Hepatology

Among people with nonalcoholic fatty liver disease (NAFLD), the fibrosis progression rate was higher among those who also had diabetes, according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

NAFLD patients with type 2 diabetes progressed by one stage about every 6 years, compared with one stage about every 8 years among patients without diabetes, said Daniel Huang, MBBS, a visiting scholar at the University of California San Diego (UCSD) NAFLD Research Center and a transplant hepatologist at National University Hospital in Singapore.

“We now know that fibrosis stage is a major determinant of liver-related outcomes in NAFLD, as well as overall mortality,” he said. “Liver fibrosis progresses by approximately one stage every 7 years for individuals with NASH (nonalcoholic steatohepatitis).”

Recent UCSD data have indicated that about 14% of patients over age 50 with type 2 diabetes have NAFLD with advanced fibrosis, he noted. Previous studies have shown that diabetes is associated with higher rates of advanced fibrosis, cirrhosis, and hepatocellular carcinoma, but limited data exist around whether the fibrosis progression rate is higher among diabetics.
 

National study cohort

Dr. Huang and colleagues conducted a multicenter, multiethnic prospective cohort study within the NASH Clinical Research Network consortium to examine the fibrosis progression rate and the fibrosis regression rate among patients with or without diabetes. The study included adult participants at eight sites across the United States who had biopsy-confirmed NAFLD and available paired liver biopsies that were at least 1 year apart.

Clinical and laboratory data were obtained at enrollment and prospectively at 48-week intervals and recorded at the time of any liver biopsies. A central pathology committee conducted the liver histology assessment, and the entire pathology committee was blinded to clinical data and the sequence of liver biopsy. The fibrosis progression and regression rates were defined as the change in fibrosis stage over time between biopsies, measured in years.

The study comprised 447 adult participants with NAFLD: 208 patients with type 2 diabetes and 239 patients without diabetes, Dr. Huang said. The mean age was 51, and the mean body mass index was 34.7. The patients with diabetes were more likely to be older, to be women, and to have metabolic syndrome, NASH, and a higher fibrosis stage.

Notably, the median HbA1c among patients with diabetes was 6.8%, indicating a cohort with fairly well-controlled blood sugar. The median time between biopsies was 3.3 years.
 

Difference in progression, not regression

Overall, 151 participants (34%) experienced fibrosis progression, the primary study outcome. In a secondary outcome, 102 participants (23%) had fibrosis regression. The remaining 194 participants (43%) had no change in fibrosis stage. About 26% of patients with types 2 diabetes progressed to advanced fibrosis, as compared with 14.1% of patients without diabetes.

Among all those with fibrosis progression, the rate was 0.15 stages per year, with an average progression rate of one stage over 6.7 years. For patients with diabetes, the progression rate was significantly higher at 0.17 stages per year, compared with 0.13 stages per year among patients without diabetes, Dr. Huang said. That translated to an average progression of one stage over 5.9 years for patients with diabetes and 7.7 years for patients without diabetes.

In contrast, the regression rate was similar between those with or without diabetes at baseline, at –0.13 stages per year for those with diabetes versus –0.14 stages per year for those without diabetes. The similar outcome translated to an average regression of one stage over 7.7 years among those with diabetes and 7.1 years among those without diabetes.

Type 2 diabetes was an independent predictor of fibrosis progression in NAFLD, in both unadjusted and multivariable adjusted models, including baseline fibrosis stage, Dr. Huang said. In addition, patients with diabetes had a significantly higher cumulative incidence of fibrosis progression at 4 years (23% versus 19%), 8 years (59% versus 49%), and 12 years (93% versus 76%).

The research team didn’t find a significant difference in HbA1c as a predictor of fibrosis progression when using a cutoff of 7%.

“It is possible that poor glycemic control may accelerate fibrosis further, but we need studies to validate this,” Dr. Huang said. “These data have important implications for clinical practice and clinical trial design. Patients with NAFLD and diabetes may require more frequent monitoring for disease progression.”

The NASH Clinical Research Network consortium is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Huang has served on an advisory board for Eisai. The other authors declared various research support and advisory roles with numerous pharmaceutical companies.

Among people with nonalcoholic fatty liver disease (NAFLD), the fibrosis progression rate was higher among those who also had diabetes, according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

NAFLD patients with type 2 diabetes progressed by one stage about every 6 years, compared with one stage about every 8 years among patients without diabetes, said Daniel Huang, MBBS, a visiting scholar at the University of California San Diego (UCSD) NAFLD Research Center and a transplant hepatologist at National University Hospital in Singapore.

“We now know that fibrosis stage is a major determinant of liver-related outcomes in NAFLD, as well as overall mortality,” he said. “Liver fibrosis progresses by approximately one stage every 7 years for individuals with NASH (nonalcoholic steatohepatitis).”

Recent UCSD data have indicated that about 14% of patients over age 50 with type 2 diabetes have NAFLD with advanced fibrosis, he noted. Previous studies have shown that diabetes is associated with higher rates of advanced fibrosis, cirrhosis, and hepatocellular carcinoma, but limited data exist around whether the fibrosis progression rate is higher among diabetics.
 

National study cohort

Dr. Huang and colleagues conducted a multicenter, multiethnic prospective cohort study within the NASH Clinical Research Network consortium to examine the fibrosis progression rate and the fibrosis regression rate among patients with or without diabetes. The study included adult participants at eight sites across the United States who had biopsy-confirmed NAFLD and available paired liver biopsies that were at least 1 year apart.

Clinical and laboratory data were obtained at enrollment and prospectively at 48-week intervals and recorded at the time of any liver biopsies. A central pathology committee conducted the liver histology assessment, and the entire pathology committee was blinded to clinical data and the sequence of liver biopsy. The fibrosis progression and regression rates were defined as the change in fibrosis stage over time between biopsies, measured in years.

The study comprised 447 adult participants with NAFLD: 208 patients with type 2 diabetes and 239 patients without diabetes, Dr. Huang said. The mean age was 51, and the mean body mass index was 34.7. The patients with diabetes were more likely to be older, to be women, and to have metabolic syndrome, NASH, and a higher fibrosis stage.

Notably, the median HbA1c among patients with diabetes was 6.8%, indicating a cohort with fairly well-controlled blood sugar. The median time between biopsies was 3.3 years.
 

Difference in progression, not regression

Overall, 151 participants (34%) experienced fibrosis progression, the primary study outcome. In a secondary outcome, 102 participants (23%) had fibrosis regression. The remaining 194 participants (43%) had no change in fibrosis stage. About 26% of patients with types 2 diabetes progressed to advanced fibrosis, as compared with 14.1% of patients without diabetes.

Among all those with fibrosis progression, the rate was 0.15 stages per year, with an average progression rate of one stage over 6.7 years. For patients with diabetes, the progression rate was significantly higher at 0.17 stages per year, compared with 0.13 stages per year among patients without diabetes, Dr. Huang said. That translated to an average progression of one stage over 5.9 years for patients with diabetes and 7.7 years for patients without diabetes.

In contrast, the regression rate was similar between those with or without diabetes at baseline, at –0.13 stages per year for those with diabetes versus –0.14 stages per year for those without diabetes. The similar outcome translated to an average regression of one stage over 7.7 years among those with diabetes and 7.1 years among those without diabetes.

Type 2 diabetes was an independent predictor of fibrosis progression in NAFLD, in both unadjusted and multivariable adjusted models, including baseline fibrosis stage, Dr. Huang said. In addition, patients with diabetes had a significantly higher cumulative incidence of fibrosis progression at 4 years (23% versus 19%), 8 years (59% versus 49%), and 12 years (93% versus 76%).

The research team didn’t find a significant difference in HbA1c as a predictor of fibrosis progression when using a cutoff of 7%.

“It is possible that poor glycemic control may accelerate fibrosis further, but we need studies to validate this,” Dr. Huang said. “These data have important implications for clinical practice and clinical trial design. Patients with NAFLD and diabetes may require more frequent monitoring for disease progression.”

The NASH Clinical Research Network consortium is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Huang has served on an advisory board for Eisai. The other authors declared various research support and advisory roles with numerous pharmaceutical companies.

Among people with nonalcoholic fatty liver disease (NAFLD), the fibrosis progression rate was higher among those who also had diabetes, according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

NAFLD patients with type 2 diabetes progressed by one stage about every 6 years, compared with one stage about every 8 years among patients without diabetes, said Daniel Huang, MBBS, a visiting scholar at the University of California San Diego (UCSD) NAFLD Research Center and a transplant hepatologist at National University Hospital in Singapore.

“We now know that fibrosis stage is a major determinant of liver-related outcomes in NAFLD, as well as overall mortality,” he said. “Liver fibrosis progresses by approximately one stage every 7 years for individuals with NASH (nonalcoholic steatohepatitis).”

Recent UCSD data have indicated that about 14% of patients over age 50 with type 2 diabetes have NAFLD with advanced fibrosis, he noted. Previous studies have shown that diabetes is associated with higher rates of advanced fibrosis, cirrhosis, and hepatocellular carcinoma, but limited data exist around whether the fibrosis progression rate is higher among diabetics.
 

National study cohort

Dr. Huang and colleagues conducted a multicenter, multiethnic prospective cohort study within the NASH Clinical Research Network consortium to examine the fibrosis progression rate and the fibrosis regression rate among patients with or without diabetes. The study included adult participants at eight sites across the United States who had biopsy-confirmed NAFLD and available paired liver biopsies that were at least 1 year apart.

Clinical and laboratory data were obtained at enrollment and prospectively at 48-week intervals and recorded at the time of any liver biopsies. A central pathology committee conducted the liver histology assessment, and the entire pathology committee was blinded to clinical data and the sequence of liver biopsy. The fibrosis progression and regression rates were defined as the change in fibrosis stage over time between biopsies, measured in years.

The study comprised 447 adult participants with NAFLD: 208 patients with type 2 diabetes and 239 patients without diabetes, Dr. Huang said. The mean age was 51, and the mean body mass index was 34.7. The patients with diabetes were more likely to be older, to be women, and to have metabolic syndrome, NASH, and a higher fibrosis stage.

Notably, the median HbA1c among patients with diabetes was 6.8%, indicating a cohort with fairly well-controlled blood sugar. The median time between biopsies was 3.3 years.
 

Difference in progression, not regression

Overall, 151 participants (34%) experienced fibrosis progression, the primary study outcome. In a secondary outcome, 102 participants (23%) had fibrosis regression. The remaining 194 participants (43%) had no change in fibrosis stage. About 26% of patients with types 2 diabetes progressed to advanced fibrosis, as compared with 14.1% of patients without diabetes.

Among all those with fibrosis progression, the rate was 0.15 stages per year, with an average progression rate of one stage over 6.7 years. For patients with diabetes, the progression rate was significantly higher at 0.17 stages per year, compared with 0.13 stages per year among patients without diabetes, Dr. Huang said. That translated to an average progression of one stage over 5.9 years for patients with diabetes and 7.7 years for patients without diabetes.

In contrast, the regression rate was similar between those with or without diabetes at baseline, at –0.13 stages per year for those with diabetes versus –0.14 stages per year for those without diabetes. The similar outcome translated to an average regression of one stage over 7.7 years among those with diabetes and 7.1 years among those without diabetes.

Type 2 diabetes was an independent predictor of fibrosis progression in NAFLD, in both unadjusted and multivariable adjusted models, including baseline fibrosis stage, Dr. Huang said. In addition, patients with diabetes had a significantly higher cumulative incidence of fibrosis progression at 4 years (23% versus 19%), 8 years (59% versus 49%), and 12 years (93% versus 76%).

The research team didn’t find a significant difference in HbA1c as a predictor of fibrosis progression when using a cutoff of 7%.

“It is possible that poor glycemic control may accelerate fibrosis further, but we need studies to validate this,” Dr. Huang said. “These data have important implications for clinical practice and clinical trial design. Patients with NAFLD and diabetes may require more frequent monitoring for disease progression.”

The NASH Clinical Research Network consortium is sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Huang has served on an advisory board for Eisai. The other authors declared various research support and advisory roles with numerous pharmaceutical companies.

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

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

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

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

WASHINGTON – In patients with cirrhosis associated with nonalcoholic steatohepatitis, 1 year of treatment with the investigational oral thyromimetic agent resmetirom (MGL-3196) was safe and effective at lowering markers of both cardiovascular risk and NASH fibrosis, new research has found.

Two cohorts comprising a total of 180 patients with well-compensated NASH cirrhosis enrolled in an open-label arm of the phase 3 MAESTRO-NAFLD-1 trial. Researchers found that 52 weeks of treatment with resmetirom was associated with reductions in MRI proton density fat fraction (MRI-PDFF), FibroScan controlled attenuation parameter, FibroScan vibration-controlled transient elastography (VCTE), magnetic resonance elastography, liver and spleen volumes, liver enzyme levels, and lipids.

“Importantly, there was a statistically significant reduction in liver volume by an average of 20%, and also the potential to monitor spleen volume as a surrogate for portal hypertension, with the caveat that further research needs to be done in this area to understand that better,” said Stephen Harrison, MD, medical director for Pinnacle Clinical Research in San Antonio, Tex.

Dr. Harrison presented the findings at the annual meeting of the American Association for the Study of Liver Diseases.
 

Building on early findings

The thyroid hormone receptor–beta pathway helps to maintain liver health through control of de novo lipogenesis, fatty acid oxidation, mitophagy and mitochondrial biogenesis, cholesterol metabolism, and anti-inflammatory and antifibrotic effects, Dr. Harrison said.

Resmetirom (Madrigal Pharmaceuticals) is a selective thyroid hormone receptor-beta agonist that is reputed to offer optimal beneficial effects on the liver, while minimizing adverse cardiovascular and bone metabolic events that are mediated through a different pathway by the thyroid hormone receptor–alpha.

In 2019, Dr. Harrison and colleagues reported results of a phase 2, double-blind, placebo-controlled trial of resmetirom in adults with biopsy-confirmed NASH (fibrosis stages 1-3) and hepatic fat content greater than 10% as assessed by MRI-PDFF.

In that study, patients who received resmetirom had significantly greater reductions in relative hepatic fat content compared with patients who received placebo at both 12 weeks and 36 weeks of follow-up. Overall, 60% of patients who took resmetirom had at least a 30% fat reduction compared with 18% of those who took placebo.

In addition, the investigators presented data on a cohort of 105 patients with well-compensated NASH cirrhosis who were treated in an open-label study. Those data were presented at the International Liver Conference in London in June.

At the AASLD meeting, Dr. Harrison presented data on the same cohort combined with data on an additional cohort of 75 patients with well-compensated NASH cirrhosis and no prior history of decompensation.
 

‘Real-world’ conditions

In an attempt to mimic real-world conditions, patients in the trial did not receive a baseline biopsy but were determined to have NASH or presumed NASH with either results of a previous liver biopsy or noninvasive techniques, including FibroScan and MRI-PDFF.

Patients were started on oral resmetirom 80 mg daily, which could be titrated upward to 100 mg daily based on pharmacokinetic data from a 2-week sample.

The investigators first compared reductions in liver enzymes in both cohorts, with median reductions in ALT, AST, and gamma-glutamyl transferase of –20%, –18%, and –32%, respectively, in the original cohort, and –30%, –23%, and –37% in the more recent cohort.

Reductions in other parameters, including MRI-PDFF, liver volume, and lipids were also similar between the cohorts.

Given the similarities, researchers opted to treat the second cohort as a validation set, and combined data from the two cohorts to look at additional differences between baseline and 1-year follow-up.

Looking at imaging biomarkers in the combined cohorts of patients with responses, they saw that of patients with at least a 25% change over baseline in FibroScan VCTE, 48% of patients with baseline PDFF of 5% or less, and 42% of those with baseline PDFF greater than 5% had significant improvement at 1 year.

Among patients with changes in MR elastography of at least 15%, a fifth (22%) of those with baseline PDFF of 5% or less and about a quarter (26%) with baseline PDFF greater than 5% had improvement.

Independent of baseline cirrhosis severity, 73% of patients had a 15% or greater reduction in liver volume after 52 weeks of resmetirom. The investigators did not find a correlation of liver reduction with MRI-PDFF reduction among patients with PDFF of 5% or less at baseline.

The study found similar reductions in harmful lipids across all patient subgroups in both cohorts. Decreases in both systolic and diastolic blood pressure consistent with those seen in noncirrhotic NASH patients were also seen, independent of cirrhosis severity.

Among patients with at least a 10% change in spleen volume, 31% of those with low baseline PDFF readings and 45% of those with high readings had a decrease in volume.

The investigators found no differences in adverse events between cirrhosis severity groups or compared with noncirrhotic NASH patients.

The most common adverse events were intermittent loose stools or nausea at start of resmetirom therapy, and most were mild.

There were no changes in the central thyroid axis, apart from about a 10% decrease in prohormone FT4, which had been reported in other studies of resmetirom. No changes in active hormone FT3 or thyroid-stimulating hormone were found.

Although the study did not have a placebo control, it supports the rationale for the ongoing MAESTRO-NASH Outcomes trial, an event-driven trial comparing outcomes with resmetirom versus placebo in patients with well-compensated Child-Pugh A NASH cirrhosis, Dr. Harrison concluded.
 

Encouraging data

The data on resmetirom look promising as an approach to the treatment of NASH and related diseases, Cyrielle Caussy, MD, PhD, from the University Hospital of Lyon (France), said in an interview. Dr. Caussy, who was not involved in the study, was a moderator of the session where Dr. Harrison presented the data.

It does seem to be beneficial in NASH, she said. But we also have seen improvements in lipid metabolism with this drug; as shown in Dr. Harrison’s presentation, there is a difference in cardiovascular risk factors, Dr. Caussy added.

“I do think it could be one of the drugs that really improves outcomes for patients with NASH,” Dr. Caussy said.

The study was supported by Madrigal Pharmaceuticals. Dr. Harrison reported conflict of interest with numerous pharmaceutical companies.

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

Noninvasive ultrasound- and serum-based fibrosis biomarkers have similar prognostic performance to histology for nonalcoholic fatty liver disease (NAFLD), according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.

“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”

Noninvasive ultrasound- and serum-based fibrosis biomarkers have similar prognostic performance to histology for nonalcoholic fatty liver disease (NAFLD), according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.

“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”

Noninvasive ultrasound- and serum-based fibrosis biomarkers have similar prognostic performance to histology for nonalcoholic fatty liver disease (NAFLD), according to new findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

Fibrosis stages and liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE) through FibroScan were significant predictors of event-free survival, said Ferenc Mozes, DPhil, a postdoctoral research assistant at the University of Oxford, England, who has worked on biomarker evaluation of nonalcoholic steatohepatitis (NASH) as a member of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) consortium.

“Liver histology is highly prognostic of liver-related outcomes in patients with NAFLD and NASH,” he said. “Not just that, but liver histology is also accepted, and furthermore mandated by the FDA, as a surrogate endpoint in pharmaceutical trials for NASH.”

A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.

“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”

Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.

Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.

Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.

All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.

“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”

Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.

The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.

The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.

The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.

The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.

In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.

Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.

“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”

Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.

“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”

The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
 

A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.

“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”

Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.

Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.

Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.

All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.

“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”

Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.

The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.

The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.

The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.

The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.

In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.

Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.

“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”

Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.

“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”

The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
 

A low-carbohydrate diet appears to be an effective weight-loss intervention in liver transplant recipients with obesity as compared with a calorie-restrictive diet, according to interim findings presented at the annual meeting of the American Association for the Study of Liver Diseases.

In particular, the intervention showed significant improvements in the metabophenotype profile, including visceral adipose tissue and abdominal subcutaneous adipose tissue, said Mohammad Siddiqui, MD, a gastroenterologist and liver transplant specialist at Virginia Commonwealth University, Richmond.

“Weight gain and obesity after liver transplantation is common,” he said. “Posttransplant obesity is associated with increased cardiometabolic risk burden, increased risk of cardiovascular disease and mortality, and overall mortality.”

Previously, Dr. Siddiqui and colleagues have shown that posttransplant weight loss is difficult because of metabolic inflexibility and mitochondrial inefficiency. By specifically targeting carbohydrate utilization, metabolic flexibility could be restored in liver transplant recipients, he noted.

Dr. Siddiqui and colleagues conducted a randomized controlled trial of 27 adult liver transplant recipients with obesity for 24 weeks. The primary endpoint was change in weight, and the secondary endpoints involved metabophenotype, metabolic flexibility, mitochondrial function, and metabolic risk. The research team excluded patients with end-stage disease, terminal disease, use of weight-loss medications, pregnancy, or uncontrolled psychiatric illness that could interfere with adherence.

Among the participants, 13 were randomized to a calorie restrictive diet of less than 1,200-1,500 calories per day, and 14 were randomized to a low-carbohydrate diet of 20 grams or less per day. At enrollment, the participants underwent dietary, activity, skeletal muscle, and body composition assessments, as well as metabophenotype measurements of visceral adipose tissue, abdominal subcutaneous adipose tissue, muscle fat infiltration, fat-free muscle volume, and proton density fat fraction.

All participants were advised to maintain the same level of physical activity, which was measured through 7-day accelerometry. In addition, the patients were contacted every 2 weeks throughout the 24-week study period.

“We wanted to reinforce the dietary advice. We wanted to identify factors that may lead to compliance,” Dr. Siddiqui said. “Multiple studies have documented that the more contact that patients have during weight-loss studies with medical personnel, the more effective those strategies are.”

Overall, the dietary interventions were well tolerated, and neither group showed a significant change in renal function.

The average weight loss was –7.6 kg over 6 months in the low-carbohydrate group, as compared with –0.6 kg in the calorie-restrictive group.

The low carbohydrate diet also positively affected participants’ metabophenotype profile, particularly fat deposits. As compared with the calorie-restrictive group, the low-carbohydrate group showed statistically significant improvements in visceral adipose tissue, abdominal subcutaneous adipose tissue, and muscle fat infiltration.

The liver proton density fat fraction, which is associated with fatty liver disease, decreased by 0.53% in the low-carbohydrate group and increased by 0.46% in the calorie-restrictive group, but the difference didn’t reach statistical significance.

The fat-free muscle volume decreased by about 5% in the low-carbohydrate group. Dr. Siddiqui noted that the researchers don’t know yet whether this translates to a decrease in muscle function.

In terms of metabolic risk, the low-carbohydrate diet did not affect serum lipids (such as triglycerides or cholesterol measures), renal function (such as serum creatinine, glomerular filtration rate, or blood urea nitrogen), or insulin resistance (through glucose or hemoglobin A1c). At the same time, among patients taking insulin at the time of enrollment, about 90% of patients randomized to the low-carbohydrate group were able to reduce insulin to zero during the study.

Upon completion of the current study, Dr. Siddiqui and colleagues hope to provide foundational safety and efficacy data for carbohydrate restriction in liver transplant recipients. In the ongoing study, the researchers are further investigating the dietary intervention impacts on metabolic flexibility, skeletal muscle mitochondrial function, atherogenic lipoproteins, and vascular function.

“Are we actually, on a molecular level, fixing the fundamental problem that liver transplant recipients have to improve outcomes?” he said. “We’re doing very detailed profiling of these patients, so we will have data that shows how this actually affects them.”

Dr. Siddiqui was asked about the sustainability of the low-carbohydrate diet, particularly with a restrictive parameter of 20 grams per day. During the COVID-19 pandemic, Dr. Siddiqui noted, the study was slowed and the research team was able to collect follow-up data.

“Surprisingly, we have a high rate of compliance, even after 6 months of therapy, and I think this has to do with a patient population that’s been through cirrhosis and has almost died,” he said. “They’re far more compliant, and we’re seeing that. We’re also changing the physiology and improving mitochondrial function, which improves the weight loss and weight maintenance, though I don’t know how long that’s going to last.”

The study sponsorship was not disclosed. Dr. Siddiqui reported no relevant conflicts of interest.
 

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

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

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

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

The U.S. Food and Drug Administration (FDA) has declined to approve bulevirtide, Gilead Sciences’ drug for the treatment of hepatitis delta virus (HDV) infection and compensated liver disease.

In a complete response letter, the FDA voiced concerns over the production and delivery of bulevirtide, an investigational, first-in-class HDV entry-inhibitor that received conditional approved in Europe in 2020.

The FDA did not request new studies to evaluate the safety and efficacy of bulevirtide.

As reported previously by this news organization, data from an ongoing phase 3 trial showed that after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable HDV RNA levels and normalized alanine aminotransferase levels.

Chronic HDV infection is the most severe form of viral hepatitis. It is associated with a poor prognosis and high mortality rates.

There are currently no approved treatments for HDV in the United States. Bulevirtide was granted breakthrough therapy and orphan drug designations by the FDA.

Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, wrote in a news release that the company looks forward to “continuing our active discussions with FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”

This is the second manufacturing-related complete response letter Gilead has received in the past 8 months. In March, the FDA rejected the long-acting HIV drug lenacapavir. The drug was sanctioned in Europe and the United Kingdom in September.

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

CHARLOTTE, N.C. – Metabolic and genetic risk factors for nonalcoholic fatty liver disease (NAFLD) vary across the age spectrum, but once steatosis has started, the risk of progression to cirrhosis is similar for both young and old, investigators found.

At a large Midwest medical center, younger adults were more likely than older patients to have a high-risk gene variant predisposing carriers to NAFLD. And they were less likely than their senior counterparts to have metabolic risk factors, reported Matthew J. Miller, MD, a 3rd-year resident in the department of internal medicine at the University of Michigan Hospital in Ann Arbor.

“Progression to cirrhosis was similar in patients younger than 40, compared to older patients, suggesting NAFLD in the young should not be considered more benign than in older patients,” he said in an oral abstract presented at the annual meeting of the American College of Gastroenterology.

MDedge News/Neil Osterweil

The prevalence of NAFLD among younger adults is increasing, but it’s still unknown whether the course of NAFLD is more benign in these patients than in older adults.

In addition, the rate of progression to cirrhosis in patients with NAFLD can vary, making it difficult to predict those patients most at risk for advanced liver disease, Dr. Miller said.

He and his colleagues sought to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression in patients from 18 to 40 years, 40 to 59 years, and 60 and older.

The investigators collected data on patients with documented objective evidence of NAFLD seen at the Michigan Medicine health care system from 2010 through 2021.

They identified NAFLD by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases, with the earliest date of a hepatic steatosis diagnosis determined to be the index date.

The investigators determined the presence of cirrhosis using validated International Classification of Diseases version 9 or 10 codes, with incident cirrhosis defined as any new cirrhosis diagnosis at least 1 year after the index date.

They also looked at the frequency of known NAFLD risk alleles in a subset of patients with available genetic data.

They divided 31,505 patients into three age groups for comparison: 8,252 patients age 18-39 at the time of steatosis identification, 15,035 age 40-59, and 8,218 age 60 or older.

Of the full cohort, 804 had cirrhosis at the index date, and 388 others developed incident cirrhosis during 128,090 person-years of follow-up.

The prevalence of hypertension, hyperlipidemia, and diabetes were significantly lower in the youngest group, compared with the two older groups, but the youngest patients had a higher prevalence of obesity than the other two groups, with a significantly higher prevalence of class 3 (morbid) obesity.

Of the 4,359 patients with genetic data available, the NAFLD-promoting PNPLA3-rs738409-G allele was more common in the young, compared with the other two age groups (P = .016).

When the investigators looked at the ability of three laboratory tests – the AST to Platelet Ratio Index (APRI), Fibrosis-4 (FIB4), and NAFLD fibrosis score for identifying prevalent cirrhosis – they found that the scores performed similarly for patients in the 40-59 group, but the NFS did less well among patients in the 18-39 group. There were no significant differences among the three age groups in the risk for incident cirrhosis over 10 years.

The study helps to answer some of the questions surrounding differences in risk factors across the age spectrum, commented Patricia Jones, MD, MSCR, from the University of Miami.

“We wonder how these people with fatty liver are different. Do younger people have a more malignant course? Are they going to progress more rapidly than others, or not? Because if you think of a disease like fatty liver or for that matter any metabolic syndrome–based disease, it’s a spectrum and a continuum, and by the time you’re diagnosed you’ve already had that condition, so it’s really more interesting to me when people are diagnosed, because diagnosing at a younger age allows you to intervene earlier,” she said in an interview.

Dr. Jones said that she was also interested in exploring how the genetic data might be used to improve care for patients, perhaps by testing for the high-risk allele in routine clinical practice.

“It will be interesting to see how people with this allele progress, independently of whether they’re diagnosed at 40, 50, or 60,” she said.

Dr. Jones was a moderator of the session where Dr. Williams presented his data.

Comoderator Mitchell A. Mah’moud, MD, FACG from Duke University in Durham, N.C., commented in an interview that, “with the medications we have available, maybe we can target these patients and prevent progression to cirrhosis and some of the decompensation that we see.”

The study authors did not disclose a funding source. Dr. Miller, Dr. Jones, and Dr. Mah’moud all reported having no relevant financial disclosures.

CHARLOTTE, N.C. – Metabolic and genetic risk factors for nonalcoholic fatty liver disease (NAFLD) vary across the age spectrum, but once steatosis has started, the risk of progression to cirrhosis is similar for both young and old, investigators found.

At a large Midwest medical center, younger adults were more likely than older patients to have a high-risk gene variant predisposing carriers to NAFLD. And they were less likely than their senior counterparts to have metabolic risk factors, reported Matthew J. Miller, MD, a 3rd-year resident in the department of internal medicine at the University of Michigan Hospital in Ann Arbor.

“Progression to cirrhosis was similar in patients younger than 40, compared to older patients, suggesting NAFLD in the young should not be considered more benign than in older patients,” he said in an oral abstract presented at the annual meeting of the American College of Gastroenterology.

MDedge News/Neil Osterweil

The prevalence of NAFLD among younger adults is increasing, but it’s still unknown whether the course of NAFLD is more benign in these patients than in older adults.

In addition, the rate of progression to cirrhosis in patients with NAFLD can vary, making it difficult to predict those patients most at risk for advanced liver disease, Dr. Miller said.

He and his colleagues sought to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression in patients from 18 to 40 years, 40 to 59 years, and 60 and older.

The investigators collected data on patients with documented objective evidence of NAFLD seen at the Michigan Medicine health care system from 2010 through 2021.

They identified NAFLD by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases, with the earliest date of a hepatic steatosis diagnosis determined to be the index date.

The investigators determined the presence of cirrhosis using validated International Classification of Diseases version 9 or 10 codes, with incident cirrhosis defined as any new cirrhosis diagnosis at least 1 year after the index date.

They also looked at the frequency of known NAFLD risk alleles in a subset of patients with available genetic data.

They divided 31,505 patients into three age groups for comparison: 8,252 patients age 18-39 at the time of steatosis identification, 15,035 age 40-59, and 8,218 age 60 or older.

Of the full cohort, 804 had cirrhosis at the index date, and 388 others developed incident cirrhosis during 128,090 person-years of follow-up.

The prevalence of hypertension, hyperlipidemia, and diabetes were significantly lower in the youngest group, compared with the two older groups, but the youngest patients had a higher prevalence of obesity than the other two groups, with a significantly higher prevalence of class 3 (morbid) obesity.

Of the 4,359 patients with genetic data available, the NAFLD-promoting PNPLA3-rs738409-G allele was more common in the young, compared with the other two age groups (P = .016).

When the investigators looked at the ability of three laboratory tests – the AST to Platelet Ratio Index (APRI), Fibrosis-4 (FIB4), and NAFLD fibrosis score for identifying prevalent cirrhosis – they found that the scores performed similarly for patients in the 40-59 group, but the NFS did less well among patients in the 18-39 group. There were no significant differences among the three age groups in the risk for incident cirrhosis over 10 years.

The study helps to answer some of the questions surrounding differences in risk factors across the age spectrum, commented Patricia Jones, MD, MSCR, from the University of Miami.

“We wonder how these people with fatty liver are different. Do younger people have a more malignant course? Are they going to progress more rapidly than others, or not? Because if you think of a disease like fatty liver or for that matter any metabolic syndrome–based disease, it’s a spectrum and a continuum, and by the time you’re diagnosed you’ve already had that condition, so it’s really more interesting to me when people are diagnosed, because diagnosing at a younger age allows you to intervene earlier,” she said in an interview.

Dr. Jones said that she was also interested in exploring how the genetic data might be used to improve care for patients, perhaps by testing for the high-risk allele in routine clinical practice.

“It will be interesting to see how people with this allele progress, independently of whether they’re diagnosed at 40, 50, or 60,” she said.

Dr. Jones was a moderator of the session where Dr. Williams presented his data.

Comoderator Mitchell A. Mah’moud, MD, FACG from Duke University in Durham, N.C., commented in an interview that, “with the medications we have available, maybe we can target these patients and prevent progression to cirrhosis and some of the decompensation that we see.”

The study authors did not disclose a funding source. Dr. Miller, Dr. Jones, and Dr. Mah’moud all reported having no relevant financial disclosures.

CHARLOTTE, N.C. – Metabolic and genetic risk factors for nonalcoholic fatty liver disease (NAFLD) vary across the age spectrum, but once steatosis has started, the risk of progression to cirrhosis is similar for both young and old, investigators found.

At a large Midwest medical center, younger adults were more likely than older patients to have a high-risk gene variant predisposing carriers to NAFLD. And they were less likely than their senior counterparts to have metabolic risk factors, reported Matthew J. Miller, MD, a 3rd-year resident in the department of internal medicine at the University of Michigan Hospital in Ann Arbor.

“Progression to cirrhosis was similar in patients younger than 40, compared to older patients, suggesting NAFLD in the young should not be considered more benign than in older patients,” he said in an oral abstract presented at the annual meeting of the American College of Gastroenterology.

MDedge News/Neil Osterweil

The prevalence of NAFLD among younger adults is increasing, but it’s still unknown whether the course of NAFLD is more benign in these patients than in older adults.

In addition, the rate of progression to cirrhosis in patients with NAFLD can vary, making it difficult to predict those patients most at risk for advanced liver disease, Dr. Miller said.

He and his colleagues sought to characterize genetic and metabolic risk factors for NAFLD and their effects on disease progression in patients from 18 to 40 years, 40 to 59 years, and 60 and older.

The investigators collected data on patients with documented objective evidence of NAFLD seen at the Michigan Medicine health care system from 2010 through 2021.

They identified NAFLD by hepatic steatosis on imaging, biopsy, or transient elastography in the absence of other chronic liver diseases, with the earliest date of a hepatic steatosis diagnosis determined to be the index date.

The investigators determined the presence of cirrhosis using validated International Classification of Diseases version 9 or 10 codes, with incident cirrhosis defined as any new cirrhosis diagnosis at least 1 year after the index date.

They also looked at the frequency of known NAFLD risk alleles in a subset of patients with available genetic data.

They divided 31,505 patients into three age groups for comparison: 8,252 patients age 18-39 at the time of steatosis identification, 15,035 age 40-59, and 8,218 age 60 or older.

Of the full cohort, 804 had cirrhosis at the index date, and 388 others developed incident cirrhosis during 128,090 person-years of follow-up.

The prevalence of hypertension, hyperlipidemia, and diabetes were significantly lower in the youngest group, compared with the two older groups, but the youngest patients had a higher prevalence of obesity than the other two groups, with a significantly higher prevalence of class 3 (morbid) obesity.

Of the 4,359 patients with genetic data available, the NAFLD-promoting PNPLA3-rs738409-G allele was more common in the young, compared with the other two age groups (P = .016).

When the investigators looked at the ability of three laboratory tests – the AST to Platelet Ratio Index (APRI), Fibrosis-4 (FIB4), and NAFLD fibrosis score for identifying prevalent cirrhosis – they found that the scores performed similarly for patients in the 40-59 group, but the NFS did less well among patients in the 18-39 group. There were no significant differences among the three age groups in the risk for incident cirrhosis over 10 years.

The study helps to answer some of the questions surrounding differences in risk factors across the age spectrum, commented Patricia Jones, MD, MSCR, from the University of Miami.

“We wonder how these people with fatty liver are different. Do younger people have a more malignant course? Are they going to progress more rapidly than others, or not? Because if you think of a disease like fatty liver or for that matter any metabolic syndrome–based disease, it’s a spectrum and a continuum, and by the time you’re diagnosed you’ve already had that condition, so it’s really more interesting to me when people are diagnosed, because diagnosing at a younger age allows you to intervene earlier,” she said in an interview.

Dr. Jones said that she was also interested in exploring how the genetic data might be used to improve care for patients, perhaps by testing for the high-risk allele in routine clinical practice.

“It will be interesting to see how people with this allele progress, independently of whether they’re diagnosed at 40, 50, or 60,” she said.

Dr. Jones was a moderator of the session where Dr. Williams presented his data.

Comoderator Mitchell A. Mah’moud, MD, FACG from Duke University in Durham, N.C., commented in an interview that, “with the medications we have available, maybe we can target these patients and prevent progression to cirrhosis and some of the decompensation that we see.”

The study authors did not disclose a funding source. Dr. Miller, Dr. Jones, and Dr. Mah’moud all reported having no relevant financial disclosures.

The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.

“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.

“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.

Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
 

Vulnerable group

The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.

Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).

A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).

NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).

ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.

Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.

COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
 

Blame it on lockdowns?

Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.

“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.

“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.

The study had no specific funding. The authors report no relevant financial relationships.

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

The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.

“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.

“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.

Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
 

Vulnerable group

The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.

Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).

A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).

NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).

ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.

Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.

COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
 

Blame it on lockdowns?

Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.

“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.

“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.

The study had no specific funding. The authors report no relevant financial relationships.

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

The COVID-19 pandemic fueled a sharp uptick in deaths related to chronic liver disease and cirrhosis among people with diabetes, largely owing to nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), new data show.

“Our observations confirm that COVID-19 had a higher likelihood of impacting vulnerable populations with pre-existing chronic liver diseases and diabetes, with a death rate as high as 10% in individuals with co-existing chronic liver disease and diabetes,” write the authors.

“The inability to attend regular outpatient clinics for close monitoring and treatment accompanied by diversion of health care resources to COVID-19 care may have resulted in the suboptimal or delayed clinical care of individuals with diabetes and chronic liver disease during the COVID-19 pandemic,” they add.

Donghee Kim, MD, PhD, with the Division of Gastroenterology and Hepatology, Stanford (Calif.) University School of Medicine, and colleagues report their findings in the journal Digestive and Liver Disease.
 

Vulnerable group

The researchers used U.S. national mortality data (2017-2020) to estimate chronic liver disease–related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.

Before the pandemic, the quarterly mortality for chronic liver disease remained stable (quarterly percentage change, 0.6%) but then sharply increased during the pandemic (QPC, 8.6%).

A similar trend was seen with cirrhosis-related mortality (QPC, 0.3% before the pandemic vs. 8.4% during the pandemic).

NAFLD and ALD mortality among individuals with diabetes was steadily increasing before the pandemic (QPC, 4.2% and 3.5%, respectively) but showed a more rapid increase during the pandemic (QPC, 9.6% and 7.7%, respectively).

ALD-related mortality in men was more than threefold higher than in women, while NAFLD-related mortality in women was more than twofold higher than in men.

Mortality for hepatitis C virus infection declined before the pandemic (QPC, −3.3%) and remained stable during the pandemic.

COVID-19–related mortality among adults with chronic liver disease and diabetes also rose sharply during the pandemic – from 0.4% in the first quarter of 2020 to 12.9% in the last quarter of 2020 – with no considerable difference between men and women.
 

Blame it on lockdowns?

Dr. Kim and colleagues say research is needed to better understand the direct and indirect influence of COVID-19 on coexisting chronic liver disease and diabetes.

“It is plausible that psychosocial stress and a higher predisposition to psychiatric disorders during the COVID-19 pandemic can increase the risk of alcohol use disorder and ALD,” they write.

“Furthermore, it is prudent to suspect that COVID-19–related lockdowns may increase the risk of obesity, leading to a higher risk of insulin resistance and metabolic complications, including diabetes and NAFLD. Future studies are needed to improve our understanding of these possible pathogenetic links. More importantly, emergency preparedness or contingency plans must be in place to continue and provide uninterrupted care for chronic ailments during times of disaster,” they add.

The study had no specific funding. The authors report no relevant financial relationships.

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

Adults with obesity who do not respond adequately to lifestyle interventions alone should be offered one of four suggested medications to treat obesity, with preference for semaglutide before others, according to new guidelines published by the American Gastroenterological Association in Gastroenterology.

Recommended first-line medications include semaglutide, liraglutide, phentermine-topiramate extended-release (ER), and naltrexone-buproprion ER, based on moderate-certainty evidence. Also recommended, albeit based on lower-certainty evidence, are phentermine and diethylpropion. The guidelines suggest avoiding use of orlistat. Evidence was insufficient for Gelesis100 superabsorbent hydrogel.

The substantial increase in obesity prevalence in the United States – from 30.5% to 41.9% in just the 2 decades from 2000 to 2020 – has likely contributed to increases in various obesity-related complications, wrote Eduardo Grunvald, MD, of the University of California San Diego, and colleagues. These include cardiovascular disease, stroke, type 2 diabetes mellitus, nonalcoholic steatohepatitis, obstructive sleep apnea, osteoarthritis, and certain types of cancer, such as colorectal cancer.

“Lifestyle intervention is the foundation in the management of obesity, but it has limited effectiveness and durability for most individuals,” the authors wrote. Despite a range of highly effective pharmacological therapies developed for long-term management of obesity, these agents are not widely used in routine clinical care, and practice variability is wide. There is a “small number of providers responsible for more than 90% of the prescriptions, partly due to lack of familiarity and limited access and insurance coverage,” the authors wrote.

A multidisciplinary panel of 10 experts and one patient representative, therefore, developed the guidelines by first prioritizing key clinical questions, identifying patient-centered outcomes, and conducting an evidence review of the following interventions: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 superabsorbent hydrogel. The guideline panel then developed management recommendations and provided clinical practice considerations regarding each of the pharmacologic interventions.

The authors focused on adults, noting that pharmacologic treatment of childhood obesity is beyond the scope of these guidelines. The evidence synthesis yielded nine recommendations for the pharmacological management of obesity by gastroenterologists, primary care clinicians, endocrinologists, and other providers caring for patients with overweight or obesity. The target audience of the guidelines, however, includes patients and policymakers, the authors wrote.

“These guidelines are not intended to impose a standard of care, but rather, they provide the basis for rational, informed decisions for patients and health care professionals,” the authors wrote. “No recommendation can include all the unique individual circumstances that must be considered when making recommendations for individual patients. However, discussions around benefits and harms can be used for shared decision-making, especially for conditional recommendations where patients’ values and preferences are important to consider.”

The panel conducted a systematic review and meta-analysis of randomized controlled trials of Food and Drug Administration–approved obesity medications through Jan. 1, 2022. Though they primarily included studies with at least 48 weeks follow-up, they included studies with a follow-up of less than a year if one with 48 weeks’ outcomes did not exist.

The first of the nine recommendations was to add pharmacological agents to lifestyle interventions in treating adults with obesity or overweight and weight-related complications who have not adequately responded to lifestyle interventions alone. This strong recommendation was based on moderate-certainty evidence.

“Antiobesity medications generally need to be used chronically, and the selection of the medication or intervention should be based on the clinical profile and needs of the patient, including, but not limited to, comorbidities, patients’ preferences, costs, and access to the therapy,” the authors wrote. Average difference in total body weight loss with the addition of medication to lifestyle interventions was 3%-10.8%, depending on the drug. Treatment discontinuation ranged from 34 to 219 per 1,000 people in treatment groups, but adverse event rates were low.

The panel’s second recommendation suggested prioritizing of semaglutide along with lifestyle interventions based on the large magnitude of its net benefit. The remaining recommendations describes the use of each of the other medications based on their respective magnitude of effect and risk for adverse events.

Important considerations

“These medications treat a biological disease, not a lifestyle problem,” Dr. Grunvald said in a prepared statement. “Obesity is a disease that often does not respond to lifestyle interventions alone in the long term. Using medications as an option to assist with weight loss can improve weight-related complications like joint pain, diabetes, fatty liver, and hypertension.”

The authors acknowledged that cost remains a concern for the use of these therapies, especially among vulnerable populations. They also noted that the medications should not be used in pregnant individuals or those with bulimia nervosa, and they should be used with caution in people with other eating disorders. Patients with type 2 diabetes taking insulin or sulfonylureas and patients taking antihypertensives may require dosage adjustments since these obesity medications may increase risk of hypoglycemia for the former and decrease blood pressure for the latter.

The panel advised against orlistat, although it added that ”patients who place a high value on the potential small weight loss benefit and low value on gastrointestinal side effects may reasonably choose treatment with orlistat.” Those patients should take a multivitamin daily that contains vitamins A, D, E, and K at least 2 hours apart from orlistat.

The lack of available evidence for Gelesis100 oral superabsorbent hydrogel led the panel to suggest its use only in the context of a clinical trial.

The AGA will update these guidelines no later than 2025 and may issue rapid guidance updates until then as new evidence comes to light.

The guidelines did not receive any external funding, being fully funded by the AGA. The guideline chair and guideline methodologists had no relevant or direct conflicts of interest. All conflict of interest disclosures are maintained by the AGA office.

Adults with obesity who do not respond adequately to lifestyle interventions alone should be offered one of four suggested medications to treat obesity, with preference for semaglutide before others, according to new guidelines published by the American Gastroenterological Association in Gastroenterology.

Recommended first-line medications include semaglutide, liraglutide, phentermine-topiramate extended-release (ER), and naltrexone-buproprion ER, based on moderate-certainty evidence. Also recommended, albeit based on lower-certainty evidence, are phentermine and diethylpropion. The guidelines suggest avoiding use of orlistat. Evidence was insufficient for Gelesis100 superabsorbent hydrogel.

The substantial increase in obesity prevalence in the United States – from 30.5% to 41.9% in just the 2 decades from 2000 to 2020 – has likely contributed to increases in various obesity-related complications, wrote Eduardo Grunvald, MD, of the University of California San Diego, and colleagues. These include cardiovascular disease, stroke, type 2 diabetes mellitus, nonalcoholic steatohepatitis, obstructive sleep apnea, osteoarthritis, and certain types of cancer, such as colorectal cancer.

“Lifestyle intervention is the foundation in the management of obesity, but it has limited effectiveness and durability for most individuals,” the authors wrote. Despite a range of highly effective pharmacological therapies developed for long-term management of obesity, these agents are not widely used in routine clinical care, and practice variability is wide. There is a “small number of providers responsible for more than 90% of the prescriptions, partly due to lack of familiarity and limited access and insurance coverage,” the authors wrote.

A multidisciplinary panel of 10 experts and one patient representative, therefore, developed the guidelines by first prioritizing key clinical questions, identifying patient-centered outcomes, and conducting an evidence review of the following interventions: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 superabsorbent hydrogel. The guideline panel then developed management recommendations and provided clinical practice considerations regarding each of the pharmacologic interventions.

The authors focused on adults, noting that pharmacologic treatment of childhood obesity is beyond the scope of these guidelines. The evidence synthesis yielded nine recommendations for the pharmacological management of obesity by gastroenterologists, primary care clinicians, endocrinologists, and other providers caring for patients with overweight or obesity. The target audience of the guidelines, however, includes patients and policymakers, the authors wrote.

“These guidelines are not intended to impose a standard of care, but rather, they provide the basis for rational, informed decisions for patients and health care professionals,” the authors wrote. “No recommendation can include all the unique individual circumstances that must be considered when making recommendations for individual patients. However, discussions around benefits and harms can be used for shared decision-making, especially for conditional recommendations where patients’ values and preferences are important to consider.”

The panel conducted a systematic review and meta-analysis of randomized controlled trials of Food and Drug Administration–approved obesity medications through Jan. 1, 2022. Though they primarily included studies with at least 48 weeks follow-up, they included studies with a follow-up of less than a year if one with 48 weeks’ outcomes did not exist.

The first of the nine recommendations was to add pharmacological agents to lifestyle interventions in treating adults with obesity or overweight and weight-related complications who have not adequately responded to lifestyle interventions alone. This strong recommendation was based on moderate-certainty evidence.

“Antiobesity medications generally need to be used chronically, and the selection of the medication or intervention should be based on the clinical profile and needs of the patient, including, but not limited to, comorbidities, patients’ preferences, costs, and access to the therapy,” the authors wrote. Average difference in total body weight loss with the addition of medication to lifestyle interventions was 3%-10.8%, depending on the drug. Treatment discontinuation ranged from 34 to 219 per 1,000 people in treatment groups, but adverse event rates were low.

The panel’s second recommendation suggested prioritizing of semaglutide along with lifestyle interventions based on the large magnitude of its net benefit. The remaining recommendations describes the use of each of the other medications based on their respective magnitude of effect and risk for adverse events.

Important considerations

“These medications treat a biological disease, not a lifestyle problem,” Dr. Grunvald said in a prepared statement. “Obesity is a disease that often does not respond to lifestyle interventions alone in the long term. Using medications as an option to assist with weight loss can improve weight-related complications like joint pain, diabetes, fatty liver, and hypertension.”

The authors acknowledged that cost remains a concern for the use of these therapies, especially among vulnerable populations. They also noted that the medications should not be used in pregnant individuals or those with bulimia nervosa, and they should be used with caution in people with other eating disorders. Patients with type 2 diabetes taking insulin or sulfonylureas and patients taking antihypertensives may require dosage adjustments since these obesity medications may increase risk of hypoglycemia for the former and decrease blood pressure for the latter.

The panel advised against orlistat, although it added that ”patients who place a high value on the potential small weight loss benefit and low value on gastrointestinal side effects may reasonably choose treatment with orlistat.” Those patients should take a multivitamin daily that contains vitamins A, D, E, and K at least 2 hours apart from orlistat.

The lack of available evidence for Gelesis100 oral superabsorbent hydrogel led the panel to suggest its use only in the context of a clinical trial.

The AGA will update these guidelines no later than 2025 and may issue rapid guidance updates until then as new evidence comes to light.

The guidelines did not receive any external funding, being fully funded by the AGA. The guideline chair and guideline methodologists had no relevant or direct conflicts of interest. All conflict of interest disclosures are maintained by the AGA office.

Adults with obesity who do not respond adequately to lifestyle interventions alone should be offered one of four suggested medications to treat obesity, with preference for semaglutide before others, according to new guidelines published by the American Gastroenterological Association in Gastroenterology.

Recommended first-line medications include semaglutide, liraglutide, phentermine-topiramate extended-release (ER), and naltrexone-buproprion ER, based on moderate-certainty evidence. Also recommended, albeit based on lower-certainty evidence, are phentermine and diethylpropion. The guidelines suggest avoiding use of orlistat. Evidence was insufficient for Gelesis100 superabsorbent hydrogel.

The substantial increase in obesity prevalence in the United States – from 30.5% to 41.9% in just the 2 decades from 2000 to 2020 – has likely contributed to increases in various obesity-related complications, wrote Eduardo Grunvald, MD, of the University of California San Diego, and colleagues. These include cardiovascular disease, stroke, type 2 diabetes mellitus, nonalcoholic steatohepatitis, obstructive sleep apnea, osteoarthritis, and certain types of cancer, such as colorectal cancer.

“Lifestyle intervention is the foundation in the management of obesity, but it has limited effectiveness and durability for most individuals,” the authors wrote. Despite a range of highly effective pharmacological therapies developed for long-term management of obesity, these agents are not widely used in routine clinical care, and practice variability is wide. There is a “small number of providers responsible for more than 90% of the prescriptions, partly due to lack of familiarity and limited access and insurance coverage,” the authors wrote.

A multidisciplinary panel of 10 experts and one patient representative, therefore, developed the guidelines by first prioritizing key clinical questions, identifying patient-centered outcomes, and conducting an evidence review of the following interventions: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 superabsorbent hydrogel. The guideline panel then developed management recommendations and provided clinical practice considerations regarding each of the pharmacologic interventions.

The authors focused on adults, noting that pharmacologic treatment of childhood obesity is beyond the scope of these guidelines. The evidence synthesis yielded nine recommendations for the pharmacological management of obesity by gastroenterologists, primary care clinicians, endocrinologists, and other providers caring for patients with overweight or obesity. The target audience of the guidelines, however, includes patients and policymakers, the authors wrote.

“These guidelines are not intended to impose a standard of care, but rather, they provide the basis for rational, informed decisions for patients and health care professionals,” the authors wrote. “No recommendation can include all the unique individual circumstances that must be considered when making recommendations for individual patients. However, discussions around benefits and harms can be used for shared decision-making, especially for conditional recommendations where patients’ values and preferences are important to consider.”

The panel conducted a systematic review and meta-analysis of randomized controlled trials of Food and Drug Administration–approved obesity medications through Jan. 1, 2022. Though they primarily included studies with at least 48 weeks follow-up, they included studies with a follow-up of less than a year if one with 48 weeks’ outcomes did not exist.

The first of the nine recommendations was to add pharmacological agents to lifestyle interventions in treating adults with obesity or overweight and weight-related complications who have not adequately responded to lifestyle interventions alone. This strong recommendation was based on moderate-certainty evidence.

“Antiobesity medications generally need to be used chronically, and the selection of the medication or intervention should be based on the clinical profile and needs of the patient, including, but not limited to, comorbidities, patients’ preferences, costs, and access to the therapy,” the authors wrote. Average difference in total body weight loss with the addition of medication to lifestyle interventions was 3%-10.8%, depending on the drug. Treatment discontinuation ranged from 34 to 219 per 1,000 people in treatment groups, but adverse event rates were low.

The panel’s second recommendation suggested prioritizing of semaglutide along with lifestyle interventions based on the large magnitude of its net benefit. The remaining recommendations describes the use of each of the other medications based on their respective magnitude of effect and risk for adverse events.

Important considerations

“These medications treat a biological disease, not a lifestyle problem,” Dr. Grunvald said in a prepared statement. “Obesity is a disease that often does not respond to lifestyle interventions alone in the long term. Using medications as an option to assist with weight loss can improve weight-related complications like joint pain, diabetes, fatty liver, and hypertension.”

The authors acknowledged that cost remains a concern for the use of these therapies, especially among vulnerable populations. They also noted that the medications should not be used in pregnant individuals or those with bulimia nervosa, and they should be used with caution in people with other eating disorders. Patients with type 2 diabetes taking insulin or sulfonylureas and patients taking antihypertensives may require dosage adjustments since these obesity medications may increase risk of hypoglycemia for the former and decrease blood pressure for the latter.

The panel advised against orlistat, although it added that ”patients who place a high value on the potential small weight loss benefit and low value on gastrointestinal side effects may reasonably choose treatment with orlistat.” Those patients should take a multivitamin daily that contains vitamins A, D, E, and K at least 2 hours apart from orlistat.

The lack of available evidence for Gelesis100 oral superabsorbent hydrogel led the panel to suggest its use only in the context of a clinical trial.

The AGA will update these guidelines no later than 2025 and may issue rapid guidance updates until then as new evidence comes to light.

The guidelines did not receive any external funding, being fully funded by the AGA. The guideline chair and guideline methodologists had no relevant or direct conflicts of interest. All conflict of interest disclosures are maintained by the AGA office.

Increasing mentorship opportunities for gastroenterology and hepatology residents and medical students from populations underrepresented in medicine is essential to increase diversity in the specialty and improve health disparities among patients, according to a special report published simultaneously in Gastroenterology and three other journals.

“This study helps to establish priorities for diversity, equity and inclusion in our field and informs future interventions to improve workforce diversity and eliminate health care disparities among the patients we serve,” Folasade P. May, MD, PhD, MPhil, the study’s corresponding author and an associate professor of medicine at the University of California, Los Angeles, said in a prepared statement.

The report, the result of a partnership between researchers at UCLA and the Intersociety Group on Diversity, reveals the findings of a survey aimed at assessing current perspectives on individuals underrepresented in medicine and health equity within gastroenterology and hepatology. The collaboration involved five gastroenterology professional societies: the American Association for the Study of Liver Disease; American College of Gastroenterology; American Gastroenterological Association; American Society of Gastrointestinal Endoscopy; and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

”The current racial and ethnic composition of the GI and hepatology workforce does not reflect the population of patients served or the current matriculants in medicine,” Harman K. Rahal, MD, of UCLA and Cedars-Sinai Medical Center, Los Angeles, and James H. Tabibian, MD, PhD, of UCLA and Olive View–UCLA Medical Center, and colleagues wrote. “As there are several conditions in GI and hepatology with disparities in incidence, treatment, and outcomes, representation of UIM [underrepresented in medicine] individuals is critical to address health disparities.”

The term “underrepresented in medicine” is defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.” The authors explained that these groups “have traditionally included Latino (i.e., Latino/a/x), Black (or African American), Native American (namely, American Indian, Alaska Native, and Native Hawaiian), Pacific Islander, and mainland Puerto Rican individuals.”

The five gastroenterology and hepatology societies partnered with investigators at UCLA to develop a 33-question electronic survey “to determine perspectives of current racial, ethnic, and gender diversity within GI and hepatology; to assess current views on interventions needed to increase racial, ethnic, and gender diversity in the field; and to collect data on the experiences of UIM individuals and women in our field,” according to the report’s authors. The survey was then distributed to members of those societies, with 1,219 respondents.

The report found that inadequate representation of people from those underrepresented groups in the education and training pipeline was the most frequently reported barrier to improving racial and ethnic diversity in the field (35.4%), followed by insufficient racial and ethnic minority group representation in professional leadership (27.9%) and insufficient racial and ethnic minority group representation among practicing GI and hepatology professionals in the workplace (26.6%). Only 9% of fellows in GI and hepatology are from groups underrepresented in medicine, according to data from the Accreditation Council for Graduate Medical Education. Furthermore, one study has shown that the proportion of UIM in academic faculty has never exceeded 10% at each academic rank; there has even been a decline recently among junior academic faculty positions. That study also found that only 9% of academic gastroenterologists in the United states identify as underrepresented in medicine, with little change over the last decade.

Potential contributors to this low level of representation, the authors wrote, include “lack of racial and ethnic diversity in the medical training pipeline, nondiverse leadership, bias, racial discrimination, and the notion that UIM physicians may be less likely to promote themselves or be promoted.”

Another potential contributor, however, may be complacency within the field about the need to improve diversity and taking actions to do so.

Increasing mentorship opportunities for gastroenterology and hepatology residents and medical students from populations underrepresented in medicine is essential to increase diversity in the specialty and improve health disparities among patients, according to a special report published simultaneously in Gastroenterology and three other journals.

“This study helps to establish priorities for diversity, equity and inclusion in our field and informs future interventions to improve workforce diversity and eliminate health care disparities among the patients we serve,” Folasade P. May, MD, PhD, MPhil, the study’s corresponding author and an associate professor of medicine at the University of California, Los Angeles, said in a prepared statement.

The report, the result of a partnership between researchers at UCLA and the Intersociety Group on Diversity, reveals the findings of a survey aimed at assessing current perspectives on individuals underrepresented in medicine and health equity within gastroenterology and hepatology. The collaboration involved five gastroenterology professional societies: the American Association for the Study of Liver Disease; American College of Gastroenterology; American Gastroenterological Association; American Society of Gastrointestinal Endoscopy; and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

”The current racial and ethnic composition of the GI and hepatology workforce does not reflect the population of patients served or the current matriculants in medicine,” Harman K. Rahal, MD, of UCLA and Cedars-Sinai Medical Center, Los Angeles, and James H. Tabibian, MD, PhD, of UCLA and Olive View–UCLA Medical Center, and colleagues wrote. “As there are several conditions in GI and hepatology with disparities in incidence, treatment, and outcomes, representation of UIM [underrepresented in medicine] individuals is critical to address health disparities.”

The term “underrepresented in medicine” is defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.” The authors explained that these groups “have traditionally included Latino (i.e., Latino/a/x), Black (or African American), Native American (namely, American Indian, Alaska Native, and Native Hawaiian), Pacific Islander, and mainland Puerto Rican individuals.”

The five gastroenterology and hepatology societies partnered with investigators at UCLA to develop a 33-question electronic survey “to determine perspectives of current racial, ethnic, and gender diversity within GI and hepatology; to assess current views on interventions needed to increase racial, ethnic, and gender diversity in the field; and to collect data on the experiences of UIM individuals and women in our field,” according to the report’s authors. The survey was then distributed to members of those societies, with 1,219 respondents.

The report found that inadequate representation of people from those underrepresented groups in the education and training pipeline was the most frequently reported barrier to improving racial and ethnic diversity in the field (35.4%), followed by insufficient racial and ethnic minority group representation in professional leadership (27.9%) and insufficient racial and ethnic minority group representation among practicing GI and hepatology professionals in the workplace (26.6%). Only 9% of fellows in GI and hepatology are from groups underrepresented in medicine, according to data from the Accreditation Council for Graduate Medical Education. Furthermore, one study has shown that the proportion of UIM in academic faculty has never exceeded 10% at each academic rank; there has even been a decline recently among junior academic faculty positions. That study also found that only 9% of academic gastroenterologists in the United states identify as underrepresented in medicine, with little change over the last decade.

Potential contributors to this low level of representation, the authors wrote, include “lack of racial and ethnic diversity in the medical training pipeline, nondiverse leadership, bias, racial discrimination, and the notion that UIM physicians may be less likely to promote themselves or be promoted.”

Another potential contributor, however, may be complacency within the field about the need to improve diversity and taking actions to do so.

Increasing mentorship opportunities for gastroenterology and hepatology residents and medical students from populations underrepresented in medicine is essential to increase diversity in the specialty and improve health disparities among patients, according to a special report published simultaneously in Gastroenterology and three other journals.

“This study helps to establish priorities for diversity, equity and inclusion in our field and informs future interventions to improve workforce diversity and eliminate health care disparities among the patients we serve,” Folasade P. May, MD, PhD, MPhil, the study’s corresponding author and an associate professor of medicine at the University of California, Los Angeles, said in a prepared statement.

The report, the result of a partnership between researchers at UCLA and the Intersociety Group on Diversity, reveals the findings of a survey aimed at assessing current perspectives on individuals underrepresented in medicine and health equity within gastroenterology and hepatology. The collaboration involved five gastroenterology professional societies: the American Association for the Study of Liver Disease; American College of Gastroenterology; American Gastroenterological Association; American Society of Gastrointestinal Endoscopy; and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition.

”The current racial and ethnic composition of the GI and hepatology workforce does not reflect the population of patients served or the current matriculants in medicine,” Harman K. Rahal, MD, of UCLA and Cedars-Sinai Medical Center, Los Angeles, and James H. Tabibian, MD, PhD, of UCLA and Olive View–UCLA Medical Center, and colleagues wrote. “As there are several conditions in GI and hepatology with disparities in incidence, treatment, and outcomes, representation of UIM [underrepresented in medicine] individuals is critical to address health disparities.”

The term “underrepresented in medicine” is defined by the Association of American Medical Colleges as “those racial and ethnic populations that are underrepresented in the medical profession relative to their numbers in the general population.” The authors explained that these groups “have traditionally included Latino (i.e., Latino/a/x), Black (or African American), Native American (namely, American Indian, Alaska Native, and Native Hawaiian), Pacific Islander, and mainland Puerto Rican individuals.”

The five gastroenterology and hepatology societies partnered with investigators at UCLA to develop a 33-question electronic survey “to determine perspectives of current racial, ethnic, and gender diversity within GI and hepatology; to assess current views on interventions needed to increase racial, ethnic, and gender diversity in the field; and to collect data on the experiences of UIM individuals and women in our field,” according to the report’s authors. The survey was then distributed to members of those societies, with 1,219 respondents.

The report found that inadequate representation of people from those underrepresented groups in the education and training pipeline was the most frequently reported barrier to improving racial and ethnic diversity in the field (35.4%), followed by insufficient racial and ethnic minority group representation in professional leadership (27.9%) and insufficient racial and ethnic minority group representation among practicing GI and hepatology professionals in the workplace (26.6%). Only 9% of fellows in GI and hepatology are from groups underrepresented in medicine, according to data from the Accreditation Council for Graduate Medical Education. Furthermore, one study has shown that the proportion of UIM in academic faculty has never exceeded 10% at each academic rank; there has even been a decline recently among junior academic faculty positions. That study also found that only 9% of academic gastroenterologists in the United states identify as underrepresented in medicine, with little change over the last decade.

Potential contributors to this low level of representation, the authors wrote, include “lack of racial and ethnic diversity in the medical training pipeline, nondiverse leadership, bias, racial discrimination, and the notion that UIM physicians may be less likely to promote themselves or be promoted.”

Another potential contributor, however, may be complacency within the field about the need to improve diversity and taking actions to do so.

The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).

HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.

Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.

The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.

Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.

Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.

The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).

To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.

The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).

Results of the CONFIRM trial were published in The New England Journal of Medicine.

“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.

“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.

The company plans to launch the product in the coming weeks.

The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

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

The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).

HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.

Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.

The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.

Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.

Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.

The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).

To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.

The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).

Results of the CONFIRM trial were published in The New England Journal of Medicine.

“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.

“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.

The company plans to launch the product in the coming weeks.

The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

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

The Food and Drug Administration has approved terlipressin (Terlivaz), the first and only drug approved for patients with hepatorenal syndrome (HRS).

HRS is characterized by progressive deterioration in kidney function in people with advanced liver disease.

Terlipressin is an injectable synthetic vasopressin analogue indicated for patients with HRS who are experiencing rapid deterioration of kidney function (type 1 HRS). The condition affects an estimated 35,000 Americans annually.

The safety and efficacy of terlipressin for type 1 HRS was assessed in the phase 3 CONFIRM trial, which involved 300 patients in the United States and Canada.

Patients received an injection of terlipressin (0.85 mg) or placebo every 6 hours for a maximum of 14 days. The dose was adjusted on the basis of changes in kidney function.

Twenty-nine percent of patients in the terlipressin group experienced improvement in kidney function, vs. 16% in the placebo group.

The CONFIRM trial met its primary endpoint of verified HRS reversal, defined as renal function improvement, avoidance of dialysis, and short-term survival (P = .012).

To achieve this endpoint, patients had to have two consecutive serum creatinine (SCr) values of ≤ 1.5 mg/dL at least 2 hours apart by day 14 or be discharged from the hospital.

The most commonly observed adverse reactions that occurred in at least 4% of patients treated with terlipressin were abdominal pain (19.5%), nausea (16%), respiratory failure (15.5%), diarrhea (13%), and dyspnea (12.5%).

Results of the CONFIRM trial were published in The New England Journal of Medicine.

“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” said Steven Romano, MD, executive vice president and chief scientific officer at Mallinckrodt, which makes the drug.

“Terlivaz gives physicians the first FDA-approved option for treating HRS patients with rapid reduction in kidney function that may help them improve kidney function and lessen the associated need for renal replacement therapy, such as dialysis,” Dr. Romano said.

The company plans to launch the product in the coming weeks.

The application for terlipressin for HRS was granted priority review and fast-track status, as well as orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

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