancer or who, on the other hand, are at high risk of developing this disease.”
Pioneering approach
Earlier evidence showed that some smokers develop cancer, and others don’t. “This is a very well-known fact, since everyone knows about some elderly person who has been a heavy smoker and has never developed lung cancer,” said Dr. Pérez. “Unfortunately, we oncologists encounter young smokers who have been diagnosed with this disease. However, despite the importance of understanding the causes behind these phenotypes, it is a question that has never been studied from a genetic standpoint.”
The study was conducted using DNA from 133 heavy smokers who had not developed lung cancer at a mean age of 80 years, and from another 116 heavy smokers who had developed this type of cancer at a mean age of 50 years. This DNA was sequenced using next-generation techniques, and the results were analyzed using bioinformatics and artificial intelligence systems in collaboration with the University of Navarra Applied Medical Research Center and the University of Navarra School of Engineering.
When asked how this methodology could be applied to support other research conducted along these lines, Dr. Patiño said, “The most novel thing about this research is actually its approach. It’s based on groups at the extremes, defined by the patient’s age at the time of developing lung cancer and how much they had smoked. This type of comparative design is called extreme phenotypes, and its main distinguishing characteristic – which is also its most limiting characteristic – is choosing cases and controls well. Obviously, with today’s next-generation sequencing technologies, we achieve a quantity and quality of data that would have been unattainable in years gone by.”
Speaking to the role played by bioinformatics and artificial intelligence in this research, Dr. Patiño explained that they are fairly new techniques. “In fact, these technologies could be thought of as spearheading a lot of the biomedical research being done today. They’ve also somewhat set the stage for the paradigm shift where the investigator asks the data a question, and in the case of artificial intelligence, it’s the data that answer.”
Pinpointing genetic differences
In his analysis of the most noteworthy data and conclusions from this research, Dr. Pérez noted, “The most significant thing we’ve seen is that both populations have genetic differences. This suggests that our hypothesis is correct. Of course, more studies including a larger number of individuals will be needed to confirm these findings. For the first time, our work has laid the foundation for developing this line of research.”
“Many genetic variants that we have identified as differentials in cases and controls are found in genes relevant to the immune system (HLA system), in genes related to functional pathways that are often altered in tumor development, and in structural proteins and in genes related to cell mobility,” emphasized Dr. Patiño.
Many of the genetic characteristics that were discovered are located in genes with functions related to cancer development, such as immune response, repair of genetic material, regulation of inflammation, etc. This finding is highly significant, said Dr. Pérez. “However, we must remember that these phenotypes may be attributable to multiple causes, not just one cause.”
Furthermore, the specialist explained the next steps to be taken in the context of the line opened up by this research. “First, we must expand these studies, including more individuals with, if possible, even more extreme phenotypes: more smokers who are older and younger, respectively. Once the statistical evidence is stronger, we must also confirm that the alterations observed in lab-based studies truly impact gene function.”
Earlier diagnosis
The clinician also discussed the potential ways that the conclusions of this study could be applied to clinical practice now and in the future, and how the conclusions could benefit these patients. “The results of our line of research may help in early identification of those individuals at high risk of developing lung cancer if they smoke, so that they could be included in prevention programs to keep them from smoking or to help them stop smoking,” said Dr. Pérez. “It would also allow for early diagnosis of cancer at a time when there is a much higher chance of curing it.
“However, the most important thing is that our study may allow us to better understand the mechanisms by which cancer arises and especially why some people do not develop it. This [understanding] could lead to new diagnostic techniques and new treatments for this disease. The techniques needed to develop this line of research (bioinformatic mass sequencing and artificial intelligence) are available and becoming more reliable and more accessible every day. So, we believe our strategy is very realistic,” he added.
Although the line of research opened up by this study depicts a new scenario, the specialists still must face several challenges to discover why some smokers are more likely than others to develop lung cancer.
“There are many lines of research in this regard,” said Dr. Pérez. “But to name a few, I would draw attention to the need to increase the number of cases and controls to improve the comparison, study patients with other tumors related to tobacco use, ask new questions using the data we have already collected, and apply other genomic techniques that would allow us to perform additional studies of genetic variants that have not yet been studied. And, of course, we need to use functional studies to expand our understanding of the function and activity of the genes that have already been identified.”
Dr. Patiño and Dr. Pérez declared that they have no relevant financial conflicts of interest.
This article was translated from the Medscape Spanish Edition. A version appeared on Medscape.com.
FROM ASCO 2023
Growth hormone links with worse T2D control in adolescents
SAN DIEGO – Plasma levels of three proteins involved in growth hormone activity showed significant links to the controllability of type 2 diabetes in children, a finding that suggests these proteins may serve as risk markers for incident type 2 diabetes and help identify adolescents who could benefit from aggressive preventive care.
“Plasma growth hormone mediators are associated with glycemic failure in youth with type 2 diabetes,” Chang Lu, MD, said at the at the annual scientific sessions of the American Diabetes Association. “Our hope is that these mediators could be biomarkers for predicting type 2 diabetes onset,” she added in an interview.
Another potential application is to “leverage these data to find predictive markers” that could identify adolescents with type 2 diabetes “at risk for particularly aggressive disease and target them for more intervention,” added Elvira M. Isganaitis, MD, senior author of the report and a pediatric endocrinologist at the Joslin Diabetes Center in Boston.
Does growth hormone cause incident T2D at puberty?
Changes in levels of growth hormone–associated peptides during puberty “could potentially explain why children with type 2 diabetes have a more aggressive course” of the disorder, added Dr. Lu, a pediatric endocrinologist at Joslin and at Boston’s Children’s Hospital.
Puberty-associated changes in growth hormone and related peptides “could be why type 2 diabetes starts during puberty. Type 2 diabetes is almost unheard of before children reach about age 10,” Dr. Isganaitis said in an interview.
A current hypothesis is that “high levels of growth hormone is a cause of insulin resistance during puberty, but in healthy children their beta cells overcome this by making more insulin and so they do not develop diabetes,” said Kristen J. Nadeau, MD, a pediatric endocrinologist and professor at Children’s Hospital Colorado in Denver.
“But this is a stress situation, and if someone has poor beta-cell function they may develop diabetes. The increase in growth hormone [during puberty] can unmask a physiologic and genetic predisposition” to developing type 2 diabetes, Dr. Nadeau said in an interview.
The analyses run by Dr. Lu, Dr. Isganaitis, and their coauthors used data collected in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which randomized 699 children aged 10-17 years with type 2 diabetes to one of three antidiabetes treatment regimens and tallied the subsequent incidence of glycemic failure. The study defined the latter as either 6 months with a hemoglobin A1c level of at least 8% or need for insulin treatment.
The primary outcome showed a 39%-52% incidence of failure during 5 years of follow-up depending on the specific treatments the study participants received.
Growth hormone correlates of glycemic failure
The new analyses focused on 310 study participants from TODAY who had plasma specimens available from baseline and a second specimen obtained after 3 years of follow-up. The researchers compared the levels of three peptides that mediate growth hormone signaling at baseline and after 3 years, and assessed these changes relative to the endpoint of glycemic failure.
The results showed that an increase in insulin-like growth factor-1 significantly linked with a reduced incidence of glycemic failure and improved glycemia and beta-cell function.
In contrast, Also, an increase in insulin-like growth factor binding protein-1 significantly linked with glycemic failure and hyperglycemia at 36 months, and with higher insulin sensitivity at baseline. All these analyses adjusted for baseline differences in several demographic and clinical variables.
But these post hoc analyses could not determine whether these associations resulted from, or had a causal role in, treatment failure, cautioned Dr. Lu.
Future studies should examine the relationship of growth hormone signaling and the course of glycemic control in children and adolescents with prediabetes and obesity, Dr. Lu said.
Confirming that these growth hormone-related proteins are reliable predictors of future glycemic dysfunction would open the door to studies of interventions to slow or prevent progression to type 2 diabetes in children identified as high risk.
Potential interventions include early initiation of insulin treatment, which could help preserve beta-cell function, or treatment with a glucagon-like peptide-1 (GLP-1) agonist, a class of agents that may interact with the insulin-like growth factor-1 receptors on beta cells, Dr. Lu said.
The study received no commercial funding. Dr. Lu, Dr. Isganaitis, and Dr. Nadeau reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO – Plasma levels of three proteins involved in growth hormone activity showed significant links to the controllability of type 2 diabetes in children, a finding that suggests these proteins may serve as risk markers for incident type 2 diabetes and help identify adolescents who could benefit from aggressive preventive care.
“Plasma growth hormone mediators are associated with glycemic failure in youth with type 2 diabetes,” Chang Lu, MD, said at the at the annual scientific sessions of the American Diabetes Association. “Our hope is that these mediators could be biomarkers for predicting type 2 diabetes onset,” she added in an interview.
Another potential application is to “leverage these data to find predictive markers” that could identify adolescents with type 2 diabetes “at risk for particularly aggressive disease and target them for more intervention,” added Elvira M. Isganaitis, MD, senior author of the report and a pediatric endocrinologist at the Joslin Diabetes Center in Boston.
Does growth hormone cause incident T2D at puberty?
Changes in levels of growth hormone–associated peptides during puberty “could potentially explain why children with type 2 diabetes have a more aggressive course” of the disorder, added Dr. Lu, a pediatric endocrinologist at Joslin and at Boston’s Children’s Hospital.
Puberty-associated changes in growth hormone and related peptides “could be why type 2 diabetes starts during puberty. Type 2 diabetes is almost unheard of before children reach about age 10,” Dr. Isganaitis said in an interview.
A current hypothesis is that “high levels of growth hormone is a cause of insulin resistance during puberty, but in healthy children their beta cells overcome this by making more insulin and so they do not develop diabetes,” said Kristen J. Nadeau, MD, a pediatric endocrinologist and professor at Children’s Hospital Colorado in Denver.
“But this is a stress situation, and if someone has poor beta-cell function they may develop diabetes. The increase in growth hormone [during puberty] can unmask a physiologic and genetic predisposition” to developing type 2 diabetes, Dr. Nadeau said in an interview.
The analyses run by Dr. Lu, Dr. Isganaitis, and their coauthors used data collected in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which randomized 699 children aged 10-17 years with type 2 diabetes to one of three antidiabetes treatment regimens and tallied the subsequent incidence of glycemic failure. The study defined the latter as either 6 months with a hemoglobin A1c level of at least 8% or need for insulin treatment.
The primary outcome showed a 39%-52% incidence of failure during 5 years of follow-up depending on the specific treatments the study participants received.
Growth hormone correlates of glycemic failure
The new analyses focused on 310 study participants from TODAY who had plasma specimens available from baseline and a second specimen obtained after 3 years of follow-up. The researchers compared the levels of three peptides that mediate growth hormone signaling at baseline and after 3 years, and assessed these changes relative to the endpoint of glycemic failure.
The results showed that an increase in insulin-like growth factor-1 significantly linked with a reduced incidence of glycemic failure and improved glycemia and beta-cell function.
In contrast, Also, an increase in insulin-like growth factor binding protein-1 significantly linked with glycemic failure and hyperglycemia at 36 months, and with higher insulin sensitivity at baseline. All these analyses adjusted for baseline differences in several demographic and clinical variables.
But these post hoc analyses could not determine whether these associations resulted from, or had a causal role in, treatment failure, cautioned Dr. Lu.
Future studies should examine the relationship of growth hormone signaling and the course of glycemic control in children and adolescents with prediabetes and obesity, Dr. Lu said.
Confirming that these growth hormone-related proteins are reliable predictors of future glycemic dysfunction would open the door to studies of interventions to slow or prevent progression to type 2 diabetes in children identified as high risk.
Potential interventions include early initiation of insulin treatment, which could help preserve beta-cell function, or treatment with a glucagon-like peptide-1 (GLP-1) agonist, a class of agents that may interact with the insulin-like growth factor-1 receptors on beta cells, Dr. Lu said.
The study received no commercial funding. Dr. Lu, Dr. Isganaitis, and Dr. Nadeau reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
SAN DIEGO – Plasma levels of three proteins involved in growth hormone activity showed significant links to the controllability of type 2 diabetes in children, a finding that suggests these proteins may serve as risk markers for incident type 2 diabetes and help identify adolescents who could benefit from aggressive preventive care.
“Plasma growth hormone mediators are associated with glycemic failure in youth with type 2 diabetes,” Chang Lu, MD, said at the at the annual scientific sessions of the American Diabetes Association. “Our hope is that these mediators could be biomarkers for predicting type 2 diabetes onset,” she added in an interview.
Another potential application is to “leverage these data to find predictive markers” that could identify adolescents with type 2 diabetes “at risk for particularly aggressive disease and target them for more intervention,” added Elvira M. Isganaitis, MD, senior author of the report and a pediatric endocrinologist at the Joslin Diabetes Center in Boston.
Does growth hormone cause incident T2D at puberty?
Changes in levels of growth hormone–associated peptides during puberty “could potentially explain why children with type 2 diabetes have a more aggressive course” of the disorder, added Dr. Lu, a pediatric endocrinologist at Joslin and at Boston’s Children’s Hospital.
Puberty-associated changes in growth hormone and related peptides “could be why type 2 diabetes starts during puberty. Type 2 diabetes is almost unheard of before children reach about age 10,” Dr. Isganaitis said in an interview.
A current hypothesis is that “high levels of growth hormone is a cause of insulin resistance during puberty, but in healthy children their beta cells overcome this by making more insulin and so they do not develop diabetes,” said Kristen J. Nadeau, MD, a pediatric endocrinologist and professor at Children’s Hospital Colorado in Denver.
“But this is a stress situation, and if someone has poor beta-cell function they may develop diabetes. The increase in growth hormone [during puberty] can unmask a physiologic and genetic predisposition” to developing type 2 diabetes, Dr. Nadeau said in an interview.
The analyses run by Dr. Lu, Dr. Isganaitis, and their coauthors used data collected in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which randomized 699 children aged 10-17 years with type 2 diabetes to one of three antidiabetes treatment regimens and tallied the subsequent incidence of glycemic failure. The study defined the latter as either 6 months with a hemoglobin A1c level of at least 8% or need for insulin treatment.
The primary outcome showed a 39%-52% incidence of failure during 5 years of follow-up depending on the specific treatments the study participants received.
Growth hormone correlates of glycemic failure
The new analyses focused on 310 study participants from TODAY who had plasma specimens available from baseline and a second specimen obtained after 3 years of follow-up. The researchers compared the levels of three peptides that mediate growth hormone signaling at baseline and after 3 years, and assessed these changes relative to the endpoint of glycemic failure.
The results showed that an increase in insulin-like growth factor-1 significantly linked with a reduced incidence of glycemic failure and improved glycemia and beta-cell function.
In contrast, Also, an increase in insulin-like growth factor binding protein-1 significantly linked with glycemic failure and hyperglycemia at 36 months, and with higher insulin sensitivity at baseline. All these analyses adjusted for baseline differences in several demographic and clinical variables.
But these post hoc analyses could not determine whether these associations resulted from, or had a causal role in, treatment failure, cautioned Dr. Lu.
Future studies should examine the relationship of growth hormone signaling and the course of glycemic control in children and adolescents with prediabetes and obesity, Dr. Lu said.
Confirming that these growth hormone-related proteins are reliable predictors of future glycemic dysfunction would open the door to studies of interventions to slow or prevent progression to type 2 diabetes in children identified as high risk.
Potential interventions include early initiation of insulin treatment, which could help preserve beta-cell function, or treatment with a glucagon-like peptide-1 (GLP-1) agonist, a class of agents that may interact with the insulin-like growth factor-1 receptors on beta cells, Dr. Lu said.
The study received no commercial funding. Dr. Lu, Dr. Isganaitis, and Dr. Nadeau reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
AT ADA 2023
Study highlights diagnostic challenges of differentiating lichen sclerosus from vitiligo
of cases.
Researchers who tallied symptoms and physical exam findings observed fewer statistically significant differences between LS and vitiligo patients than expected, and LS and vitiligo were sometimes misdiagnosed as each other.
“LS must be treated aggressively to prevent long-term sequelae such as permanent scarring and vulvar squamous cell carcinoma, making an accurate diagnosis crucial,” the authors write in a poster they presented at the annual meeting of the Society for Pediatric Dermatology.
LS is symptomatic and has multiple exam findings, but once treated or quiescent, the discoloration can persist and create diagnostic uncertainty, lead study author Kaiane Habeshian, MD, a pediatric dermatologist at Children’s National Hospital, Washington, told this news organization following the SPD meeting.
The diagnostic uncertainty is especially true in patients with darker skin tones, who may have vitiligoid LS, an LS variant that has overlapping features of both LS and vitiligo.
Vitiligoid LS “presents clinically as a depigmented symmetric white vulvar and perianal white patch, often with minimal signs of inflammation, but is symptomatic and appears consistent with LS on histopathology,” Dr. Habeshian said.
“In our experience, in patients with medium to dark skin tones, there is a variable amount of repigmentation after treating LS,” she added. “After use of high potency topical corticosteroids, some patients almost completely repigment, while others have minimal repigmentation, and this can fluctuate over time, sometimes independent of other signs or symptoms of a flare up. This can lead to diagnostic confusion. For example, if an LS patient is examined after treatment, and their symptoms have resolved, they may subsequently be given a diagnosis of vitiligo.”
In the study, Dr. Habeshian and her coauthors aimed to characterize differences in LS and vitiligo based on history, physical exam, and demographic findings at the time of the initial clinic visit. She and her colleagues extracted and reviewed the medical records of 98 patients with a diagnosis of LS or vitiligo who were seen at a joint pediatric dermatology-gynecology vulvar clinic over 6.8 years. The median and mean age of the study population at diagnosis was about 6 years, with ages ranging from 2 to 20. The team used descriptive statistics and Z tests for data analysis.
The researchers found that pruritus, constipation, and dysuria were the most common symptoms experienced by both LS and vitiligo patients. All were experienced more frequently by LS patients, but only pruritus reached statistical significance (P = .040). Other symptoms experienced only by LS patients included vulvar pain, bleeding, and pain with defecation.
Meanwhile, apart from hypopigmentation and erythema, all physical exam findings were more frequent in LS patients, compared with vitiligo patients, including fissures and purpura/petechiae, but only epidermal atrophy and figure-of-8 distribution of hypopigmentation reached statistical significance (P values of .047 and .036, respectively).
In other findings, LS and vitiligo were misdiagnosed as each other 15 times. Nearly half of the misdiagnoses (46.7%) were made in Black patients, who composed 38.8% of all patients in the study.
“I suspect that some vitiligo cases that were previously ‘misdiagnosed’ as LS were actually LS that just didn’t repigment and then were labeled as vitiligo in the chart,” Dr. Habeshian said.
“And some of those LS cases that previously were misdiagnosed as vitiligo likely had other more subtle LS findings that were missed (shininess and wrinkling of the skin, small fissures, constipation) or that were attributed to comorbid irritant contact dermatitis or another condition,” she said. “It was interesting to see that even in a vulvar dermatology clinic there can be confusion between these diagnoses because the literature on pediatric LS in darker skin tones is so sparse.”
She emphasized that a close exam and detailed history are needed to properly diagnose patients with anogenital skin conditions.
“Don’t forget to ask about constipation and urinary symptoms as well as psychosocial and, in the appropriate patient, sexual and reproductive function,” Dr. Habeshian said. “Based on my experience, pediatric LS is much more common in our community than the literature would suggest. Its psychosocial impact is tremendous but not well documented, particularly in pediatric patients. In my experience, the longer LS is misdiagnosed or mistreated, the more challenging it becomes to manage. You don’t want to miss LS.”
She acknowledged certain limitations of the study, including the fact that photographs were not available for review for many of the earlier years of the clinic. “Therefore, we had to depend on the diagnosis given at the time of the visit,” she said. “This likely accounts in part for the smaller number than expected of significant exam and history findings between LS and vitiligo. We need further studies utilizing a standardized approach to accurate diagnosis.”
Her coauthors were Nikita Menta, Aneka Khilnani, MS, and Tazim Dowlut-McElroy, MD. The researchers reported having no financial disclosures.
of cases.
Researchers who tallied symptoms and physical exam findings observed fewer statistically significant differences between LS and vitiligo patients than expected, and LS and vitiligo were sometimes misdiagnosed as each other.
“LS must be treated aggressively to prevent long-term sequelae such as permanent scarring and vulvar squamous cell carcinoma, making an accurate diagnosis crucial,” the authors write in a poster they presented at the annual meeting of the Society for Pediatric Dermatology.
LS is symptomatic and has multiple exam findings, but once treated or quiescent, the discoloration can persist and create diagnostic uncertainty, lead study author Kaiane Habeshian, MD, a pediatric dermatologist at Children’s National Hospital, Washington, told this news organization following the SPD meeting.
The diagnostic uncertainty is especially true in patients with darker skin tones, who may have vitiligoid LS, an LS variant that has overlapping features of both LS and vitiligo.
Vitiligoid LS “presents clinically as a depigmented symmetric white vulvar and perianal white patch, often with minimal signs of inflammation, but is symptomatic and appears consistent with LS on histopathology,” Dr. Habeshian said.
“In our experience, in patients with medium to dark skin tones, there is a variable amount of repigmentation after treating LS,” she added. “After use of high potency topical corticosteroids, some patients almost completely repigment, while others have minimal repigmentation, and this can fluctuate over time, sometimes independent of other signs or symptoms of a flare up. This can lead to diagnostic confusion. For example, if an LS patient is examined after treatment, and their symptoms have resolved, they may subsequently be given a diagnosis of vitiligo.”
In the study, Dr. Habeshian and her coauthors aimed to characterize differences in LS and vitiligo based on history, physical exam, and demographic findings at the time of the initial clinic visit. She and her colleagues extracted and reviewed the medical records of 98 patients with a diagnosis of LS or vitiligo who were seen at a joint pediatric dermatology-gynecology vulvar clinic over 6.8 years. The median and mean age of the study population at diagnosis was about 6 years, with ages ranging from 2 to 20. The team used descriptive statistics and Z tests for data analysis.
The researchers found that pruritus, constipation, and dysuria were the most common symptoms experienced by both LS and vitiligo patients. All were experienced more frequently by LS patients, but only pruritus reached statistical significance (P = .040). Other symptoms experienced only by LS patients included vulvar pain, bleeding, and pain with defecation.
Meanwhile, apart from hypopigmentation and erythema, all physical exam findings were more frequent in LS patients, compared with vitiligo patients, including fissures and purpura/petechiae, but only epidermal atrophy and figure-of-8 distribution of hypopigmentation reached statistical significance (P values of .047 and .036, respectively).
In other findings, LS and vitiligo were misdiagnosed as each other 15 times. Nearly half of the misdiagnoses (46.7%) were made in Black patients, who composed 38.8% of all patients in the study.
“I suspect that some vitiligo cases that were previously ‘misdiagnosed’ as LS were actually LS that just didn’t repigment and then were labeled as vitiligo in the chart,” Dr. Habeshian said.
“And some of those LS cases that previously were misdiagnosed as vitiligo likely had other more subtle LS findings that were missed (shininess and wrinkling of the skin, small fissures, constipation) or that were attributed to comorbid irritant contact dermatitis or another condition,” she said. “It was interesting to see that even in a vulvar dermatology clinic there can be confusion between these diagnoses because the literature on pediatric LS in darker skin tones is so sparse.”
She emphasized that a close exam and detailed history are needed to properly diagnose patients with anogenital skin conditions.
“Don’t forget to ask about constipation and urinary symptoms as well as psychosocial and, in the appropriate patient, sexual and reproductive function,” Dr. Habeshian said. “Based on my experience, pediatric LS is much more common in our community than the literature would suggest. Its psychosocial impact is tremendous but not well documented, particularly in pediatric patients. In my experience, the longer LS is misdiagnosed or mistreated, the more challenging it becomes to manage. You don’t want to miss LS.”
She acknowledged certain limitations of the study, including the fact that photographs were not available for review for many of the earlier years of the clinic. “Therefore, we had to depend on the diagnosis given at the time of the visit,” she said. “This likely accounts in part for the smaller number than expected of significant exam and history findings between LS and vitiligo. We need further studies utilizing a standardized approach to accurate diagnosis.”
Her coauthors were Nikita Menta, Aneka Khilnani, MS, and Tazim Dowlut-McElroy, MD. The researchers reported having no financial disclosures.
of cases.
Researchers who tallied symptoms and physical exam findings observed fewer statistically significant differences between LS and vitiligo patients than expected, and LS and vitiligo were sometimes misdiagnosed as each other.
“LS must be treated aggressively to prevent long-term sequelae such as permanent scarring and vulvar squamous cell carcinoma, making an accurate diagnosis crucial,” the authors write in a poster they presented at the annual meeting of the Society for Pediatric Dermatology.
LS is symptomatic and has multiple exam findings, but once treated or quiescent, the discoloration can persist and create diagnostic uncertainty, lead study author Kaiane Habeshian, MD, a pediatric dermatologist at Children’s National Hospital, Washington, told this news organization following the SPD meeting.
The diagnostic uncertainty is especially true in patients with darker skin tones, who may have vitiligoid LS, an LS variant that has overlapping features of both LS and vitiligo.
Vitiligoid LS “presents clinically as a depigmented symmetric white vulvar and perianal white patch, often with minimal signs of inflammation, but is symptomatic and appears consistent with LS on histopathology,” Dr. Habeshian said.
“In our experience, in patients with medium to dark skin tones, there is a variable amount of repigmentation after treating LS,” she added. “After use of high potency topical corticosteroids, some patients almost completely repigment, while others have minimal repigmentation, and this can fluctuate over time, sometimes independent of other signs or symptoms of a flare up. This can lead to diagnostic confusion. For example, if an LS patient is examined after treatment, and their symptoms have resolved, they may subsequently be given a diagnosis of vitiligo.”
In the study, Dr. Habeshian and her coauthors aimed to characterize differences in LS and vitiligo based on history, physical exam, and demographic findings at the time of the initial clinic visit. She and her colleagues extracted and reviewed the medical records of 98 patients with a diagnosis of LS or vitiligo who were seen at a joint pediatric dermatology-gynecology vulvar clinic over 6.8 years. The median and mean age of the study population at diagnosis was about 6 years, with ages ranging from 2 to 20. The team used descriptive statistics and Z tests for data analysis.
The researchers found that pruritus, constipation, and dysuria were the most common symptoms experienced by both LS and vitiligo patients. All were experienced more frequently by LS patients, but only pruritus reached statistical significance (P = .040). Other symptoms experienced only by LS patients included vulvar pain, bleeding, and pain with defecation.
Meanwhile, apart from hypopigmentation and erythema, all physical exam findings were more frequent in LS patients, compared with vitiligo patients, including fissures and purpura/petechiae, but only epidermal atrophy and figure-of-8 distribution of hypopigmentation reached statistical significance (P values of .047 and .036, respectively).
In other findings, LS and vitiligo were misdiagnosed as each other 15 times. Nearly half of the misdiagnoses (46.7%) were made in Black patients, who composed 38.8% of all patients in the study.
“I suspect that some vitiligo cases that were previously ‘misdiagnosed’ as LS were actually LS that just didn’t repigment and then were labeled as vitiligo in the chart,” Dr. Habeshian said.
“And some of those LS cases that previously were misdiagnosed as vitiligo likely had other more subtle LS findings that were missed (shininess and wrinkling of the skin, small fissures, constipation) or that were attributed to comorbid irritant contact dermatitis or another condition,” she said. “It was interesting to see that even in a vulvar dermatology clinic there can be confusion between these diagnoses because the literature on pediatric LS in darker skin tones is so sparse.”
She emphasized that a close exam and detailed history are needed to properly diagnose patients with anogenital skin conditions.
“Don’t forget to ask about constipation and urinary symptoms as well as psychosocial and, in the appropriate patient, sexual and reproductive function,” Dr. Habeshian said. “Based on my experience, pediatric LS is much more common in our community than the literature would suggest. Its psychosocial impact is tremendous but not well documented, particularly in pediatric patients. In my experience, the longer LS is misdiagnosed or mistreated, the more challenging it becomes to manage. You don’t want to miss LS.”
She acknowledged certain limitations of the study, including the fact that photographs were not available for review for many of the earlier years of the clinic. “Therefore, we had to depend on the diagnosis given at the time of the visit,” she said. “This likely accounts in part for the smaller number than expected of significant exam and history findings between LS and vitiligo. We need further studies utilizing a standardized approach to accurate diagnosis.”
Her coauthors were Nikita Menta, Aneka Khilnani, MS, and Tazim Dowlut-McElroy, MD. The researchers reported having no financial disclosures.
FROM SPD 2023
Rising viral load on dolutegravir? Investigators try fix before switch
Brisbane, Australia – , according to new data from the ADVANCE trial.
“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” said Andrew Hill, MD, from the department of pharmacology and therapeutics at the University of Liverpool, England.
The new data was presented here at the International AIDS Society conference on HIV Science. The ADVANCE trial is a three-arm randomized study involving 1,053 treatment-naive individuals comparing two triple-therapy combinations — dolutegravir, emtricitabine, and one of two tenofovir prodrugs – with a standard care regimen of tenofovir disoproxil fumarate, emtricitabine, and efavirenz.
Although the usual approach for someone in a clinical trial who experiences elevations in HIV RNA levels while on a dolutegravir-based treatment is to switch them to another therapy, the ADVANCE investigators opted for a different strategy.
“We actually continued treatment despite high viral load, and we didn’t have standard discontinuation preferences,” Dr. Hill said at the meeting. They instead provided counseling about adherence, which gave an opportunity to examine viral resuppression rates in participants in both the dolutegravir and efavirenz arms.
This revealed that 95% of patients in the two dolutegravir arms of the study were able to achieve resuppression of their viral load – defined as below 50 viral RNA copies per mL – without any emergence of resistance.
The guidelines
Current World Health Organization guidelines recommend that anyone whose viral load goes above 1,000 copies per mL who is on a non-nucleoside reverse transcriptase inhibitor such as efavirenz should be switched to an appropriate regimen.
Those who experience viremia on an integrase inhibitor such as dolutegravir should receive adherence counseling, have a repeat viral load test done in 3 months, and – if their viral load is still elevated – be switched to another regimen.
Dr. Hill and his team were examining how this might play out in a clinical trial setting and they found that there were a similar number of episodes of initial virologic failure in both the dolutegravir and efavirenz groups.
But after adherence counseling, testing for resistance and – if no resistance was evident – continuation with treatment, they saw differences emerge between the two groups.
“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” he said.
Time to viral resuppression
At 24 weeks after restarting treatment, 88% of people in the dolutegravir group had resuppressed their viral RNA, compared with 46% of people in the efavirenz group. At 48 weeks, those figures were 95% and 66%, respectively.
Dr. Hill pointed out that a significant number of people were lost to follow-up after virologic failure, and genotyping was not performed at baseline.
We addressed the question of how much adherence counseling should be undertaken in people who experienced viremia while on dolutegravir therapy, Dr. Hill said, particularly as there were often very good reasons for lack of adherence, such as homelessness.
“If you can get through those difficult phases, people can go back on their meds,” he said in an interview. “It’s almost a sociological problem rather than a clinical issue.”
And with efavirenz and the lower rates of resuppression observed in the study, Dr. Hill said it was a more fragile drug, so viremia therefore provided the opportunity for resistance to emerge, “and then once the resistant virus is there, you can’t get virus undetectable.”
Laura Waters, MD, a genitourinary and HIV medicine consultant at the Mortimer Market Centre in London, who was not involved in the study, said the results support recommendations to give people on drugs such as dolutegravir, which have a high genetic barrier to resistance, more time to improve their adherence before switching to another therapy.
“Although it provides that reassuring proof of concept, it doesn’t negate the importance of having to continue to monitor, because nothing is infallible,” she told this news organization. “We’ve talked about high-barrier drugs in the past, and you do start seeing resistance emerge.”
A version of this article first appeared on Medscape.com.
Brisbane, Australia – , according to new data from the ADVANCE trial.
“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” said Andrew Hill, MD, from the department of pharmacology and therapeutics at the University of Liverpool, England.
The new data was presented here at the International AIDS Society conference on HIV Science. The ADVANCE trial is a three-arm randomized study involving 1,053 treatment-naive individuals comparing two triple-therapy combinations — dolutegravir, emtricitabine, and one of two tenofovir prodrugs – with a standard care regimen of tenofovir disoproxil fumarate, emtricitabine, and efavirenz.
Although the usual approach for someone in a clinical trial who experiences elevations in HIV RNA levels while on a dolutegravir-based treatment is to switch them to another therapy, the ADVANCE investigators opted for a different strategy.
“We actually continued treatment despite high viral load, and we didn’t have standard discontinuation preferences,” Dr. Hill said at the meeting. They instead provided counseling about adherence, which gave an opportunity to examine viral resuppression rates in participants in both the dolutegravir and efavirenz arms.
This revealed that 95% of patients in the two dolutegravir arms of the study were able to achieve resuppression of their viral load – defined as below 50 viral RNA copies per mL – without any emergence of resistance.
The guidelines
Current World Health Organization guidelines recommend that anyone whose viral load goes above 1,000 copies per mL who is on a non-nucleoside reverse transcriptase inhibitor such as efavirenz should be switched to an appropriate regimen.
Those who experience viremia on an integrase inhibitor such as dolutegravir should receive adherence counseling, have a repeat viral load test done in 3 months, and – if their viral load is still elevated – be switched to another regimen.
Dr. Hill and his team were examining how this might play out in a clinical trial setting and they found that there were a similar number of episodes of initial virologic failure in both the dolutegravir and efavirenz groups.
But after adherence counseling, testing for resistance and – if no resistance was evident – continuation with treatment, they saw differences emerge between the two groups.
“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” he said.
Time to viral resuppression
At 24 weeks after restarting treatment, 88% of people in the dolutegravir group had resuppressed their viral RNA, compared with 46% of people in the efavirenz group. At 48 weeks, those figures were 95% and 66%, respectively.
Dr. Hill pointed out that a significant number of people were lost to follow-up after virologic failure, and genotyping was not performed at baseline.
We addressed the question of how much adherence counseling should be undertaken in people who experienced viremia while on dolutegravir therapy, Dr. Hill said, particularly as there were often very good reasons for lack of adherence, such as homelessness.
“If you can get through those difficult phases, people can go back on their meds,” he said in an interview. “It’s almost a sociological problem rather than a clinical issue.”
And with efavirenz and the lower rates of resuppression observed in the study, Dr. Hill said it was a more fragile drug, so viremia therefore provided the opportunity for resistance to emerge, “and then once the resistant virus is there, you can’t get virus undetectable.”
Laura Waters, MD, a genitourinary and HIV medicine consultant at the Mortimer Market Centre in London, who was not involved in the study, said the results support recommendations to give people on drugs such as dolutegravir, which have a high genetic barrier to resistance, more time to improve their adherence before switching to another therapy.
“Although it provides that reassuring proof of concept, it doesn’t negate the importance of having to continue to monitor, because nothing is infallible,” she told this news organization. “We’ve talked about high-barrier drugs in the past, and you do start seeing resistance emerge.”
A version of this article first appeared on Medscape.com.
Brisbane, Australia – , according to new data from the ADVANCE trial.
“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” said Andrew Hill, MD, from the department of pharmacology and therapeutics at the University of Liverpool, England.
The new data was presented here at the International AIDS Society conference on HIV Science. The ADVANCE trial is a three-arm randomized study involving 1,053 treatment-naive individuals comparing two triple-therapy combinations — dolutegravir, emtricitabine, and one of two tenofovir prodrugs – with a standard care regimen of tenofovir disoproxil fumarate, emtricitabine, and efavirenz.
Although the usual approach for someone in a clinical trial who experiences elevations in HIV RNA levels while on a dolutegravir-based treatment is to switch them to another therapy, the ADVANCE investigators opted for a different strategy.
“We actually continued treatment despite high viral load, and we didn’t have standard discontinuation preferences,” Dr. Hill said at the meeting. They instead provided counseling about adherence, which gave an opportunity to examine viral resuppression rates in participants in both the dolutegravir and efavirenz arms.
This revealed that 95% of patients in the two dolutegravir arms of the study were able to achieve resuppression of their viral load – defined as below 50 viral RNA copies per mL – without any emergence of resistance.
The guidelines
Current World Health Organization guidelines recommend that anyone whose viral load goes above 1,000 copies per mL who is on a non-nucleoside reverse transcriptase inhibitor such as efavirenz should be switched to an appropriate regimen.
Those who experience viremia on an integrase inhibitor such as dolutegravir should receive adherence counseling, have a repeat viral load test done in 3 months, and – if their viral load is still elevated – be switched to another regimen.
Dr. Hill and his team were examining how this might play out in a clinical trial setting and they found that there were a similar number of episodes of initial virologic failure in both the dolutegravir and efavirenz groups.
But after adherence counseling, testing for resistance and – if no resistance was evident – continuation with treatment, they saw differences emerge between the two groups.
“What we saw was a faster time to resuppression in the people followed-up long term on dolutegravir and also a higher percentage of people becoming suppressed when they remained on dolutegravir,” he said.
Time to viral resuppression
At 24 weeks after restarting treatment, 88% of people in the dolutegravir group had resuppressed their viral RNA, compared with 46% of people in the efavirenz group. At 48 weeks, those figures were 95% and 66%, respectively.
Dr. Hill pointed out that a significant number of people were lost to follow-up after virologic failure, and genotyping was not performed at baseline.
We addressed the question of how much adherence counseling should be undertaken in people who experienced viremia while on dolutegravir therapy, Dr. Hill said, particularly as there were often very good reasons for lack of adherence, such as homelessness.
“If you can get through those difficult phases, people can go back on their meds,” he said in an interview. “It’s almost a sociological problem rather than a clinical issue.”
And with efavirenz and the lower rates of resuppression observed in the study, Dr. Hill said it was a more fragile drug, so viremia therefore provided the opportunity for resistance to emerge, “and then once the resistant virus is there, you can’t get virus undetectable.”
Laura Waters, MD, a genitourinary and HIV medicine consultant at the Mortimer Market Centre in London, who was not involved in the study, said the results support recommendations to give people on drugs such as dolutegravir, which have a high genetic barrier to resistance, more time to improve their adherence before switching to another therapy.
“Although it provides that reassuring proof of concept, it doesn’t negate the importance of having to continue to monitor, because nothing is infallible,” she told this news organization. “We’ve talked about high-barrier drugs in the past, and you do start seeing resistance emerge.”
A version of this article first appeared on Medscape.com.
AT IAS 2023
Results from halted islatravir antiretroviral trial presented
Brisbane, Australia – , according to investigators.
The nucleoside reverse transcriptase translocation inhibitor hit a roadblock in December 2021 when the U.S. Food and Drug Administration put a hold on investigational new drug applications for both the oral and implant formulations of islatravir after some patients in clinical trials showed decreases in total lymphocyte and CD4+ cell counts.
A phase 3, double-blind, randomized, controlled trial was underway at the time of once-daily islatravir (0.75 mg) in combination with 100 mg doravirine, compared with bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) as initial therapy for HIV infection in treatment-naïve individuals. Recruitment was stopped, 83 participants short of the planned 680, but the trial could continue the full 48 weeks.
Jürgen Rockstroh, MD, professor of medicine and head of the HIV Outpatient Clinic at the University of Bonn, Germany, presented the latest results from that trial of 597 patients at the International AIDS Society conference on HIV Science.
At week 48 after starting therapy, 88.9% of participants in the islatravir and doravirine arm and 88.3% of patients in the B/F/TAF arm achieved the primary outcome of HIV-1 RNA levels below 50 copies/mL.
One patient treated with islatravir and doravirine and four patients taking B/F/TAF experienced virologic failure.
Dr. Rockstroh told the conference the patient who developed viremia with the new islatravir combination had very high viral load at baseline but showed a rapid response to treatment, which reduced his viral load down to around 1,200 copies/mL by week 4.
However, by week 24, his islatravir concentration had reduced below detectable levels, suggesting a problem with adherence. His viral load increased again, and three treatment-resistant mutations were detected.
While both arms of the study showed a significant increase in CD4+ T cell counts, Dr. Rockstroh pointed out that some individuals in the islatravir and doravirine arm had a lower absolute increase in lymphocyte counts at week 48.
Overall, the mean change in CD4+ T cell counts was 182 cells/mL in the islatravir and doravirine group, compared with 234 cells/mL in the B/F/TAF group.
More patients in the islatravir combination arm discontinued treatment due to a decrease in CD4+ T cell or total lymphocyte counts – 5.4%, compared with 2% in the B/F/TAF arm, however.
“These changes in lymphocyte counts did not lead to any difference in the amount of infection-related adverse events, which happened in both arms in relatively comparable percentages,” Dr. Rockstroh said at the conference.
New lower dose
Because of persistent concerns about the impact on CD4+ T cells and total lymphocytes, Dr. Rockstroh said another phase 3 trial is now underway using a lower 0.25 mg dose of islatravir, again combined with 100 mg doravirine, in people who are treatment-naïve and virologically suppressed.
The study also examined the impact of both treatments on weight gain and found the mean change in weight was similar between both arms – 3.45 kg gain in those on islatravir with doravirine and 3.32 kg gain in those on B/F/TAF, which was not significantly different.
There are several important reasons it is a good idea to have more treatment options available for people with HIV, Dr. Rockstroh said in an interview.
With integrase inhibitors potentially interfering with metabolic health, weight gain, hypertension, insulin resistance, and possible diabetes, “I think it’s wise that we at least have alternative strategies,” he said.
James McMahon, MD, PhD, an infectious diseases physician and head of the Infectious Diseases Clinical Research Unit at the Alfred Hospital and Monash University in Melbourne, said there is always a need for new HIV treatments, particularly ones that are more powerful.
“Whenever you get a drug that’s potent at low dose, it means you can have smaller pills, [and] you can then consider giving more of it in long-acting formulations,” Dr. McMahon said.
He pointed out that the study did not show any signal of increased infections with the lower CD4+ T cell counts in the islatravir and doravirine arm, “but that difference is enough to raise that concern that it’s not ideal, and it should be moved forward with a lower dose, which is what they’ve done.”
A version of this article first appeared on Medscape.com.
Brisbane, Australia – , according to investigators.
The nucleoside reverse transcriptase translocation inhibitor hit a roadblock in December 2021 when the U.S. Food and Drug Administration put a hold on investigational new drug applications for both the oral and implant formulations of islatravir after some patients in clinical trials showed decreases in total lymphocyte and CD4+ cell counts.
A phase 3, double-blind, randomized, controlled trial was underway at the time of once-daily islatravir (0.75 mg) in combination with 100 mg doravirine, compared with bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) as initial therapy for HIV infection in treatment-naïve individuals. Recruitment was stopped, 83 participants short of the planned 680, but the trial could continue the full 48 weeks.
Jürgen Rockstroh, MD, professor of medicine and head of the HIV Outpatient Clinic at the University of Bonn, Germany, presented the latest results from that trial of 597 patients at the International AIDS Society conference on HIV Science.
At week 48 after starting therapy, 88.9% of participants in the islatravir and doravirine arm and 88.3% of patients in the B/F/TAF arm achieved the primary outcome of HIV-1 RNA levels below 50 copies/mL.
One patient treated with islatravir and doravirine and four patients taking B/F/TAF experienced virologic failure.
Dr. Rockstroh told the conference the patient who developed viremia with the new islatravir combination had very high viral load at baseline but showed a rapid response to treatment, which reduced his viral load down to around 1,200 copies/mL by week 4.
However, by week 24, his islatravir concentration had reduced below detectable levels, suggesting a problem with adherence. His viral load increased again, and three treatment-resistant mutations were detected.
While both arms of the study showed a significant increase in CD4+ T cell counts, Dr. Rockstroh pointed out that some individuals in the islatravir and doravirine arm had a lower absolute increase in lymphocyte counts at week 48.
Overall, the mean change in CD4+ T cell counts was 182 cells/mL in the islatravir and doravirine group, compared with 234 cells/mL in the B/F/TAF group.
More patients in the islatravir combination arm discontinued treatment due to a decrease in CD4+ T cell or total lymphocyte counts – 5.4%, compared with 2% in the B/F/TAF arm, however.
“These changes in lymphocyte counts did not lead to any difference in the amount of infection-related adverse events, which happened in both arms in relatively comparable percentages,” Dr. Rockstroh said at the conference.
New lower dose
Because of persistent concerns about the impact on CD4+ T cells and total lymphocytes, Dr. Rockstroh said another phase 3 trial is now underway using a lower 0.25 mg dose of islatravir, again combined with 100 mg doravirine, in people who are treatment-naïve and virologically suppressed.
The study also examined the impact of both treatments on weight gain and found the mean change in weight was similar between both arms – 3.45 kg gain in those on islatravir with doravirine and 3.32 kg gain in those on B/F/TAF, which was not significantly different.
There are several important reasons it is a good idea to have more treatment options available for people with HIV, Dr. Rockstroh said in an interview.
With integrase inhibitors potentially interfering with metabolic health, weight gain, hypertension, insulin resistance, and possible diabetes, “I think it’s wise that we at least have alternative strategies,” he said.
James McMahon, MD, PhD, an infectious diseases physician and head of the Infectious Diseases Clinical Research Unit at the Alfred Hospital and Monash University in Melbourne, said there is always a need for new HIV treatments, particularly ones that are more powerful.
“Whenever you get a drug that’s potent at low dose, it means you can have smaller pills, [and] you can then consider giving more of it in long-acting formulations,” Dr. McMahon said.
He pointed out that the study did not show any signal of increased infections with the lower CD4+ T cell counts in the islatravir and doravirine arm, “but that difference is enough to raise that concern that it’s not ideal, and it should be moved forward with a lower dose, which is what they’ve done.”
A version of this article first appeared on Medscape.com.
Brisbane, Australia – , according to investigators.
The nucleoside reverse transcriptase translocation inhibitor hit a roadblock in December 2021 when the U.S. Food and Drug Administration put a hold on investigational new drug applications for both the oral and implant formulations of islatravir after some patients in clinical trials showed decreases in total lymphocyte and CD4+ cell counts.
A phase 3, double-blind, randomized, controlled trial was underway at the time of once-daily islatravir (0.75 mg) in combination with 100 mg doravirine, compared with bictegravir, emtricitabine, tenofovir alafenamide (B/F/TAF) as initial therapy for HIV infection in treatment-naïve individuals. Recruitment was stopped, 83 participants short of the planned 680, but the trial could continue the full 48 weeks.
Jürgen Rockstroh, MD, professor of medicine and head of the HIV Outpatient Clinic at the University of Bonn, Germany, presented the latest results from that trial of 597 patients at the International AIDS Society conference on HIV Science.
At week 48 after starting therapy, 88.9% of participants in the islatravir and doravirine arm and 88.3% of patients in the B/F/TAF arm achieved the primary outcome of HIV-1 RNA levels below 50 copies/mL.
One patient treated with islatravir and doravirine and four patients taking B/F/TAF experienced virologic failure.
Dr. Rockstroh told the conference the patient who developed viremia with the new islatravir combination had very high viral load at baseline but showed a rapid response to treatment, which reduced his viral load down to around 1,200 copies/mL by week 4.
However, by week 24, his islatravir concentration had reduced below detectable levels, suggesting a problem with adherence. His viral load increased again, and three treatment-resistant mutations were detected.
While both arms of the study showed a significant increase in CD4+ T cell counts, Dr. Rockstroh pointed out that some individuals in the islatravir and doravirine arm had a lower absolute increase in lymphocyte counts at week 48.
Overall, the mean change in CD4+ T cell counts was 182 cells/mL in the islatravir and doravirine group, compared with 234 cells/mL in the B/F/TAF group.
More patients in the islatravir combination arm discontinued treatment due to a decrease in CD4+ T cell or total lymphocyte counts – 5.4%, compared with 2% in the B/F/TAF arm, however.
“These changes in lymphocyte counts did not lead to any difference in the amount of infection-related adverse events, which happened in both arms in relatively comparable percentages,” Dr. Rockstroh said at the conference.
New lower dose
Because of persistent concerns about the impact on CD4+ T cells and total lymphocytes, Dr. Rockstroh said another phase 3 trial is now underway using a lower 0.25 mg dose of islatravir, again combined with 100 mg doravirine, in people who are treatment-naïve and virologically suppressed.
The study also examined the impact of both treatments on weight gain and found the mean change in weight was similar between both arms – 3.45 kg gain in those on islatravir with doravirine and 3.32 kg gain in those on B/F/TAF, which was not significantly different.
There are several important reasons it is a good idea to have more treatment options available for people with HIV, Dr. Rockstroh said in an interview.
With integrase inhibitors potentially interfering with metabolic health, weight gain, hypertension, insulin resistance, and possible diabetes, “I think it’s wise that we at least have alternative strategies,” he said.
James McMahon, MD, PhD, an infectious diseases physician and head of the Infectious Diseases Clinical Research Unit at the Alfred Hospital and Monash University in Melbourne, said there is always a need for new HIV treatments, particularly ones that are more powerful.
“Whenever you get a drug that’s potent at low dose, it means you can have smaller pills, [and] you can then consider giving more of it in long-acting formulations,” Dr. McMahon said.
He pointed out that the study did not show any signal of increased infections with the lower CD4+ T cell counts in the islatravir and doravirine arm, “but that difference is enough to raise that concern that it’s not ideal, and it should be moved forward with a lower dose, which is what they’ve done.”
A version of this article first appeared on Medscape.com.
Studies link GLP-1 agonists to progression of diabetic retinopathy
SEATTLE – A family of blockbuster drugs for managing blood glucose – and now for promoting weight loss – has been linked to exacerbation of macular disease that frequently accompanies diabetes, new data show.
Two studies presented at the annual meeting of the American Society of Retina Specialists (ASRS) have found that
Clinicians should be aware of these effects of GLP-1 inhibitors to ensure appropriate monitoring of patients for the possibility that retinopathy may accelerate, according to Ehsan Rahimy, MD, an adjunct clinical professor at Stanford (Calif.) University, and colleagues.
Dr. Rahimy presented results of a retrospective study of retinopathy progression in patients taking either GLP-1 agonists or sodium-glucose transporter-2 (SGLT-2) inhibitors, also known as gliflozins. “When we looked at the conversion to proliferative disease, you can see it was statistically higher in the GLP-1 group at all time points,” he said.
GLP-1 agonists can promote considerable weight loss in patients with and without diabetes. Moreover, the finding that gliflozins improve cardiovascular and renal function in patients with type 2 diabetes has accelerated the use of these agents for blood glucose control.
Using a repository of data from more than 13,500 people taking either of the two kinds of medication, the researchers looked for conversion of diabetic eye disease to proliferative diabetic retinopathy (PDR) or DME. Secondary outcomes were the need for intravitreal injections, panretinal photocoagulation (PRP), or pars plana vitrectomy (PPV).
Propensity score matching for age, sex, race, ethnicity, and baseline hemoglobin A1c resulted in the inclusion of 5,446 participants in each treatment group. After matching, the mean age of participants in either group was 64 years, and the mean A1c was 8.5%. Slightly more than half the participants were insulin-dependent.
Patients taking GLP-1 inhibitors had higher rates of conversion to PDR than those taking gliflozins at 3 years (6% vs. 4%; P < .01), the researchers found. Nearly 25% of those taking a GLP-1 agonist had progressed to DME after 3 years, compared with 18% of those taking a gliflozin.
People in the group taking GLP-1 inhibitors also had a greater need for interventions than those on a gliflozin; 8% vs. roughly 6%, respectively, required intravitreal injections, Dr. Rahimy reported. Similar trends were noted for need for PRP and PPV, he added, although the absolute numbers of patients were small.
Albiglutide the key culprit?
In other research reported at the meeting, a meta-analysis of data collected in 93 randomized clinical trials of the seven currently available GLP-1 agonists found only albiglutide was associated with diabetic retinopathy to a statistically significant degree. Compared with placebo, albiglutide more than doubled the risk for early-stage diabetic retinopathy (relative risk 2.18; 95% confidence interval, 1.01-4.67; P = .05).
Other GLP-1 agonists evaluated in the meta-analysis included semaglutide, tirzepatide, dulaglutide, exenatide, liraglutide, and lixisenatide. These findings were reported in a poster presented at the meeting by Ishani Kapoor, MD candidate, Drexel University, Philadelphia.
“The strength of these effects depends on the specific GLP-1 receptor agonist used, patient-specific clinical characteristics, and demographics,” Ms. Kapoor and coauthors reported. “Further studies are needed to clarify the patient populations that would benefit from GLP-1 receptor agonists and those at risk for [the] development of additional ocular damage.”
What causes progression?
Whether worsening of retinopathy stems from rapid weight loss and acute reductions in concentrations of blood glucose or is a direct effect of GLP-1 agonists on the eye is unclear.
“That rapid reduction is thought to play some role,” Dr. Rahimy said. “But if you actually look out there in the basic science literature, it’s suggested that there are direct effects of these medications on the retina too. That being said, it’s suggested that they may be protective to the retina. And I think that’s where we’ve gotten a lot of mixed signals in our community between what we’ve seen on the basic science side vs. what we’re seeing on the real-world side.”
The study was independently funded. Dr. Rahimy reports consultancies or speakerships with AbbVie, Allergan, Apellis, Carl Zeiss, Genentech, and Google, and research support from Regeneron. Ms. Kapoor reports no relevant financial relationships.
A version of this article appeared on Medscape.com.
SEATTLE – A family of blockbuster drugs for managing blood glucose – and now for promoting weight loss – has been linked to exacerbation of macular disease that frequently accompanies diabetes, new data show.
Two studies presented at the annual meeting of the American Society of Retina Specialists (ASRS) have found that
Clinicians should be aware of these effects of GLP-1 inhibitors to ensure appropriate monitoring of patients for the possibility that retinopathy may accelerate, according to Ehsan Rahimy, MD, an adjunct clinical professor at Stanford (Calif.) University, and colleagues.
Dr. Rahimy presented results of a retrospective study of retinopathy progression in patients taking either GLP-1 agonists or sodium-glucose transporter-2 (SGLT-2) inhibitors, also known as gliflozins. “When we looked at the conversion to proliferative disease, you can see it was statistically higher in the GLP-1 group at all time points,” he said.
GLP-1 agonists can promote considerable weight loss in patients with and without diabetes. Moreover, the finding that gliflozins improve cardiovascular and renal function in patients with type 2 diabetes has accelerated the use of these agents for blood glucose control.
Using a repository of data from more than 13,500 people taking either of the two kinds of medication, the researchers looked for conversion of diabetic eye disease to proliferative diabetic retinopathy (PDR) or DME. Secondary outcomes were the need for intravitreal injections, panretinal photocoagulation (PRP), or pars plana vitrectomy (PPV).
Propensity score matching for age, sex, race, ethnicity, and baseline hemoglobin A1c resulted in the inclusion of 5,446 participants in each treatment group. After matching, the mean age of participants in either group was 64 years, and the mean A1c was 8.5%. Slightly more than half the participants were insulin-dependent.
Patients taking GLP-1 inhibitors had higher rates of conversion to PDR than those taking gliflozins at 3 years (6% vs. 4%; P < .01), the researchers found. Nearly 25% of those taking a GLP-1 agonist had progressed to DME after 3 years, compared with 18% of those taking a gliflozin.
People in the group taking GLP-1 inhibitors also had a greater need for interventions than those on a gliflozin; 8% vs. roughly 6%, respectively, required intravitreal injections, Dr. Rahimy reported. Similar trends were noted for need for PRP and PPV, he added, although the absolute numbers of patients were small.
Albiglutide the key culprit?
In other research reported at the meeting, a meta-analysis of data collected in 93 randomized clinical trials of the seven currently available GLP-1 agonists found only albiglutide was associated with diabetic retinopathy to a statistically significant degree. Compared with placebo, albiglutide more than doubled the risk for early-stage diabetic retinopathy (relative risk 2.18; 95% confidence interval, 1.01-4.67; P = .05).
Other GLP-1 agonists evaluated in the meta-analysis included semaglutide, tirzepatide, dulaglutide, exenatide, liraglutide, and lixisenatide. These findings were reported in a poster presented at the meeting by Ishani Kapoor, MD candidate, Drexel University, Philadelphia.
“The strength of these effects depends on the specific GLP-1 receptor agonist used, patient-specific clinical characteristics, and demographics,” Ms. Kapoor and coauthors reported. “Further studies are needed to clarify the patient populations that would benefit from GLP-1 receptor agonists and those at risk for [the] development of additional ocular damage.”
What causes progression?
Whether worsening of retinopathy stems from rapid weight loss and acute reductions in concentrations of blood glucose or is a direct effect of GLP-1 agonists on the eye is unclear.
“That rapid reduction is thought to play some role,” Dr. Rahimy said. “But if you actually look out there in the basic science literature, it’s suggested that there are direct effects of these medications on the retina too. That being said, it’s suggested that they may be protective to the retina. And I think that’s where we’ve gotten a lot of mixed signals in our community between what we’ve seen on the basic science side vs. what we’re seeing on the real-world side.”
The study was independently funded. Dr. Rahimy reports consultancies or speakerships with AbbVie, Allergan, Apellis, Carl Zeiss, Genentech, and Google, and research support from Regeneron. Ms. Kapoor reports no relevant financial relationships.
A version of this article appeared on Medscape.com.
SEATTLE – A family of blockbuster drugs for managing blood glucose – and now for promoting weight loss – has been linked to exacerbation of macular disease that frequently accompanies diabetes, new data show.
Two studies presented at the annual meeting of the American Society of Retina Specialists (ASRS) have found that
Clinicians should be aware of these effects of GLP-1 inhibitors to ensure appropriate monitoring of patients for the possibility that retinopathy may accelerate, according to Ehsan Rahimy, MD, an adjunct clinical professor at Stanford (Calif.) University, and colleagues.
Dr. Rahimy presented results of a retrospective study of retinopathy progression in patients taking either GLP-1 agonists or sodium-glucose transporter-2 (SGLT-2) inhibitors, also known as gliflozins. “When we looked at the conversion to proliferative disease, you can see it was statistically higher in the GLP-1 group at all time points,” he said.
GLP-1 agonists can promote considerable weight loss in patients with and without diabetes. Moreover, the finding that gliflozins improve cardiovascular and renal function in patients with type 2 diabetes has accelerated the use of these agents for blood glucose control.
Using a repository of data from more than 13,500 people taking either of the two kinds of medication, the researchers looked for conversion of diabetic eye disease to proliferative diabetic retinopathy (PDR) or DME. Secondary outcomes were the need for intravitreal injections, panretinal photocoagulation (PRP), or pars plana vitrectomy (PPV).
Propensity score matching for age, sex, race, ethnicity, and baseline hemoglobin A1c resulted in the inclusion of 5,446 participants in each treatment group. After matching, the mean age of participants in either group was 64 years, and the mean A1c was 8.5%. Slightly more than half the participants were insulin-dependent.
Patients taking GLP-1 inhibitors had higher rates of conversion to PDR than those taking gliflozins at 3 years (6% vs. 4%; P < .01), the researchers found. Nearly 25% of those taking a GLP-1 agonist had progressed to DME after 3 years, compared with 18% of those taking a gliflozin.
People in the group taking GLP-1 inhibitors also had a greater need for interventions than those on a gliflozin; 8% vs. roughly 6%, respectively, required intravitreal injections, Dr. Rahimy reported. Similar trends were noted for need for PRP and PPV, he added, although the absolute numbers of patients were small.
Albiglutide the key culprit?
In other research reported at the meeting, a meta-analysis of data collected in 93 randomized clinical trials of the seven currently available GLP-1 agonists found only albiglutide was associated with diabetic retinopathy to a statistically significant degree. Compared with placebo, albiglutide more than doubled the risk for early-stage diabetic retinopathy (relative risk 2.18; 95% confidence interval, 1.01-4.67; P = .05).
Other GLP-1 agonists evaluated in the meta-analysis included semaglutide, tirzepatide, dulaglutide, exenatide, liraglutide, and lixisenatide. These findings were reported in a poster presented at the meeting by Ishani Kapoor, MD candidate, Drexel University, Philadelphia.
“The strength of these effects depends on the specific GLP-1 receptor agonist used, patient-specific clinical characteristics, and demographics,” Ms. Kapoor and coauthors reported. “Further studies are needed to clarify the patient populations that would benefit from GLP-1 receptor agonists and those at risk for [the] development of additional ocular damage.”
What causes progression?
Whether worsening of retinopathy stems from rapid weight loss and acute reductions in concentrations of blood glucose or is a direct effect of GLP-1 agonists on the eye is unclear.
“That rapid reduction is thought to play some role,” Dr. Rahimy said. “But if you actually look out there in the basic science literature, it’s suggested that there are direct effects of these medications on the retina too. That being said, it’s suggested that they may be protective to the retina. And I think that’s where we’ve gotten a lot of mixed signals in our community between what we’ve seen on the basic science side vs. what we’re seeing on the real-world side.”
The study was independently funded. Dr. Rahimy reports consultancies or speakerships with AbbVie, Allergan, Apellis, Carl Zeiss, Genentech, and Google, and research support from Regeneron. Ms. Kapoor reports no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM ASRS 2023
Time-restricted eating gains for weight and glycemic control
Time-restricted eating (TRE) can be a practical, easy-to-follow way for some people to control their daily food intake and lose weight. It precludes a person’s need to pay close attention to how much they eat as long as they confine consumption to a limited time window. Plus, results from several recent studies show TRE can further benefit people with type 2 diabetes as well as obesity via mechanisms beyond weight loss.
The most tested and recommended eating window is 8 hours long, although periods up to roughly 10 hours may provide some benefits. Results from multiple studies document that TRE produces modest but consistent weight loss of less than 5% in many people. A recent meta-analysis of 17 randomized controlled studies involving 899 people showed an overall incremental weight loss, compared with controls of 1.60 kg on a TRE regimen.
The more limited data collected so far in people with type 2 diabetes show additional metabolic benefits from TRE, including improved beta-cell responsiveness, increased insulin sensitivity, nonoxidative glucose disposal, increased time in glycemic range, and virtually no hypoglycemic events, Courtney Peterson, PhD, said at the annual scientific sessions of the American Diabetes Association.
said Dr. Peterson, a researcher in the department of nutrition sciences at the University of Alabama, Birmingham.
‘Eating earlier is better’
An advantage of TRE is that it is “agnostic to food preferences and quality,” said Lisa S. Chow, MD, during a separate session at the meeting. TRE “may have benefits beyond calorie restriction” that appear related to “the timing of eating and the extent of the eating window restriction. Eating earlier [in the day] is better” for markers of metabolic health regardless of how much weight a person may lose on a TRE regimen, noted Dr. Chow, an endocrinologist and professor at the University of Minnesota Medical School, Minneapolis.
But the TRE paradigm seems amenable to some flexibility on the timing for the eating window while still having benefit.
“Self-selected eating windows are usually late,” Dr. Chow observed, and because compliance with a constrained eating window matters, it may be worth allowing people to choose whichever time window for eating works best for them.
“If you let people pick their eating window, they typically include dinner,” said Dr. Chow, who has run a small TRE study that showed this.
“To maximize the effects [of TRE] people should use the eating window that best fits their life,” agreed Kelsey Gabel, PhD, who also gave a TRE talk during the meeting. “Eating most of your [daily] calories first thing in the morning would have the best cardiometabolic benefit, but reduced adherence would mitigate the benefit,” said Dr. Gabel, a nutrition researcher at the University of Illinois.
‘Meeting people where they’re at’
“We can have a larger public health impact by meeting people where they’re at. People should position their eating window where it best fits so they can achieve calorie restriction without even knowing it,” Dr. Gabel advised.
She cited a report as evidence that most people prefer a later eating window. The report reviewed observational data from nearly 800,000 people who used either of two different TRE phone apps. The data showed that most people opted to start their daily eating during 11:00 AM-1:00 PM, and then stop during 6:00 PM-8:00 PM.
“TRE will not solve all of our obesity problems, but it’s a good place to start,” Dr. Gabel declared.
For people who include dinner at a typical evening time in their TRE window, a key message is that “dinner is your last food of the day. There’s no snacking later,” said Dr. Chow.
“The biggest challenge is adherence,” said Dr. Peterson. “Fewer people want to do TRE than you think. We know that calorie restriction works. We just need a way for people to do it,” and for at least some people, TRE is that way. While no evidence clearly shows that 8 hours is the best eating-window duration, “we think 8 hours is a good sweet-spot for motivated people,” she said.
Sparser data on TRE in people with T2D
Fewer studies have examined the impact of TRE on glycemic control, insulin sensitivity, and related effects in people with type 2 diabetes. According to Dr. Peterson, published reports currently include two randomized controlled studies and three single-arm studies in people with type 2 diabetes and an additional two studies in people with prediabetes.
The largest of these reports randomized 120 adults in China with type 2 diabetes and overweight to TRE using a 10-hour eating window (8:00 AM-6:00 PM) or unrestricted eating for 12 weeks. By the end of the study, those on the TRE regimen had an average reduction in their hemoglobin A1c from baseline that was 0.88 percentage points greater than among the controls, and the TRE arm had also lost an average of nearly 2.15 kg more from baseline than the controls.
Dr. Peterson highlighted the importance of expanding research using TRE in people with type 2 diabetes.
Dr. Peterson and Dr. Gabel report no relevant financial relationships. Dr. Chow has received research support from Dexcom.
A version of this article first appeared on Medscape.com.
Time-restricted eating (TRE) can be a practical, easy-to-follow way for some people to control their daily food intake and lose weight. It precludes a person’s need to pay close attention to how much they eat as long as they confine consumption to a limited time window. Plus, results from several recent studies show TRE can further benefit people with type 2 diabetes as well as obesity via mechanisms beyond weight loss.
The most tested and recommended eating window is 8 hours long, although periods up to roughly 10 hours may provide some benefits. Results from multiple studies document that TRE produces modest but consistent weight loss of less than 5% in many people. A recent meta-analysis of 17 randomized controlled studies involving 899 people showed an overall incremental weight loss, compared with controls of 1.60 kg on a TRE regimen.
The more limited data collected so far in people with type 2 diabetes show additional metabolic benefits from TRE, including improved beta-cell responsiveness, increased insulin sensitivity, nonoxidative glucose disposal, increased time in glycemic range, and virtually no hypoglycemic events, Courtney Peterson, PhD, said at the annual scientific sessions of the American Diabetes Association.
said Dr. Peterson, a researcher in the department of nutrition sciences at the University of Alabama, Birmingham.
‘Eating earlier is better’
An advantage of TRE is that it is “agnostic to food preferences and quality,” said Lisa S. Chow, MD, during a separate session at the meeting. TRE “may have benefits beyond calorie restriction” that appear related to “the timing of eating and the extent of the eating window restriction. Eating earlier [in the day] is better” for markers of metabolic health regardless of how much weight a person may lose on a TRE regimen, noted Dr. Chow, an endocrinologist and professor at the University of Minnesota Medical School, Minneapolis.
But the TRE paradigm seems amenable to some flexibility on the timing for the eating window while still having benefit.
“Self-selected eating windows are usually late,” Dr. Chow observed, and because compliance with a constrained eating window matters, it may be worth allowing people to choose whichever time window for eating works best for them.
“If you let people pick their eating window, they typically include dinner,” said Dr. Chow, who has run a small TRE study that showed this.
“To maximize the effects [of TRE] people should use the eating window that best fits their life,” agreed Kelsey Gabel, PhD, who also gave a TRE talk during the meeting. “Eating most of your [daily] calories first thing in the morning would have the best cardiometabolic benefit, but reduced adherence would mitigate the benefit,” said Dr. Gabel, a nutrition researcher at the University of Illinois.
‘Meeting people where they’re at’
“We can have a larger public health impact by meeting people where they’re at. People should position their eating window where it best fits so they can achieve calorie restriction without even knowing it,” Dr. Gabel advised.
She cited a report as evidence that most people prefer a later eating window. The report reviewed observational data from nearly 800,000 people who used either of two different TRE phone apps. The data showed that most people opted to start their daily eating during 11:00 AM-1:00 PM, and then stop during 6:00 PM-8:00 PM.
“TRE will not solve all of our obesity problems, but it’s a good place to start,” Dr. Gabel declared.
For people who include dinner at a typical evening time in their TRE window, a key message is that “dinner is your last food of the day. There’s no snacking later,” said Dr. Chow.
“The biggest challenge is adherence,” said Dr. Peterson. “Fewer people want to do TRE than you think. We know that calorie restriction works. We just need a way for people to do it,” and for at least some people, TRE is that way. While no evidence clearly shows that 8 hours is the best eating-window duration, “we think 8 hours is a good sweet-spot for motivated people,” she said.
Sparser data on TRE in people with T2D
Fewer studies have examined the impact of TRE on glycemic control, insulin sensitivity, and related effects in people with type 2 diabetes. According to Dr. Peterson, published reports currently include two randomized controlled studies and three single-arm studies in people with type 2 diabetes and an additional two studies in people with prediabetes.
The largest of these reports randomized 120 adults in China with type 2 diabetes and overweight to TRE using a 10-hour eating window (8:00 AM-6:00 PM) or unrestricted eating for 12 weeks. By the end of the study, those on the TRE regimen had an average reduction in their hemoglobin A1c from baseline that was 0.88 percentage points greater than among the controls, and the TRE arm had also lost an average of nearly 2.15 kg more from baseline than the controls.
Dr. Peterson highlighted the importance of expanding research using TRE in people with type 2 diabetes.
Dr. Peterson and Dr. Gabel report no relevant financial relationships. Dr. Chow has received research support from Dexcom.
A version of this article first appeared on Medscape.com.
Time-restricted eating (TRE) can be a practical, easy-to-follow way for some people to control their daily food intake and lose weight. It precludes a person’s need to pay close attention to how much they eat as long as they confine consumption to a limited time window. Plus, results from several recent studies show TRE can further benefit people with type 2 diabetes as well as obesity via mechanisms beyond weight loss.
The most tested and recommended eating window is 8 hours long, although periods up to roughly 10 hours may provide some benefits. Results from multiple studies document that TRE produces modest but consistent weight loss of less than 5% in many people. A recent meta-analysis of 17 randomized controlled studies involving 899 people showed an overall incremental weight loss, compared with controls of 1.60 kg on a TRE regimen.
The more limited data collected so far in people with type 2 diabetes show additional metabolic benefits from TRE, including improved beta-cell responsiveness, increased insulin sensitivity, nonoxidative glucose disposal, increased time in glycemic range, and virtually no hypoglycemic events, Courtney Peterson, PhD, said at the annual scientific sessions of the American Diabetes Association.
said Dr. Peterson, a researcher in the department of nutrition sciences at the University of Alabama, Birmingham.
‘Eating earlier is better’
An advantage of TRE is that it is “agnostic to food preferences and quality,” said Lisa S. Chow, MD, during a separate session at the meeting. TRE “may have benefits beyond calorie restriction” that appear related to “the timing of eating and the extent of the eating window restriction. Eating earlier [in the day] is better” for markers of metabolic health regardless of how much weight a person may lose on a TRE regimen, noted Dr. Chow, an endocrinologist and professor at the University of Minnesota Medical School, Minneapolis.
But the TRE paradigm seems amenable to some flexibility on the timing for the eating window while still having benefit.
“Self-selected eating windows are usually late,” Dr. Chow observed, and because compliance with a constrained eating window matters, it may be worth allowing people to choose whichever time window for eating works best for them.
“If you let people pick their eating window, they typically include dinner,” said Dr. Chow, who has run a small TRE study that showed this.
“To maximize the effects [of TRE] people should use the eating window that best fits their life,” agreed Kelsey Gabel, PhD, who also gave a TRE talk during the meeting. “Eating most of your [daily] calories first thing in the morning would have the best cardiometabolic benefit, but reduced adherence would mitigate the benefit,” said Dr. Gabel, a nutrition researcher at the University of Illinois.
‘Meeting people where they’re at’
“We can have a larger public health impact by meeting people where they’re at. People should position their eating window where it best fits so they can achieve calorie restriction without even knowing it,” Dr. Gabel advised.
She cited a report as evidence that most people prefer a later eating window. The report reviewed observational data from nearly 800,000 people who used either of two different TRE phone apps. The data showed that most people opted to start their daily eating during 11:00 AM-1:00 PM, and then stop during 6:00 PM-8:00 PM.
“TRE will not solve all of our obesity problems, but it’s a good place to start,” Dr. Gabel declared.
For people who include dinner at a typical evening time in their TRE window, a key message is that “dinner is your last food of the day. There’s no snacking later,” said Dr. Chow.
“The biggest challenge is adherence,” said Dr. Peterson. “Fewer people want to do TRE than you think. We know that calorie restriction works. We just need a way for people to do it,” and for at least some people, TRE is that way. While no evidence clearly shows that 8 hours is the best eating-window duration, “we think 8 hours is a good sweet-spot for motivated people,” she said.
Sparser data on TRE in people with T2D
Fewer studies have examined the impact of TRE on glycemic control, insulin sensitivity, and related effects in people with type 2 diabetes. According to Dr. Peterson, published reports currently include two randomized controlled studies and three single-arm studies in people with type 2 diabetes and an additional two studies in people with prediabetes.
The largest of these reports randomized 120 adults in China with type 2 diabetes and overweight to TRE using a 10-hour eating window (8:00 AM-6:00 PM) or unrestricted eating for 12 weeks. By the end of the study, those on the TRE regimen had an average reduction in their hemoglobin A1c from baseline that was 0.88 percentage points greater than among the controls, and the TRE arm had also lost an average of nearly 2.15 kg more from baseline than the controls.
Dr. Peterson highlighted the importance of expanding research using TRE in people with type 2 diabetes.
Dr. Peterson and Dr. Gabel report no relevant financial relationships. Dr. Chow has received research support from Dexcom.
A version of this article first appeared on Medscape.com.
FROM ADA 2023
Pandemic blamed for failed trial of inhaled antibiotic
NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.
“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.
The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.
The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.
Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.
The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.
On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).
With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.
Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.
There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.
While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” obscuring a benefit that would have been otherwise shown.
Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.
Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”
If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.
Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.
Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”
Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.
“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.
Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.
“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.
The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.
The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.
Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.
The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.
On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).
With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.
Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.
There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.
While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” obscuring a benefit that would have been otherwise shown.
Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.
Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”
If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.
Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.
Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”
Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.
“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.
Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
NEW YORK – When data were combined from two parallel phase 3 bronchiectasis treatment trials, inhaled colistimethate sodium failed to significantly reduce the rate of exacerbations associated with Pseudomonas aeruginosa infection, but the disparity in the findings from the two trials, presented at the 6th World Bronchiectasis & NTM Conference (WBC) 2023, strongly suggests that this therapy is effective after all.
“The totality of the evidence supports a consistent and clinically meaningful benefit [of this therapy] outside of pandemic conditions,” reported Charles Haworth, MD, director, Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, England.
The key phrase is “outside of pandemic conditions.” PROMIS I, which was fully enrolled before the COVID-19 pandemic descended, associated the inhaled therapy with highly significant benefits. PROMIS II, which was initiated later and enrolled 40% of its participants during the pandemic, did not.
The difference between these two trials, which were essentially identical, was the timing, according to Dr. Haworth. By starting later, PROMIS II caught the onset of the pandemic, which he believes introduced numerous problems that defeated the opportunity to show an advantage for the inhaled antibiotic.
Injectable colistimethate sodium, a decades-old formulation of colistin, is already approved in the United States for gram-negative infections and is considered helpful even in challenging diseases, such as cystic fibrosis. Positive results from a phase 2 trial with inhaled colistimethate sodium in bronchiectasis patients with P. aeruginosa infection provided the rationale for the phase 3 PROMIS program.
The key entry criterion of PROMIS I and PROMIS II, each with nearly 90 participating study sites, was a history of bronchiectasis and ≥ two P. aeruginosa infections requiring oral therapy or ≥ 1 infection requiring intravenous therapy in the prior 12 months. Patients were randomly assigned to receive colistimethate sodium delivered in the proprietary I-neb nebulizer (CMS I-neb) or a matching placebo.
On the primary endpoint of annualized rate of exacerbations, the figures per year were 0.58 for CMS I-neb and 0.95 for placebo in the PROMIS I trial. This produced a rate ratio of 0.65, signaling a significant 35% (P = .00101) reduction in risk. In PROMIS II, the annualized rates of exacerbation were essentially identical in the experimental and control arms (0.089 vs. 0.088; P = .97).
With “no signal of benefit” in the PROMIS II trial, the numerical advantage of CMS I-neb for the combined data did not reach statistical significance, Dr. Haworth reported.
Other endpoints told the same story. For example, the time to first exacerbation was reduced by 41% in PROMIS I (HR, 0.59; P = .0074) but was not reduced significantly (P = .603) in PROMIS II. In PROMIS I, there was a nearly 60% reduction in the risk of severe exacerbations associated with CMS I-neb, but the risk ratio of severe infections was slightly but not significantly higher on CMS I-neb in PROMIS II.
There were signals of benefit in PROMIS II. For example, the reductions in P. aeruginosa density were similar in the two studies (P < .00001 in both), and assessment with the Severe Exacerbations and Quality of Life (SQOL) tool associated CMS I-neb with end-of-study improvement in QOL for the experimental arm in both studies.
While Dr. Haworth acknowledged that he recognizes the “issues of post hoc analysis with any data,” obscuring a benefit that would have been otherwise shown.
Besides the dramatic reduction in rates of hospitalization during the pandemic, an obstacle for showing differences in exacerbations, and other COVID-related factors with the potential to skew results, Dr. Haworth also provided several sets of objective data to make his point.
Most importantly, Dr. Haworth and his coinvestigators conducted a meta-analysis that combined data from the phase 2 trial, data from PROMIS I, and data from the patients enrolled in PROMIS II prior to the COVID pandemic. In this analysis the rate ratio for annualized exacerbations was a “pretty impressive” 0.65 favoring CMS I-neb. Moreover, in contrast to data from the PROMIS II patients enrolled during the COVID pandemic, the other three sets of data were “remarkably consistent.”
If PROMIS II data collected from patients enrolled during COVID are compared with the other sets of data, they are “the clear outlier,” he asserted.
Many guidelines in Europe, including those from the European Respiratory Society and the British Thoracic Society, already recommend inhaled colistin in patients with bronchiectasis for the treatment of P. aeruginosa. Although Dr. Haworth believes that the preponderance of controlled data now argue that CMS I-neb is effective as well as safe (adverse events in the experimental and placebo arms of PROMIS I and II were similar), he is not sure what steps will be taken to confirm a benefit to regulatory authorities. According to Dr. Haworth, there are no approved inhaled antibiotics in the United States.
Referring to Zambon, which funded the trials and is developing CMS I-neb, Dr. Haworth said, “This will be a company decision. There are some logistical hurdles to doing another trial.”
Not least of these hurdles is that clinicians and patients already consider inhalational antibiotics in general and inhaled colistin specifically to be effective for several types of infections, including P. aeruginosa, according to Eva Polverino, MD, PhD, a pulmonologist associated with the Hospital Clinic of Barcelona. She said that these drugs are already a standard of care in her own country as well as in many other countries in Europe.
“There has been a loss of equipoise needed to conduct a randomized placebo-controlled trial,” Dr. Polverino said. In her opinion, the U.S. FDA “should start thinking of other pathways to approval.” She thinks that enrollment in a placebo-controlled trial is no longer appropriate.
Dr. Haworth and Dr. Polverino have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM WBC 2023