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Guselkumab Efficacy in Crohn’s Disease Unaffected by Prior Biologic Use
VIENNA — according to a pooled analysis of the two phase 3 double-blind GALAXI 2 and 3 studies.
“We found that guselkumab was effective in both biologic-naive and biologic-inadequate subpopulations,” said coinvestigator Bruce E. Sands, MD, AGAF, gastroenterologist from Icahn School of Medicine at Mount Sinai, New York City.
These latest results add to the primary results of these studies reported earlier in 2024 that guselkumab was shown to be superior to both placebo and ustekinumab in the same patient population with moderately to severely active CD.
Sands reported the new data in a presentation at the United European Gastroenterology (UEG) Week 2024.
Guselkumab potently blocks interleukin (IL)–23 and binds to CD64, a receptor on cells that produce IL-23. The dual-acting IL-23p19 subunit inhibitor agent is currently under review by the Food and Drug Administration (FDA) for moderately to severely active CD. In September, guselkumab (Tremfya, Johnson & Johnson) was approved for use in moderately to severely active ulcerative colitis.
GALAXI 2 and 3 Pooled Dataset
In the two independent, identically designed GALAXI 2 and 3 studies, patients were randomized to guselkumab treatment at either 200 mg intravenous (IV) induction at weeks 0, 4, and 8, followed by 200 mg subcutaneous maintenance every 4 weeks, starting at week 12, or 200 mg IV induction at weeks 0, 4, and 8, followed by 100 mg subcutaneous maintenance every 8 weeks, starting at week 16; or to ustekinumab; or to placebo.
Participants were required to remain on their treatment of initial randomization for a long-term extension study (up to 5 years) looking at clinical, endoscopic, and safety outcomes, except for participants on placebo who were allowed to switch to ustekinumab if clinical response was not met at week 12.
Inclusion criteria for the studies comprised a Crohn’s Disease Activity Index score between 220 and 450, a mean daily stool frequency count > 3 or an abdominal pain score > 1, and a simple endoscopic score for CD score ≥ 6. Participants were also required to have shown an inadequate response or intolerance to oral corticosteroids, 6-mercaptopurine/azathioprine/methotrexate, or biologic therapies.
The pooled dataset included patients on either dose of guselkumab and patients on placebo (total n = 730). Of these, 52% of participants had shown a prior inadequate response to a biologic, 42% were biologic naive, and 6% had prior exposure to biologics but no documented failure. Patients on ustekinumab were not included in this analysis.
Almost all patients (97%) in the biologic-inadequate response group had previously received at least one anti–tumor necrosis factor agent, and around 15% had received vedolizumab. As expected, the biologic-inadequate responders were a lot sicker than the biologic-naive patients, Sands reported.
The composite co–primary endpoints for each guselkumab regimen vs placebo were clinical response at week 12 plus clinical remission at week 48, and clinical response at week 12 plus endoscopic response at week 48.
The major secondary endpoints comprised clinical remission at week 12 and endoscopic response also at week 12.
Short- and Long-Term Endpoints in Both Subgroups
In the biologic-naive subgroup, 54.7% of patients receiving the 200-mg dose regimen of guselkumab and 51.7% of those receiving the 100-mg dose regimen showed a clinical response at week 12 plus clinical remission at week 48, compared with 11.5% in the placebo group (P < .001 for both compared with placebo).
In the biologic-inadequate response group, 49.7% of those receiving the 200-mg dose regimen of guselkumab and 45.8% on the 100-mg dose regimen reached the composite endpoint, compared with the placebo response of 12.8% (P < .001 for both compared with placebo).
“You can see a slight decrease in response in the biologic-inadequate responders, but on the whole, the confidence intervals are highly overlapping,” said Sands.
Turning to major secondary endpoints at week 12, clinical remission was reached by 49.6% of the biologic-naive group on the 200-mg guselkumab regimen vs 16.4% on placebo, and by 46.0% of the biologic-inadequate group on the 200-mg regimen vs 19.2% on placebo (P < .001 for both subgroups). Endoscopic response was achieved by 46.3% of patients in the biologic-naive group and 29.0% in the biologic-inadequate group on the 200-mg regimen vs 18.0% and 6.4%, respectively, on placebo (P < .001 for both subgroups).
Sands noted that the drug has an excellent safety profile.
“These data show the drug works for naive patients who have failed conventional therapies, as well as for those who have failed biologic therapies,” so it could be used as a first- or second-line biologic, he added.
Sands reported potential conflicts of interest with AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Microbiotica, Mobius Care, Morphic Therapeutic, MRM Health, Pfizer, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sun Pharma, Surrozen, Target RWE, Takeda, Teva, Theravance Biopharma, TLL Pharmaceutical, Tr1X, UNION Therapeutics, and Ventyx Biosciences.
A version of this article appeared on Medscape.com.
VIENNA — according to a pooled analysis of the two phase 3 double-blind GALAXI 2 and 3 studies.
“We found that guselkumab was effective in both biologic-naive and biologic-inadequate subpopulations,” said coinvestigator Bruce E. Sands, MD, AGAF, gastroenterologist from Icahn School of Medicine at Mount Sinai, New York City.
These latest results add to the primary results of these studies reported earlier in 2024 that guselkumab was shown to be superior to both placebo and ustekinumab in the same patient population with moderately to severely active CD.
Sands reported the new data in a presentation at the United European Gastroenterology (UEG) Week 2024.
Guselkumab potently blocks interleukin (IL)–23 and binds to CD64, a receptor on cells that produce IL-23. The dual-acting IL-23p19 subunit inhibitor agent is currently under review by the Food and Drug Administration (FDA) for moderately to severely active CD. In September, guselkumab (Tremfya, Johnson & Johnson) was approved for use in moderately to severely active ulcerative colitis.
GALAXI 2 and 3 Pooled Dataset
In the two independent, identically designed GALAXI 2 and 3 studies, patients were randomized to guselkumab treatment at either 200 mg intravenous (IV) induction at weeks 0, 4, and 8, followed by 200 mg subcutaneous maintenance every 4 weeks, starting at week 12, or 200 mg IV induction at weeks 0, 4, and 8, followed by 100 mg subcutaneous maintenance every 8 weeks, starting at week 16; or to ustekinumab; or to placebo.
Participants were required to remain on their treatment of initial randomization for a long-term extension study (up to 5 years) looking at clinical, endoscopic, and safety outcomes, except for participants on placebo who were allowed to switch to ustekinumab if clinical response was not met at week 12.
Inclusion criteria for the studies comprised a Crohn’s Disease Activity Index score between 220 and 450, a mean daily stool frequency count > 3 or an abdominal pain score > 1, and a simple endoscopic score for CD score ≥ 6. Participants were also required to have shown an inadequate response or intolerance to oral corticosteroids, 6-mercaptopurine/azathioprine/methotrexate, or biologic therapies.
The pooled dataset included patients on either dose of guselkumab and patients on placebo (total n = 730). Of these, 52% of participants had shown a prior inadequate response to a biologic, 42% were biologic naive, and 6% had prior exposure to biologics but no documented failure. Patients on ustekinumab were not included in this analysis.
Almost all patients (97%) in the biologic-inadequate response group had previously received at least one anti–tumor necrosis factor agent, and around 15% had received vedolizumab. As expected, the biologic-inadequate responders were a lot sicker than the biologic-naive patients, Sands reported.
The composite co–primary endpoints for each guselkumab regimen vs placebo were clinical response at week 12 plus clinical remission at week 48, and clinical response at week 12 plus endoscopic response at week 48.
The major secondary endpoints comprised clinical remission at week 12 and endoscopic response also at week 12.
Short- and Long-Term Endpoints in Both Subgroups
In the biologic-naive subgroup, 54.7% of patients receiving the 200-mg dose regimen of guselkumab and 51.7% of those receiving the 100-mg dose regimen showed a clinical response at week 12 plus clinical remission at week 48, compared with 11.5% in the placebo group (P < .001 for both compared with placebo).
In the biologic-inadequate response group, 49.7% of those receiving the 200-mg dose regimen of guselkumab and 45.8% on the 100-mg dose regimen reached the composite endpoint, compared with the placebo response of 12.8% (P < .001 for both compared with placebo).
“You can see a slight decrease in response in the biologic-inadequate responders, but on the whole, the confidence intervals are highly overlapping,” said Sands.
Turning to major secondary endpoints at week 12, clinical remission was reached by 49.6% of the biologic-naive group on the 200-mg guselkumab regimen vs 16.4% on placebo, and by 46.0% of the biologic-inadequate group on the 200-mg regimen vs 19.2% on placebo (P < .001 for both subgroups). Endoscopic response was achieved by 46.3% of patients in the biologic-naive group and 29.0% in the biologic-inadequate group on the 200-mg regimen vs 18.0% and 6.4%, respectively, on placebo (P < .001 for both subgroups).
Sands noted that the drug has an excellent safety profile.
“These data show the drug works for naive patients who have failed conventional therapies, as well as for those who have failed biologic therapies,” so it could be used as a first- or second-line biologic, he added.
Sands reported potential conflicts of interest with AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Microbiotica, Mobius Care, Morphic Therapeutic, MRM Health, Pfizer, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sun Pharma, Surrozen, Target RWE, Takeda, Teva, Theravance Biopharma, TLL Pharmaceutical, Tr1X, UNION Therapeutics, and Ventyx Biosciences.
A version of this article appeared on Medscape.com.
VIENNA — according to a pooled analysis of the two phase 3 double-blind GALAXI 2 and 3 studies.
“We found that guselkumab was effective in both biologic-naive and biologic-inadequate subpopulations,” said coinvestigator Bruce E. Sands, MD, AGAF, gastroenterologist from Icahn School of Medicine at Mount Sinai, New York City.
These latest results add to the primary results of these studies reported earlier in 2024 that guselkumab was shown to be superior to both placebo and ustekinumab in the same patient population with moderately to severely active CD.
Sands reported the new data in a presentation at the United European Gastroenterology (UEG) Week 2024.
Guselkumab potently blocks interleukin (IL)–23 and binds to CD64, a receptor on cells that produce IL-23. The dual-acting IL-23p19 subunit inhibitor agent is currently under review by the Food and Drug Administration (FDA) for moderately to severely active CD. In September, guselkumab (Tremfya, Johnson & Johnson) was approved for use in moderately to severely active ulcerative colitis.
GALAXI 2 and 3 Pooled Dataset
In the two independent, identically designed GALAXI 2 and 3 studies, patients were randomized to guselkumab treatment at either 200 mg intravenous (IV) induction at weeks 0, 4, and 8, followed by 200 mg subcutaneous maintenance every 4 weeks, starting at week 12, or 200 mg IV induction at weeks 0, 4, and 8, followed by 100 mg subcutaneous maintenance every 8 weeks, starting at week 16; or to ustekinumab; or to placebo.
Participants were required to remain on their treatment of initial randomization for a long-term extension study (up to 5 years) looking at clinical, endoscopic, and safety outcomes, except for participants on placebo who were allowed to switch to ustekinumab if clinical response was not met at week 12.
Inclusion criteria for the studies comprised a Crohn’s Disease Activity Index score between 220 and 450, a mean daily stool frequency count > 3 or an abdominal pain score > 1, and a simple endoscopic score for CD score ≥ 6. Participants were also required to have shown an inadequate response or intolerance to oral corticosteroids, 6-mercaptopurine/azathioprine/methotrexate, or biologic therapies.
The pooled dataset included patients on either dose of guselkumab and patients on placebo (total n = 730). Of these, 52% of participants had shown a prior inadequate response to a biologic, 42% were biologic naive, and 6% had prior exposure to biologics but no documented failure. Patients on ustekinumab were not included in this analysis.
Almost all patients (97%) in the biologic-inadequate response group had previously received at least one anti–tumor necrosis factor agent, and around 15% had received vedolizumab. As expected, the biologic-inadequate responders were a lot sicker than the biologic-naive patients, Sands reported.
The composite co–primary endpoints for each guselkumab regimen vs placebo were clinical response at week 12 plus clinical remission at week 48, and clinical response at week 12 plus endoscopic response at week 48.
The major secondary endpoints comprised clinical remission at week 12 and endoscopic response also at week 12.
Short- and Long-Term Endpoints in Both Subgroups
In the biologic-naive subgroup, 54.7% of patients receiving the 200-mg dose regimen of guselkumab and 51.7% of those receiving the 100-mg dose regimen showed a clinical response at week 12 plus clinical remission at week 48, compared with 11.5% in the placebo group (P < .001 for both compared with placebo).
In the biologic-inadequate response group, 49.7% of those receiving the 200-mg dose regimen of guselkumab and 45.8% on the 100-mg dose regimen reached the composite endpoint, compared with the placebo response of 12.8% (P < .001 for both compared with placebo).
“You can see a slight decrease in response in the biologic-inadequate responders, but on the whole, the confidence intervals are highly overlapping,” said Sands.
Turning to major secondary endpoints at week 12, clinical remission was reached by 49.6% of the biologic-naive group on the 200-mg guselkumab regimen vs 16.4% on placebo, and by 46.0% of the biologic-inadequate group on the 200-mg regimen vs 19.2% on placebo (P < .001 for both subgroups). Endoscopic response was achieved by 46.3% of patients in the biologic-naive group and 29.0% in the biologic-inadequate group on the 200-mg regimen vs 18.0% and 6.4%, respectively, on placebo (P < .001 for both subgroups).
Sands noted that the drug has an excellent safety profile.
“These data show the drug works for naive patients who have failed conventional therapies, as well as for those who have failed biologic therapies,” so it could be used as a first- or second-line biologic, he added.
Sands reported potential conflicts of interest with AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Microbiotica, Mobius Care, Morphic Therapeutic, MRM Health, Pfizer, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sun Pharma, Surrozen, Target RWE, Takeda, Teva, Theravance Biopharma, TLL Pharmaceutical, Tr1X, UNION Therapeutics, and Ventyx Biosciences.
A version of this article appeared on Medscape.com.
FROM UEG 2024
Patients With IBD More Likely to Develop, or Have Prior, T1D
VIENNA —
Their findings showed that patients with IBD had a moderately increased risk for T1D and higher odds of having prior T1D than the general population. These bidirectional associations were partially independent of shared familial factors.
Although the absolute risk for T1D is low in patients with IBD, these findings suggest that if there are nonspecific symptoms, such as weight loss and fatigue, which are typical of T1D but not of IBD, then it might be reasonable to test for diabetes, lead researcher Jiangwei Sun, PhD, postdoctoral researcher at the Karolinska Institutet, Stockholm, Sweden, told this news organization.
“Patients with IBD and T1D also tend to have worse disease outcomes for both diseases, but these two diseases are not recognized as comorbidities in the clinical guidelines,” he said.
Anecdotally, “many clinicians believe there is a higher risk of autoimmune disease in patients with IBD but not much attention is paid to type 1 diabetes,” he added.
Sun presented the study at United European Gastroenterology (UEG) Week 2024. It was also published recently in The Lancet.
Exploring the Bidirectional Relationship
Prior research in the form of a systematic review found no association between IBD and T1D, which was surprising, Sun said. Further studies found an association between IBD and incident T1D; however, these studies did not explore bidirectionality between the two diseases.
These studies also did not take shared genetic and environmental factors into consideration, though “there is known to be familial co-aggregation of IBD and T1D based on previous findings,” he said.
In this current study, Sun and colleagues compared patients with IBD with the general population, as well as with siblings without IBD to consider the potential influence of shared genetics and earlier environmental factors.
The research used two approaches to look for a bidirectional association: A nationwide matched cohort study (IBD and incident T1D) and a case-control study (IBD and prior T1D).
The cohort study included 20,314 patients with IBD aged ≤ 28 years, who were identified between 1987 and 2017. Of these, 7277 had Crohn’s disease, 10,112 had ulcerative colitis, and 2925 had unclassified IBD. There were 99,200 individually matched reference individuals.
The case-control study included 87,001 patients with IBD (without age restriction) and 431,054 matched control individuals.
Risk ratios were calculated using an adjusted hazard ratio (aHR) of incident T1D in the cohort study and an adjusted odds ratio (aOR) of prior T1D in the case-control study.
In the cohort study, the median follow-up was 14 years. Over that time, 116 patients with IBD and 353 reference individuals developed T1D. The aHR for a patient with IBD developing T1D was 1.58 (95% CI, 1.27-1.95). For patients with ulcerative colitis, the aHR of developing T1D increased to 2.02 (95% CI, 1.51-2.70); however, the association was not found for Crohn’s disease or unclassified IBD possibly because of the sample size of these latter categories, noted Sun.
In the case-control study, Sun and colleagues identified 1018 (1.2%) patients with IBD and 3496 (0.8%) control individuals who had been previously diagnosed with T1D. Patients with IBD had higher odds of having prior T1D than those without IBD (aOR, 1.36; 95% CI, 1.26-1.46). This positive association was observed in all IBD subtypes, said Sun, who added that the sample size was larger in this analysis than in the cohort analysis.
Upon comparing patients with IBD with their siblings without IBD, analyses showed similar associations between IBD and T1D; the aHR was 1.44 (95% CI, 0.97-2.15) for developing T1D, and the aOR was 1.32 (95% CI, 1.18-1.49) for prior T1D.
That these positive associations between IBD and T1D exist even when comparing patients with IBD with their siblings without IBD suggests genetics and shared environmental factors do not fully explain the association, and that later environmental factors might play a role, said Sun.
“I’m not surprised with these results,” he added. “They make sense because we know that both IBD and T1D are immunity-related diseases and have some shared pathways.”
Commenting on the study, Tine Jess, MD, director, Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Aalborg University in Copenhagen, Denmark, said: “The really interesting finding here is that type 1 diabetes may precede IBD, which points toward common etiologies rather than one disease leading to the other.”
“This is in line with mounting evidence that IBD is measurable at the molecular level years prior to diagnosis,” she added.
Awareness of the bidirectional association may facilitate early detection of both conditions, Sun and his colleagues noted.
Sun reported no relevant financial relationships. Jess reported receiving consultancy fees from Ferring and Pfizer.
A version of this article appeared on Medscape.com.
VIENNA —
Their findings showed that patients with IBD had a moderately increased risk for T1D and higher odds of having prior T1D than the general population. These bidirectional associations were partially independent of shared familial factors.
Although the absolute risk for T1D is low in patients with IBD, these findings suggest that if there are nonspecific symptoms, such as weight loss and fatigue, which are typical of T1D but not of IBD, then it might be reasonable to test for diabetes, lead researcher Jiangwei Sun, PhD, postdoctoral researcher at the Karolinska Institutet, Stockholm, Sweden, told this news organization.
“Patients with IBD and T1D also tend to have worse disease outcomes for both diseases, but these two diseases are not recognized as comorbidities in the clinical guidelines,” he said.
Anecdotally, “many clinicians believe there is a higher risk of autoimmune disease in patients with IBD but not much attention is paid to type 1 diabetes,” he added.
Sun presented the study at United European Gastroenterology (UEG) Week 2024. It was also published recently in The Lancet.
Exploring the Bidirectional Relationship
Prior research in the form of a systematic review found no association between IBD and T1D, which was surprising, Sun said. Further studies found an association between IBD and incident T1D; however, these studies did not explore bidirectionality between the two diseases.
These studies also did not take shared genetic and environmental factors into consideration, though “there is known to be familial co-aggregation of IBD and T1D based on previous findings,” he said.
In this current study, Sun and colleagues compared patients with IBD with the general population, as well as with siblings without IBD to consider the potential influence of shared genetics and earlier environmental factors.
The research used two approaches to look for a bidirectional association: A nationwide matched cohort study (IBD and incident T1D) and a case-control study (IBD and prior T1D).
The cohort study included 20,314 patients with IBD aged ≤ 28 years, who were identified between 1987 and 2017. Of these, 7277 had Crohn’s disease, 10,112 had ulcerative colitis, and 2925 had unclassified IBD. There were 99,200 individually matched reference individuals.
The case-control study included 87,001 patients with IBD (without age restriction) and 431,054 matched control individuals.
Risk ratios were calculated using an adjusted hazard ratio (aHR) of incident T1D in the cohort study and an adjusted odds ratio (aOR) of prior T1D in the case-control study.
In the cohort study, the median follow-up was 14 years. Over that time, 116 patients with IBD and 353 reference individuals developed T1D. The aHR for a patient with IBD developing T1D was 1.58 (95% CI, 1.27-1.95). For patients with ulcerative colitis, the aHR of developing T1D increased to 2.02 (95% CI, 1.51-2.70); however, the association was not found for Crohn’s disease or unclassified IBD possibly because of the sample size of these latter categories, noted Sun.
In the case-control study, Sun and colleagues identified 1018 (1.2%) patients with IBD and 3496 (0.8%) control individuals who had been previously diagnosed with T1D. Patients with IBD had higher odds of having prior T1D than those without IBD (aOR, 1.36; 95% CI, 1.26-1.46). This positive association was observed in all IBD subtypes, said Sun, who added that the sample size was larger in this analysis than in the cohort analysis.
Upon comparing patients with IBD with their siblings without IBD, analyses showed similar associations between IBD and T1D; the aHR was 1.44 (95% CI, 0.97-2.15) for developing T1D, and the aOR was 1.32 (95% CI, 1.18-1.49) for prior T1D.
That these positive associations between IBD and T1D exist even when comparing patients with IBD with their siblings without IBD suggests genetics and shared environmental factors do not fully explain the association, and that later environmental factors might play a role, said Sun.
“I’m not surprised with these results,” he added. “They make sense because we know that both IBD and T1D are immunity-related diseases and have some shared pathways.”
Commenting on the study, Tine Jess, MD, director, Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Aalborg University in Copenhagen, Denmark, said: “The really interesting finding here is that type 1 diabetes may precede IBD, which points toward common etiologies rather than one disease leading to the other.”
“This is in line with mounting evidence that IBD is measurable at the molecular level years prior to diagnosis,” she added.
Awareness of the bidirectional association may facilitate early detection of both conditions, Sun and his colleagues noted.
Sun reported no relevant financial relationships. Jess reported receiving consultancy fees from Ferring and Pfizer.
A version of this article appeared on Medscape.com.
VIENNA —
Their findings showed that patients with IBD had a moderately increased risk for T1D and higher odds of having prior T1D than the general population. These bidirectional associations were partially independent of shared familial factors.
Although the absolute risk for T1D is low in patients with IBD, these findings suggest that if there are nonspecific symptoms, such as weight loss and fatigue, which are typical of T1D but not of IBD, then it might be reasonable to test for diabetes, lead researcher Jiangwei Sun, PhD, postdoctoral researcher at the Karolinska Institutet, Stockholm, Sweden, told this news organization.
“Patients with IBD and T1D also tend to have worse disease outcomes for both diseases, but these two diseases are not recognized as comorbidities in the clinical guidelines,” he said.
Anecdotally, “many clinicians believe there is a higher risk of autoimmune disease in patients with IBD but not much attention is paid to type 1 diabetes,” he added.
Sun presented the study at United European Gastroenterology (UEG) Week 2024. It was also published recently in The Lancet.
Exploring the Bidirectional Relationship
Prior research in the form of a systematic review found no association between IBD and T1D, which was surprising, Sun said. Further studies found an association between IBD and incident T1D; however, these studies did not explore bidirectionality between the two diseases.
These studies also did not take shared genetic and environmental factors into consideration, though “there is known to be familial co-aggregation of IBD and T1D based on previous findings,” he said.
In this current study, Sun and colleagues compared patients with IBD with the general population, as well as with siblings without IBD to consider the potential influence of shared genetics and earlier environmental factors.
The research used two approaches to look for a bidirectional association: A nationwide matched cohort study (IBD and incident T1D) and a case-control study (IBD and prior T1D).
The cohort study included 20,314 patients with IBD aged ≤ 28 years, who were identified between 1987 and 2017. Of these, 7277 had Crohn’s disease, 10,112 had ulcerative colitis, and 2925 had unclassified IBD. There were 99,200 individually matched reference individuals.
The case-control study included 87,001 patients with IBD (without age restriction) and 431,054 matched control individuals.
Risk ratios were calculated using an adjusted hazard ratio (aHR) of incident T1D in the cohort study and an adjusted odds ratio (aOR) of prior T1D in the case-control study.
In the cohort study, the median follow-up was 14 years. Over that time, 116 patients with IBD and 353 reference individuals developed T1D. The aHR for a patient with IBD developing T1D was 1.58 (95% CI, 1.27-1.95). For patients with ulcerative colitis, the aHR of developing T1D increased to 2.02 (95% CI, 1.51-2.70); however, the association was not found for Crohn’s disease or unclassified IBD possibly because of the sample size of these latter categories, noted Sun.
In the case-control study, Sun and colleagues identified 1018 (1.2%) patients with IBD and 3496 (0.8%) control individuals who had been previously diagnosed with T1D. Patients with IBD had higher odds of having prior T1D than those without IBD (aOR, 1.36; 95% CI, 1.26-1.46). This positive association was observed in all IBD subtypes, said Sun, who added that the sample size was larger in this analysis than in the cohort analysis.
Upon comparing patients with IBD with their siblings without IBD, analyses showed similar associations between IBD and T1D; the aHR was 1.44 (95% CI, 0.97-2.15) for developing T1D, and the aOR was 1.32 (95% CI, 1.18-1.49) for prior T1D.
That these positive associations between IBD and T1D exist even when comparing patients with IBD with their siblings without IBD suggests genetics and shared environmental factors do not fully explain the association, and that later environmental factors might play a role, said Sun.
“I’m not surprised with these results,” he added. “They make sense because we know that both IBD and T1D are immunity-related diseases and have some shared pathways.”
Commenting on the study, Tine Jess, MD, director, Center for Molecular Prediction of Inflammatory Bowel Disease, PREDICT, Aalborg University in Copenhagen, Denmark, said: “The really interesting finding here is that type 1 diabetes may precede IBD, which points toward common etiologies rather than one disease leading to the other.”
“This is in line with mounting evidence that IBD is measurable at the molecular level years prior to diagnosis,” she added.
Awareness of the bidirectional association may facilitate early detection of both conditions, Sun and his colleagues noted.
Sun reported no relevant financial relationships. Jess reported receiving consultancy fees from Ferring and Pfizer.
A version of this article appeared on Medscape.com.
FROM UEG 2024
Ultraprocessed Foods Associated With Relapse Risk in Crohn’s Disease
VIENNA —
Certain subgroups of UPFs, specifically bread, pastries, and starch as well as oil and spreads, exhibited the strongest association with relapse risks of approximately threefold.
“In addition to treating active inflammatory bowel disease (IBD), we want to maintain remission for the long term,” Chen Sarbagili Shabat, PhD, clinical dietitian from Tel Aviv Medical Center in Israel, said in an interview. “It’s highly important. We know environmental factors are associated with the disease, which is why we can treat active disease with diet. Likewise, we can manage CD in a remission state with diet.”
This is the first prospective study of this particular level of UPFs in people with Crohn’s disease who are in remission, noted Shabat, who presented the findings at United European Gastroenterology (UEG) Week 2024.
Previously, a meta-analysis of prospective cohort studies showed that a diet high in UPFs is associated with a 70% increased risk for development of CD, and a longitudinal study showed that “Western” dietary patterns were associated with relapse risk in patients with IBD, Shabat reported.
Effect of High vs Low Intake of UPFs
The current single-center, prospective cohort study, followed 111 patients with CD every 3 months until relapse for up to 1 year.
Participants were aged 18-75 years (mean age, 38 years), with a median disease duration of 8.7 years. They were required to have maintained steroid-free clinical remission (Harvey-Bradshaw Index (HBI), < 5) for 3 months or more. The median duration of clinical remission at recruitment was 3 years.
Data collection included HBI level, medication type and dosage to ensure constant therapy and full compliance, and a stool sample for fecal calprotectin measurement.
The primary outcome comprised a clinical relapse HBI ≥ 5 over the 12-month follow-up or a change in disease activity requiring a change in medication, hospitalization, or any IBD-related surgery.
Participants were asked to complete a processed food questionnaire to assess the intake of UPFs and a food frequency questionnaire to assess the total intake of energy, macronutrients, and micronutrients. UPFs were divided into high and low intakes using a median cutoff of 3.6 servings/day.
The low intake group included 57 participants, and the high intake group included 54.
A total of 24 patients (21.6%) experienced a clinical relapse event, 7 in the low intake group vs 17 in the high intake group (hazard ratio [HR], 3.86; 95% CI, 1.30-11.47; P = .015 after adjustments).
In a subset of 97 patients with baseline fecal calprotectin measurements, 6 (n = 50) in the low intake group experienced a clinical relapse vs 15 (n = 47) in the high intake group (HR, 4.32; 95% CI, 1.36-13.73; P = .013 after adjustments).
Fecal calprotectin results were also suggestive of an association between high intake of UPFs and gut inflammation, Shabat reported.
Food Groups and Emulsifiers
UPFs were divided into subgroups: Bread, pastries, and starch; oils and spreads; ultraprocessed meat; sweet products and desserts; and ultraprocessed beverages.
The highest associations with relapse were in the subgroup of bread, pastries, and starch (HR, 3.37; 95% CI, 1.26-8.25) and the subgroup of oils and spreads (HR, 2.76; 95% CI, 1.02-7.45).
“The selection of healthy food is highly important, especially since we know that certain food ingredients can contribute to the pathogenesis of CD,” Shabat said. Patients can use partial enteral nutrition to provide 40%-50% of daily caloric intake in order to maintain remission, but she acknowledged it can be really difficult to adhere to.
She concluded by asserting that the study results, along with future research, should contribute to establishing nutritional guidelines to reduce UPF consumption in patients with CD in order to maintain remission.
Commenting on the study, Kevin Whelan, PhD, professor of dietetics and head of the Department of Nutritional Sciences at King’s College London in England, said that he was intrigued by the subgroup analysis that showed breads, pastries, oils, and spreads as having the strongest association with relapse risk.
He also remarked that these foods almost ubiquitously contain emulsifiers, and so the association might have less to do with UPFs in general and more to do with emulsifiers.
Concurring, Shabat noted that, while emulsifiers can negatively influence the microbiota and the gut barrier function, as well as contribute to intestinal inflammation, further mechanistic studies are required to understand these effects.
We need to determine if all additives have the same effect on the inflammatory process and also need studies looking at UPFs alone, she added.
Shabat reported receiving personal fees from Nestle Health Science (Wolfson Medical Center IP) for consulting and speaking and from Takeda and Ferring for speaking. Whelan reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
VIENNA —
Certain subgroups of UPFs, specifically bread, pastries, and starch as well as oil and spreads, exhibited the strongest association with relapse risks of approximately threefold.
“In addition to treating active inflammatory bowel disease (IBD), we want to maintain remission for the long term,” Chen Sarbagili Shabat, PhD, clinical dietitian from Tel Aviv Medical Center in Israel, said in an interview. “It’s highly important. We know environmental factors are associated with the disease, which is why we can treat active disease with diet. Likewise, we can manage CD in a remission state with diet.”
This is the first prospective study of this particular level of UPFs in people with Crohn’s disease who are in remission, noted Shabat, who presented the findings at United European Gastroenterology (UEG) Week 2024.
Previously, a meta-analysis of prospective cohort studies showed that a diet high in UPFs is associated with a 70% increased risk for development of CD, and a longitudinal study showed that “Western” dietary patterns were associated with relapse risk in patients with IBD, Shabat reported.
Effect of High vs Low Intake of UPFs
The current single-center, prospective cohort study, followed 111 patients with CD every 3 months until relapse for up to 1 year.
Participants were aged 18-75 years (mean age, 38 years), with a median disease duration of 8.7 years. They were required to have maintained steroid-free clinical remission (Harvey-Bradshaw Index (HBI), < 5) for 3 months or more. The median duration of clinical remission at recruitment was 3 years.
Data collection included HBI level, medication type and dosage to ensure constant therapy and full compliance, and a stool sample for fecal calprotectin measurement.
The primary outcome comprised a clinical relapse HBI ≥ 5 over the 12-month follow-up or a change in disease activity requiring a change in medication, hospitalization, or any IBD-related surgery.
Participants were asked to complete a processed food questionnaire to assess the intake of UPFs and a food frequency questionnaire to assess the total intake of energy, macronutrients, and micronutrients. UPFs were divided into high and low intakes using a median cutoff of 3.6 servings/day.
The low intake group included 57 participants, and the high intake group included 54.
A total of 24 patients (21.6%) experienced a clinical relapse event, 7 in the low intake group vs 17 in the high intake group (hazard ratio [HR], 3.86; 95% CI, 1.30-11.47; P = .015 after adjustments).
In a subset of 97 patients with baseline fecal calprotectin measurements, 6 (n = 50) in the low intake group experienced a clinical relapse vs 15 (n = 47) in the high intake group (HR, 4.32; 95% CI, 1.36-13.73; P = .013 after adjustments).
Fecal calprotectin results were also suggestive of an association between high intake of UPFs and gut inflammation, Shabat reported.
Food Groups and Emulsifiers
UPFs were divided into subgroups: Bread, pastries, and starch; oils and spreads; ultraprocessed meat; sweet products and desserts; and ultraprocessed beverages.
The highest associations with relapse were in the subgroup of bread, pastries, and starch (HR, 3.37; 95% CI, 1.26-8.25) and the subgroup of oils and spreads (HR, 2.76; 95% CI, 1.02-7.45).
“The selection of healthy food is highly important, especially since we know that certain food ingredients can contribute to the pathogenesis of CD,” Shabat said. Patients can use partial enteral nutrition to provide 40%-50% of daily caloric intake in order to maintain remission, but she acknowledged it can be really difficult to adhere to.
She concluded by asserting that the study results, along with future research, should contribute to establishing nutritional guidelines to reduce UPF consumption in patients with CD in order to maintain remission.
Commenting on the study, Kevin Whelan, PhD, professor of dietetics and head of the Department of Nutritional Sciences at King’s College London in England, said that he was intrigued by the subgroup analysis that showed breads, pastries, oils, and spreads as having the strongest association with relapse risk.
He also remarked that these foods almost ubiquitously contain emulsifiers, and so the association might have less to do with UPFs in general and more to do with emulsifiers.
Concurring, Shabat noted that, while emulsifiers can negatively influence the microbiota and the gut barrier function, as well as contribute to intestinal inflammation, further mechanistic studies are required to understand these effects.
We need to determine if all additives have the same effect on the inflammatory process and also need studies looking at UPFs alone, she added.
Shabat reported receiving personal fees from Nestle Health Science (Wolfson Medical Center IP) for consulting and speaking and from Takeda and Ferring for speaking. Whelan reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
VIENNA —
Certain subgroups of UPFs, specifically bread, pastries, and starch as well as oil and spreads, exhibited the strongest association with relapse risks of approximately threefold.
“In addition to treating active inflammatory bowel disease (IBD), we want to maintain remission for the long term,” Chen Sarbagili Shabat, PhD, clinical dietitian from Tel Aviv Medical Center in Israel, said in an interview. “It’s highly important. We know environmental factors are associated with the disease, which is why we can treat active disease with diet. Likewise, we can manage CD in a remission state with diet.”
This is the first prospective study of this particular level of UPFs in people with Crohn’s disease who are in remission, noted Shabat, who presented the findings at United European Gastroenterology (UEG) Week 2024.
Previously, a meta-analysis of prospective cohort studies showed that a diet high in UPFs is associated with a 70% increased risk for development of CD, and a longitudinal study showed that “Western” dietary patterns were associated with relapse risk in patients with IBD, Shabat reported.
Effect of High vs Low Intake of UPFs
The current single-center, prospective cohort study, followed 111 patients with CD every 3 months until relapse for up to 1 year.
Participants were aged 18-75 years (mean age, 38 years), with a median disease duration of 8.7 years. They were required to have maintained steroid-free clinical remission (Harvey-Bradshaw Index (HBI), < 5) for 3 months or more. The median duration of clinical remission at recruitment was 3 years.
Data collection included HBI level, medication type and dosage to ensure constant therapy and full compliance, and a stool sample for fecal calprotectin measurement.
The primary outcome comprised a clinical relapse HBI ≥ 5 over the 12-month follow-up or a change in disease activity requiring a change in medication, hospitalization, or any IBD-related surgery.
Participants were asked to complete a processed food questionnaire to assess the intake of UPFs and a food frequency questionnaire to assess the total intake of energy, macronutrients, and micronutrients. UPFs were divided into high and low intakes using a median cutoff of 3.6 servings/day.
The low intake group included 57 participants, and the high intake group included 54.
A total of 24 patients (21.6%) experienced a clinical relapse event, 7 in the low intake group vs 17 in the high intake group (hazard ratio [HR], 3.86; 95% CI, 1.30-11.47; P = .015 after adjustments).
In a subset of 97 patients with baseline fecal calprotectin measurements, 6 (n = 50) in the low intake group experienced a clinical relapse vs 15 (n = 47) in the high intake group (HR, 4.32; 95% CI, 1.36-13.73; P = .013 after adjustments).
Fecal calprotectin results were also suggestive of an association between high intake of UPFs and gut inflammation, Shabat reported.
Food Groups and Emulsifiers
UPFs were divided into subgroups: Bread, pastries, and starch; oils and spreads; ultraprocessed meat; sweet products and desserts; and ultraprocessed beverages.
The highest associations with relapse were in the subgroup of bread, pastries, and starch (HR, 3.37; 95% CI, 1.26-8.25) and the subgroup of oils and spreads (HR, 2.76; 95% CI, 1.02-7.45).
“The selection of healthy food is highly important, especially since we know that certain food ingredients can contribute to the pathogenesis of CD,” Shabat said. Patients can use partial enteral nutrition to provide 40%-50% of daily caloric intake in order to maintain remission, but she acknowledged it can be really difficult to adhere to.
She concluded by asserting that the study results, along with future research, should contribute to establishing nutritional guidelines to reduce UPF consumption in patients with CD in order to maintain remission.
Commenting on the study, Kevin Whelan, PhD, professor of dietetics and head of the Department of Nutritional Sciences at King’s College London in England, said that he was intrigued by the subgroup analysis that showed breads, pastries, oils, and spreads as having the strongest association with relapse risk.
He also remarked that these foods almost ubiquitously contain emulsifiers, and so the association might have less to do with UPFs in general and more to do with emulsifiers.
Concurring, Shabat noted that, while emulsifiers can negatively influence the microbiota and the gut barrier function, as well as contribute to intestinal inflammation, further mechanistic studies are required to understand these effects.
We need to determine if all additives have the same effect on the inflammatory process and also need studies looking at UPFs alone, she added.
Shabat reported receiving personal fees from Nestle Health Science (Wolfson Medical Center IP) for consulting and speaking and from Takeda and Ferring for speaking. Whelan reported no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM UEG 2024
Cendakimab That Targets IL-13 Shows Promise in Eosinophilic Esophagitis
VIENNA — , according to interim results of a pivotal phase 3 trial.
Treatment with cendakimab also improved key endoscopic and histologic features, even in patients who had an inadequate response or intolerance to steroids, reported Alain Schoepfer, MD, gastroenterologist from Centre Hospitalier Universitaire Vaudois and University of Lausanne, in Switzerland.
The drug was generally safe and well tolerated up to 24 weeks of treatment, added Schoepfer, who presented the results during a presentation at the United European Gastroenterology (UEG) Week 2024.
Targeting IL-13 Shows ‘Surprisingly Good Results’
EoE is a chronic, progressive, immune-mediated, inflammatory disease that is mainly driven by the cytokine, IL-13.
In a prior phase 2 study, cendakimab, which selectively binds to IL-13 and blocks its interaction with both the IL-13Ra1 and the IL-13Ra2 receptors, was shown to improve symptoms and endoscopic features of EoE.
For the current phase 3 trial, participants were required to have a peak eosinophil count (PEC) of ≥ 15 eosinophils (eos)/high power field (hpf) and 4 or more days of dysphagia over the 2 weeks prior to the start of the study. In addition, they had to have shown a complete lack of response to proton pump inhibitor (PPI) treatment for 8 weeks or more.
A total of 430 patients were randomized 1:1:1 to subcutaneous cendakimab (360 mg) once weekly for 48 weeks; subcutaneous cendakimab (360 mg) once weekly for 24 weeks, then once every 2 weeks for a further 24 weeks; or subcutaneous placebo once weekly for 48 weeks.
Patient characteristics were similar across randomization groups. The majority of participants were men, with a mean age of 35 years (range, 12-75 years); adolescents comprised 6%-11% of the total. The disease duration was around 5-6 years for all participants, of which 45% were on a stable PPI dosage and around 65% had steroid intolerance or an inadequate response. The endoscopic reference score was around 10 across all groups. The mean PEC was around 160 eos/hpf in the cendakimab arms vs 200 eos/hpf in the placebo arm.
Schoepfer reported results for the coprimary endpoints — the mean change from baseline in dysphagia days and the proportion of patients with eosinophil histologic response (PEC ≤ 6 eos/hpf) — at week 24. At this point, a total of 286 patients had received treatment with 360 mg of cendakimab once weekly, and 143 had received placebo.
The change in dysphagia days was −6.1 in patients on cendakimab once weekly vs −4.2 in patients on placebo (P = .0005). The proportion of patients with eosinophil histologic response was 28.6% in the treatment arm vs 2.2% in the placebo arm.
The results were similar for patients who were classified as having had a steroid inadequate response. The change in dysphagia days was −6.3 in the cendakimab group vs −4.7 in the placebo group (P = .0156). The eosinophil histologic response was 29.5% in the treatment group vs 2.1% in the placebo group (P < .0001).
Endoscopic response, a key secondary endpoint, showed a change from baseline to week 24 in the endoscopic features of EoE. The total endoscopic reference scores were −5.2 for patients on cendakimab once weekly and −1.2 for patients on placebo (P < .0001).
The safety profile of cendakimab was “unspectacular,” Schoepfer said, with adverse events related to the study drug occurring in 30% of patients in the treatment arm vs 18.9% of those in the placebo arm. He noted that as the trial was conducted during the COVID pandemic, there were some infections.
Serious adverse events, which were assessed by investigators to not be related to the study drug, occurred in 1.8% and 2.8% of patients on cendakimab and placebo, respectively. Drug discontinuation occurred in 1.4% in the cendakimab group and 0.7% in the placebo group. There were no deaths.
“We really need drugs for this disease, given that there are very few alternatives to steroids and PPIs,” Co-moderator Ram Dickman, MD, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, said in an interview.
Right now, we have dupilumab, which targets two receptors: IL-4 and IL-13. But targeting IL-13 by itself “is showing surprisingly good results,” so cendakimab is a good candidate to be in “the first line of biologic treatments,” Dickman said.
“It’s safe and works rapidly,” he added. “Given this is a phase 3 study, I believe we’ll see it on the market.”
Schoepfer has served as a consultant for Regeneron/Sanofi, Adare/Ellodi, AbbVie, AstraZeneca, Celgene/Receptos/Bristol Myers Squibb, Dr. Falk Pharma, Gossamer Bio, GSK, Janssen, MSD, Pfizer, Regeneron/Sanofi, Takeda, and Vifor; received grant/research support from Adare/Ellodi, Celgene/Receptos/Bristol Myers Squibb, GSK, and Regeneron/Sanofi. Dickman has declared no relevant disclosures.
A version of this article appeared on Medscape.com.
VIENNA — , according to interim results of a pivotal phase 3 trial.
Treatment with cendakimab also improved key endoscopic and histologic features, even in patients who had an inadequate response or intolerance to steroids, reported Alain Schoepfer, MD, gastroenterologist from Centre Hospitalier Universitaire Vaudois and University of Lausanne, in Switzerland.
The drug was generally safe and well tolerated up to 24 weeks of treatment, added Schoepfer, who presented the results during a presentation at the United European Gastroenterology (UEG) Week 2024.
Targeting IL-13 Shows ‘Surprisingly Good Results’
EoE is a chronic, progressive, immune-mediated, inflammatory disease that is mainly driven by the cytokine, IL-13.
In a prior phase 2 study, cendakimab, which selectively binds to IL-13 and blocks its interaction with both the IL-13Ra1 and the IL-13Ra2 receptors, was shown to improve symptoms and endoscopic features of EoE.
For the current phase 3 trial, participants were required to have a peak eosinophil count (PEC) of ≥ 15 eosinophils (eos)/high power field (hpf) and 4 or more days of dysphagia over the 2 weeks prior to the start of the study. In addition, they had to have shown a complete lack of response to proton pump inhibitor (PPI) treatment for 8 weeks or more.
A total of 430 patients were randomized 1:1:1 to subcutaneous cendakimab (360 mg) once weekly for 48 weeks; subcutaneous cendakimab (360 mg) once weekly for 24 weeks, then once every 2 weeks for a further 24 weeks; or subcutaneous placebo once weekly for 48 weeks.
Patient characteristics were similar across randomization groups. The majority of participants were men, with a mean age of 35 years (range, 12-75 years); adolescents comprised 6%-11% of the total. The disease duration was around 5-6 years for all participants, of which 45% were on a stable PPI dosage and around 65% had steroid intolerance or an inadequate response. The endoscopic reference score was around 10 across all groups. The mean PEC was around 160 eos/hpf in the cendakimab arms vs 200 eos/hpf in the placebo arm.
Schoepfer reported results for the coprimary endpoints — the mean change from baseline in dysphagia days and the proportion of patients with eosinophil histologic response (PEC ≤ 6 eos/hpf) — at week 24. At this point, a total of 286 patients had received treatment with 360 mg of cendakimab once weekly, and 143 had received placebo.
The change in dysphagia days was −6.1 in patients on cendakimab once weekly vs −4.2 in patients on placebo (P = .0005). The proportion of patients with eosinophil histologic response was 28.6% in the treatment arm vs 2.2% in the placebo arm.
The results were similar for patients who were classified as having had a steroid inadequate response. The change in dysphagia days was −6.3 in the cendakimab group vs −4.7 in the placebo group (P = .0156). The eosinophil histologic response was 29.5% in the treatment group vs 2.1% in the placebo group (P < .0001).
Endoscopic response, a key secondary endpoint, showed a change from baseline to week 24 in the endoscopic features of EoE. The total endoscopic reference scores were −5.2 for patients on cendakimab once weekly and −1.2 for patients on placebo (P < .0001).
The safety profile of cendakimab was “unspectacular,” Schoepfer said, with adverse events related to the study drug occurring in 30% of patients in the treatment arm vs 18.9% of those in the placebo arm. He noted that as the trial was conducted during the COVID pandemic, there were some infections.
Serious adverse events, which were assessed by investigators to not be related to the study drug, occurred in 1.8% and 2.8% of patients on cendakimab and placebo, respectively. Drug discontinuation occurred in 1.4% in the cendakimab group and 0.7% in the placebo group. There were no deaths.
“We really need drugs for this disease, given that there are very few alternatives to steroids and PPIs,” Co-moderator Ram Dickman, MD, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, said in an interview.
Right now, we have dupilumab, which targets two receptors: IL-4 and IL-13. But targeting IL-13 by itself “is showing surprisingly good results,” so cendakimab is a good candidate to be in “the first line of biologic treatments,” Dickman said.
“It’s safe and works rapidly,” he added. “Given this is a phase 3 study, I believe we’ll see it on the market.”
Schoepfer has served as a consultant for Regeneron/Sanofi, Adare/Ellodi, AbbVie, AstraZeneca, Celgene/Receptos/Bristol Myers Squibb, Dr. Falk Pharma, Gossamer Bio, GSK, Janssen, MSD, Pfizer, Regeneron/Sanofi, Takeda, and Vifor; received grant/research support from Adare/Ellodi, Celgene/Receptos/Bristol Myers Squibb, GSK, and Regeneron/Sanofi. Dickman has declared no relevant disclosures.
A version of this article appeared on Medscape.com.
VIENNA — , according to interim results of a pivotal phase 3 trial.
Treatment with cendakimab also improved key endoscopic and histologic features, even in patients who had an inadequate response or intolerance to steroids, reported Alain Schoepfer, MD, gastroenterologist from Centre Hospitalier Universitaire Vaudois and University of Lausanne, in Switzerland.
The drug was generally safe and well tolerated up to 24 weeks of treatment, added Schoepfer, who presented the results during a presentation at the United European Gastroenterology (UEG) Week 2024.
Targeting IL-13 Shows ‘Surprisingly Good Results’
EoE is a chronic, progressive, immune-mediated, inflammatory disease that is mainly driven by the cytokine, IL-13.
In a prior phase 2 study, cendakimab, which selectively binds to IL-13 and blocks its interaction with both the IL-13Ra1 and the IL-13Ra2 receptors, was shown to improve symptoms and endoscopic features of EoE.
For the current phase 3 trial, participants were required to have a peak eosinophil count (PEC) of ≥ 15 eosinophils (eos)/high power field (hpf) and 4 or more days of dysphagia over the 2 weeks prior to the start of the study. In addition, they had to have shown a complete lack of response to proton pump inhibitor (PPI) treatment for 8 weeks or more.
A total of 430 patients were randomized 1:1:1 to subcutaneous cendakimab (360 mg) once weekly for 48 weeks; subcutaneous cendakimab (360 mg) once weekly for 24 weeks, then once every 2 weeks for a further 24 weeks; or subcutaneous placebo once weekly for 48 weeks.
Patient characteristics were similar across randomization groups. The majority of participants were men, with a mean age of 35 years (range, 12-75 years); adolescents comprised 6%-11% of the total. The disease duration was around 5-6 years for all participants, of which 45% were on a stable PPI dosage and around 65% had steroid intolerance or an inadequate response. The endoscopic reference score was around 10 across all groups. The mean PEC was around 160 eos/hpf in the cendakimab arms vs 200 eos/hpf in the placebo arm.
Schoepfer reported results for the coprimary endpoints — the mean change from baseline in dysphagia days and the proportion of patients with eosinophil histologic response (PEC ≤ 6 eos/hpf) — at week 24. At this point, a total of 286 patients had received treatment with 360 mg of cendakimab once weekly, and 143 had received placebo.
The change in dysphagia days was −6.1 in patients on cendakimab once weekly vs −4.2 in patients on placebo (P = .0005). The proportion of patients with eosinophil histologic response was 28.6% in the treatment arm vs 2.2% in the placebo arm.
The results were similar for patients who were classified as having had a steroid inadequate response. The change in dysphagia days was −6.3 in the cendakimab group vs −4.7 in the placebo group (P = .0156). The eosinophil histologic response was 29.5% in the treatment group vs 2.1% in the placebo group (P < .0001).
Endoscopic response, a key secondary endpoint, showed a change from baseline to week 24 in the endoscopic features of EoE. The total endoscopic reference scores were −5.2 for patients on cendakimab once weekly and −1.2 for patients on placebo (P < .0001).
The safety profile of cendakimab was “unspectacular,” Schoepfer said, with adverse events related to the study drug occurring in 30% of patients in the treatment arm vs 18.9% of those in the placebo arm. He noted that as the trial was conducted during the COVID pandemic, there were some infections.
Serious adverse events, which were assessed by investigators to not be related to the study drug, occurred in 1.8% and 2.8% of patients on cendakimab and placebo, respectively. Drug discontinuation occurred in 1.4% in the cendakimab group and 0.7% in the placebo group. There were no deaths.
“We really need drugs for this disease, given that there are very few alternatives to steroids and PPIs,” Co-moderator Ram Dickman, MD, Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel, said in an interview.
Right now, we have dupilumab, which targets two receptors: IL-4 and IL-13. But targeting IL-13 by itself “is showing surprisingly good results,” so cendakimab is a good candidate to be in “the first line of biologic treatments,” Dickman said.
“It’s safe and works rapidly,” he added. “Given this is a phase 3 study, I believe we’ll see it on the market.”
Schoepfer has served as a consultant for Regeneron/Sanofi, Adare/Ellodi, AbbVie, AstraZeneca, Celgene/Receptos/Bristol Myers Squibb, Dr. Falk Pharma, Gossamer Bio, GSK, Janssen, MSD, Pfizer, Regeneron/Sanofi, Takeda, and Vifor; received grant/research support from Adare/Ellodi, Celgene/Receptos/Bristol Myers Squibb, GSK, and Regeneron/Sanofi. Dickman has declared no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM UEG 2024
When It Comes to Polyp Diagnosis With CADx, Location Matters
VIENNA —
In particular, the diagnostic performance of CADx for polyps showed significantly lower specificity in the proximal colon than in the distal colon.
“While current CADx systems are suitable for use in the distal colon, they should not be employed for diagnosing polyps in the proximal colon until new, higher performing systems are developed specifically for these lesions,” said study lead Tommy Rizkala, MD, Endoscopy Unit, IRCCS Humanitas Clinical and Research Center, Rozzano, Italy.
The “main strength” of the review is that the researchers contacted each study author for more specific information and were therefore able to divide the data into the proximal colon and the rectosigmoid colon, he explained.
“This is the first paper that has really collected these data. Most papers provide data for the entire colon or just for the rectosigmoid colon,” said Rizkala, who presented the findings at the United European Gastroenterology (UEG) Week 2024.
The study was also recently published in Clinical Gastroenterology and Hepatology.
Optical diagnosis enables real-time histologic predictions of polyps 5 mm or smaller during colonoscopy, offering potential clinical and cost-saving benefits. Two optical diagnostic strategies are used for polyps in this size range based on location: A leave-in-situ strategy (applied only in the rectosigmoid colon when there is high confidence of non-neoplastic polyps) and a resect-and-discard strategy (applied only in the whole colon when there is high confidence of neoplastic polyps upon optical diagnosis).
Rizkala carried out a review of studies that evaluated the performance of real-time CADx alone — independent of endoscopist judgment — for predicting the histology of colorectal polyps 5 mm or smaller. The primary endpoints were CADx sensitivity and specificity in the proximal colon (the portion extending from the descending colon to the cecum) and the distal colon (limited to the rectosigmoid region). Secondary outcomes were the negative predictive value (NPV), positive predictive value (PPV), and accuracy of the CADx alone in the proximal colon and the distal colon.
Lower Specificity in the Proximal Colon
An analysis of data based on 7782 polyps ≤ 5 mm from 11 studies found specificity values of 0.62 (95% CI, 0.52-0.71) and 0.85 (95% CI, 0.75-0.92) for the proximal and distal regions of the colon, respectively, with a risk ratio (RR) of 0.74 (95% CI, 0.72-0.84), meaning that CADx accuracy was significantly lower in the proximal colon than in the distal colon.
“According to the optical diagnosis strategy, we can use the leave-in-situ approach for the distal colon because the performance is adequate, but for the rest of the colon, CADx requires further enhancement,” Rizkala said.
Sensitivity values were 0.89 (95% CI, 0.83-0.93) and 0.87 (95% CI, 0.80-0.92) for the proximal and distal regions, respectively, with an RR of 1.00 (95% CI, 0.97-1.03).
Regarding the secondary outcomes, the NPV was 0.64 vs 0.93 for the proximal vs distal colon, with an RR of 0.71 (95% CI, 0.64-0.79), and accuracy was 0.81 vs 0.86, with an RR of 0.95 (95% CI, 0.91-0.99).
With the higher prevalence of neoplastic lesions in the proximal colon than in the distal colon, a lower NPV was observed in the proximal colon, Rizkala noted.
The PPV was 0.87 vs 0.76 for the proximal vs distal colon, with an RR of 1.11 (95% CI, 1.06-1.17), so the two parts of the colon were comparable, he reported.
In the future, CADx systems should focus on using lesions from the proximal colon to train more accurately because currently CADx systems are trained on the available endoscopic data in which most of those polyps are from the rectosigmoid colon, Rizkala said.
We would also “like manufacturers of CADx systems to provide public access to data balanced between the proximal and distal regions of the colon,” he added.
Diagnosis More Challenging Than Detection With CADx
Commenting on the study, comoderator David G. Graham, MD, consultant gastroenterologist at University College London Hospital in England, remarked: “The key questions here relate to why are these systems underperforming in the proximal colon, and how can we improve this?”
Are these results “due to the very different appearance of adenomas in the distal colon vs the proximal colon on CADx (which is not what we see as endoscopists but seems to be what the systems are seeing), or is it due to a different characterization of polyps,” that is, more sessile serrated lesions in the proximal colon than in the distal colon, he asked.
Also commenting on the study was Raf Bisschops, MD, head of endoscopy at KU Leuven in Belgium. He remarked that the review underscores the fact that optical diagnosis by artificial intelligence is a more challenging task than detection.
It is “not entirely clear” what would explain the difference in performance of CADx between the distal colon and proximal colon, he said. It can’t be excluded that the inclusion of different CADx systems, some of which clearly underperformed, may account for the difference.
He went on to suggest that the differences might be down to location beyond proximal and distal.
“The difference in performance between the right and left colon is also interesting, since recent insights in the molecular and morphological features of hyperplastic polyps indicates that there are different classes with more goblet cell–rich hyperplastic polyps in the right colon, and more microvesicular hyperplastic polyps in the left.”
These have “distinct microscopic and endoscopic appearances” that could account for a difference in performance of a CADx system if not included in the training and validation sets, he explained.
Rizkala and Graham reported no relevant disclosures. Bisschops reported receiving research grants and speaker fees from Medtronic, Fujifilm, and Pentax.
A version of this article first appeared on Medscape.com.
VIENNA —
In particular, the diagnostic performance of CADx for polyps showed significantly lower specificity in the proximal colon than in the distal colon.
“While current CADx systems are suitable for use in the distal colon, they should not be employed for diagnosing polyps in the proximal colon until new, higher performing systems are developed specifically for these lesions,” said study lead Tommy Rizkala, MD, Endoscopy Unit, IRCCS Humanitas Clinical and Research Center, Rozzano, Italy.
The “main strength” of the review is that the researchers contacted each study author for more specific information and were therefore able to divide the data into the proximal colon and the rectosigmoid colon, he explained.
“This is the first paper that has really collected these data. Most papers provide data for the entire colon or just for the rectosigmoid colon,” said Rizkala, who presented the findings at the United European Gastroenterology (UEG) Week 2024.
The study was also recently published in Clinical Gastroenterology and Hepatology.
Optical diagnosis enables real-time histologic predictions of polyps 5 mm or smaller during colonoscopy, offering potential clinical and cost-saving benefits. Two optical diagnostic strategies are used for polyps in this size range based on location: A leave-in-situ strategy (applied only in the rectosigmoid colon when there is high confidence of non-neoplastic polyps) and a resect-and-discard strategy (applied only in the whole colon when there is high confidence of neoplastic polyps upon optical diagnosis).
Rizkala carried out a review of studies that evaluated the performance of real-time CADx alone — independent of endoscopist judgment — for predicting the histology of colorectal polyps 5 mm or smaller. The primary endpoints were CADx sensitivity and specificity in the proximal colon (the portion extending from the descending colon to the cecum) and the distal colon (limited to the rectosigmoid region). Secondary outcomes were the negative predictive value (NPV), positive predictive value (PPV), and accuracy of the CADx alone in the proximal colon and the distal colon.
Lower Specificity in the Proximal Colon
An analysis of data based on 7782 polyps ≤ 5 mm from 11 studies found specificity values of 0.62 (95% CI, 0.52-0.71) and 0.85 (95% CI, 0.75-0.92) for the proximal and distal regions of the colon, respectively, with a risk ratio (RR) of 0.74 (95% CI, 0.72-0.84), meaning that CADx accuracy was significantly lower in the proximal colon than in the distal colon.
“According to the optical diagnosis strategy, we can use the leave-in-situ approach for the distal colon because the performance is adequate, but for the rest of the colon, CADx requires further enhancement,” Rizkala said.
Sensitivity values were 0.89 (95% CI, 0.83-0.93) and 0.87 (95% CI, 0.80-0.92) for the proximal and distal regions, respectively, with an RR of 1.00 (95% CI, 0.97-1.03).
Regarding the secondary outcomes, the NPV was 0.64 vs 0.93 for the proximal vs distal colon, with an RR of 0.71 (95% CI, 0.64-0.79), and accuracy was 0.81 vs 0.86, with an RR of 0.95 (95% CI, 0.91-0.99).
With the higher prevalence of neoplastic lesions in the proximal colon than in the distal colon, a lower NPV was observed in the proximal colon, Rizkala noted.
The PPV was 0.87 vs 0.76 for the proximal vs distal colon, with an RR of 1.11 (95% CI, 1.06-1.17), so the two parts of the colon were comparable, he reported.
In the future, CADx systems should focus on using lesions from the proximal colon to train more accurately because currently CADx systems are trained on the available endoscopic data in which most of those polyps are from the rectosigmoid colon, Rizkala said.
We would also “like manufacturers of CADx systems to provide public access to data balanced between the proximal and distal regions of the colon,” he added.
Diagnosis More Challenging Than Detection With CADx
Commenting on the study, comoderator David G. Graham, MD, consultant gastroenterologist at University College London Hospital in England, remarked: “The key questions here relate to why are these systems underperforming in the proximal colon, and how can we improve this?”
Are these results “due to the very different appearance of adenomas in the distal colon vs the proximal colon on CADx (which is not what we see as endoscopists but seems to be what the systems are seeing), or is it due to a different characterization of polyps,” that is, more sessile serrated lesions in the proximal colon than in the distal colon, he asked.
Also commenting on the study was Raf Bisschops, MD, head of endoscopy at KU Leuven in Belgium. He remarked that the review underscores the fact that optical diagnosis by artificial intelligence is a more challenging task than detection.
It is “not entirely clear” what would explain the difference in performance of CADx between the distal colon and proximal colon, he said. It can’t be excluded that the inclusion of different CADx systems, some of which clearly underperformed, may account for the difference.
He went on to suggest that the differences might be down to location beyond proximal and distal.
“The difference in performance between the right and left colon is also interesting, since recent insights in the molecular and morphological features of hyperplastic polyps indicates that there are different classes with more goblet cell–rich hyperplastic polyps in the right colon, and more microvesicular hyperplastic polyps in the left.”
These have “distinct microscopic and endoscopic appearances” that could account for a difference in performance of a CADx system if not included in the training and validation sets, he explained.
Rizkala and Graham reported no relevant disclosures. Bisschops reported receiving research grants and speaker fees from Medtronic, Fujifilm, and Pentax.
A version of this article first appeared on Medscape.com.
VIENNA —
In particular, the diagnostic performance of CADx for polyps showed significantly lower specificity in the proximal colon than in the distal colon.
“While current CADx systems are suitable for use in the distal colon, they should not be employed for diagnosing polyps in the proximal colon until new, higher performing systems are developed specifically for these lesions,” said study lead Tommy Rizkala, MD, Endoscopy Unit, IRCCS Humanitas Clinical and Research Center, Rozzano, Italy.
The “main strength” of the review is that the researchers contacted each study author for more specific information and were therefore able to divide the data into the proximal colon and the rectosigmoid colon, he explained.
“This is the first paper that has really collected these data. Most papers provide data for the entire colon or just for the rectosigmoid colon,” said Rizkala, who presented the findings at the United European Gastroenterology (UEG) Week 2024.
The study was also recently published in Clinical Gastroenterology and Hepatology.
Optical diagnosis enables real-time histologic predictions of polyps 5 mm or smaller during colonoscopy, offering potential clinical and cost-saving benefits. Two optical diagnostic strategies are used for polyps in this size range based on location: A leave-in-situ strategy (applied only in the rectosigmoid colon when there is high confidence of non-neoplastic polyps) and a resect-and-discard strategy (applied only in the whole colon when there is high confidence of neoplastic polyps upon optical diagnosis).
Rizkala carried out a review of studies that evaluated the performance of real-time CADx alone — independent of endoscopist judgment — for predicting the histology of colorectal polyps 5 mm or smaller. The primary endpoints were CADx sensitivity and specificity in the proximal colon (the portion extending from the descending colon to the cecum) and the distal colon (limited to the rectosigmoid region). Secondary outcomes were the negative predictive value (NPV), positive predictive value (PPV), and accuracy of the CADx alone in the proximal colon and the distal colon.
Lower Specificity in the Proximal Colon
An analysis of data based on 7782 polyps ≤ 5 mm from 11 studies found specificity values of 0.62 (95% CI, 0.52-0.71) and 0.85 (95% CI, 0.75-0.92) for the proximal and distal regions of the colon, respectively, with a risk ratio (RR) of 0.74 (95% CI, 0.72-0.84), meaning that CADx accuracy was significantly lower in the proximal colon than in the distal colon.
“According to the optical diagnosis strategy, we can use the leave-in-situ approach for the distal colon because the performance is adequate, but for the rest of the colon, CADx requires further enhancement,” Rizkala said.
Sensitivity values were 0.89 (95% CI, 0.83-0.93) and 0.87 (95% CI, 0.80-0.92) for the proximal and distal regions, respectively, with an RR of 1.00 (95% CI, 0.97-1.03).
Regarding the secondary outcomes, the NPV was 0.64 vs 0.93 for the proximal vs distal colon, with an RR of 0.71 (95% CI, 0.64-0.79), and accuracy was 0.81 vs 0.86, with an RR of 0.95 (95% CI, 0.91-0.99).
With the higher prevalence of neoplastic lesions in the proximal colon than in the distal colon, a lower NPV was observed in the proximal colon, Rizkala noted.
The PPV was 0.87 vs 0.76 for the proximal vs distal colon, with an RR of 1.11 (95% CI, 1.06-1.17), so the two parts of the colon were comparable, he reported.
In the future, CADx systems should focus on using lesions from the proximal colon to train more accurately because currently CADx systems are trained on the available endoscopic data in which most of those polyps are from the rectosigmoid colon, Rizkala said.
We would also “like manufacturers of CADx systems to provide public access to data balanced between the proximal and distal regions of the colon,” he added.
Diagnosis More Challenging Than Detection With CADx
Commenting on the study, comoderator David G. Graham, MD, consultant gastroenterologist at University College London Hospital in England, remarked: “The key questions here relate to why are these systems underperforming in the proximal colon, and how can we improve this?”
Are these results “due to the very different appearance of adenomas in the distal colon vs the proximal colon on CADx (which is not what we see as endoscopists but seems to be what the systems are seeing), or is it due to a different characterization of polyps,” that is, more sessile serrated lesions in the proximal colon than in the distal colon, he asked.
Also commenting on the study was Raf Bisschops, MD, head of endoscopy at KU Leuven in Belgium. He remarked that the review underscores the fact that optical diagnosis by artificial intelligence is a more challenging task than detection.
It is “not entirely clear” what would explain the difference in performance of CADx between the distal colon and proximal colon, he said. It can’t be excluded that the inclusion of different CADx systems, some of which clearly underperformed, may account for the difference.
He went on to suggest that the differences might be down to location beyond proximal and distal.
“The difference in performance between the right and left colon is also interesting, since recent insights in the molecular and morphological features of hyperplastic polyps indicates that there are different classes with more goblet cell–rich hyperplastic polyps in the right colon, and more microvesicular hyperplastic polyps in the left.”
These have “distinct microscopic and endoscopic appearances” that could account for a difference in performance of a CADx system if not included in the training and validation sets, he explained.
Rizkala and Graham reported no relevant disclosures. Bisschops reported receiving research grants and speaker fees from Medtronic, Fujifilm, and Pentax.
A version of this article first appeared on Medscape.com.
FROM UEG 2024
Exocrine Pancreatic Insufficiency: Optimal PERT Dose Varies by Primary Pancreatic Disease
VIENNA, AUSTRIA — according to results of a prospective study using European registry data.
Specifically, patients with EPI caused by pancreatic cancer or pancreatectomy need significantly more enzyme replacement than patients with insufficiency caused by chronic pancreatitis and acute pancreatitis. The need to add a proton pump inhibitor (PPI) to achieve the therapeutic goal also varies by condition, the study showed. 
One of the main symptoms of EPI is malnutrition, and successful PERT is defined as the resolution of nutritional deficiencies and relief of symptoms and signs associated with insufficiency, said study lead Enrique Domínguez Muñoz, MD, director of the department of gastroenterology and hepatology at University Hospital of Santiago de Compostela, Spain.
Our findings show that, “in order to achieve this, enzyme dose escalation and sometimes additional treatment with a [PPI] should be applied as required by the individual”, he reported in a presentation at the United European Gastroenterology (UEG) Week 2024.
Therefore, having dose recommendations for PERT for different causes of EPI is very helpful, said Domínguez Muñoz.
Pancreatic enzyme preparations, specifically pancreatin, are the recommended first-line treatment for EPI, but the initial doses of PERT vary depending on the patient’s age (whether adult or child), the severity of the insufficiency, and the fat content of the meal eaten.
Domínguez Muñoz and colleagues wanted to explore whether — and how — the severity of EPI varied with different diseases, therefore varying the optimal dose of PERT.
Optimal Dosing to Achieve Therapeutic Goal
The prospective study drew on data from a European multicenter registry of patients diagnosed with EPI being treated with PERT in expert centers.
The researchers evaluated the dose of PERT required to achieve symptom relief and normalization of the nutritional status in adult patients with EPI secondary to different pancreatic diseases and conditions. The percentage of patients who required the addition of a PPI to PERT to achieve the therapeutic goal was also determined.
Decisions on the initial enzyme dose (including the addition of a PPI) and any necessary adjustments during follow-up to achieve the therapeutic goal were made by the participants’ clinicians.
A total of 678 patients (mean age, 61.2 ± 13.8 years; 63.6% male) were stratified according to disease: 50% had chronic pancreatitis, 10% had acute pancreatitis, 17% had undergone pancreaticoduodenectomy, 15% had pancreatic cancer, and 8% had another pancreatic condition.
To achieve the therapeutic goal, the median optimal enzyme doses with the main meal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy, were 40,000, 50,000, 70,000, and 75,000 Ph.U, respectively. The respective optimal daily enzyme doses were 100,000, 150,000, 210,000, and 225,000 Ph.U.
The highest enzyme doses required with the main meal to achieve the therapeutic goal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy were 125,000, 210,000, 175,000, and 210,000 Ph.U, respectively. The respective highest daily enzyme doses were 400,000, 625,000, 675,000, and 750,000 Ph.U.
The need for additional therapy with twice-daily PPI to achieve the therapeutic goal also varied according to the underlying disease. It was administered to 44.1% of patients with acute pancreatitis, 37.2% of patients with chronic pancreatitis, 78.8% of patients with pancreatic cancer, and 74.1% of patients who had undergone pancreaticoduodenectomy.
“This shows us that sometimes we really do need to significantly increase the dose of pancreatic enzyme replacement therapy,” reported Domínguez Muñoz.
Clear Direction on Where to Start
Comoderator Kasper Overbeek, MD, from the department of gastroenterology and hepatology, Erasmus MC Cancer Institute, University Medical Center, the Netherlands, commented: “It’s a useful study because it gives us practical advice on what to do in specific cases.”
Until now, we’ve done the same thing for everyone, he said, “but these data clearly show that this is not optimal.”
In addition, “it is often the case with enzyme replacement therapy that doctors under-dose so it is necessary to increase the dose,” he said.
“This work gives us a clearer direction on where to start,” Overbeek said. “For example, with patients who have cancer, because they do not have time to start low and titrate up, they need a higher dose than patients with chronic pancreatitis.”
This pragmatic and novel guidance will “help us in our clinical practice,” he added.
Domínguez Muñoz reports receiving speaking and consultancy fees from Viatris, Abbott Pharmaceuticals, and Boston Scientific. Overbeek reports no relevant disclosures.
A version of this article first appeared on Medscape.com.
VIENNA, AUSTRIA — according to results of a prospective study using European registry data.
Specifically, patients with EPI caused by pancreatic cancer or pancreatectomy need significantly more enzyme replacement than patients with insufficiency caused by chronic pancreatitis and acute pancreatitis. The need to add a proton pump inhibitor (PPI) to achieve the therapeutic goal also varies by condition, the study showed.
One of the main symptoms of EPI is malnutrition, and successful PERT is defined as the resolution of nutritional deficiencies and relief of symptoms and signs associated with insufficiency, said study lead Enrique Domínguez Muñoz, MD, director of the department of gastroenterology and hepatology at University Hospital of Santiago de Compostela, Spain.
Our findings show that, “in order to achieve this, enzyme dose escalation and sometimes additional treatment with a [PPI] should be applied as required by the individual”, he reported in a presentation at the United European Gastroenterology (UEG) Week 2024.
Therefore, having dose recommendations for PERT for different causes of EPI is very helpful, said Domínguez Muñoz.
Pancreatic enzyme preparations, specifically pancreatin, are the recommended first-line treatment for EPI, but the initial doses of PERT vary depending on the patient’s age (whether adult or child), the severity of the insufficiency, and the fat content of the meal eaten.
Domínguez Muñoz and colleagues wanted to explore whether — and how — the severity of EPI varied with different diseases, therefore varying the optimal dose of PERT.
Optimal Dosing to Achieve Therapeutic Goal
The prospective study drew on data from a European multicenter registry of patients diagnosed with EPI being treated with PERT in expert centers.
The researchers evaluated the dose of PERT required to achieve symptom relief and normalization of the nutritional status in adult patients with EPI secondary to different pancreatic diseases and conditions. The percentage of patients who required the addition of a PPI to PERT to achieve the therapeutic goal was also determined.
Decisions on the initial enzyme dose (including the addition of a PPI) and any necessary adjustments during follow-up to achieve the therapeutic goal were made by the participants’ clinicians.
A total of 678 patients (mean age, 61.2 ± 13.8 years; 63.6% male) were stratified according to disease: 50% had chronic pancreatitis, 10% had acute pancreatitis, 17% had undergone pancreaticoduodenectomy, 15% had pancreatic cancer, and 8% had another pancreatic condition.
To achieve the therapeutic goal, the median optimal enzyme doses with the main meal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy, were 40,000, 50,000, 70,000, and 75,000 Ph.U, respectively. The respective optimal daily enzyme doses were 100,000, 150,000, 210,000, and 225,000 Ph.U.
The highest enzyme doses required with the main meal to achieve the therapeutic goal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy were 125,000, 210,000, 175,000, and 210,000 Ph.U, respectively. The respective highest daily enzyme doses were 400,000, 625,000, 675,000, and 750,000 Ph.U.
The need for additional therapy with twice-daily PPI to achieve the therapeutic goal also varied according to the underlying disease. It was administered to 44.1% of patients with acute pancreatitis, 37.2% of patients with chronic pancreatitis, 78.8% of patients with pancreatic cancer, and 74.1% of patients who had undergone pancreaticoduodenectomy.
“This shows us that sometimes we really do need to significantly increase the dose of pancreatic enzyme replacement therapy,” reported Domínguez Muñoz.
Clear Direction on Where to Start
Comoderator Kasper Overbeek, MD, from the department of gastroenterology and hepatology, Erasmus MC Cancer Institute, University Medical Center, the Netherlands, commented: “It’s a useful study because it gives us practical advice on what to do in specific cases.”
Until now, we’ve done the same thing for everyone, he said, “but these data clearly show that this is not optimal.”
In addition, “it is often the case with enzyme replacement therapy that doctors under-dose so it is necessary to increase the dose,” he said.
“This work gives us a clearer direction on where to start,” Overbeek said. “For example, with patients who have cancer, because they do not have time to start low and titrate up, they need a higher dose than patients with chronic pancreatitis.”
This pragmatic and novel guidance will “help us in our clinical practice,” he added.
Domínguez Muñoz reports receiving speaking and consultancy fees from Viatris, Abbott Pharmaceuticals, and Boston Scientific. Overbeek reports no relevant disclosures.
A version of this article first appeared on Medscape.com.
VIENNA, AUSTRIA — according to results of a prospective study using European registry data.
Specifically, patients with EPI caused by pancreatic cancer or pancreatectomy need significantly more enzyme replacement than patients with insufficiency caused by chronic pancreatitis and acute pancreatitis. The need to add a proton pump inhibitor (PPI) to achieve the therapeutic goal also varies by condition, the study showed.
One of the main symptoms of EPI is malnutrition, and successful PERT is defined as the resolution of nutritional deficiencies and relief of symptoms and signs associated with insufficiency, said study lead Enrique Domínguez Muñoz, MD, director of the department of gastroenterology and hepatology at University Hospital of Santiago de Compostela, Spain.
Our findings show that, “in order to achieve this, enzyme dose escalation and sometimes additional treatment with a [PPI] should be applied as required by the individual”, he reported in a presentation at the United European Gastroenterology (UEG) Week 2024.
Therefore, having dose recommendations for PERT for different causes of EPI is very helpful, said Domínguez Muñoz.
Pancreatic enzyme preparations, specifically pancreatin, are the recommended first-line treatment for EPI, but the initial doses of PERT vary depending on the patient’s age (whether adult or child), the severity of the insufficiency, and the fat content of the meal eaten.
Domínguez Muñoz and colleagues wanted to explore whether — and how — the severity of EPI varied with different diseases, therefore varying the optimal dose of PERT.
Optimal Dosing to Achieve Therapeutic Goal
The prospective study drew on data from a European multicenter registry of patients diagnosed with EPI being treated with PERT in expert centers.
The researchers evaluated the dose of PERT required to achieve symptom relief and normalization of the nutritional status in adult patients with EPI secondary to different pancreatic diseases and conditions. The percentage of patients who required the addition of a PPI to PERT to achieve the therapeutic goal was also determined.
Decisions on the initial enzyme dose (including the addition of a PPI) and any necessary adjustments during follow-up to achieve the therapeutic goal were made by the participants’ clinicians.
A total of 678 patients (mean age, 61.2 ± 13.8 years; 63.6% male) were stratified according to disease: 50% had chronic pancreatitis, 10% had acute pancreatitis, 17% had undergone pancreaticoduodenectomy, 15% had pancreatic cancer, and 8% had another pancreatic condition.
To achieve the therapeutic goal, the median optimal enzyme doses with the main meal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy, were 40,000, 50,000, 70,000, and 75,000 Ph.U, respectively. The respective optimal daily enzyme doses were 100,000, 150,000, 210,000, and 225,000 Ph.U.
The highest enzyme doses required with the main meal to achieve the therapeutic goal for patients with acute pancreatitis, chronic pancreatitis, pancreatic cancer, and pancreaticoduodenectomy were 125,000, 210,000, 175,000, and 210,000 Ph.U, respectively. The respective highest daily enzyme doses were 400,000, 625,000, 675,000, and 750,000 Ph.U.
The need for additional therapy with twice-daily PPI to achieve the therapeutic goal also varied according to the underlying disease. It was administered to 44.1% of patients with acute pancreatitis, 37.2% of patients with chronic pancreatitis, 78.8% of patients with pancreatic cancer, and 74.1% of patients who had undergone pancreaticoduodenectomy.
“This shows us that sometimes we really do need to significantly increase the dose of pancreatic enzyme replacement therapy,” reported Domínguez Muñoz.
Clear Direction on Where to Start
Comoderator Kasper Overbeek, MD, from the department of gastroenterology and hepatology, Erasmus MC Cancer Institute, University Medical Center, the Netherlands, commented: “It’s a useful study because it gives us practical advice on what to do in specific cases.”
Until now, we’ve done the same thing for everyone, he said, “but these data clearly show that this is not optimal.”
In addition, “it is often the case with enzyme replacement therapy that doctors under-dose so it is necessary to increase the dose,” he said.
“This work gives us a clearer direction on where to start,” Overbeek said. “For example, with patients who have cancer, because they do not have time to start low and titrate up, they need a higher dose than patients with chronic pancreatitis.”
This pragmatic and novel guidance will “help us in our clinical practice,” he added.
Domínguez Muñoz reports receiving speaking and consultancy fees from Viatris, Abbott Pharmaceuticals, and Boston Scientific. Overbeek reports no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM UEG 2024
Type 2 Diabetes: Insulin-Free for 24 Months After Novel Endoscopic Procedure
TOPLINE:
VIENNA, AUSTRIA —
METHODOLOGY:
- ReCET technology, manufactured by Endogenex, uses a specialized catheter that ablates the duodenal mucosa with electroporation, enhancing sensitivity to endogenous insulin.
- In the first-in-human study, a total of 14 participants (aged 28-75 years; body mass index, 24-40) underwent the ReCET procedure. They then followed a 2-week isocaloric liquid diet, after which they were initiated on semaglutide and gradually titrated up to 1 mg/wk.
- Patients were followed for a total of 24 months.
TAKEAWAY:
- Of the 14 participants, 12 (86%) no longer required insulin at the 6- and 12-month follow-ups.
- At the 24-month follow-up, 11 patients were still insulin-free while maintaining A1c levels below 7.5%. (One patient withdrew consent at 18 months.)
- Semaglutide at the maximum dose was well-tolerated by 93% of participants. One patient experienced nausea that limited titration to the maximum dose. There were no serious adverse events to the ReCET procedure.
- Researchers have started the EMINENT-2 trial that will compare the use of ReCET with a sham procedure. All patients will still receive semaglutide.
IN PRACTICE:
- “These findings are very encouraging, suggesting that ReCET is a safe and feasible procedure that, when combined with semaglutide, can effectively eliminate the need for insulin therapy,” said the study’s lead author.
- It’s a novel way of treating type 2 diabetes using a single endoscopic procedure instead of repeated insulin injections, Busch explained. “But we do need to consider whether repeat treatment will be necessary because I don’t believe this will be forever.”
SOURCE:
This study was led by Celine Busch, MBBS, a PhD candidate in gastroenterology at Amsterdam University Medical Center, Amsterdam, the Netherlands, and was presented (abstract OP049) at the United European Gastroenterology (UEG) Week 2024 in Vienna, Austria, on October 14, 2024.
LIMITATIONS:
Limitations included the small sample size, uncontrolled nature, and bias due to combination therapy.
DISCLOSURES:
This study received an unrestricted research grant from Endogenex. No other relevant disclosures were declared.
A version of this article first appeared on Medscape.com.
TOPLINE:
VIENNA, AUSTRIA —
METHODOLOGY:
- ReCET technology, manufactured by Endogenex, uses a specialized catheter that ablates the duodenal mucosa with electroporation, enhancing sensitivity to endogenous insulin.
- In the first-in-human study, a total of 14 participants (aged 28-75 years; body mass index, 24-40) underwent the ReCET procedure. They then followed a 2-week isocaloric liquid diet, after which they were initiated on semaglutide and gradually titrated up to 1 mg/wk.
- Patients were followed for a total of 24 months.
TAKEAWAY:
- Of the 14 participants, 12 (86%) no longer required insulin at the 6- and 12-month follow-ups.
- At the 24-month follow-up, 11 patients were still insulin-free while maintaining A1c levels below 7.5%. (One patient withdrew consent at 18 months.)
- Semaglutide at the maximum dose was well-tolerated by 93% of participants. One patient experienced nausea that limited titration to the maximum dose. There were no serious adverse events to the ReCET procedure.
- Researchers have started the EMINENT-2 trial that will compare the use of ReCET with a sham procedure. All patients will still receive semaglutide.
IN PRACTICE:
- “These findings are very encouraging, suggesting that ReCET is a safe and feasible procedure that, when combined with semaglutide, can effectively eliminate the need for insulin therapy,” said the study’s lead author.
- It’s a novel way of treating type 2 diabetes using a single endoscopic procedure instead of repeated insulin injections, Busch explained. “But we do need to consider whether repeat treatment will be necessary because I don’t believe this will be forever.”
SOURCE:
This study was led by Celine Busch, MBBS, a PhD candidate in gastroenterology at Amsterdam University Medical Center, Amsterdam, the Netherlands, and was presented (abstract OP049) at the United European Gastroenterology (UEG) Week 2024 in Vienna, Austria, on October 14, 2024.
LIMITATIONS:
Limitations included the small sample size, uncontrolled nature, and bias due to combination therapy.
DISCLOSURES:
This study received an unrestricted research grant from Endogenex. No other relevant disclosures were declared.
A version of this article first appeared on Medscape.com.
TOPLINE:
VIENNA, AUSTRIA —
METHODOLOGY:
- ReCET technology, manufactured by Endogenex, uses a specialized catheter that ablates the duodenal mucosa with electroporation, enhancing sensitivity to endogenous insulin.
- In the first-in-human study, a total of 14 participants (aged 28-75 years; body mass index, 24-40) underwent the ReCET procedure. They then followed a 2-week isocaloric liquid diet, after which they were initiated on semaglutide and gradually titrated up to 1 mg/wk.
- Patients were followed for a total of 24 months.
TAKEAWAY:
- Of the 14 participants, 12 (86%) no longer required insulin at the 6- and 12-month follow-ups.
- At the 24-month follow-up, 11 patients were still insulin-free while maintaining A1c levels below 7.5%. (One patient withdrew consent at 18 months.)
- Semaglutide at the maximum dose was well-tolerated by 93% of participants. One patient experienced nausea that limited titration to the maximum dose. There were no serious adverse events to the ReCET procedure.
- Researchers have started the EMINENT-2 trial that will compare the use of ReCET with a sham procedure. All patients will still receive semaglutide.
IN PRACTICE:
- “These findings are very encouraging, suggesting that ReCET is a safe and feasible procedure that, when combined with semaglutide, can effectively eliminate the need for insulin therapy,” said the study’s lead author.
- It’s a novel way of treating type 2 diabetes using a single endoscopic procedure instead of repeated insulin injections, Busch explained. “But we do need to consider whether repeat treatment will be necessary because I don’t believe this will be forever.”
SOURCE:
This study was led by Celine Busch, MBBS, a PhD candidate in gastroenterology at Amsterdam University Medical Center, Amsterdam, the Netherlands, and was presented (abstract OP049) at the United European Gastroenterology (UEG) Week 2024 in Vienna, Austria, on October 14, 2024.
LIMITATIONS:
Limitations included the small sample size, uncontrolled nature, and bias due to combination therapy.
DISCLOSURES:
This study received an unrestricted research grant from Endogenex. No other relevant disclosures were declared.
A version of this article first appeared on Medscape.com.
GPs Urged to Embed Lifestyle Medicine into Primary Care
LIVERPOOL — “Healthy doctors make healthy patients”, stated a GP during a workshop at the Royal College of General Practitioners (RCGP) annual meeting. The session aimed to encourage GPs to embed lifestyle medicine into primary care through collaborative action.
Callum Leese from Aberfeldy Medical Practice in Scotland, who is also a lecturer at the University of Dundee for the Scottish Clinical Research Excellence Development Scheme (SCREDS), discussed the benefits of lifestyle medicine services in addressing lifestyle-related diseases, reducing their contribution towards the prevalence of chronic conditions, and helping prevent premature mortality.
Leese is leading a project to make Aberfeldy the healthiest town in Scotland by promoting physical activities, such as the 2-km, 5-km, and 7-km Santa Stride walking group in November, and a recent food festival to encourage healthy cooking and eating. “There’s loads of things that can be done to try and inspire change,” he said. “The research is fairly unequivocal in that healthy doctors make healthy patients,” Leese asserted. “The most important thing we can do is target our doctors and our nurses and make them advocates for what we want to see with our patients.”
Speaking to this news organization, he emphasized that, “if the doctors are moving, they’re much more likely to promote it, and if they’re eating well, they’re much more likely to be able to be evangelistic.”
Physical Activity Advice Shows High Return
About one-third of the population in the United Kingdom are physically inactive, which costs the economy £7.2 billion, with £1 billion attributed directly to the NHS, he informed the workshop.
As an honorary support fellow in physical activity and lifestyle medicine at the RCGP, Leese specializes in integrating physical activity into primary care settings. “We know it’s cost effective. If we compare it to smoking cessation advice, we know that we need to give advice to one person about 50 times for one person to stop smoking in primary care. But for physical activity, you need to give advice to 12 people for one person to increase their physical activity levels to meet the guidance,” he noted.
Leese stressed the importance of short but effective discussions between GPs and patients. He gave examples of online resources to recommend to patients, such as Moving Medicine, which aims to help healthcare professionals integrate physical activity into routine clinical conversations, or the RCGP toolkit (the Physical Activity Hub). “It really takes 1 minute of asking if the patient has ever considered being more active, and briefly explaining that being more active might have really significant outcomes for their condition,” he said.
In primary care, most patients who need to be more physically activity are directed toward 12-week exercise referral schemes, and sometimes we use social prescribing, for example, inviting patients to walk in groups, Leese explained. “However, despite the best intentions, about 78% of GPs aren’t doing it [advising on physical activity] regularly,” he noted. He cited four main challenges: lack of time, knowledge, resources, and financial support.
Geographical Variation in Social Prescribing
Social prescribing, which links patients with non–medical community support, also varies widely across the United Kingdom. “Social prescribing is a real example of that because it’s really well established in some places and not in others,” Leese remarked. He noted that inner-city and rural areas often have different needs. Contrary to some expectations, city dwellers are sometimes more active than those living in rural areas because despite having lots of green space for physical activity, “they tend to park the car outside the front door and park again right outside their place of work, whereas in London, for example, you can persuade people to get off a stop early on the Tube or a stop early in the bus.”
MAN v FAT 5-a-side Football
Leese also emphasized the importance of innovation in implementing lifestyle medicine, pointing out that nonmedical personnel, social prescribers, and health coaches can alleviate time pressures on GPs.
Citing an example of a physical activity-related intervention, he described a UK-wide organization developed for men in the 40s-50s age group, called MAN v FAT, which involves a novel weight-related way of playing five-a-side football. Players have a weigh-in before each game and teams are rewarded with points on the pitch for every pound lost as a team since their last match.
However, Leese acknowledged the need to tailor physical activity advice to different age groups. For example, “in an 80-year-old, physical activity might improve their balance and they’re less likely to fall and break something.”
Lifestyle Clinics
Leese cited the PCN Lifestyle Clinics, originating from the Leamington Primary Care Network (PCN), as an example of successful lifestyle medicine integration to help address the needs of people living with chronic conditions. “We don’t want to prescribe a model, but we can draw on a program run by the Leamington Spa PCN, that involves four group sessions of 6-10 people focused on lifestyle,” he said.
The weekly group-based sessions are run by a GP, a health and wellbeing coach, a dietitian, and a psychiatrist. Together, they cover four aspects of lifestyle and health comprising individual challenges, how community influences behavior and vice versa, food and nutrition, and physical activity for health and wellbeing.
“We try to debunk some of those myths around nutrition, compared with diet, and physical activity, compared with exercise. So, for example, the idea that exercise is usually considered to be using an elliptical cross-trainer whereas physical activity, which might be just dancing in your kitchen while you’re making dinner, is something that can be done more easily,” explained Leese.
Physical activities include running and swimming in collaboration with a leisure center. “It’s an amazing program,” he remarked.
Outcomes from 142 patients who attended the Lifestyle Clinic at a North Leamington GP practice over 14 months showed that 53% gained confidence in making lifestyle changes, 60% noticed a positive impact on their physical health, and 77% reported positive impacts on their mental health.
GP Embraces Lifestyle Medicine
Rachel Burnett, a GP from Park Medical Practice in Derby, a delegate who attended the session, commented on the central idea of incorporating lifestyle medicine into primary care practice. She told this news organization that, “I think it could prevent a lot of ill health and therefore a lot of health inequalities just by embedding lifestyle medicine into our work. To hear about the Leamington Spa project and how it›s been a success was really inspiring.”
Referring to her own practice, Burnett said: “My patients are familiar with the way I go on and on about lifestyle measures, but I believe the way forward is with group sessions because we need to give the same advice to a large number of patients, for example, with prediabetes. This could save time and resource, and I think patients who are more likely to make the changes will actually attend the sessions so we’re not wasting our breath.”
Neither Leese nor Burnett declared any relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
LIVERPOOL — “Healthy doctors make healthy patients”, stated a GP during a workshop at the Royal College of General Practitioners (RCGP) annual meeting. The session aimed to encourage GPs to embed lifestyle medicine into primary care through collaborative action.
Callum Leese from Aberfeldy Medical Practice in Scotland, who is also a lecturer at the University of Dundee for the Scottish Clinical Research Excellence Development Scheme (SCREDS), discussed the benefits of lifestyle medicine services in addressing lifestyle-related diseases, reducing their contribution towards the prevalence of chronic conditions, and helping prevent premature mortality.
Leese is leading a project to make Aberfeldy the healthiest town in Scotland by promoting physical activities, such as the 2-km, 5-km, and 7-km Santa Stride walking group in November, and a recent food festival to encourage healthy cooking and eating. “There’s loads of things that can be done to try and inspire change,” he said. “The research is fairly unequivocal in that healthy doctors make healthy patients,” Leese asserted. “The most important thing we can do is target our doctors and our nurses and make them advocates for what we want to see with our patients.”
Speaking to this news organization, he emphasized that, “if the doctors are moving, they’re much more likely to promote it, and if they’re eating well, they’re much more likely to be able to be evangelistic.”
Physical Activity Advice Shows High Return
About one-third of the population in the United Kingdom are physically inactive, which costs the economy £7.2 billion, with £1 billion attributed directly to the NHS, he informed the workshop.
As an honorary support fellow in physical activity and lifestyle medicine at the RCGP, Leese specializes in integrating physical activity into primary care settings. “We know it’s cost effective. If we compare it to smoking cessation advice, we know that we need to give advice to one person about 50 times for one person to stop smoking in primary care. But for physical activity, you need to give advice to 12 people for one person to increase their physical activity levels to meet the guidance,” he noted.
Leese stressed the importance of short but effective discussions between GPs and patients. He gave examples of online resources to recommend to patients, such as Moving Medicine, which aims to help healthcare professionals integrate physical activity into routine clinical conversations, or the RCGP toolkit (the Physical Activity Hub). “It really takes 1 minute of asking if the patient has ever considered being more active, and briefly explaining that being more active might have really significant outcomes for their condition,” he said.
In primary care, most patients who need to be more physically activity are directed toward 12-week exercise referral schemes, and sometimes we use social prescribing, for example, inviting patients to walk in groups, Leese explained. “However, despite the best intentions, about 78% of GPs aren’t doing it [advising on physical activity] regularly,” he noted. He cited four main challenges: lack of time, knowledge, resources, and financial support.
Geographical Variation in Social Prescribing
Social prescribing, which links patients with non–medical community support, also varies widely across the United Kingdom. “Social prescribing is a real example of that because it’s really well established in some places and not in others,” Leese remarked. He noted that inner-city and rural areas often have different needs. Contrary to some expectations, city dwellers are sometimes more active than those living in rural areas because despite having lots of green space for physical activity, “they tend to park the car outside the front door and park again right outside their place of work, whereas in London, for example, you can persuade people to get off a stop early on the Tube or a stop early in the bus.”
MAN v FAT 5-a-side Football
Leese also emphasized the importance of innovation in implementing lifestyle medicine, pointing out that nonmedical personnel, social prescribers, and health coaches can alleviate time pressures on GPs.
Citing an example of a physical activity-related intervention, he described a UK-wide organization developed for men in the 40s-50s age group, called MAN v FAT, which involves a novel weight-related way of playing five-a-side football. Players have a weigh-in before each game and teams are rewarded with points on the pitch for every pound lost as a team since their last match.
However, Leese acknowledged the need to tailor physical activity advice to different age groups. For example, “in an 80-year-old, physical activity might improve their balance and they’re less likely to fall and break something.”
Lifestyle Clinics
Leese cited the PCN Lifestyle Clinics, originating from the Leamington Primary Care Network (PCN), as an example of successful lifestyle medicine integration to help address the needs of people living with chronic conditions. “We don’t want to prescribe a model, but we can draw on a program run by the Leamington Spa PCN, that involves four group sessions of 6-10 people focused on lifestyle,” he said.
The weekly group-based sessions are run by a GP, a health and wellbeing coach, a dietitian, and a psychiatrist. Together, they cover four aspects of lifestyle and health comprising individual challenges, how community influences behavior and vice versa, food and nutrition, and physical activity for health and wellbeing.
“We try to debunk some of those myths around nutrition, compared with diet, and physical activity, compared with exercise. So, for example, the idea that exercise is usually considered to be using an elliptical cross-trainer whereas physical activity, which might be just dancing in your kitchen while you’re making dinner, is something that can be done more easily,” explained Leese.
Physical activities include running and swimming in collaboration with a leisure center. “It’s an amazing program,” he remarked.
Outcomes from 142 patients who attended the Lifestyle Clinic at a North Leamington GP practice over 14 months showed that 53% gained confidence in making lifestyle changes, 60% noticed a positive impact on their physical health, and 77% reported positive impacts on their mental health.
GP Embraces Lifestyle Medicine
Rachel Burnett, a GP from Park Medical Practice in Derby, a delegate who attended the session, commented on the central idea of incorporating lifestyle medicine into primary care practice. She told this news organization that, “I think it could prevent a lot of ill health and therefore a lot of health inequalities just by embedding lifestyle medicine into our work. To hear about the Leamington Spa project and how it›s been a success was really inspiring.”
Referring to her own practice, Burnett said: “My patients are familiar with the way I go on and on about lifestyle measures, but I believe the way forward is with group sessions because we need to give the same advice to a large number of patients, for example, with prediabetes. This could save time and resource, and I think patients who are more likely to make the changes will actually attend the sessions so we’re not wasting our breath.”
Neither Leese nor Burnett declared any relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
LIVERPOOL — “Healthy doctors make healthy patients”, stated a GP during a workshop at the Royal College of General Practitioners (RCGP) annual meeting. The session aimed to encourage GPs to embed lifestyle medicine into primary care through collaborative action.
Callum Leese from Aberfeldy Medical Practice in Scotland, who is also a lecturer at the University of Dundee for the Scottish Clinical Research Excellence Development Scheme (SCREDS), discussed the benefits of lifestyle medicine services in addressing lifestyle-related diseases, reducing their contribution towards the prevalence of chronic conditions, and helping prevent premature mortality.
Leese is leading a project to make Aberfeldy the healthiest town in Scotland by promoting physical activities, such as the 2-km, 5-km, and 7-km Santa Stride walking group in November, and a recent food festival to encourage healthy cooking and eating. “There’s loads of things that can be done to try and inspire change,” he said. “The research is fairly unequivocal in that healthy doctors make healthy patients,” Leese asserted. “The most important thing we can do is target our doctors and our nurses and make them advocates for what we want to see with our patients.”
Speaking to this news organization, he emphasized that, “if the doctors are moving, they’re much more likely to promote it, and if they’re eating well, they’re much more likely to be able to be evangelistic.”
Physical Activity Advice Shows High Return
About one-third of the population in the United Kingdom are physically inactive, which costs the economy £7.2 billion, with £1 billion attributed directly to the NHS, he informed the workshop.
As an honorary support fellow in physical activity and lifestyle medicine at the RCGP, Leese specializes in integrating physical activity into primary care settings. “We know it’s cost effective. If we compare it to smoking cessation advice, we know that we need to give advice to one person about 50 times for one person to stop smoking in primary care. But for physical activity, you need to give advice to 12 people for one person to increase their physical activity levels to meet the guidance,” he noted.
Leese stressed the importance of short but effective discussions between GPs and patients. He gave examples of online resources to recommend to patients, such as Moving Medicine, which aims to help healthcare professionals integrate physical activity into routine clinical conversations, or the RCGP toolkit (the Physical Activity Hub). “It really takes 1 minute of asking if the patient has ever considered being more active, and briefly explaining that being more active might have really significant outcomes for their condition,” he said.
In primary care, most patients who need to be more physically activity are directed toward 12-week exercise referral schemes, and sometimes we use social prescribing, for example, inviting patients to walk in groups, Leese explained. “However, despite the best intentions, about 78% of GPs aren’t doing it [advising on physical activity] regularly,” he noted. He cited four main challenges: lack of time, knowledge, resources, and financial support.
Geographical Variation in Social Prescribing
Social prescribing, which links patients with non–medical community support, also varies widely across the United Kingdom. “Social prescribing is a real example of that because it’s really well established in some places and not in others,” Leese remarked. He noted that inner-city and rural areas often have different needs. Contrary to some expectations, city dwellers are sometimes more active than those living in rural areas because despite having lots of green space for physical activity, “they tend to park the car outside the front door and park again right outside their place of work, whereas in London, for example, you can persuade people to get off a stop early on the Tube or a stop early in the bus.”
MAN v FAT 5-a-side Football
Leese also emphasized the importance of innovation in implementing lifestyle medicine, pointing out that nonmedical personnel, social prescribers, and health coaches can alleviate time pressures on GPs.
Citing an example of a physical activity-related intervention, he described a UK-wide organization developed for men in the 40s-50s age group, called MAN v FAT, which involves a novel weight-related way of playing five-a-side football. Players have a weigh-in before each game and teams are rewarded with points on the pitch for every pound lost as a team since their last match.
However, Leese acknowledged the need to tailor physical activity advice to different age groups. For example, “in an 80-year-old, physical activity might improve their balance and they’re less likely to fall and break something.”
Lifestyle Clinics
Leese cited the PCN Lifestyle Clinics, originating from the Leamington Primary Care Network (PCN), as an example of successful lifestyle medicine integration to help address the needs of people living with chronic conditions. “We don’t want to prescribe a model, but we can draw on a program run by the Leamington Spa PCN, that involves four group sessions of 6-10 people focused on lifestyle,” he said.
The weekly group-based sessions are run by a GP, a health and wellbeing coach, a dietitian, and a psychiatrist. Together, they cover four aspects of lifestyle and health comprising individual challenges, how community influences behavior and vice versa, food and nutrition, and physical activity for health and wellbeing.
“We try to debunk some of those myths around nutrition, compared with diet, and physical activity, compared with exercise. So, for example, the idea that exercise is usually considered to be using an elliptical cross-trainer whereas physical activity, which might be just dancing in your kitchen while you’re making dinner, is something that can be done more easily,” explained Leese.
Physical activities include running and swimming in collaboration with a leisure center. “It’s an amazing program,” he remarked.
Outcomes from 142 patients who attended the Lifestyle Clinic at a North Leamington GP practice over 14 months showed that 53% gained confidence in making lifestyle changes, 60% noticed a positive impact on their physical health, and 77% reported positive impacts on their mental health.
GP Embraces Lifestyle Medicine
Rachel Burnett, a GP from Park Medical Practice in Derby, a delegate who attended the session, commented on the central idea of incorporating lifestyle medicine into primary care practice. She told this news organization that, “I think it could prevent a lot of ill health and therefore a lot of health inequalities just by embedding lifestyle medicine into our work. To hear about the Leamington Spa project and how it›s been a success was really inspiring.”
Referring to her own practice, Burnett said: “My patients are familiar with the way I go on and on about lifestyle measures, but I believe the way forward is with group sessions because we need to give the same advice to a large number of patients, for example, with prediabetes. This could save time and resource, and I think patients who are more likely to make the changes will actually attend the sessions so we’re not wasting our breath.”
Neither Leese nor Burnett declared any relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
New Guidelines Emphasize Liver Care in T2D, Obesity
MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.
“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.
“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.
Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.
“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.
Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.
The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
A Metabolic Condition
In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.
“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.
According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.
MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.
In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).
The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
Case-Finding and Diagnosis
Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.
The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.
Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.
Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.
“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.
“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.”
The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.
Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.
“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.”
“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.
“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
Management of MASLD — Lifestyle and Treatment
“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.
“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”
She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced.
If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.
Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”
There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.
Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”
These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.
“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”
Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.
A version of this article first appeared on Medscape.com.
MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.
“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.
“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.
Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.
“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.
Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.
The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
A Metabolic Condition
In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.
“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.
According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.
MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.
In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).
The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
Case-Finding and Diagnosis
Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.
The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.
Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.
Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.
“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.
“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.”
The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.
Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.
“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.”
“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.
“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
Management of MASLD — Lifestyle and Treatment
“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.
“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”
She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced.
If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.
Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”
There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.
Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”
These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.
“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”
Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.
A version of this article first appeared on Medscape.com.
MADRID — Individuals with type 2 diabetes and/or obesity plus one or more metabolic risk factors are at a higher risk for metabolic dysfunction–associated steatotic liver disease (MASLD) with fibrosis and progression to more severe liver disease, stated new European guidelines that provide recommendations for diagnosis and management.
“The availability of improved treatment options underlines the need to identify at-risk individuals with MASLD early, as we now possess the tools to positively influence the course of the diseases, which is expected to prevent relevant clinical events,” stated the clinical practice guidelines, updated for the first time since 2016.
“Now we have guidelines that tell clinicians how to monitor the liver,” said Amalia Gastaldelli, PhD, research director at the Institute of Clinical Physiology of the National Research Council in Pisa, Italy, and a member of the panel that developed the guidelines.
Dr. Gastaldelli moderated a session focused on the guidelines at the annual meeting of the European Association for the Study of Diabetes (EASD). In an interview after the session, Dr. Gastaldelli, who leads a cardiometabolic risk research group, stressed the importance of the liver’s role in the body and the need for diabetes specialists to start paying more attention to this vital organ.
“It’s an important organ for monitoring because liver disease is silent, and the patient doesn’t feel unwell until disease is severe,” she said. “Diabetologists already monitor the eye, the heart, the kidney, and so on, but the liver is often neglected,” she said. A 2024 study found that the global pooled prevalence of MASLD among patients with type 2 diabetes was 65.33%.
Dr. Gastaldelli noted the importance of liver status in diabetes care. The liver makes triglycerides and very-low-density lipoprotein cholesterol, which are all major risk factors for atherosclerosis and cardiovascular disease (CVD), she said, as well as producing glucose, which in excess can lead to hyperglycemia.
The guidelines were jointly written by EASD, the European Association for the Study of the Liver, and the European Association for the Study of Obesity, and published in Diabetologia, The Journal of Hepatology, and Obesity Facts.
A Metabolic Condition
In the EASD meeting session, Dr. Gastaldelli discussed the reasons for, and implications of, shifting the name from nonalcoholic fatty liver disease (NAFLD) to MASLD.
“The name change focuses on the fact that this is a metabolic disease, while NAFLD had no mention of this and was considered stigmatizing by patients, especially in relation to the words ‘fatty’ and ‘nonalcoholic,’” she said.
According to the guidelines, MASLD is defined as liver steatosis in the presence of one or more cardiometabolic risk factor(s) and the absence of excess alcohol intake.
MASLD has become the most common chronic liver disease and includes isolated steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), MASH-related fibrosis, and cirrhosis.
In the overarching group of steatotic liver disease, a totally new intermediate category has been added: MASLD with moderate (increased) alcohol intake (MetALD), which represents MASLD in people who consume greater amounts of alcohol per week (140-350 g/week and 210-420 g/week for women and men, respectively).
The change in the nomenclature has been incremental and regional, Dr. Gastaldelli said. “The definition first changed from NAFLD to MAFLD, which recognizes the importance of metabolism in the pathophysiology of this disease but does not take into account alcohol intake. MAFLD is still used in Asia, Australasia, and North Africa, while Europe and the Americas have endorsed MASLD.”
Case-Finding and Diagnosis
Identifying MASLD cases in people at risk remains incidental, largely because it is a silent disease and is symptom-free until it becomes severe, said Dr. Gastaldelli.
The guideline recognizes that individuals with type 2 diabetes or obesity with additional metabolic risk factor(s) are at a higher risk for MASLD with fibrosis and progression to MASH.
Assessment strategies for severe liver fibrosis in MASLD include the use of noninvasive tests in people who have cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity or in the presence of one or more metabolic risk factors.
Dr. Gastaldelli noted that type 2 diabetes, metabolic syndrome, and obesity, including abdominal obesity identified by large waist circumference, are the major risk factors and should be warning signs.
“We need to consider abdominal obesity too — we’ve published data in relatively lean people, body mass index < 25, with MASH but without diabetes. Most of the patients accumulated fat viscerally and in the liver and had hypertriglyceridemia and hypercholesterolemia,” she said.
“The guidelines reflect this because the definition of MASLD includes steatosis plus at least one metabolic factor — waist circumference, for example, which is related to visceral fat, hyperlipidemia, or hyperglycemia. Of note, in both pharmacological and diet-induced weight loss, the decrease in liver fat was associated with the decrease in visceral fat.”
The noninvasive biomarker test, Fibrosis-4 (FIB-4) may be used to assess the risk for liver fibrosis. The FIB-4 index is calculated using a patient’s age and results of three blood tests — aspartate aminotransferase, alanine aminotransferase, and platelet count.
Advanced fibrosis (grade F3-F4) “is a major risk factor for severe outcomes,” said Dr. Gastaldelli. A FIB-4 test result below 1.3 indicates low risk for advanced liver fibrosis, 1.30-2.67 indicates intermediate risk, and above 2.67 indicates high risk.
“When fibrosis increases, then liver enzymes increase and the platelets decrease,” said Dr. Gastaldelli. “It is not a perfect tool, and we need to add in age because at a young age, it is prone to false negatives and when very old — false positives. It’s important to take a global view, especially if the patient has persistent high liver enzymes, but FIB-4 is low.”
“And if they have more than one metabolic risk factor, proceed with more tests, for example, transient elastography,” she advised. Imaging techniques such as transient elastography may rule out or rule in advanced fibrosis, which is predictive of liver-related outcomes.
“However, imaging techniques only diagnose steatosis and fibrosis, and right now, MASH can only be diagnosed with liver biopsy because we do not have any markers of liver inflammation and ballooning. In the future, noninvasive tests based on imaging and blood tests will be used to identify patients with MASH,” she added.
Management of MASLD — Lifestyle and Treatment
“Pharmacological treatments are designed for [patients] with MASH and fibrosis grade F2 or F3, but not MASLD,” Dr. Gastaldelli said. As such, lifestyle interventions are the mainstay of management — including weight loss, dietary changes, physical exercise, and low to no alcohol consumption. “Eating good-quality food and reducing calories are both important because the metabolism responds differently to different nutrients,” Dr. Gastaldelli said.
“In particular, the guidelines advise dietary management because some foods carry liver toxicity, for example, sugary foods with sucrose/fructose especially,” she said, adding that, “complex carbohydrates are less harmful than refined carbohydrates. Processed foods should be avoided if possible because they contain sugars, [as well as] saturated fats and hydrogenated fat, which is particularly bad for the liver. Olive oil is better than butter or margarine, which are rich in saturated fat, and fish and white meat are preferable.”
She added that a diet to help manage type 2 diabetes was not so dissimilar because sugar again needs to be reduced.
If a patient has severe obesity (and MASLD), data show that bariatric surgery is beneficial. “It not only helps weight loss, but it improves liver histology and has been shown to improve or resolve type 2 diabetes and reduce CVD risk. Importantly, regarding fibrosis, nutritional management after the bariatric surgery is the most important thing,” said Dr. Gastaldelli.
Optimal management of comorbidities — including the use of incretin-based therapies such as semaglutide or tirzepatide for type 2 diabetes or obesity, if indicated — is advised, according to the guidelines.
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have been shown to have a beneficial effect on MASH, said Dr. Gastaldelli. “They have not shown effectiveness in the resolution of fibrosis, but this might take longer to manifest. However, if the medication is started early enough, it may prevent severe fibrosis. Significant weight loss, both with lifestyle and pharmacological treatment, should lead to an improvement in the liver too.”
There are currently no drugs available in Europe for the treatment of noncirrhotic MASH and severe fibrosis (stage ≥ 2). Resmetirom is the first approved MASH-targeted treatment in noncirrhotic MASH and significant liver fibrosis, with histological effectiveness on steatohepatitis and fibrosis, together with an acceptable safety and tolerability profile, but, for the moment, this agent is only available in United States.
Finally, turning to MASH-related cirrhosis, the guidelines advise adaptations of metabolic drugs, nutritional counseling, and surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.
After the session, this news organization spoke to Tushy Kailayanathan, MBBS BSc, medical director of the liver MRI company, Perspectum, who reviewed the limitations of the FIB-4 test. The FIB-4 test identifies those with advanced fibrosis in the liver, for example, patients with hepatitis C, she noted; however, “it performs worse in type 2 diabetic patients and in the elderly. There is little clinical guidance on the adjustment of FIB-4 thresholds needed for these high cardiometabolic risk groups. The priority patients are missed by FIB-4 because those individuals with early and active disease may not yet have progressed to advanced disease detected by FIB-4.”
These individuals are exactly those amenable to primary care prevention strategies, said Dr. Kailayanathan. Because of the nature of early and active liver disease in patients with high cardiometabolic risk, it would make sense to shift some diagnostic protocols into primary care.
“These individuals are exactly those amenable to primary care prevention strategies at annual diabetic review because they are likely to have modifiable cardiometabolic risk factors such as metabolic syndrome and would benefit from lifestyle and therapeutic intervention, including GLP-1 RAs and SGLT2is [sodium-glucose cotransporter-2 inhibitors],” she said. “Case-finding and detection of early-stage MASLD is a priority in diabetics, and there is an unmet need for accurate biomarkers to measure liver fat and inflammation early.”
Dr. Gastaldelli has been on the advisory board or consulting for Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Fractyl, Pfizer, Merck-MSD, MetaDeq and a speaker for Eli Lilly, Novo Nordisk, and Pfizer. Dr. Kailayanathan is medical director at Perspectum, a UK-based company involved in liver imaging technology.
A version of this article first appeared on Medscape.com.
FROM EASD 2024
‘Remarkable’ Weight Loss Seen With Safe, Tolerable Novel Oral Combination
MADRID — Amycretin, a dual-pathway, oral weight loss drug, led to up to 13% body weight loss in participants with overweight or obesity according to phase 1, first-in-human study data presented at the European Association for the Study of Diabetes (EASD) 2024 annual meeting.
Body weight loss was “remarkable for an orally delivered biologic,” said Agnes Gasiorek, PhD, senior clinical pharmacology specialist at Novo Nordisk, Måløv, Denmark, who presented the results. And “there was no plateauing of weight loss in the treatment period.”
With respect to the primary endpoint, stepwise dose escalation demonstrated that all tested dose levels up to and including 2 × 50 mg over a 12-week escalation period were safe and tolerable, Dr. Gasiorek reported.
The adverse events were in line with what was expected from targeting these receptors, and no new safety signals appeared during the study, she added.
Dual Pathways
Amycretin is a novel protein-based unimolecular amylin combined with a glucagon-like peptide 1 receptor agonist (GLP-1 RA) and is the first oral formulation of this combination under development.
The two components are both known to reduce appetite and energy intake and increase satiety, said Dr. Gasiorek, but amylin is considered to potentially increase leptin sensitivity and GLP-1 RAs are known to increase insulin secretion and biosynthesis. Together, the two components improve insulin sensitivity, decrease glucagon secretion, and lead to acute delay in gastric emptying.
The single-center, placebo-controlled, double-blind phase 1 study enrolled men and women aged 18-55 years (mean, 38-42 years across groups) with a body mass index of 25.0-39.9, without diabetes, and considered otherwise healthy.
Participants were randomly assigned to receive to receive oral amycretin (n = 95) or placebo (n = 29) once a day for up to 12 weeks. Study arms comprised single-ascending dosing (increasing from 1 mg/d to 25 mg), and multiple-ascending dosing. The latter consisted of multiple ascending doses (from 3 to 12 mg) over 10 days and multiple ascending doses (stepwise dose escalation, from 3 mg up to a final dose of 2 × 50 mg) over 12 weeks.
In her presentation at the EASD meeting, Dr. Gasiorek focused on results of the 12-week multiple ascending dose schedule with amycretin 50 mg (n = 16), amycretin 2 × 50 mg (n = 16), and placebo (n = 12).
The primary endpoint of the study was the number of treatment-emergent adverse events, while the area under the amycretin plasma concentration time curve and the maximum plasma concentration of amycretin were secondary endpoints.
The researchers also added percentage change in body weight after 12 weeks of treatment as an exploratory endpoint.
Safety Findings of Multiple Dosing
A total of 242 treatment-emergent adverse events were reported in the combined active and placebo groups and were of mild to moderate severity.
Treatment-emergent adverse events were found in 75% of the amycretin 50 mg group, 93.8% of the amycretin 2 × 50 mg group, and 33.3% of placebo recipients.
“Most adverse events reported were mild to moderate in severity and related to gastrointestinal discomfort (nausea and vomiting) and occurred in a dose-proportional manner,” reported Dr. Gasiorek.
Gastrointestinal events were experienced by 50%, 87.5%, and 16.7% of participants receiving amycretin 50 mg, amycretin 2 × 50 mg, and placebo, respectively (112 in total).
Decreased appetite was also found in 56.3%, 81.3%, and 16.7% of the amycretin 50 mg, amycretin 2 × 50 mg, and placebo groups, respectively.
Two serious adverse events occurred, one of which was acute cholecystitis and the other diabetic ketoacidosis; “however, the [latter] participant was found to have autoantibodies for beta cells before treatment and was later diagnosed with type 1 diabetes,” Dr. Gasiorek said.
Body Weight Reduction
Participants on 50 mg amycretin lost an average of 10.4% of their body weight (estimated treatment difference vs placebo, –9.2; 95% CI, –12.0 to –6.5), whereas those on 2 × 50 mg amycretin lost 13.1% of their body weight (estimated treatment difference vs placebo, –11.8; 95% CI, –14.6 to –9.0). Placebo group participants lost 1.2% of their body weight over the 12 weeks.
Although no plateauing of weight loss was seen, said Dr. Gasiorek, it is important to consider the relatively short treatment duration and the limited time on the final dose, which could potentially introduce bias.
To date, weight loss medications based on GLP-1 RA technology are injectables. A combination of the injectable amylin analogue cagrilintide and the GLP-1 RA semaglutide is also being explored as a subcutaneous treatment solution.
In a comment, Martin Holst Lange, MD, PhD, executive vice president of development at Novo Nordisk, said that “amycretin is the first treatment to harness the two distinct biological pathways stimulated by amylin and GLP-1 in a single molecule.”
The safety and tolerability profiles and the magnitude of weight loss support further development of amycretin in patients with overweight or obesity, said Dr. Lange, who noted that the company was awaiting data from the ongoing phase 1 trial with subcutaneous amycretin, expected in 2025.
Having heard the presentation, co-moderator Timo Müller, PhD, professor at Ludwig Maximilian University of Munich, Germany, gave a considered response. “The drug was relatively well tolerated, with the typical GLP-1–induced GI [gastrointestinal] adverse effects being the most frequently reported.”
But he pointed out that questions remain. “We still need to know whether, at the given dose, the drug outperforms best-in-class drugs like semaglutide or tirzepatide at the highest approved doses. Furthermore, it warrants clarification if and to what extent the activation of the amylin receptor contributes to the shown effect and if and to what extent the glycemic benefits result from activation of the glucagon receptor (amylin improved glycemia by decreasing the secretion of glucagon). In any way, the current data remain friendly and support phase 2 development.”
Oral Meds Could Bring Down Cost
Commenting on the data, Nerys Astbury, PhD, associate professor of diet and obesity at Nuffield Department of Primary Health Care Sciences, University of Oxford, England, said, “It is important to note that whilst the participants in this trial did lose weight over the 12-week study — and this was statistically more weight than in the placebo group — this study was not designed or powered to detect differences in body weight over longer periods of time.”
If the results are confirmed in future studies, amycretin might widen the treatment options and introduce competition, probably bringing down the costs in the longer-term, said Dr. Astbury, who welcomes the prospect.
“It is possible that some people might find the oral medications more acceptable than the injectable GLP-1 agonists currently available,” she said. And the current options are expensive, “which raises challenges to a taxpayer-funded health system like the NHS [National Health Service].”
“Furthermore, if the growing number of oral obesity medications prove safe, tolerable, and effective ... they are likely to significantly reduce the risks of developing many complications of obesity.”
Naveed Sattar, MD, professor of cardiometabolic medicine and honorary consultant, University of Glasgow, Scotland, agreed. “The more medicines coming forward to treat obesity, the better,” he said. In particular, oral medications would be more easily available, and cheaper, “for the many millions around the world struggling with obesity and its complications.”
Dr. Gasiorek declares she is an employee of and a shareholder in Novo Nordisk. Dr. Astbury declares no financial disclosures. Dr. Sattar declares having consulted for several companies that make diabetes medicines but also contributed to several lifestyle trials. For Novo Nordisk, he has consulted for the company on advisory boards, but not on any of their weight loss drug trial committees, and he is on the steering committee for the ZEUS trial, which is not a weight loss trial product but an anti-inflammatory. He does not have any shares for any product in health etc. He declares consulting fees and/or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. Dr. Müller received financial support or an honorarium from Novo Nordisk, Merck, Eli Lilly, Boehringer Ingelheim, and Mercodia; he further holds stocks at Novo Nordisk and Eli Lilly and is cofounder of Bluewater Biosciences.
A version of this article first appeared on Medscape.com.
MADRID — Amycretin, a dual-pathway, oral weight loss drug, led to up to 13% body weight loss in participants with overweight or obesity according to phase 1, first-in-human study data presented at the European Association for the Study of Diabetes (EASD) 2024 annual meeting.
Body weight loss was “remarkable for an orally delivered biologic,” said Agnes Gasiorek, PhD, senior clinical pharmacology specialist at Novo Nordisk, Måløv, Denmark, who presented the results. And “there was no plateauing of weight loss in the treatment period.”
With respect to the primary endpoint, stepwise dose escalation demonstrated that all tested dose levels up to and including 2 × 50 mg over a 12-week escalation period were safe and tolerable, Dr. Gasiorek reported.
The adverse events were in line with what was expected from targeting these receptors, and no new safety signals appeared during the study, she added.
Dual Pathways
Amycretin is a novel protein-based unimolecular amylin combined with a glucagon-like peptide 1 receptor agonist (GLP-1 RA) and is the first oral formulation of this combination under development.
The two components are both known to reduce appetite and energy intake and increase satiety, said Dr. Gasiorek, but amylin is considered to potentially increase leptin sensitivity and GLP-1 RAs are known to increase insulin secretion and biosynthesis. Together, the two components improve insulin sensitivity, decrease glucagon secretion, and lead to acute delay in gastric emptying.
The single-center, placebo-controlled, double-blind phase 1 study enrolled men and women aged 18-55 years (mean, 38-42 years across groups) with a body mass index of 25.0-39.9, without diabetes, and considered otherwise healthy.
Participants were randomly assigned to receive to receive oral amycretin (n = 95) or placebo (n = 29) once a day for up to 12 weeks. Study arms comprised single-ascending dosing (increasing from 1 mg/d to 25 mg), and multiple-ascending dosing. The latter consisted of multiple ascending doses (from 3 to 12 mg) over 10 days and multiple ascending doses (stepwise dose escalation, from 3 mg up to a final dose of 2 × 50 mg) over 12 weeks.
In her presentation at the EASD meeting, Dr. Gasiorek focused on results of the 12-week multiple ascending dose schedule with amycretin 50 mg (n = 16), amycretin 2 × 50 mg (n = 16), and placebo (n = 12).
The primary endpoint of the study was the number of treatment-emergent adverse events, while the area under the amycretin plasma concentration time curve and the maximum plasma concentration of amycretin were secondary endpoints.
The researchers also added percentage change in body weight after 12 weeks of treatment as an exploratory endpoint.
Safety Findings of Multiple Dosing
A total of 242 treatment-emergent adverse events were reported in the combined active and placebo groups and were of mild to moderate severity.
Treatment-emergent adverse events were found in 75% of the amycretin 50 mg group, 93.8% of the amycretin 2 × 50 mg group, and 33.3% of placebo recipients.
“Most adverse events reported were mild to moderate in severity and related to gastrointestinal discomfort (nausea and vomiting) and occurred in a dose-proportional manner,” reported Dr. Gasiorek.
Gastrointestinal events were experienced by 50%, 87.5%, and 16.7% of participants receiving amycretin 50 mg, amycretin 2 × 50 mg, and placebo, respectively (112 in total).
Decreased appetite was also found in 56.3%, 81.3%, and 16.7% of the amycretin 50 mg, amycretin 2 × 50 mg, and placebo groups, respectively.
Two serious adverse events occurred, one of which was acute cholecystitis and the other diabetic ketoacidosis; “however, the [latter] participant was found to have autoantibodies for beta cells before treatment and was later diagnosed with type 1 diabetes,” Dr. Gasiorek said.
Body Weight Reduction
Participants on 50 mg amycretin lost an average of 10.4% of their body weight (estimated treatment difference vs placebo, –9.2; 95% CI, –12.0 to –6.5), whereas those on 2 × 50 mg amycretin lost 13.1% of their body weight (estimated treatment difference vs placebo, –11.8; 95% CI, –14.6 to –9.0). Placebo group participants lost 1.2% of their body weight over the 12 weeks.
Although no plateauing of weight loss was seen, said Dr. Gasiorek, it is important to consider the relatively short treatment duration and the limited time on the final dose, which could potentially introduce bias.
To date, weight loss medications based on GLP-1 RA technology are injectables. A combination of the injectable amylin analogue cagrilintide and the GLP-1 RA semaglutide is also being explored as a subcutaneous treatment solution.
In a comment, Martin Holst Lange, MD, PhD, executive vice president of development at Novo Nordisk, said that “amycretin is the first treatment to harness the two distinct biological pathways stimulated by amylin and GLP-1 in a single molecule.”
The safety and tolerability profiles and the magnitude of weight loss support further development of amycretin in patients with overweight or obesity, said Dr. Lange, who noted that the company was awaiting data from the ongoing phase 1 trial with subcutaneous amycretin, expected in 2025.
Having heard the presentation, co-moderator Timo Müller, PhD, professor at Ludwig Maximilian University of Munich, Germany, gave a considered response. “The drug was relatively well tolerated, with the typical GLP-1–induced GI [gastrointestinal] adverse effects being the most frequently reported.”
But he pointed out that questions remain. “We still need to know whether, at the given dose, the drug outperforms best-in-class drugs like semaglutide or tirzepatide at the highest approved doses. Furthermore, it warrants clarification if and to what extent the activation of the amylin receptor contributes to the shown effect and if and to what extent the glycemic benefits result from activation of the glucagon receptor (amylin improved glycemia by decreasing the secretion of glucagon). In any way, the current data remain friendly and support phase 2 development.”
Oral Meds Could Bring Down Cost
Commenting on the data, Nerys Astbury, PhD, associate professor of diet and obesity at Nuffield Department of Primary Health Care Sciences, University of Oxford, England, said, “It is important to note that whilst the participants in this trial did lose weight over the 12-week study — and this was statistically more weight than in the placebo group — this study was not designed or powered to detect differences in body weight over longer periods of time.”
If the results are confirmed in future studies, amycretin might widen the treatment options and introduce competition, probably bringing down the costs in the longer-term, said Dr. Astbury, who welcomes the prospect.
“It is possible that some people might find the oral medications more acceptable than the injectable GLP-1 agonists currently available,” she said. And the current options are expensive, “which raises challenges to a taxpayer-funded health system like the NHS [National Health Service].”
“Furthermore, if the growing number of oral obesity medications prove safe, tolerable, and effective ... they are likely to significantly reduce the risks of developing many complications of obesity.”
Naveed Sattar, MD, professor of cardiometabolic medicine and honorary consultant, University of Glasgow, Scotland, agreed. “The more medicines coming forward to treat obesity, the better,” he said. In particular, oral medications would be more easily available, and cheaper, “for the many millions around the world struggling with obesity and its complications.”
Dr. Gasiorek declares she is an employee of and a shareholder in Novo Nordisk. Dr. Astbury declares no financial disclosures. Dr. Sattar declares having consulted for several companies that make diabetes medicines but also contributed to several lifestyle trials. For Novo Nordisk, he has consulted for the company on advisory boards, but not on any of their weight loss drug trial committees, and he is on the steering committee for the ZEUS trial, which is not a weight loss trial product but an anti-inflammatory. He does not have any shares for any product in health etc. He declares consulting fees and/or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. Dr. Müller received financial support or an honorarium from Novo Nordisk, Merck, Eli Lilly, Boehringer Ingelheim, and Mercodia; he further holds stocks at Novo Nordisk and Eli Lilly and is cofounder of Bluewater Biosciences.
A version of this article first appeared on Medscape.com.
MADRID — Amycretin, a dual-pathway, oral weight loss drug, led to up to 13% body weight loss in participants with overweight or obesity according to phase 1, first-in-human study data presented at the European Association for the Study of Diabetes (EASD) 2024 annual meeting.
Body weight loss was “remarkable for an orally delivered biologic,” said Agnes Gasiorek, PhD, senior clinical pharmacology specialist at Novo Nordisk, Måløv, Denmark, who presented the results. And “there was no plateauing of weight loss in the treatment period.”
With respect to the primary endpoint, stepwise dose escalation demonstrated that all tested dose levels up to and including 2 × 50 mg over a 12-week escalation period were safe and tolerable, Dr. Gasiorek reported.
The adverse events were in line with what was expected from targeting these receptors, and no new safety signals appeared during the study, she added.
Dual Pathways
Amycretin is a novel protein-based unimolecular amylin combined with a glucagon-like peptide 1 receptor agonist (GLP-1 RA) and is the first oral formulation of this combination under development.
The two components are both known to reduce appetite and energy intake and increase satiety, said Dr. Gasiorek, but amylin is considered to potentially increase leptin sensitivity and GLP-1 RAs are known to increase insulin secretion and biosynthesis. Together, the two components improve insulin sensitivity, decrease glucagon secretion, and lead to acute delay in gastric emptying.
The single-center, placebo-controlled, double-blind phase 1 study enrolled men and women aged 18-55 years (mean, 38-42 years across groups) with a body mass index of 25.0-39.9, without diabetes, and considered otherwise healthy.
Participants were randomly assigned to receive to receive oral amycretin (n = 95) or placebo (n = 29) once a day for up to 12 weeks. Study arms comprised single-ascending dosing (increasing from 1 mg/d to 25 mg), and multiple-ascending dosing. The latter consisted of multiple ascending doses (from 3 to 12 mg) over 10 days and multiple ascending doses (stepwise dose escalation, from 3 mg up to a final dose of 2 × 50 mg) over 12 weeks.
In her presentation at the EASD meeting, Dr. Gasiorek focused on results of the 12-week multiple ascending dose schedule with amycretin 50 mg (n = 16), amycretin 2 × 50 mg (n = 16), and placebo (n = 12).
The primary endpoint of the study was the number of treatment-emergent adverse events, while the area under the amycretin plasma concentration time curve and the maximum plasma concentration of amycretin were secondary endpoints.
The researchers also added percentage change in body weight after 12 weeks of treatment as an exploratory endpoint.
Safety Findings of Multiple Dosing
A total of 242 treatment-emergent adverse events were reported in the combined active and placebo groups and were of mild to moderate severity.
Treatment-emergent adverse events were found in 75% of the amycretin 50 mg group, 93.8% of the amycretin 2 × 50 mg group, and 33.3% of placebo recipients.
“Most adverse events reported were mild to moderate in severity and related to gastrointestinal discomfort (nausea and vomiting) and occurred in a dose-proportional manner,” reported Dr. Gasiorek.
Gastrointestinal events were experienced by 50%, 87.5%, and 16.7% of participants receiving amycretin 50 mg, amycretin 2 × 50 mg, and placebo, respectively (112 in total).
Decreased appetite was also found in 56.3%, 81.3%, and 16.7% of the amycretin 50 mg, amycretin 2 × 50 mg, and placebo groups, respectively.
Two serious adverse events occurred, one of which was acute cholecystitis and the other diabetic ketoacidosis; “however, the [latter] participant was found to have autoantibodies for beta cells before treatment and was later diagnosed with type 1 diabetes,” Dr. Gasiorek said.
Body Weight Reduction
Participants on 50 mg amycretin lost an average of 10.4% of their body weight (estimated treatment difference vs placebo, –9.2; 95% CI, –12.0 to –6.5), whereas those on 2 × 50 mg amycretin lost 13.1% of their body weight (estimated treatment difference vs placebo, –11.8; 95% CI, –14.6 to –9.0). Placebo group participants lost 1.2% of their body weight over the 12 weeks.
Although no plateauing of weight loss was seen, said Dr. Gasiorek, it is important to consider the relatively short treatment duration and the limited time on the final dose, which could potentially introduce bias.
To date, weight loss medications based on GLP-1 RA technology are injectables. A combination of the injectable amylin analogue cagrilintide and the GLP-1 RA semaglutide is also being explored as a subcutaneous treatment solution.
In a comment, Martin Holst Lange, MD, PhD, executive vice president of development at Novo Nordisk, said that “amycretin is the first treatment to harness the two distinct biological pathways stimulated by amylin and GLP-1 in a single molecule.”
The safety and tolerability profiles and the magnitude of weight loss support further development of amycretin in patients with overweight or obesity, said Dr. Lange, who noted that the company was awaiting data from the ongoing phase 1 trial with subcutaneous amycretin, expected in 2025.
Having heard the presentation, co-moderator Timo Müller, PhD, professor at Ludwig Maximilian University of Munich, Germany, gave a considered response. “The drug was relatively well tolerated, with the typical GLP-1–induced GI [gastrointestinal] adverse effects being the most frequently reported.”
But he pointed out that questions remain. “We still need to know whether, at the given dose, the drug outperforms best-in-class drugs like semaglutide or tirzepatide at the highest approved doses. Furthermore, it warrants clarification if and to what extent the activation of the amylin receptor contributes to the shown effect and if and to what extent the glycemic benefits result from activation of the glucagon receptor (amylin improved glycemia by decreasing the secretion of glucagon). In any way, the current data remain friendly and support phase 2 development.”
Oral Meds Could Bring Down Cost
Commenting on the data, Nerys Astbury, PhD, associate professor of diet and obesity at Nuffield Department of Primary Health Care Sciences, University of Oxford, England, said, “It is important to note that whilst the participants in this trial did lose weight over the 12-week study — and this was statistically more weight than in the placebo group — this study was not designed or powered to detect differences in body weight over longer periods of time.”
If the results are confirmed in future studies, amycretin might widen the treatment options and introduce competition, probably bringing down the costs in the longer-term, said Dr. Astbury, who welcomes the prospect.
“It is possible that some people might find the oral medications more acceptable than the injectable GLP-1 agonists currently available,” she said. And the current options are expensive, “which raises challenges to a taxpayer-funded health system like the NHS [National Health Service].”
“Furthermore, if the growing number of oral obesity medications prove safe, tolerable, and effective ... they are likely to significantly reduce the risks of developing many complications of obesity.”
Naveed Sattar, MD, professor of cardiometabolic medicine and honorary consultant, University of Glasgow, Scotland, agreed. “The more medicines coming forward to treat obesity, the better,” he said. In particular, oral medications would be more easily available, and cheaper, “for the many millions around the world struggling with obesity and its complications.”
Dr. Gasiorek declares she is an employee of and a shareholder in Novo Nordisk. Dr. Astbury declares no financial disclosures. Dr. Sattar declares having consulted for several companies that make diabetes medicines but also contributed to several lifestyle trials. For Novo Nordisk, he has consulted for the company on advisory boards, but not on any of their weight loss drug trial committees, and he is on the steering committee for the ZEUS trial, which is not a weight loss trial product but an anti-inflammatory. He does not have any shares for any product in health etc. He declares consulting fees and/or speaker honoraria from Abbott Laboratories, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, and grant support paid to his university from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. Dr. Müller received financial support or an honorarium from Novo Nordisk, Merck, Eli Lilly, Boehringer Ingelheim, and Mercodia; he further holds stocks at Novo Nordisk and Eli Lilly and is cofounder of Bluewater Biosciences.
A version of this article first appeared on Medscape.com.
FROM EASD 2024