Liam Davenport

Proposed updates to the tumor-node-metastasis (TNM) classification for lung cancer will affect the way patients are staged, experts say.

The updates for the 9th edition of the TNM Classification of Malignant Tumors: Lung Cancer were presented at the annual World Conference on Lung Cancer. The final version will be published Jan. 1, 2024.

The core proposed change, according to Hisao Asamura, MD, chair of the IASLC Staging and Prognostic Factors Committee, is to divide N2 and M1c disease into two subcategories, while leaving the T descriptors unchanged.

This update is based on large survival differences among patients with these tumor characteristics, following an analysis of outcomes in more than 87,000 individuals diagnosed with lung cancer.

Session cochair Ramón Rami-Porta, MD, PhD, explained that previous editions of the classification were based on “pathologic stage, not clinical stage” but ultimately “we could not validate those findings” clinically.

“This is the first time that some sort of very simple quantification” of lung tumors “could be validated at the clinical stage as well,” which means that clinical staging can improve all over the world, said Dr. Rami-Porta, medical oncologist at Hospital Universitari Mútua Terrassa (Spain).

Session cochair Paul Van Schil, MD, PhD, of Antwerp (the Netherlands) University Hospital explained that the proposed changes reflect what clinicians already see in their daily practice.

The latest TNM classification included data submitted on 124,581 patients diagnosed with lung cancer between 2011 and 2019, 56% of whom were from Asia/Australia, 25% from Europe, and 16% from North America.

Overall, 87,339 patients were included in the analysis – 83% with non–small cell lung cancer (NSCLC) and 7% with small cell lung cancer (SCLC). Most (62%) underwent surgery, either alone (47%), alongside chemotherapy (13%), or plus radiotherapy (2%). A minority (13%) received chemotherapy alone, and 13% received all three modalities.

The committee working on the update to the TNM classification had 112 members and comprised 14 subcommittees, which focused on different aspects of diagnosing and assessing the disease.

The committee agreed there should be no changes to the T category in the upcoming 9th Edition.

Evaluating the T category, some members expressed concern that patients with T3 disease embedded in the chest wall have worse survival outcomes than those with other forms of T3 disease. But, Dr. Asamura explained, the pathological versus clinical findings were inconsistent.

On pathological assessment, patients with T3 disease in the chest wall had a worse prognosis but clinical assessment indicated no survival difference. Given the lack of consensus, “we do not recommend any changes” to the current criteria, said Dr. Asamura.

Turning to the N category, Dr. Asamura explained that N2 disease will be divided into two subcategories: N2a, categorized by single N2 station involvement, and N2b, defined as multiple N2 station involvement.

Further analysis indicated that the estimated 5-year survival was significantly worse for patients with N2b disease on clinical assessment (31% vs. 42% with N2a disease; hazard ratio for death, 1.27; P < .0001) and on pathological assessment (HR, 1.46; P < .0001).

The committee also proposed a change to the M category, dividing M1c disease into two subcategories:

• M1c1 – defined as multiple extrathoracic metastases in a single organ system
• M1c2 – defined as multiple extrathoracic metastases in multiple organ systems

This change was driven by estimates of 5-year survival among patients with M1c1 (27%) versus M1c2 disease (19%). Compared with M1b disease, M1c1 was associated with a lower risk for death than M1c2 disease (HR, 1.27 vs. 1.39).

These changes, particularly those for the N category, will have a notable impact on how patients are staged, Dr. Asamura said.

Dividing the N2 category into N2a and N2b disease will push patients with T1, N1 disease from the IIB category (8th edition) to the IIA category (9th edition). The 8th edition categorized all T1, N2 patients as IIIA but the new edition would categorize patients with T1, N2a disease as IIB overall and those with N2b disease as IIIA. And patients with T2, N2a disease will be staged as IIIA — the same category as T2, N2 disease in the 8th edition – while those with N2b disease will be staged as IIIB.

By contrast, the division of M1c into M1c1 and M1c2 disease will not affect a patient’s overall stage, which will be IVB in all cases.

Upal Basu Roy, PhD, MPH, who was not part of the committee, said the TNM classification stage of cancers is “incredibly important in cataloguing the extent of disease” and to “decide the optimal treatment option.”

TNM classification is also “used to describe the burden of disease to be eligible for a clinical trial,” said Dr. Roy, executive director of research, LUNGevity Foundation, Chicago.

The changes in N staging may require sampling more lymph nodes than the current sampling frame of six, Dr. Roy said, adding that “surgeons and pathologists may need to be educated about the need for additional sampling.”

The subcategories for M1c disease will also need to be aligned with definitions of oligometastatic disease. “This is critical,” Dr. Roy said, as this staging may affect treatment choices.

No funding was declared. Dr. Asamura declares relationships with Medtronic, Taiho Pharmaceutical, Johnson & Johnson, Lily, Astellas, and Ono Pharmaceutical. Dr. Roy declared no relevant financial relationships.

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

Proposed updates to the tumor-node-metastasis (TNM) classification for lung cancer will affect the way patients are staged, experts say.

The updates for the 9th edition of the TNM Classification of Malignant Tumors: Lung Cancer were presented at the annual World Conference on Lung Cancer. The final version will be published Jan. 1, 2024.

The core proposed change, according to Hisao Asamura, MD, chair of the IASLC Staging and Prognostic Factors Committee, is to divide N2 and M1c disease into two subcategories, while leaving the T descriptors unchanged.

This update is based on large survival differences among patients with these tumor characteristics, following an analysis of outcomes in more than 87,000 individuals diagnosed with lung cancer.

Session cochair Ramón Rami-Porta, MD, PhD, explained that previous editions of the classification were based on “pathologic stage, not clinical stage” but ultimately “we could not validate those findings” clinically.

“This is the first time that some sort of very simple quantification” of lung tumors “could be validated at the clinical stage as well,” which means that clinical staging can improve all over the world, said Dr. Rami-Porta, medical oncologist at Hospital Universitari Mútua Terrassa (Spain).

Session cochair Paul Van Schil, MD, PhD, of Antwerp (the Netherlands) University Hospital explained that the proposed changes reflect what clinicians already see in their daily practice.

The latest TNM classification included data submitted on 124,581 patients diagnosed with lung cancer between 2011 and 2019, 56% of whom were from Asia/Australia, 25% from Europe, and 16% from North America.

Overall, 87,339 patients were included in the analysis – 83% with non–small cell lung cancer (NSCLC) and 7% with small cell lung cancer (SCLC). Most (62%) underwent surgery, either alone (47%), alongside chemotherapy (13%), or plus radiotherapy (2%). A minority (13%) received chemotherapy alone, and 13% received all three modalities.

The committee working on the update to the TNM classification had 112 members and comprised 14 subcommittees, which focused on different aspects of diagnosing and assessing the disease.

The committee agreed there should be no changes to the T category in the upcoming 9th Edition.

Evaluating the T category, some members expressed concern that patients with T3 disease embedded in the chest wall have worse survival outcomes than those with other forms of T3 disease. But, Dr. Asamura explained, the pathological versus clinical findings were inconsistent.

On pathological assessment, patients with T3 disease in the chest wall had a worse prognosis but clinical assessment indicated no survival difference. Given the lack of consensus, “we do not recommend any changes” to the current criteria, said Dr. Asamura.

Turning to the N category, Dr. Asamura explained that N2 disease will be divided into two subcategories: N2a, categorized by single N2 station involvement, and N2b, defined as multiple N2 station involvement.

Further analysis indicated that the estimated 5-year survival was significantly worse for patients with N2b disease on clinical assessment (31% vs. 42% with N2a disease; hazard ratio for death, 1.27; P < .0001) and on pathological assessment (HR, 1.46; P < .0001).

The committee also proposed a change to the M category, dividing M1c disease into two subcategories:

• M1c1 – defined as multiple extrathoracic metastases in a single organ system
• M1c2 – defined as multiple extrathoracic metastases in multiple organ systems

This change was driven by estimates of 5-year survival among patients with M1c1 (27%) versus M1c2 disease (19%). Compared with M1b disease, M1c1 was associated with a lower risk for death than M1c2 disease (HR, 1.27 vs. 1.39).

These changes, particularly those for the N category, will have a notable impact on how patients are staged, Dr. Asamura said.

Dividing the N2 category into N2a and N2b disease will push patients with T1, N1 disease from the IIB category (8th edition) to the IIA category (9th edition). The 8th edition categorized all T1, N2 patients as IIIA but the new edition would categorize patients with T1, N2a disease as IIB overall and those with N2b disease as IIIA. And patients with T2, N2a disease will be staged as IIIA — the same category as T2, N2 disease in the 8th edition – while those with N2b disease will be staged as IIIB.

By contrast, the division of M1c into M1c1 and M1c2 disease will not affect a patient’s overall stage, which will be IVB in all cases.

Upal Basu Roy, PhD, MPH, who was not part of the committee, said the TNM classification stage of cancers is “incredibly important in cataloguing the extent of disease” and to “decide the optimal treatment option.”

TNM classification is also “used to describe the burden of disease to be eligible for a clinical trial,” said Dr. Roy, executive director of research, LUNGevity Foundation, Chicago.

The changes in N staging may require sampling more lymph nodes than the current sampling frame of six, Dr. Roy said, adding that “surgeons and pathologists may need to be educated about the need for additional sampling.”

The subcategories for M1c disease will also need to be aligned with definitions of oligometastatic disease. “This is critical,” Dr. Roy said, as this staging may affect treatment choices.

No funding was declared. Dr. Asamura declares relationships with Medtronic, Taiho Pharmaceutical, Johnson & Johnson, Lily, Astellas, and Ono Pharmaceutical. Dr. Roy declared no relevant financial relationships.

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

Proposed updates to the tumor-node-metastasis (TNM) classification for lung cancer will affect the way patients are staged, experts say.

The updates for the 9th edition of the TNM Classification of Malignant Tumors: Lung Cancer were presented at the annual World Conference on Lung Cancer. The final version will be published Jan. 1, 2024.

The core proposed change, according to Hisao Asamura, MD, chair of the IASLC Staging and Prognostic Factors Committee, is to divide N2 and M1c disease into two subcategories, while leaving the T descriptors unchanged.

This update is based on large survival differences among patients with these tumor characteristics, following an analysis of outcomes in more than 87,000 individuals diagnosed with lung cancer.

Session cochair Ramón Rami-Porta, MD, PhD, explained that previous editions of the classification were based on “pathologic stage, not clinical stage” but ultimately “we could not validate those findings” clinically.

“This is the first time that some sort of very simple quantification” of lung tumors “could be validated at the clinical stage as well,” which means that clinical staging can improve all over the world, said Dr. Rami-Porta, medical oncologist at Hospital Universitari Mútua Terrassa (Spain).

Session cochair Paul Van Schil, MD, PhD, of Antwerp (the Netherlands) University Hospital explained that the proposed changes reflect what clinicians already see in their daily practice.

The latest TNM classification included data submitted on 124,581 patients diagnosed with lung cancer between 2011 and 2019, 56% of whom were from Asia/Australia, 25% from Europe, and 16% from North America.

Overall, 87,339 patients were included in the analysis – 83% with non–small cell lung cancer (NSCLC) and 7% with small cell lung cancer (SCLC). Most (62%) underwent surgery, either alone (47%), alongside chemotherapy (13%), or plus radiotherapy (2%). A minority (13%) received chemotherapy alone, and 13% received all three modalities.

The committee working on the update to the TNM classification had 112 members and comprised 14 subcommittees, which focused on different aspects of diagnosing and assessing the disease.

The committee agreed there should be no changes to the T category in the upcoming 9th Edition.

Evaluating the T category, some members expressed concern that patients with T3 disease embedded in the chest wall have worse survival outcomes than those with other forms of T3 disease. But, Dr. Asamura explained, the pathological versus clinical findings were inconsistent.

On pathological assessment, patients with T3 disease in the chest wall had a worse prognosis but clinical assessment indicated no survival difference. Given the lack of consensus, “we do not recommend any changes” to the current criteria, said Dr. Asamura.

Turning to the N category, Dr. Asamura explained that N2 disease will be divided into two subcategories: N2a, categorized by single N2 station involvement, and N2b, defined as multiple N2 station involvement.

Further analysis indicated that the estimated 5-year survival was significantly worse for patients with N2b disease on clinical assessment (31% vs. 42% with N2a disease; hazard ratio for death, 1.27; P < .0001) and on pathological assessment (HR, 1.46; P < .0001).

The committee also proposed a change to the M category, dividing M1c disease into two subcategories:

• M1c1 – defined as multiple extrathoracic metastases in a single organ system
• M1c2 – defined as multiple extrathoracic metastases in multiple organ systems

This change was driven by estimates of 5-year survival among patients with M1c1 (27%) versus M1c2 disease (19%). Compared with M1b disease, M1c1 was associated with a lower risk for death than M1c2 disease (HR, 1.27 vs. 1.39).

These changes, particularly those for the N category, will have a notable impact on how patients are staged, Dr. Asamura said.

Dividing the N2 category into N2a and N2b disease will push patients with T1, N1 disease from the IIB category (8th edition) to the IIA category (9th edition). The 8th edition categorized all T1, N2 patients as IIIA but the new edition would categorize patients with T1, N2a disease as IIB overall and those with N2b disease as IIIA. And patients with T2, N2a disease will be staged as IIIA — the same category as T2, N2 disease in the 8th edition – while those with N2b disease will be staged as IIIB.

By contrast, the division of M1c into M1c1 and M1c2 disease will not affect a patient’s overall stage, which will be IVB in all cases.

Upal Basu Roy, PhD, MPH, who was not part of the committee, said the TNM classification stage of cancers is “incredibly important in cataloguing the extent of disease” and to “decide the optimal treatment option.”

TNM classification is also “used to describe the burden of disease to be eligible for a clinical trial,” said Dr. Roy, executive director of research, LUNGevity Foundation, Chicago.

The changes in N staging may require sampling more lymph nodes than the current sampling frame of six, Dr. Roy said, adding that “surgeons and pathologists may need to be educated about the need for additional sampling.”

The subcategories for M1c disease will also need to be aligned with definitions of oligometastatic disease. “This is critical,” Dr. Roy said, as this staging may affect treatment choices.

No funding was declared. Dr. Asamura declares relationships with Medtronic, Taiho Pharmaceutical, Johnson & Johnson, Lily, Astellas, and Ono Pharmaceutical. Dr. Roy declared no relevant financial relationships.

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

Adding platinum-based chemotherapy to osimertinib (Tagrisso) in the first-line treatment of EGFR-mutated advanced non–small cell lung cancer (NSCLC) improved progression-free survival (PFS), according to interim results from the FLAURA2 trial.

Combining the third-generation tyrosine kinase inhibitor (TKI) with platinum-based chemotherapy achieved “statistically significant and clinically meaningful improvement in PFS over osimertinib monotherapy,” said Pasi A. Jänne, MD, PhD, professor of medicine at Harvard Medical School and director of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, both in Boston, who presented the interim findings at the annual World Conference on Lung Cancer.

However, experts raised some questions about whether the combination would also offer improved overall survival and whether the accompanying toxicity would be acceptable to patients.

Yi-Long Wu, MD, PhD, who was not involved in the research, said that although the combination regimen does appear to offer a benefit, it may come at a steep cost.

Patients who received the combination had an almost fourfold greater risk of grade 3 or higher adverse events related to treatment, said Dr. Wu, professor of oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

And, notably, because the overall survival data in the interim analysis are immature, it’s unclear whether the combination will offer an overall survival benefit over osimertinib monotherapy, Dr. Wu said.

The 2019 FLAURA trial, which compared TKI monotherapy, demonstrated an overall survival advantage among patients who received osimertinib vs. a first-generation EGFR TKI, such as gefitinib (Iressa) or erlotinib (Tarceva). These data established the third-generation TKI as the preferred first-line treatment for patients with advanced EGFR NSCLC.

But resistance to EGFR TKIs remains a problem, which has led experts to explore combination strategies that might overcome resistance and improve clinical outcomes. Recent data indicate that combining first-generation EGFR TKIs with chemotherapy may have an additive effect and further improve outcomes with the drugs. And a recent study of untreated EGFR-mutated advanced NSCLC found patients receiving osimertinib plus platinum-pemetrexed demonstrated a promising objective response rate; however, Dr. Jänne noted that the combination has not been tested in a randomized trial.

To better understand the potential additive benefit of osimertinib and chemotherapy, the team conduced a global, open-label study in patients with pathologically confirmed nonsquamous NSCLC who had received no prior systemic therapy for advanced NSCLC and had a performance status of 0 or 1.

The team randomly assigned 557 patients to daily osimertinib alone or osimertinib plus chemotherapy with pemetrexed and carboplatin or cisplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed every 3 weeks.

Treatment was continued until radiological disease progression, as defined using the RECIST 1.1 criteria, or other withdrawal criteria were met. The patients were assessed at weeks 6 and 12, and again every 12 weeks.

The median age of the patients was about 61 years, approximately 61% were female, and about 25% were Asian. Around two-thirds were never-smokers, about 60% had either Ex19del or L858R EGFR mutations, and about 40% had central nervous system metastases.

At the data cutoff, the median follow-up was 16.5 months in the osimertinib monotherapy arm and 19.5 months in the combination arm. Overall, 45% of patients on monotherapy and 56% in the combination arm were still on treatment.

Dr. Jänne reported that osimertinib plus chemotherapy was associated with a greater objective response rate than monotherapy – 83.2% vs. 75.5% – and a longer median duration of response – 24 months vs. 15.3 months.

Patients receiving the combination showed significant improvements in PFS – 25.5 months vs. 16.7 months (hazard ratio, 0.62; P < .0001). At 24 months, 57% of the patients in the combination arm were disease-free vs. 41% in the monotherapy group.

The benefit held across all patient subgroups, including age, sex, smoking history, and EGFR mutation type at baseline.

The PFS benefit appeared most pronounced among patients with CNS metastases at baseline – a median of 24.9 months in the combination arm vs. 13.8 months with monotherapy (HR, 0.47). But patients without CNS metastases who received the combination therapy also showed improvements in PFS (HR, 0.75).

Should there be an overall survival improvement, then the regimen used in FLAURA2 could become the “new standard of care in EGFR-mutated NSCLC in the first-line setting,” particularly in patients with CNS metastases and/or an exon21 mutation, Dr. Wu said. If, however, further analysis indicates no overall survival benefit, then patients will have experienced chemotherapy side effects earlier and longer than those receiving monotherapy, with no life gain.

Dr. Wu pointed out that the future role and sequence of the combination will also hinge on understanding how patients become resistant to it as well as whether the toxicity is manageable.

The FLAURA2 safety data indicated that the combination led to higher rates of grade 3 or higher adverse events overall – 64% vs. 27% – and higher rates of grade 3 or higher adverse events possibly related to treatment – 53% vs. 11%.

Experts who commented on the study findings via X (formerly Twitter) echoed Dr. Wu’s sentiments about the study findings and implications.

Mohana Roy, MD, said she did not find the results surprising, given that “many of us are adding chemo on slow progression on osimertinib already,” but noted that “questions of sequencing” remain.

Christian Rolfo, MD, PhD, MBA, commented that questions about the “real benefit” of osimertinib plus chemotherapy in subgroups and degree of resistance remain. Further toxicity and overall survival data “will clarify the future of the combination,” said Dr. Rolfo, of Icahn School of Medicine at Mount Sinai, New York.

The study was funded by AstraZeneca. Dr. Jänne declared relationships with Gatekeeper Pharmaceuticals, Labcorp, Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Revolution Medicines, Takeda Oncology, Biocartis, Mirati Therapeutics, Transcenta, ACEA Biosciences, Araxes, Bayer, Chugai Pharmaceuticals, Eisai, Ignyta, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, and Voronoi.

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

Adding platinum-based chemotherapy to osimertinib (Tagrisso) in the first-line treatment of EGFR-mutated advanced non–small cell lung cancer (NSCLC) improved progression-free survival (PFS), according to interim results from the FLAURA2 trial.

Combining the third-generation tyrosine kinase inhibitor (TKI) with platinum-based chemotherapy achieved “statistically significant and clinically meaningful improvement in PFS over osimertinib monotherapy,” said Pasi A. Jänne, MD, PhD, professor of medicine at Harvard Medical School and director of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, both in Boston, who presented the interim findings at the annual World Conference on Lung Cancer.

However, experts raised some questions about whether the combination would also offer improved overall survival and whether the accompanying toxicity would be acceptable to patients.

Yi-Long Wu, MD, PhD, who was not involved in the research, said that although the combination regimen does appear to offer a benefit, it may come at a steep cost.

Patients who received the combination had an almost fourfold greater risk of grade 3 or higher adverse events related to treatment, said Dr. Wu, professor of oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

And, notably, because the overall survival data in the interim analysis are immature, it’s unclear whether the combination will offer an overall survival benefit over osimertinib monotherapy, Dr. Wu said.

The 2019 FLAURA trial, which compared TKI monotherapy, demonstrated an overall survival advantage among patients who received osimertinib vs. a first-generation EGFR TKI, such as gefitinib (Iressa) or erlotinib (Tarceva). These data established the third-generation TKI as the preferred first-line treatment for patients with advanced EGFR NSCLC.

But resistance to EGFR TKIs remains a problem, which has led experts to explore combination strategies that might overcome resistance and improve clinical outcomes. Recent data indicate that combining first-generation EGFR TKIs with chemotherapy may have an additive effect and further improve outcomes with the drugs. And a recent study of untreated EGFR-mutated advanced NSCLC found patients receiving osimertinib plus platinum-pemetrexed demonstrated a promising objective response rate; however, Dr. Jänne noted that the combination has not been tested in a randomized trial.

To better understand the potential additive benefit of osimertinib and chemotherapy, the team conduced a global, open-label study in patients with pathologically confirmed nonsquamous NSCLC who had received no prior systemic therapy for advanced NSCLC and had a performance status of 0 or 1.

The team randomly assigned 557 patients to daily osimertinib alone or osimertinib plus chemotherapy with pemetrexed and carboplatin or cisplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed every 3 weeks.

Treatment was continued until radiological disease progression, as defined using the RECIST 1.1 criteria, or other withdrawal criteria were met. The patients were assessed at weeks 6 and 12, and again every 12 weeks.

The median age of the patients was about 61 years, approximately 61% were female, and about 25% were Asian. Around two-thirds were never-smokers, about 60% had either Ex19del or L858R EGFR mutations, and about 40% had central nervous system metastases.

At the data cutoff, the median follow-up was 16.5 months in the osimertinib monotherapy arm and 19.5 months in the combination arm. Overall, 45% of patients on monotherapy and 56% in the combination arm were still on treatment.

Dr. Jänne reported that osimertinib plus chemotherapy was associated with a greater objective response rate than monotherapy – 83.2% vs. 75.5% – and a longer median duration of response – 24 months vs. 15.3 months.

Patients receiving the combination showed significant improvements in PFS – 25.5 months vs. 16.7 months (hazard ratio, 0.62; P < .0001). At 24 months, 57% of the patients in the combination arm were disease-free vs. 41% in the monotherapy group.

The benefit held across all patient subgroups, including age, sex, smoking history, and EGFR mutation type at baseline.

The PFS benefit appeared most pronounced among patients with CNS metastases at baseline – a median of 24.9 months in the combination arm vs. 13.8 months with monotherapy (HR, 0.47). But patients without CNS metastases who received the combination therapy also showed improvements in PFS (HR, 0.75).

Should there be an overall survival improvement, then the regimen used in FLAURA2 could become the “new standard of care in EGFR-mutated NSCLC in the first-line setting,” particularly in patients with CNS metastases and/or an exon21 mutation, Dr. Wu said. If, however, further analysis indicates no overall survival benefit, then patients will have experienced chemotherapy side effects earlier and longer than those receiving monotherapy, with no life gain.

Dr. Wu pointed out that the future role and sequence of the combination will also hinge on understanding how patients become resistant to it as well as whether the toxicity is manageable.

The FLAURA2 safety data indicated that the combination led to higher rates of grade 3 or higher adverse events overall – 64% vs. 27% – and higher rates of grade 3 or higher adverse events possibly related to treatment – 53% vs. 11%.

Experts who commented on the study findings via X (formerly Twitter) echoed Dr. Wu’s sentiments about the study findings and implications.

Mohana Roy, MD, said she did not find the results surprising, given that “many of us are adding chemo on slow progression on osimertinib already,” but noted that “questions of sequencing” remain.

Christian Rolfo, MD, PhD, MBA, commented that questions about the “real benefit” of osimertinib plus chemotherapy in subgroups and degree of resistance remain. Further toxicity and overall survival data “will clarify the future of the combination,” said Dr. Rolfo, of Icahn School of Medicine at Mount Sinai, New York.

The study was funded by AstraZeneca. Dr. Jänne declared relationships with Gatekeeper Pharmaceuticals, Labcorp, Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Revolution Medicines, Takeda Oncology, Biocartis, Mirati Therapeutics, Transcenta, ACEA Biosciences, Araxes, Bayer, Chugai Pharmaceuticals, Eisai, Ignyta, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, and Voronoi.

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

Adding platinum-based chemotherapy to osimertinib (Tagrisso) in the first-line treatment of EGFR-mutated advanced non–small cell lung cancer (NSCLC) improved progression-free survival (PFS), according to interim results from the FLAURA2 trial.

Combining the third-generation tyrosine kinase inhibitor (TKI) with platinum-based chemotherapy achieved “statistically significant and clinically meaningful improvement in PFS over osimertinib monotherapy,” said Pasi A. Jänne, MD, PhD, professor of medicine at Harvard Medical School and director of the Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, both in Boston, who presented the interim findings at the annual World Conference on Lung Cancer.

However, experts raised some questions about whether the combination would also offer improved overall survival and whether the accompanying toxicity would be acceptable to patients.

Yi-Long Wu, MD, PhD, who was not involved in the research, said that although the combination regimen does appear to offer a benefit, it may come at a steep cost.

Patients who received the combination had an almost fourfold greater risk of grade 3 or higher adverse events related to treatment, said Dr. Wu, professor of oncology, Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

And, notably, because the overall survival data in the interim analysis are immature, it’s unclear whether the combination will offer an overall survival benefit over osimertinib monotherapy, Dr. Wu said.

The 2019 FLAURA trial, which compared TKI monotherapy, demonstrated an overall survival advantage among patients who received osimertinib vs. a first-generation EGFR TKI, such as gefitinib (Iressa) or erlotinib (Tarceva). These data established the third-generation TKI as the preferred first-line treatment for patients with advanced EGFR NSCLC.

But resistance to EGFR TKIs remains a problem, which has led experts to explore combination strategies that might overcome resistance and improve clinical outcomes. Recent data indicate that combining first-generation EGFR TKIs with chemotherapy may have an additive effect and further improve outcomes with the drugs. And a recent study of untreated EGFR-mutated advanced NSCLC found patients receiving osimertinib plus platinum-pemetrexed demonstrated a promising objective response rate; however, Dr. Jänne noted that the combination has not been tested in a randomized trial.

To better understand the potential additive benefit of osimertinib and chemotherapy, the team conduced a global, open-label study in patients with pathologically confirmed nonsquamous NSCLC who had received no prior systemic therapy for advanced NSCLC and had a performance status of 0 or 1.

The team randomly assigned 557 patients to daily osimertinib alone or osimertinib plus chemotherapy with pemetrexed and carboplatin or cisplatin every 3 weeks for four cycles, followed by maintenance osimertinib plus pemetrexed every 3 weeks.

Treatment was continued until radiological disease progression, as defined using the RECIST 1.1 criteria, or other withdrawal criteria were met. The patients were assessed at weeks 6 and 12, and again every 12 weeks.

The median age of the patients was about 61 years, approximately 61% were female, and about 25% were Asian. Around two-thirds were never-smokers, about 60% had either Ex19del or L858R EGFR mutations, and about 40% had central nervous system metastases.

At the data cutoff, the median follow-up was 16.5 months in the osimertinib monotherapy arm and 19.5 months in the combination arm. Overall, 45% of patients on monotherapy and 56% in the combination arm were still on treatment.

Dr. Jänne reported that osimertinib plus chemotherapy was associated with a greater objective response rate than monotherapy – 83.2% vs. 75.5% – and a longer median duration of response – 24 months vs. 15.3 months.

Patients receiving the combination showed significant improvements in PFS – 25.5 months vs. 16.7 months (hazard ratio, 0.62; P < .0001). At 24 months, 57% of the patients in the combination arm were disease-free vs. 41% in the monotherapy group.

The benefit held across all patient subgroups, including age, sex, smoking history, and EGFR mutation type at baseline.

The PFS benefit appeared most pronounced among patients with CNS metastases at baseline – a median of 24.9 months in the combination arm vs. 13.8 months with monotherapy (HR, 0.47). But patients without CNS metastases who received the combination therapy also showed improvements in PFS (HR, 0.75).

Should there be an overall survival improvement, then the regimen used in FLAURA2 could become the “new standard of care in EGFR-mutated NSCLC in the first-line setting,” particularly in patients with CNS metastases and/or an exon21 mutation, Dr. Wu said. If, however, further analysis indicates no overall survival benefit, then patients will have experienced chemotherapy side effects earlier and longer than those receiving monotherapy, with no life gain.

Dr. Wu pointed out that the future role and sequence of the combination will also hinge on understanding how patients become resistant to it as well as whether the toxicity is manageable.

The FLAURA2 safety data indicated that the combination led to higher rates of grade 3 or higher adverse events overall – 64% vs. 27% – and higher rates of grade 3 or higher adverse events possibly related to treatment – 53% vs. 11%.

Experts who commented on the study findings via X (formerly Twitter) echoed Dr. Wu’s sentiments about the study findings and implications.

Mohana Roy, MD, said she did not find the results surprising, given that “many of us are adding chemo on slow progression on osimertinib already,” but noted that “questions of sequencing” remain.

Christian Rolfo, MD, PhD, MBA, commented that questions about the “real benefit” of osimertinib plus chemotherapy in subgroups and degree of resistance remain. Further toxicity and overall survival data “will clarify the future of the combination,” said Dr. Rolfo, of Icahn School of Medicine at Mount Sinai, New York.

The study was funded by AstraZeneca. Dr. Jänne declared relationships with Gatekeeper Pharmaceuticals, Labcorp, Astellas Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, PUMA, Revolution Medicines, Takeda Oncology, Biocartis, Mirati Therapeutics, Transcenta, ACEA Biosciences, Araxes, Bayer, Chugai Pharmaceuticals, Eisai, Ignyta, Novartis, Nuvalent, Pfizer, Roche/Genentech, Sanofi, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, and Voronoi.

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

SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.

In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.

HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.

The results were simultaneously published in the Journal of Clinical Oncology.

Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.

And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.

HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.

HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.

After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.

Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”

The current findings focus on the 225 patients in the fixed-dose arm.

About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.

After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.

The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.

Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.

To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.

Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.

The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.

Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.

“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.

Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.

However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”

Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”

The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.

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

SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.

In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.

HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.

The results were simultaneously published in the Journal of Clinical Oncology.

Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.

And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.

HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.

HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.

After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.

Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”

The current findings focus on the 225 patients in the fixed-dose arm.

About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.

After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.

The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.

Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.

To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.

Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.

The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.

Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.

“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.

Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.

However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”

Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”

The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.

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

SINGAPORE – Heavily pretreated patients with EGFR-mutated non–small cell lung cancer (NSCLC) may experience a clinically meaningful benefit with the antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd), new phase 2 trial results suggest.

In the trial, almost 30% of patients receiving HER3-DXd achieved an objective response, and patients’ median overall survival approached 1 year.

HER3-DXd has “emerged as a promising therapy” in this patient population, “for whom available treatment options provide only limited efficacy,” concluded lead study author Helena A. Yu, MD, from Memorial Sloan Kettering Cancer Center, New York City, who presented findings from the HERTHENA-Lung01 trial at the 2023 World Conference on Lung Cancer.

The results were simultaneously published in the Journal of Clinical Oncology.

Acquired resistance to therapy among heavily pretreated patients with EGFR-mutated NSCLC is “universal,” Dr. Yu explained. The mechanisms of resistance to first-line osimertinib are also “diverse” and hard to identify. Salvage therapies after failed EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy offer “only a limited and transient and clinical benefit,” she said.

And with limited treatment options available to patients resistant to TKIs, there is a “high unmet medical need” for new therapies, said Helena Linardou, MD, PhD, who was not involved in the study.

HER3-DXd consists of a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab) attached to a topoisomerase I inhibitor payload (DXd) via a tetrapeptide-based cleavable linker.

HER3, Dr. Linardou explained, is a “biologically and clinically important target” in NSCLC. It is highly expressed in NSCLC, upregulated in TKI-resistant EGFR-mutated NSCLC, and is associated with a poor prognosis.

After promising phase 1 data, Dr. Yu and colleagues conducted a phase 2 trial in patients with advanced EGFR-mutated NSCLC who had progressed on systematic therapy and had received EGFR TKI and platinum-based chemotherapy. Patients could have active or previously treated asymptomatic brain metastases.

Patients were initially randomized either to a fixed-dose arm of HER3-DXd 5.6 mg/kg once every 3 weeks or an uptitration arm with doses escalating from 3.2 mg/kg to 4.8 mg/kg to 6.4 mg/kg over three cycles. However, Dr. Yu noted, enrollment in the uptitration arm closed early based on a “benefit-risk assessment.”

The current findings focus on the 225 patients in the fixed-dose arm.

About half of patients had a history of central nervous system metastasis, and patients had a median of three prior lines of systemic therapy. Most patients (92.9%) had previously received a third-generation EGFR TKI, about 40% had received immunotherapy, and all had received platinum-based chemotherapy.

After a median follow-up of 18.9 months, the confirmed objective response rate with HER3-DXd across the whole patient population was 29.8%. The median duration of response was 6.4 months, median progression-free survival was 5.5 months, and median overall survival was 11.9 months.

The results were virtually identical when looking only at patients who had received a third-generation EGFR TKI versus any EGFR TKI. Response rates were also similar regardless of the driver of EGFR TKI resistance.

Among the 30 patients with measurable brain metastases at baseline, 33.3% had a confirmed objective response to therapy. In this group, the disease control rate was 76.7% and the intracranial duration of response was 8.4 months.

To identify biomarkers of response to HER3-DXd, the team stratified the patients by baseline tumor HER3 membrane H-scores. Dr. Yu and colleagues found no differences in the likelihood of having a complete or partial response, stable disease, or progressive disease based on HER3 expression at study entry.

Looking at the safety of the ADC, only 7.1% of patients experienced a treatment-emergent adverse event associated with treatment discontinuation, but close to half of patients (45.3%) experienced a grade 3 or higher treatment-emergent adverse event. Interstitial lung disease, for instance, occurred in 5.3% of patients, including one patient who died.

The safety profile of HER3-DXd in this population appeared to be consistent with previous reports, Dr. Yu noted.

Overall, the findings suggest that “HER3-DXd provided clinically meaningful and durable efficacy” in patients with advanced EGFR-mutant NSCLC that has progressed after EGFR TKI and platinum-based chemotherapy, Dr. Yu said.

“Efficacy was observed across diverse mechanisms of resistance and across a broad range of pretreatment tumor HER3 expression” and the ADC demonstrated “clinically meaningful intracranial antitumor activity,” she added.

Dr. Linardou agreed that the current results suggest that HER3-DXd was associated with a “meaningful and durable efficacy,” including in patients with intracranial metastases, and she pointed to its “easy dosing schedule” and activity across patient subgroups.

However, she noted that, despite the researchers’ best efforts with the data available, “we don’t have a biomarker of activity,” which is a “general issue with ADCs.”

Still, Dr. Linardou said, “HER3 is now a clinically actionable therapeutic target, and this is a great bonus.”

The study was sponsored by Daiichi Sankyo. Dr. Yu declared relationships with AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, and others. Other authors declare numerous relationships.

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

Anxiety and depression are prevalent in patients with gastroesophageal reflux disease (GERD), according to a large-scale analysis that also found evidence for a possible underlying causal link between GERD and the common psychiatric conditions.

In a systematic review and meta-analysis, researchers found that anxiety and depressive symptoms were more than twice as likely in patients with GERD than in healthy controls. Among individuals with GERD, up to one-third and one-fourth were affected by anxiety and depressive symptoms, respectively.

Moreover, a Mendelian randomization analysis suggested that a genetic risk for GERD increased the risk of developing depression or anxiety and vice versa.

A genetic predisposition seems to underlie GERD and anxiety or depression, said Nicholas J. Talley, MD, PhD, School of Medicine and Public Health, University of Newcastle, Australia, and corresponding author of the review, published online in the American Journal of Gastroenterology.

Scientifically, the possible underlying link “suggests there are different disease subsets within reflux that probably have a different pathogenesis, and these relationships are an expression of whatever the underlying causal pathways are,” Dr. Talley told this news organization.

Clinically, “if you’ve got a patient with reflux, you should be asking one or two questions about anxiety and particularly depression ... because it may impact on how well patients respond to therapy, and how well they do in the longer term,” Dr. Talley said.
 

A deeper look

In the review, the authors note that GERD affects about 15% of the general population worldwide and has a negative impact on the health-related quality of life.

The pathogenesis is complex and may be associated with psychological distress alongside the well-known predisposing anatomical factors, aggravated by lifestyle factors such as obesity and smoking.

Individual studies examining the association between GERD and the prevalence of anxiety or depressive symptoms have had mixed results, “perhaps limited by heterogeneous study design, the severity of disease included, and diagnostic criteria for depression and anxiety,” the researchers wrote.

They therefore set out to perform a systematic review and meta-analysis to assess the issue in greater depth. They looked at three primary outcomes – the prevalence of symptoms of anxiety and depression in individuals with GERD, the epidemiological risk of developing GERD in people with anxiety or depression and vice versa, and the cause-and-effect relationship between anxiety or depression and GERD.

They searched the Embase, PubMed, Scopus, and Web of Science databases, and found 36 eligible studies published between 2003 and 2023.

Of the total, 30 were observational studies that examined the prevalence of anxiety and/or depressive symptoms using validated questionnaires in ≥ 100 individuals aged 18 years or older.

These included 26 studies of anxiety symptoms among 10,378 individuals with GERD, 30 that looked at depressive symptoms among 14,030 subjects with GERD, and four that reported the prevalence of simultaneous anxiety and depressive symptoms in 3,878 patients with GERD. Some studies were population based and others were hospital based. The extracted data were combined using a random-effects model.

The overall pooled analyses revealed a prevalence of anxiety symptoms of 34.4% among individuals with GERD, at an adjusted odds ratio versus healthy controls of 4.46 (95% confidence interval [CI], 1.94-10.25).

The pooled prevalence of depressive symptoms among those with GERD was 24.2%, at an adjusted odds ratio compared with healthy controls of 2.56 (95% CI, 1.11-5.87).

The pooled prevalence of simultaneous anxiety and depression in people with GERD was 22.3% (95% CI, 7.0-37.7).

Next, the team added three cohort studies that explored the risk for GERD in individuals with anxiety or depression in the vice versa scenario, as well as three Mendelian randomization studies that assessed the cause-and-effect relationship between anxiety or depression and GERD.

The cohort studies could not be pooled, but individuals with depression had a significantly increased risk for GERD versus those without depression, at an adjusted odds ratio in one study of 2.01 (95% CI, 1.96-2.07) and an adjusted hazard ratio in another study of 1.72 (95% CI, 1.60-1.85). A similar pattern was seen for anxiety.

The Mendelian randomization studies suggested that a genetic risk for depression was associated with an increased risk of developing GERD, at an odds ratio of 1.36 (95% CI, 1.21-1.51), and that a genetic risk for GERD was linked to an increased risk of developing depression, at an odds ratio of 1.30 (95% CI, 1.17-1.43).

One study reported a similar effect of a genetic risk for GERD on the risk for anxiety.

“We don’t really know what causes reflux disease. We know the pathophysiology, but we don’t really know what the etiology is, and depression is the same,” Dr. Talley noted. “It’s obviously thought to be a brain disease, but sometimes it might be coming from the gut as well, for all we know, and there is certainly evidence for that.”
 

The ‘chicken and egg’ question

Experts welcomed the findings, saying they supported their observations and validated the idea of looking outside the gut for complicating factors in patients with GERD, but some questioned the clinical relevance of the Mendelian randomization.

Approached for comment, Amir E. Masoud, MD, medical codirector, Hartford HealthCare Neurogastroenterology and Motility Center, Fairfield, Conn., said the study’s most important contribution is increased recognition of the connection between GERD and anxiety or depression.

“There is a psychological component” to GERD, he said, and it is an “important area for investigation and possible intervention for patients who don’t respond to traditional therapies.”

Dr. Masoud singled out the study design. The researchers “tried to tee this up with something we’ve always thought about,” he told this news organization, referring to the “chicken and egg” question about the relationship between GERD and anxiety or depressive symptoms.

As such, it provides evidence for a common observation in the clinic, he said. “A lot of times, when a therapy that should work does not work for something like GERD, for example, we tend to think of psychological factors that could be playing a role.”
 

No longer a taboo topic

Rena Yadlapati, MD, medical director, Center for Esophageal Diseases, UC San Diego Health, told this news organization that the study is “validating, in terms of the conversations with patients and some of the nontraditional methods we are trying to explore in their management.”

She noted the bidirectional relationship revealed by the Mendelian randomization, but cautioned that the approach relied on a small number of studies and hasn’t been utilized in gastroenterology as much as in other fields.

“We need to understand that this is hypothesis generating, and there are probably some important limitations,” she added, even if the results “certainly make sense.”

From a clinical perspective, the idea of anxiety or depression being linked to GERD has been a “taboo topic” for a long time, Dr. Yadlapati said.

“But if we can effectively communicate that relationship between the brain and gut and this whole cyclical process [to patients], there’s power to gain patient insight and engagement.”

Another key aspect is to consider a psychological referral for patients, as well as engaging them with “simple things like relaxation strategies and diaphragmatic breathing and referring them to people who can do cognitive behavioral therapy.”

Dr. Yadlapati emphasized that “it doesn’t necessarily have to be a psychologist. There are a lot of other ways to provide that access to patients.”
 

Practical clinical implications

Philip O. Katz, MD, director of motility laboratories, division of gastroenterology, Weill Cornell Medicine, New York, said that the study, like many of its kind, reinforces that there are multiple cofactors associated with managing patients with reflux disease.

As for the bidirectional relationship identified through the Mendelian randomization, he was skeptical about its clinical value and pointed out that the odds ratios are “relatively small.”

“It is commonplace for people to look for genetic predispositions to a lot of disease,” Katz told Medscape Medical News, but, “in clinical practice, I don’t believe that it’s particularly meaningful, to be honest.”

However, there is no doubt that GERD symptoms are augmented by times of what is generically called “stress,” he added.

“Regardless of those findings, it doesn’t change the way I view the importance of this article, which is when someone’s not responding to medication to look for reasons other than the original diagnosis,” Dr. Katz said.

“There is so much overlap between true GERD and symptoms that sound like GERD” that clinicians need “to be aware that both anxiety and depression are cofactors,” he said.

Dr. Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre of Research Excellence in Digestive Health, and he holds an NHMRC Investigator grant. He declared relationships with Norgine, Bristol Myers Squibb, Allakos, Bayer, Planet Innovation, twoXAR, Viscera Labs, Dr Falk Pharma, Sanofi, Glutagen, ISOVive, BluMaiden, Rose Pharma, Intrinsic Medicine, Comvita Manuka Honey, GlaxoSmithKline Australia, and AstraZeneca; and holds numerous patents. Dr. Masoud declared no relevant relationships. Dr. Yadlapati declared relationships with Medtronic, Phathom Pharmaceuticals, Ironwood Pharmaceuticals, and RJS Mediagnostix. Dr. Katz declared relationships with Phathom Pharma, Sebella, and Syneos.

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

Anxiety and depression are prevalent in patients with gastroesophageal reflux disease (GERD), according to a large-scale analysis that also found evidence for a possible underlying causal link between GERD and the common psychiatric conditions.

In a systematic review and meta-analysis, researchers found that anxiety and depressive symptoms were more than twice as likely in patients with GERD than in healthy controls. Among individuals with GERD, up to one-third and one-fourth were affected by anxiety and depressive symptoms, respectively.

Moreover, a Mendelian randomization analysis suggested that a genetic risk for GERD increased the risk of developing depression or anxiety and vice versa.

A genetic predisposition seems to underlie GERD and anxiety or depression, said Nicholas J. Talley, MD, PhD, School of Medicine and Public Health, University of Newcastle, Australia, and corresponding author of the review, published online in the American Journal of Gastroenterology.

Scientifically, the possible underlying link “suggests there are different disease subsets within reflux that probably have a different pathogenesis, and these relationships are an expression of whatever the underlying causal pathways are,” Dr. Talley told this news organization.

Clinically, “if you’ve got a patient with reflux, you should be asking one or two questions about anxiety and particularly depression ... because it may impact on how well patients respond to therapy, and how well they do in the longer term,” Dr. Talley said.
 

A deeper look

In the review, the authors note that GERD affects about 15% of the general population worldwide and has a negative impact on the health-related quality of life.

The pathogenesis is complex and may be associated with psychological distress alongside the well-known predisposing anatomical factors, aggravated by lifestyle factors such as obesity and smoking.

Individual studies examining the association between GERD and the prevalence of anxiety or depressive symptoms have had mixed results, “perhaps limited by heterogeneous study design, the severity of disease included, and diagnostic criteria for depression and anxiety,” the researchers wrote.

They therefore set out to perform a systematic review and meta-analysis to assess the issue in greater depth. They looked at three primary outcomes – the prevalence of symptoms of anxiety and depression in individuals with GERD, the epidemiological risk of developing GERD in people with anxiety or depression and vice versa, and the cause-and-effect relationship between anxiety or depression and GERD.

They searched the Embase, PubMed, Scopus, and Web of Science databases, and found 36 eligible studies published between 2003 and 2023.

Of the total, 30 were observational studies that examined the prevalence of anxiety and/or depressive symptoms using validated questionnaires in ≥ 100 individuals aged 18 years or older.

These included 26 studies of anxiety symptoms among 10,378 individuals with GERD, 30 that looked at depressive symptoms among 14,030 subjects with GERD, and four that reported the prevalence of simultaneous anxiety and depressive symptoms in 3,878 patients with GERD. Some studies were population based and others were hospital based. The extracted data were combined using a random-effects model.

The overall pooled analyses revealed a prevalence of anxiety symptoms of 34.4% among individuals with GERD, at an adjusted odds ratio versus healthy controls of 4.46 (95% confidence interval [CI], 1.94-10.25).

The pooled prevalence of depressive symptoms among those with GERD was 24.2%, at an adjusted odds ratio compared with healthy controls of 2.56 (95% CI, 1.11-5.87).

The pooled prevalence of simultaneous anxiety and depression in people with GERD was 22.3% (95% CI, 7.0-37.7).

Next, the team added three cohort studies that explored the risk for GERD in individuals with anxiety or depression in the vice versa scenario, as well as three Mendelian randomization studies that assessed the cause-and-effect relationship between anxiety or depression and GERD.

The cohort studies could not be pooled, but individuals with depression had a significantly increased risk for GERD versus those without depression, at an adjusted odds ratio in one study of 2.01 (95% CI, 1.96-2.07) and an adjusted hazard ratio in another study of 1.72 (95% CI, 1.60-1.85). A similar pattern was seen for anxiety.

The Mendelian randomization studies suggested that a genetic risk for depression was associated with an increased risk of developing GERD, at an odds ratio of 1.36 (95% CI, 1.21-1.51), and that a genetic risk for GERD was linked to an increased risk of developing depression, at an odds ratio of 1.30 (95% CI, 1.17-1.43).

One study reported a similar effect of a genetic risk for GERD on the risk for anxiety.

“We don’t really know what causes reflux disease. We know the pathophysiology, but we don’t really know what the etiology is, and depression is the same,” Dr. Talley noted. “It’s obviously thought to be a brain disease, but sometimes it might be coming from the gut as well, for all we know, and there is certainly evidence for that.”
 

The ‘chicken and egg’ question

Experts welcomed the findings, saying they supported their observations and validated the idea of looking outside the gut for complicating factors in patients with GERD, but some questioned the clinical relevance of the Mendelian randomization.

Approached for comment, Amir E. Masoud, MD, medical codirector, Hartford HealthCare Neurogastroenterology and Motility Center, Fairfield, Conn., said the study’s most important contribution is increased recognition of the connection between GERD and anxiety or depression.

“There is a psychological component” to GERD, he said, and it is an “important area for investigation and possible intervention for patients who don’t respond to traditional therapies.”

Dr. Masoud singled out the study design. The researchers “tried to tee this up with something we’ve always thought about,” he told this news organization, referring to the “chicken and egg” question about the relationship between GERD and anxiety or depressive symptoms.

As such, it provides evidence for a common observation in the clinic, he said. “A lot of times, when a therapy that should work does not work for something like GERD, for example, we tend to think of psychological factors that could be playing a role.”
 

No longer a taboo topic

Rena Yadlapati, MD, medical director, Center for Esophageal Diseases, UC San Diego Health, told this news organization that the study is “validating, in terms of the conversations with patients and some of the nontraditional methods we are trying to explore in their management.”

She noted the bidirectional relationship revealed by the Mendelian randomization, but cautioned that the approach relied on a small number of studies and hasn’t been utilized in gastroenterology as much as in other fields.

“We need to understand that this is hypothesis generating, and there are probably some important limitations,” she added, even if the results “certainly make sense.”

From a clinical perspective, the idea of anxiety or depression being linked to GERD has been a “taboo topic” for a long time, Dr. Yadlapati said.

“But if we can effectively communicate that relationship between the brain and gut and this whole cyclical process [to patients], there’s power to gain patient insight and engagement.”

Another key aspect is to consider a psychological referral for patients, as well as engaging them with “simple things like relaxation strategies and diaphragmatic breathing and referring them to people who can do cognitive behavioral therapy.”

Dr. Yadlapati emphasized that “it doesn’t necessarily have to be a psychologist. There are a lot of other ways to provide that access to patients.”
 

Practical clinical implications

Philip O. Katz, MD, director of motility laboratories, division of gastroenterology, Weill Cornell Medicine, New York, said that the study, like many of its kind, reinforces that there are multiple cofactors associated with managing patients with reflux disease.

As for the bidirectional relationship identified through the Mendelian randomization, he was skeptical about its clinical value and pointed out that the odds ratios are “relatively small.”

“It is commonplace for people to look for genetic predispositions to a lot of disease,” Katz told Medscape Medical News, but, “in clinical practice, I don’t believe that it’s particularly meaningful, to be honest.”

However, there is no doubt that GERD symptoms are augmented by times of what is generically called “stress,” he added.

“Regardless of those findings, it doesn’t change the way I view the importance of this article, which is when someone’s not responding to medication to look for reasons other than the original diagnosis,” Dr. Katz said.

“There is so much overlap between true GERD and symptoms that sound like GERD” that clinicians need “to be aware that both anxiety and depression are cofactors,” he said.

Dr. Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre of Research Excellence in Digestive Health, and he holds an NHMRC Investigator grant. He declared relationships with Norgine, Bristol Myers Squibb, Allakos, Bayer, Planet Innovation, twoXAR, Viscera Labs, Dr Falk Pharma, Sanofi, Glutagen, ISOVive, BluMaiden, Rose Pharma, Intrinsic Medicine, Comvita Manuka Honey, GlaxoSmithKline Australia, and AstraZeneca; and holds numerous patents. Dr. Masoud declared no relevant relationships. Dr. Yadlapati declared relationships with Medtronic, Phathom Pharmaceuticals, Ironwood Pharmaceuticals, and RJS Mediagnostix. Dr. Katz declared relationships with Phathom Pharma, Sebella, and Syneos.

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

Anxiety and depression are prevalent in patients with gastroesophageal reflux disease (GERD), according to a large-scale analysis that also found evidence for a possible underlying causal link between GERD and the common psychiatric conditions.

In a systematic review and meta-analysis, researchers found that anxiety and depressive symptoms were more than twice as likely in patients with GERD than in healthy controls. Among individuals with GERD, up to one-third and one-fourth were affected by anxiety and depressive symptoms, respectively.

Moreover, a Mendelian randomization analysis suggested that a genetic risk for GERD increased the risk of developing depression or anxiety and vice versa.

A genetic predisposition seems to underlie GERD and anxiety or depression, said Nicholas J. Talley, MD, PhD, School of Medicine and Public Health, University of Newcastle, Australia, and corresponding author of the review, published online in the American Journal of Gastroenterology.

Scientifically, the possible underlying link “suggests there are different disease subsets within reflux that probably have a different pathogenesis, and these relationships are an expression of whatever the underlying causal pathways are,” Dr. Talley told this news organization.

Clinically, “if you’ve got a patient with reflux, you should be asking one or two questions about anxiety and particularly depression ... because it may impact on how well patients respond to therapy, and how well they do in the longer term,” Dr. Talley said.
 

A deeper look

In the review, the authors note that GERD affects about 15% of the general population worldwide and has a negative impact on the health-related quality of life.

The pathogenesis is complex and may be associated with psychological distress alongside the well-known predisposing anatomical factors, aggravated by lifestyle factors such as obesity and smoking.

Individual studies examining the association between GERD and the prevalence of anxiety or depressive symptoms have had mixed results, “perhaps limited by heterogeneous study design, the severity of disease included, and diagnostic criteria for depression and anxiety,” the researchers wrote.

They therefore set out to perform a systematic review and meta-analysis to assess the issue in greater depth. They looked at three primary outcomes – the prevalence of symptoms of anxiety and depression in individuals with GERD, the epidemiological risk of developing GERD in people with anxiety or depression and vice versa, and the cause-and-effect relationship between anxiety or depression and GERD.

They searched the Embase, PubMed, Scopus, and Web of Science databases, and found 36 eligible studies published between 2003 and 2023.

Of the total, 30 were observational studies that examined the prevalence of anxiety and/or depressive symptoms using validated questionnaires in ≥ 100 individuals aged 18 years or older.

These included 26 studies of anxiety symptoms among 10,378 individuals with GERD, 30 that looked at depressive symptoms among 14,030 subjects with GERD, and four that reported the prevalence of simultaneous anxiety and depressive symptoms in 3,878 patients with GERD. Some studies were population based and others were hospital based. The extracted data were combined using a random-effects model.

The overall pooled analyses revealed a prevalence of anxiety symptoms of 34.4% among individuals with GERD, at an adjusted odds ratio versus healthy controls of 4.46 (95% confidence interval [CI], 1.94-10.25).

The pooled prevalence of depressive symptoms among those with GERD was 24.2%, at an adjusted odds ratio compared with healthy controls of 2.56 (95% CI, 1.11-5.87).

The pooled prevalence of simultaneous anxiety and depression in people with GERD was 22.3% (95% CI, 7.0-37.7).

Next, the team added three cohort studies that explored the risk for GERD in individuals with anxiety or depression in the vice versa scenario, as well as three Mendelian randomization studies that assessed the cause-and-effect relationship between anxiety or depression and GERD.

The cohort studies could not be pooled, but individuals with depression had a significantly increased risk for GERD versus those without depression, at an adjusted odds ratio in one study of 2.01 (95% CI, 1.96-2.07) and an adjusted hazard ratio in another study of 1.72 (95% CI, 1.60-1.85). A similar pattern was seen for anxiety.

The Mendelian randomization studies suggested that a genetic risk for depression was associated with an increased risk of developing GERD, at an odds ratio of 1.36 (95% CI, 1.21-1.51), and that a genetic risk for GERD was linked to an increased risk of developing depression, at an odds ratio of 1.30 (95% CI, 1.17-1.43).

One study reported a similar effect of a genetic risk for GERD on the risk for anxiety.

“We don’t really know what causes reflux disease. We know the pathophysiology, but we don’t really know what the etiology is, and depression is the same,” Dr. Talley noted. “It’s obviously thought to be a brain disease, but sometimes it might be coming from the gut as well, for all we know, and there is certainly evidence for that.”
 

The ‘chicken and egg’ question

Experts welcomed the findings, saying they supported their observations and validated the idea of looking outside the gut for complicating factors in patients with GERD, but some questioned the clinical relevance of the Mendelian randomization.

Approached for comment, Amir E. Masoud, MD, medical codirector, Hartford HealthCare Neurogastroenterology and Motility Center, Fairfield, Conn., said the study’s most important contribution is increased recognition of the connection between GERD and anxiety or depression.

“There is a psychological component” to GERD, he said, and it is an “important area for investigation and possible intervention for patients who don’t respond to traditional therapies.”

Dr. Masoud singled out the study design. The researchers “tried to tee this up with something we’ve always thought about,” he told this news organization, referring to the “chicken and egg” question about the relationship between GERD and anxiety or depressive symptoms.

As such, it provides evidence for a common observation in the clinic, he said. “A lot of times, when a therapy that should work does not work for something like GERD, for example, we tend to think of psychological factors that could be playing a role.”
 

No longer a taboo topic

Rena Yadlapati, MD, medical director, Center for Esophageal Diseases, UC San Diego Health, told this news organization that the study is “validating, in terms of the conversations with patients and some of the nontraditional methods we are trying to explore in their management.”

She noted the bidirectional relationship revealed by the Mendelian randomization, but cautioned that the approach relied on a small number of studies and hasn’t been utilized in gastroenterology as much as in other fields.

“We need to understand that this is hypothesis generating, and there are probably some important limitations,” she added, even if the results “certainly make sense.”

From a clinical perspective, the idea of anxiety or depression being linked to GERD has been a “taboo topic” for a long time, Dr. Yadlapati said.

“But if we can effectively communicate that relationship between the brain and gut and this whole cyclical process [to patients], there’s power to gain patient insight and engagement.”

Another key aspect is to consider a psychological referral for patients, as well as engaging them with “simple things like relaxation strategies and diaphragmatic breathing and referring them to people who can do cognitive behavioral therapy.”

Dr. Yadlapati emphasized that “it doesn’t necessarily have to be a psychologist. There are a lot of other ways to provide that access to patients.”
 

Practical clinical implications

Philip O. Katz, MD, director of motility laboratories, division of gastroenterology, Weill Cornell Medicine, New York, said that the study, like many of its kind, reinforces that there are multiple cofactors associated with managing patients with reflux disease.

As for the bidirectional relationship identified through the Mendelian randomization, he was skeptical about its clinical value and pointed out that the odds ratios are “relatively small.”

“It is commonplace for people to look for genetic predispositions to a lot of disease,” Katz told Medscape Medical News, but, “in clinical practice, I don’t believe that it’s particularly meaningful, to be honest.”

However, there is no doubt that GERD symptoms are augmented by times of what is generically called “stress,” he added.

“Regardless of those findings, it doesn’t change the way I view the importance of this article, which is when someone’s not responding to medication to look for reasons other than the original diagnosis,” Dr. Katz said.

“There is so much overlap between true GERD and symptoms that sound like GERD” that clinicians need “to be aware that both anxiety and depression are cofactors,” he said.

Dr. Talley is supported by funding from the National Health and Medical Research Council (NHMRC) to the Centre of Research Excellence in Digestive Health, and he holds an NHMRC Investigator grant. He declared relationships with Norgine, Bristol Myers Squibb, Allakos, Bayer, Planet Innovation, twoXAR, Viscera Labs, Dr Falk Pharma, Sanofi, Glutagen, ISOVive, BluMaiden, Rose Pharma, Intrinsic Medicine, Comvita Manuka Honey, GlaxoSmithKline Australia, and AstraZeneca; and holds numerous patents. Dr. Masoud declared no relevant relationships. Dr. Yadlapati declared relationships with Medtronic, Phathom Pharmaceuticals, Ironwood Pharmaceuticals, and RJS Mediagnostix. Dr. Katz declared relationships with Phathom Pharma, Sebella, and Syneos.

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

Brown fat, or thermogenic adipose tissue, appears to act as a “nutrient sink,” consuming glucose and lactate, among other metabolites, say U.S. researchers in a mouse study that supports its potential role in tackling obesity and even cancer.

The research, published recently in Nature Metabolism, was led by David A. Guertin, PhD, of the program in molecular medicine, University of Massachusetts, Worcester.

To find out more about the study, its clinical implications, and whether the results are translatable to humans, this news organization interviewed Dr. Guertin, asking him to explain some of the concepts behind the research.
 

What is adaptive thermogenesis, and why is it important in temperature regulation?

Adaptive thermogenesis is a physiologic process that occurs in a special type of fat cell, called a brown adipocyte, in which intracellular stored lipids and nutrients taken up from the blood are catabolized to generate heat.

The heat generated by these thermogenic adipocytes is critical for warming the blood and maintaining body temperature in cold environments, and is especially critical in human infants and small mammals, which are more sensitive to low temperatures.

The process is stimulated by the sympathetic nervous system, especially in response to feeling cold, but it can be activated by other stresses as well.

While adaptative thermogenesis is also called nonshivering thermogenesis to distinguish it from muscle shivering, both means of generating heat can work together to maintain body temperature.
 

Why is it considered a potential target for obesity?

Adult humans have brown adipocytes in specific locations in the body called brown adipose tissues (BAT) or, more simply, “brown fat.”

Intriguingly, clinical data show that the more BAT you have, the more likely you are to be protected against cardiometabolic disorders associated with obesity.

Since obesity results from an imbalance between energy intake and energy expenditure, one model proposes that brown adipocytes rebalance this formula by expending the excess energy (calories) as heat rather than storing it.

This has been referred to as the “nutrient sink” model, and the ability to activate this process therapeutically is a very attractive antiobesity strategy.
 

Why was it important to understand which circulating metabolites BAT uses for thermogenesis?

It is still not clear why brown fat is so beneficial for human health, and thus there is strong rationale for understanding its metabolism and how it cooperates with other tissues in the body.

For example, prior to our work, the field lacked a broad quantitative picture of how much any individual nutrient from the blood was used by brown fat, or which specific nutrients brown fat prefers to use to make heat – such as lipids, glucose, amino acids, etc. Knowing this information helps us identify more precise strategies to activate brown fat.

In addition, circulating metabolites sometimes also have messenger functions, similar to those of hormones, that stimulate physiologic processes such as adaptative thermogenesis. Highly metabolic tissues also put metabolites back into the blood, which can send messages to the brain and other tissues.

We don’t have a lot of information yet on how brown fat might engage in these processes, and so our study also aimed at finding these special metabolite messengers. 
 

You found that glucose and lactate predominate as BAT fuel sources. What does that tell us?

The major fuels used by brown fat have been debated for a long time.

Our study suggests that BAT in mice mainly prefers glucose and lactate, which is generated from glucose. On one hand, this shows us that thermogenic adipocytes may be especially useful in treating hyperglycemia, or even tumors, by reducing the amount of circulating glucose.

It also tells us that we need to focus more on why brown fat needs so much glucose. Other studies suggest that glucose is not just used as a fuel to generate heat but also may have other important functions in keeping brown adipocytes active and healthy.

We need to know that information so that therapeutic strategies targeting brown adipocytes can be optimized to have the best chance of success.

It’s worth noting that we did our study in mice that had free access to food. If the mice were fasting, they would use more lipids from the blood to supplement for the lack of available glucose, but we think that a baseline amount of glucose is still necessary.
 

What could be the clinical implications of your results if replicated in humans?

They suggest that glucose is an important resource that thermogenic adipocytes cannot do without, and moreover, that glucose is more than just a carbon source.

Resolving those other functions of glucose may provide insight into mechanisms to stimulate these cells or help explain why overweight or obese people who are insulin resistant have less brown fat activity, as insulin stimulates glucose uptake.

Beyond glucose, if any of these other metabolites made or released by brown fat have beneficial messenger functions, there may be ways to pharmacologically mimic them.
 

How easily do you think your findings could be applied to humans?

On a fundamental level, the basic cellular mechanisms that drive adaptative thermogenesis are likely the same between mice and humans, but the wiring to the sympathetic nervous system is a bit different.

This is why it’s important to look deeply at brown fat metabolism in mouse models to find pathways fundamental to the basic mechanisms of adaptative thermogenesis in both mice and humans, which could reveal unique therapeutic opportunities.

Another big challenge with comparing humans and mice is that humans typically keep their environment warm, so their brown fat is not that active.

In contrast, mice are often raised their entire lives in a facility kept at room temperature, around 22° C (72° F). While comfortable for the humans working with them, it’s cold for a small mouse, and so mice live with constantly active brown fat.

We can change the mouse environment to alter mouse brown fat activity, but that can’t be done with people. This makes comparative studies difficult.

Nevertheless, studies have shown that people who live in cold climates often have more brown fat, and, conversely, mice raised in warmer environments have brown fat that looks a lot more like human brown fat.
 

What further research do you have planned, or are looking forward to, in this area?

This is the most fun part of what we do, and I’ve been fortunate to have an amazing team passionately working on these questions.

One is to figure out why glucose is so important for these fascinating cells, which will keep us busy for years. We also need to modify the dietary conditions to determine whether the body prioritizes the use of glucose for adaptive thermogenesis even when there isn’t much available.

Another goal is to test whether any of the other metabolites we identified have bioactive functions. We also discovered a unique role for glutamine metabolism in brown fat, through the consumption of amino acids, that we haven’t yet resolved.

Finally, we want to understand how and why brown fat protects other organs from metabolic diseases, and we are just at the tip of the iceberg here.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases; the National Institute on Alcohol Abuse and Alcoholism; the National Heart, Lung, & Blood Institute; the National Institutes of Health; the AASLD Foundation Pinnacle Research Award in Liver Disease; the Edward Mallinckrodt Jr. Foundation Award; and the Basic Science Research Program of the Ministry of Education (South Korea). No relevant financial relationships were disclosed.

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

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

COPENHAGEN – Giving patients with Parkinson’s disease and constipation a probiotic for 3 months improved not only their gut microbiome but also nonmotor symptoms such as sleep, fatigue, and constipation, results of a new randomized trial show.

Participants taking the probiotic also saw a reduced delay in “time to on” of treatment with levodopa, thus reducing the delay until effectiveness of the treatment, said study presenter Valentina Leta, MD, PhD, department of neurosciences, King’s College London Institute of Psychiatry, Psychology and Neuroscience.

Dr. Leta presented the findings at the International Congress of Parkinson’s Disease and Movement Disorders.

“Virtually every person with Parkinson’s might have some degree of gastrointestinal dysfunction, and virtually the entire tract might be affected, from the mouth to the rectum,” Dr. Leta told attendees of the congress.

A number of different mechanisms have been associated with this gastrointestinal dysfunction, she noted, including proinflammatory changes in the gut microbiota, so a modulatory intervention “could be a therapeutic strategy for Parkinson’s disease.”

However, “despite numerous preclinical studies showing potential beneficial effects on a variety of pathological mechanisms involved in Parkinson’s disease, the clinical evidence is limited ... to the treatment of constipation,” she explained.

The team therefore conducted a multicenter, randomized, double-blind, placebo-controlled trial, in which patients with both Parkinson’s disease and constipation, based on the Rome IV criteria, were randomly assigned to receive a probiotic or placebo for 3 months.

The probiotic used was a liquid formulation (Symprove) and contained four strains: Lacticaseibacillus rhamnosus, Enterococcus faecium, Lactobacillus acidophilus, and Lactiplantibacillus plantarum.

A total of 74 patients were randomly assigned to the two study arms. The two groups were well matched for sociodemographics, Parkinson’s disease, and constipation-related characteristics, Dr. Leta reported, and only 3 patients in each arm discontinued the study. The probiotic intervention had a “good tolerability and safety profile, with a similar number of adverse events between the two groups, and no serious adverse events.”
 

Increase in healthy bacteria

The study met its primary outcome of changes in gut microbiome at the end of the 12-week intervention, as measured on shallow shotgun sequencing.

The probiotic was associated with a “statistically significant increase of the abundance of bacteria which are known to have beneficial health related properties, such as Odoribacteraceae,” Dr. Leta said.

This bacterium is “known to be reduced in people with Parkinson’s disease,” she explained, “and is involved in the production of short-chain fatty acids, which are known to have beneficial health-related properties.”

The secondary endpoint of the study included changes in motor and nonmotor symptoms, and the probiotic was associated with a significant improvement in the “time to on” with levodopa treatment, shortening this period from an average of 31.43 minutes at baseline to 23.95 minutes at the postintervention assessment (P < .027).

There was also a significant improvement in the Non-Motor Symptoms Scale (NMSS) score between baseline and the postintervention assessment in patients given the probiotic, from 70.71 to 61.34 (P = .005).

This, Dr. Leta observed, was “driven by improvements in the sleep, fatigue, and gastrointestinal domains.”

No such significant improvements were observed in the placebo arm.
 

Probiotics ‘hot topic’ among patients

Claudia Trenkwalder, MD, full professor of neurology at University Medical Center Goettingen (Germany), said in an interview that the use of probiotics is a “hot topic in Parkinson’s disease research, especially among patients.”

Dr. Trenkwalder, who was not involved in the study, noted that Lactobacillus strains “are established in Parkinson’s disease constipation treatment, with randomized controlled trials showing a significant improvement in constipation.

“Therefore, this is a useful treatment. The question here is: Do we have additional effects that can be measured in the microbiome and in clinical symptomatology?”

The trial showed that the probiotic studied “did alter the microbiome and did improve the constipation,” said Dr. Trenkwalder; however, the current data cannot prove whether the probiotic influenced the symptoms of Parkinson’s disease because the improvement in NMSS scores “is driven by the improvement in constipation.”

This, she argued, could have resulted in better absorption of levodopa.

A dietitian in the audience agreed. She asked whether the probiotic was doing anything “besides improving constipation,” adding that the resulting increased ability to absorb levodopa is also “going to help your sleep.”
 

Beyond constipation?

Dr. Leta replied that “we can assume that there is a link between the reduction in the ‘time to on’ and the improvement in constipation. We are doing some analyses in terms of levodopa pharmacokinetics to really understand the mechanisms behind this result.”

Although the improvement in constipation is “one of the possible hypotheses for the improvement in ‘time to on,’” she continued, “there is a more speculative one” in which the probiotics are modulating inflammatory parameters that could contribute to the improvement in sleep.

Veronica Bruno, MD, MPH, assistant professor in the department of clinical neurosciences at the University of Calgary (Alta.), commented in a press release that there has been “increasing interest” in examining the relationship between gut dysbiosis and the “gut-brain axis” in Parkinson’s disease.

The current study “stands out as a significant contribution to this area of study,” she said.

“While the implications of the observed changes in gut microbiota remain a captivating realm for further investigation, a particularly noteworthy finding revolves around the reduction in the ‘time to on’ observed within the active treatment group.”

Dr. Bruno said that shortening of the time to on “holds promise for substantial enhancements in patients’ lives” by reducing “difficult ‘off’ intervals and enhancing overall well-being.”

The study was funded by the UK National Institute for Health Research Mental Health Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust, and King’s College London. No relevant financial relationships were declared.

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

Performing any level of leisure-time physical activity reduces the risk for neuropathy and nephropathy in individuals with type 2 diabetes, by between one-fifth and one third, although the impact on retinopathy is weaker, reveals a cohort study of U.K. individuals.

The research, based on data from more than 18,000 participants in the U.K. Biobank, suggests that the minimal level of self-reported activity to reduce the risk for both neuropathy and nephropathy may be the equivalent of less than 1.5 hours of walking per week.

The results are “encouraging and reassuring for both physicians and patients,” lead author Frederik P.B. Kristensen, MSc, PhD student, department of clinical epidemiology, Aarhus (Denmark) University, said in an interview.

Ariel Skelley/Getty Images

Impact of exercise on microvascular complications in T2D has been uncertain

The authors point out that microvascular complications – such as nerve damage (neuropathy), kidney problems (nephropathy), and eye complications (retinopathy) – occur in more than 50% of individuals with type 2 diabetes and have a “substantial impact” on quality of life, on top of the impact of macrovascular complications (such as cardiovascular disease), disability, and mortality.

Although physical activity is seen as a “cornerstone in the multifactorial management of type 2 diabetes because of its beneficial effects on metabolic risk factors,” the impact on microvascular complications is “uncertain” and the evidence is limited and “conflicting.”

The researchers therefore sought to examine the dose-response association, including the minimal effective level, between leisure-time physical activity and neuropathy, nephropathy, and retinopathy.

They conducted a cohort study of individuals aged 37-82 years from the U.K. Biobank who had type 2 diabetes, which was identified using the Eastwood algorithm and/or an A1c greater than or equal to 48 mmol/mol (6.5%).

Individuals with type 1 diabetes or gestational diabetes were excluded, as were those with major disabling somatic disorders, neurodegenerative diseases, and mental disorders, among others.

Leisure-time physical activity was based on the self-reported frequency, duration, and types of physical activities and was combined to calculate the total leisure time activity in MET-hours per week.

Using the American Diabetes Association/World Health Organization recommendations of 150-300 minutes of moderate to vigorous leisure-time physical activity per week, the researchers determined the recommended moderate activity level to be 150 minutes, (equivalent to 2.5 hours, or 7.5 MET-hours per week).

In all, 18,092 individuals with type 2 diabetes were included in the analysis, of whom 37% were women. The mean age was 60 years.

Ten percent of participants performed no leisure-time physical activity, 38% performed activity below the threshold for moderate activity, 20% performed at the recommended level, and 32% were more active.

Those performing no physical activity were more likely to be women, to be younger, to have a higher body mass index, and to have a greater average A1c, as well as have a more unfavorable sociodemographic and behavioral profile.

Over a median follow-up of 12.1 years, 3.7% of the participants were diagnosed with neuropathy, 10.2% with nephropathy, and 11.7% with retinopathy, equating to an incidence per 1,000 person-years of 3.5, 9,8, and 11.4, respectively.

The researchers found that any level of physical activity was associated with an approximate reduction in the risk for neuropathy and nephropathy.

Multivariate analysis indicated that, compared with no physical activity, activity below the recommended level was associated with an adjusted hazard ratio (aHR) for neuropathy of 0.71, whereas the aHR for activity at the recommended level was 0.73 and that for activity above the recommended level was 0.67.

The aHR for nephropathy, compared with no physical activity, was 0.79 for activity below the recommended level, 0.80 for activity at the recommended level, and 0.80 for activity above the recommended level.

The association between physical activity and retinopathy was weaker, however, at aHRs of 0.91, 0.91, and 0.98 for activity below, at, and above the recommended level, respectively.

The researchers suggest that this lower association could be due to differences in the etiology of the different forms of microvascular complications.

Hyperglycemia is the key driver in the development of retinopathy, they note, whereas other metabolic risk factors, such as obesity, insulin resistance, inflammation, dyslipidemia, and hypertension, play a role in neuropathy and nephropathy.

The associations were also less pronounced in women.

Mr. Kristensen said that this is “an important area that needs to be addressed.”

“While different rates between men and women regarding incidence of type 2 diabetes, metabolic risk factors, complications, and the initiation of, and adherence to, therapy have been found,” he continued, “the exact mechanisms remain unclear. We need a further understanding of sex-differences in metabolic regulation, as well as in material living conditions, social and psychological factors, and access to health care, which may influence the risk of complications.”

Mr. Kristensen added, “Sex differences may be present in more areas than we are aware.”

Mr. Kristensen is supported by a PhD grant from Aarhus University. Other authors received funding from the Danish Diabetes Association, the Australian National Health and Medical Research Council, the New South Wales Government, the Spanish Ministry of Universities, the European Union NextGenerationEU/PRTR (Plan de Recuperación) through a Margarita Salas contract of the University of Vigo, and the Government of Andalusia, Research Talent Recruitment Programme. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Performing any level of leisure-time physical activity reduces the risk for neuropathy and nephropathy in individuals with type 2 diabetes, by between one-fifth and one third, although the impact on retinopathy is weaker, reveals a cohort study of U.K. individuals.

The research, based on data from more than 18,000 participants in the U.K. Biobank, suggests that the minimal level of self-reported activity to reduce the risk for both neuropathy and nephropathy may be the equivalent of less than 1.5 hours of walking per week.

The results are “encouraging and reassuring for both physicians and patients,” lead author Frederik P.B. Kristensen, MSc, PhD student, department of clinical epidemiology, Aarhus (Denmark) University, said in an interview.

Ariel Skelley/Getty Images

Impact of exercise on microvascular complications in T2D has been uncertain

The authors point out that microvascular complications – such as nerve damage (neuropathy), kidney problems (nephropathy), and eye complications (retinopathy) – occur in more than 50% of individuals with type 2 diabetes and have a “substantial impact” on quality of life, on top of the impact of macrovascular complications (such as cardiovascular disease), disability, and mortality.

Although physical activity is seen as a “cornerstone in the multifactorial management of type 2 diabetes because of its beneficial effects on metabolic risk factors,” the impact on microvascular complications is “uncertain” and the evidence is limited and “conflicting.”

The researchers therefore sought to examine the dose-response association, including the minimal effective level, between leisure-time physical activity and neuropathy, nephropathy, and retinopathy.

They conducted a cohort study of individuals aged 37-82 years from the U.K. Biobank who had type 2 diabetes, which was identified using the Eastwood algorithm and/or an A1c greater than or equal to 48 mmol/mol (6.5%).

Individuals with type 1 diabetes or gestational diabetes were excluded, as were those with major disabling somatic disorders, neurodegenerative diseases, and mental disorders, among others.

Leisure-time physical activity was based on the self-reported frequency, duration, and types of physical activities and was combined to calculate the total leisure time activity in MET-hours per week.

Using the American Diabetes Association/World Health Organization recommendations of 150-300 minutes of moderate to vigorous leisure-time physical activity per week, the researchers determined the recommended moderate activity level to be 150 minutes, (equivalent to 2.5 hours, or 7.5 MET-hours per week).

In all, 18,092 individuals with type 2 diabetes were included in the analysis, of whom 37% were women. The mean age was 60 years.

Ten percent of participants performed no leisure-time physical activity, 38% performed activity below the threshold for moderate activity, 20% performed at the recommended level, and 32% were more active.

Those performing no physical activity were more likely to be women, to be younger, to have a higher body mass index, and to have a greater average A1c, as well as have a more unfavorable sociodemographic and behavioral profile.

Over a median follow-up of 12.1 years, 3.7% of the participants were diagnosed with neuropathy, 10.2% with nephropathy, and 11.7% with retinopathy, equating to an incidence per 1,000 person-years of 3.5, 9,8, and 11.4, respectively.

The researchers found that any level of physical activity was associated with an approximate reduction in the risk for neuropathy and nephropathy.

Multivariate analysis indicated that, compared with no physical activity, activity below the recommended level was associated with an adjusted hazard ratio (aHR) for neuropathy of 0.71, whereas the aHR for activity at the recommended level was 0.73 and that for activity above the recommended level was 0.67.

The aHR for nephropathy, compared with no physical activity, was 0.79 for activity below the recommended level, 0.80 for activity at the recommended level, and 0.80 for activity above the recommended level.

The association between physical activity and retinopathy was weaker, however, at aHRs of 0.91, 0.91, and 0.98 for activity below, at, and above the recommended level, respectively.

The researchers suggest that this lower association could be due to differences in the etiology of the different forms of microvascular complications.

Hyperglycemia is the key driver in the development of retinopathy, they note, whereas other metabolic risk factors, such as obesity, insulin resistance, inflammation, dyslipidemia, and hypertension, play a role in neuropathy and nephropathy.

The associations were also less pronounced in women.

Mr. Kristensen said that this is “an important area that needs to be addressed.”

“While different rates between men and women regarding incidence of type 2 diabetes, metabolic risk factors, complications, and the initiation of, and adherence to, therapy have been found,” he continued, “the exact mechanisms remain unclear. We need a further understanding of sex-differences in metabolic regulation, as well as in material living conditions, social and psychological factors, and access to health care, which may influence the risk of complications.”

Mr. Kristensen added, “Sex differences may be present in more areas than we are aware.”

Mr. Kristensen is supported by a PhD grant from Aarhus University. Other authors received funding from the Danish Diabetes Association, the Australian National Health and Medical Research Council, the New South Wales Government, the Spanish Ministry of Universities, the European Union NextGenerationEU/PRTR (Plan de Recuperación) through a Margarita Salas contract of the University of Vigo, and the Government of Andalusia, Research Talent Recruitment Programme. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

Performing any level of leisure-time physical activity reduces the risk for neuropathy and nephropathy in individuals with type 2 diabetes, by between one-fifth and one third, although the impact on retinopathy is weaker, reveals a cohort study of U.K. individuals.

The research, based on data from more than 18,000 participants in the U.K. Biobank, suggests that the minimal level of self-reported activity to reduce the risk for both neuropathy and nephropathy may be the equivalent of less than 1.5 hours of walking per week.

The results are “encouraging and reassuring for both physicians and patients,” lead author Frederik P.B. Kristensen, MSc, PhD student, department of clinical epidemiology, Aarhus (Denmark) University, said in an interview.

Ariel Skelley/Getty Images

Impact of exercise on microvascular complications in T2D has been uncertain

The authors point out that microvascular complications – such as nerve damage (neuropathy), kidney problems (nephropathy), and eye complications (retinopathy) – occur in more than 50% of individuals with type 2 diabetes and have a “substantial impact” on quality of life, on top of the impact of macrovascular complications (such as cardiovascular disease), disability, and mortality.

Although physical activity is seen as a “cornerstone in the multifactorial management of type 2 diabetes because of its beneficial effects on metabolic risk factors,” the impact on microvascular complications is “uncertain” and the evidence is limited and “conflicting.”

The researchers therefore sought to examine the dose-response association, including the minimal effective level, between leisure-time physical activity and neuropathy, nephropathy, and retinopathy.

They conducted a cohort study of individuals aged 37-82 years from the U.K. Biobank who had type 2 diabetes, which was identified using the Eastwood algorithm and/or an A1c greater than or equal to 48 mmol/mol (6.5%).

Individuals with type 1 diabetes or gestational diabetes were excluded, as were those with major disabling somatic disorders, neurodegenerative diseases, and mental disorders, among others.

Leisure-time physical activity was based on the self-reported frequency, duration, and types of physical activities and was combined to calculate the total leisure time activity in MET-hours per week.

Using the American Diabetes Association/World Health Organization recommendations of 150-300 minutes of moderate to vigorous leisure-time physical activity per week, the researchers determined the recommended moderate activity level to be 150 minutes, (equivalent to 2.5 hours, or 7.5 MET-hours per week).

In all, 18,092 individuals with type 2 diabetes were included in the analysis, of whom 37% were women. The mean age was 60 years.

Ten percent of participants performed no leisure-time physical activity, 38% performed activity below the threshold for moderate activity, 20% performed at the recommended level, and 32% were more active.

Those performing no physical activity were more likely to be women, to be younger, to have a higher body mass index, and to have a greater average A1c, as well as have a more unfavorable sociodemographic and behavioral profile.

Over a median follow-up of 12.1 years, 3.7% of the participants were diagnosed with neuropathy, 10.2% with nephropathy, and 11.7% with retinopathy, equating to an incidence per 1,000 person-years of 3.5, 9,8, and 11.4, respectively.

The researchers found that any level of physical activity was associated with an approximate reduction in the risk for neuropathy and nephropathy.

Multivariate analysis indicated that, compared with no physical activity, activity below the recommended level was associated with an adjusted hazard ratio (aHR) for neuropathy of 0.71, whereas the aHR for activity at the recommended level was 0.73 and that for activity above the recommended level was 0.67.

The aHR for nephropathy, compared with no physical activity, was 0.79 for activity below the recommended level, 0.80 for activity at the recommended level, and 0.80 for activity above the recommended level.

The association between physical activity and retinopathy was weaker, however, at aHRs of 0.91, 0.91, and 0.98 for activity below, at, and above the recommended level, respectively.

The researchers suggest that this lower association could be due to differences in the etiology of the different forms of microvascular complications.

Hyperglycemia is the key driver in the development of retinopathy, they note, whereas other metabolic risk factors, such as obesity, insulin resistance, inflammation, dyslipidemia, and hypertension, play a role in neuropathy and nephropathy.

The associations were also less pronounced in women.

Mr. Kristensen said that this is “an important area that needs to be addressed.”

“While different rates between men and women regarding incidence of type 2 diabetes, metabolic risk factors, complications, and the initiation of, and adherence to, therapy have been found,” he continued, “the exact mechanisms remain unclear. We need a further understanding of sex-differences in metabolic regulation, as well as in material living conditions, social and psychological factors, and access to health care, which may influence the risk of complications.”

Mr. Kristensen added, “Sex differences may be present in more areas than we are aware.”

Mr. Kristensen is supported by a PhD grant from Aarhus University. Other authors received funding from the Danish Diabetes Association, the Australian National Health and Medical Research Council, the New South Wales Government, the Spanish Ministry of Universities, the European Union NextGenerationEU/PRTR (Plan de Recuperación) through a Margarita Salas contract of the University of Vigo, and the Government of Andalusia, Research Talent Recruitment Programme. No relevant financial relationships were declared.

A version of this article appeared on Medscape.com.

TOPLINE:

Both short and long sleep durations appear to increase the risk for type 2 diabetes, independent of lifestyle and cardiovascular risk factors, suggests an analysis of a Dutch study.

METHODOLOGY:

• Data on 5,561 participants aged 40–75 years from The Maastricht Study who completed the baseline survey between November 2010 and January 2018 and had full data available were included.
• Sleep duration was assessed as the in-bed time in minutes, using a median of 7 nights’ data from an activPAL3 (PAL Technologies) accelerometer, which is worn on the thigh.
• Glucose metabolism was determined via an oral glucose tolerance test and categorized as prediabetes or type 2 diabetes in line with World Health Organization diagnostic criteria.
• The association between sleep duration and type 2 diabetes was assessed on multivariate logistic regression analysis, taking into account a range of potential confounding factors.

TAKEAWAY:

• The mean age of the participants was 60.1 years, and there was an even split between men and women. In all, 832 had prediabetes and 1,341 type 2 diabetes, and the mean sleep duration was 8.3 hours.
• The results indicated there was a U-shaped relationship between sleep duration and type 2 diabetes, so that both long and short sleep durations increased the risk.
• In the fully adjusted model, a sleep duration of 5 hours was associated with an odds ratio for type 2 diabetes versus 8 hours sleep of 2.9. For a sleep duration of 12 hours, the odds ratio was 1.8.
• The association between sleep duration and diabetes was not significant.

IN PRACTICE:

The results “support the idea that sleep duration could be a relevant risk factor for type 2 diabetes independent of lifestyle risk factors, including diet, physical activity, smoking behavior, and alcohol consumption,” wrote the authors.

“These findings underpin the importance of promoting healthy sleep habits to avoid sleep deprivation,” they added.
 

STUDY DETAILS:

The research was led by Jeroen D. Albers, MSc, department of social medicine, Maastricht (the Netherlands) University, and published in Sleep Health. It is an analysis of The Maastricht Study.

LIMITATIONS:

The study is limited by its cross-sectional nature, particularly because there are “plausible causal paths between sleep duration and type 2 in both directions,” the authors note. The accelerometer used in the study also cannot reliably distinguish between waking and sleeping time in bed, with the potential for misclassification. Daytime naps were also not included, and long-term changes sleep patterns were not measured. In addition, it was not possible to control for some potential confounding factors.

DISCLOSURES:

The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs, Stichting De Weijerhorst, the Pearl String Initiative Diabetes, the School for Cardiovascular Diseases, the School for Public Health and Primary Care, the School for Nutrition and Translational Research in Metabolism, Stichting Annadal, Health Foundation Limburg, and unrestricted grants from Janssen-Cilag, Novo Nordisk, and Sanofi Aventis Netherlands. One author declares a relationship with Novo Nordisk outside the submitted work. No other relevant financial relationships were declared.

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

TOPLINE:

Both short and long sleep durations appear to increase the risk for type 2 diabetes, independent of lifestyle and cardiovascular risk factors, suggests an analysis of a Dutch study.

METHODOLOGY:

• Data on 5,561 participants aged 40–75 years from The Maastricht Study who completed the baseline survey between November 2010 and January 2018 and had full data available were included.
• Sleep duration was assessed as the in-bed time in minutes, using a median of 7 nights’ data from an activPAL3 (PAL Technologies) accelerometer, which is worn on the thigh.
• Glucose metabolism was determined via an oral glucose tolerance test and categorized as prediabetes or type 2 diabetes in line with World Health Organization diagnostic criteria.
• The association between sleep duration and type 2 diabetes was assessed on multivariate logistic regression analysis, taking into account a range of potential confounding factors.

TAKEAWAY:

• The mean age of the participants was 60.1 years, and there was an even split between men and women. In all, 832 had prediabetes and 1,341 type 2 diabetes, and the mean sleep duration was 8.3 hours.
• The results indicated there was a U-shaped relationship between sleep duration and type 2 diabetes, so that both long and short sleep durations increased the risk.
• In the fully adjusted model, a sleep duration of 5 hours was associated with an odds ratio for type 2 diabetes versus 8 hours sleep of 2.9. For a sleep duration of 12 hours, the odds ratio was 1.8.
• The association between sleep duration and diabetes was not significant.

IN PRACTICE:

The results “support the idea that sleep duration could be a relevant risk factor for type 2 diabetes independent of lifestyle risk factors, including diet, physical activity, smoking behavior, and alcohol consumption,” wrote the authors.

“These findings underpin the importance of promoting healthy sleep habits to avoid sleep deprivation,” they added.
 

STUDY DETAILS:

The research was led by Jeroen D. Albers, MSc, department of social medicine, Maastricht (the Netherlands) University, and published in Sleep Health. It is an analysis of The Maastricht Study.

LIMITATIONS:

The study is limited by its cross-sectional nature, particularly because there are “plausible causal paths between sleep duration and type 2 in both directions,” the authors note. The accelerometer used in the study also cannot reliably distinguish between waking and sleeping time in bed, with the potential for misclassification. Daytime naps were also not included, and long-term changes sleep patterns were not measured. In addition, it was not possible to control for some potential confounding factors.

DISCLOSURES:

The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs, Stichting De Weijerhorst, the Pearl String Initiative Diabetes, the School for Cardiovascular Diseases, the School for Public Health and Primary Care, the School for Nutrition and Translational Research in Metabolism, Stichting Annadal, Health Foundation Limburg, and unrestricted grants from Janssen-Cilag, Novo Nordisk, and Sanofi Aventis Netherlands. One author declares a relationship with Novo Nordisk outside the submitted work. No other relevant financial relationships were declared.

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

TOPLINE:

Both short and long sleep durations appear to increase the risk for type 2 diabetes, independent of lifestyle and cardiovascular risk factors, suggests an analysis of a Dutch study.

METHODOLOGY:

• Data on 5,561 participants aged 40–75 years from The Maastricht Study who completed the baseline survey between November 2010 and January 2018 and had full data available were included.
• Sleep duration was assessed as the in-bed time in minutes, using a median of 7 nights’ data from an activPAL3 (PAL Technologies) accelerometer, which is worn on the thigh.
• Glucose metabolism was determined via an oral glucose tolerance test and categorized as prediabetes or type 2 diabetes in line with World Health Organization diagnostic criteria.
• The association between sleep duration and type 2 diabetes was assessed on multivariate logistic regression analysis, taking into account a range of potential confounding factors.

TAKEAWAY:

• The mean age of the participants was 60.1 years, and there was an even split between men and women. In all, 832 had prediabetes and 1,341 type 2 diabetes, and the mean sleep duration was 8.3 hours.
• The results indicated there was a U-shaped relationship between sleep duration and type 2 diabetes, so that both long and short sleep durations increased the risk.
• In the fully adjusted model, a sleep duration of 5 hours was associated with an odds ratio for type 2 diabetes versus 8 hours sleep of 2.9. For a sleep duration of 12 hours, the odds ratio was 1.8.
• The association between sleep duration and diabetes was not significant.

IN PRACTICE:

The results “support the idea that sleep duration could be a relevant risk factor for type 2 diabetes independent of lifestyle risk factors, including diet, physical activity, smoking behavior, and alcohol consumption,” wrote the authors.

“These findings underpin the importance of promoting healthy sleep habits to avoid sleep deprivation,” they added.
 

STUDY DETAILS:

The research was led by Jeroen D. Albers, MSc, department of social medicine, Maastricht (the Netherlands) University, and published in Sleep Health. It is an analysis of The Maastricht Study.

LIMITATIONS:

The study is limited by its cross-sectional nature, particularly because there are “plausible causal paths between sleep duration and type 2 in both directions,” the authors note. The accelerometer used in the study also cannot reliably distinguish between waking and sleeping time in bed, with the potential for misclassification. Daytime naps were also not included, and long-term changes sleep patterns were not measured. In addition, it was not possible to control for some potential confounding factors.

DISCLOSURES:

The Maastricht Study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs, Stichting De Weijerhorst, the Pearl String Initiative Diabetes, the School for Cardiovascular Diseases, the School for Public Health and Primary Care, the School for Nutrition and Translational Research in Metabolism, Stichting Annadal, Health Foundation Limburg, and unrestricted grants from Janssen-Cilag, Novo Nordisk, and Sanofi Aventis Netherlands. One author declares a relationship with Novo Nordisk outside the submitted work. No other relevant financial relationships were declared.

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

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

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

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

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

Measuring four circulating biomarkers through a simple blood test in patients with type 2 diabetes and kidney disease may predict their risk of heart and kidney disease progression, suggests an analysis of the CREDENCE trial.

The research, published online in the journal Circulation, also revealed that patients treated with the sodium-glucose cotransporter-2 inhibitor canagliflozin (Invokana, Invokamet) had lower levels of the biomarkers after 1 year compared with those given placebo.

Examination of biomarker levels in more than 2,600 patients from CREDENCE showed that high baseline concentrations of the individual biomarkers were able to predict the future risk for a composite endpoint of renal and heart outcomes.

The combination of all four biomarkers into a single panel revealed that patients with the highest levels were more than four times as likely to experience the composite endpoint than were those with the lowest levels.

As two of the biomarkers used in the study have yet to have established prognostic thresholds, the results remain exploratory.

Lead author James L. Januzzi, MD, director of the Heart Failure and Biomarker Trials at the Baim Institute for Clinical Research, Boston, said that further study will help refine the predictive value of the panel.

“Given that the American Heart Association/American College of Cardiology and the American Diabetes Association now all recommend measurement of biomarkers to enhance the ability to predict risk in persons with type 2 diabetes, these results may considerably extend the reach of biomarker-based testing, refining accuracy even further,” he said in a press release.

In an interview, Dr. Januzzi said that “three out of the four biomarkers are already clinically and commercially available,” while the fourth, for insulin-like growth factor binding protein 7 (IGFBP7), is “on the near horizon.”

He stressed that the “future for multiple biomarker testing, however, will be less about ordering each individual test, and ultimately will revolve around panels of blood work that are ordered as a single test.”

Dr. Januzzi added that “rather than using the rather primitive approach that we took” of looking at the individual biomarkers in adjusted models, the next stage “will be to utilize algorithms to combine the results into a single value.

“A clinician will not have to struggle with looking at individual results but will just receive one aggregated test result that informs them whether a patient is at low, medium or higher risk,” he explained.

However, this will require determining the relative importance of each biomarker and weighting them in the final model.

Consequently, the current results “set the foundation for identifying some very powerful individual tests that may ultimately, in aggregate, help us to help our patients with diabetes avoid a major complication,” Dr. Januzzi said.

By revealing that some individuals with both type 2 diabetes and kidney disease are at higher risk than others, he also hopes the findings can be leveraged to treat patients with “varying degrees of intensity with proven therapies, including weight loss, dietary adjustment, and pharmacologic intervention.”

Dr. Januzzi added: “Diabetes affects a dramatic, and growing, percentage of our population, and this type of personalized strategy to reduce the major complications of this rather common disease is an important step forward.”

The authors noted that there is a “bidirectional relationship” between cardiovascular disease and chronic kidney disease (CKD), such that either diagnosis may increase the risk of, or exacerbate, the other. 

Individuals with type 2 diabetes and CKD albuminuria, they added, are at particularly high risk for major cardiovascular events, and studies have shown that several circulating cardiorenal stress biomarkers may predict the onset and progression of CKD in type 2 diabetes, as well as predict cardiovascular events.
 

Several biomarkers associated with myocardial stress and necrosis

The recent CANVAS trial revealed that, among individuals with type 2 diabetes with and without CKD, several biomarkers were associated with myocardial stress and necrosis, and renal tubular injury, predicting the progression of CKD with albuminuria, and the risk for heart failure events.

Taking inspiration from those findings, the current researchers studied a panel of similar cardiac and renal biomarkers among participants from the CREDENCE trial, for which 4,401 patients with type 2 diabetes and CKD at high risk of progression were randomly assigned to canagliflozin or placebo.

The current analysis involved 2,627 participants who had baseline plasma samples available for analysis of four circulating biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), growth differentiation factor-15 (GDF-15), and IGFBP7.

Among those, 2,385 participants also had year 1 plasma samples available for analysis, while year 3 plasma samples were available for 895 individuals.

The results showed that, in general, median baseline concentrations of each biomarker in both treatment groups were elevated compared with healthy reference populations.

Baseline log-transformed concentrations of each biomarker were also strongly predictive of cardiac and renal outcomes, including heart failure and progression of CKD.

For example, each unit increase in baseline NT-proBNP concentrations was associated with a hazard ratio of 1.35 for the primary composite endpoint of end-stage kidney disease, doubling of serum creatinine levels, renal death, or cardiovascular disease (P < .001).

For each unit increase in hs-cTnT levels, the hazard ratio for the primary composite was 1.73 (P < .001), for GDF-15 it was 1.84 (P < .0001), and for IGFBP7 the hazard ratio was 3.14 (P < .001).

Combining the four biomarkers into a single multimarker panel revealed that, compared with individuals with a low-risk score, those with a high-risk score had a hazard ratio for the primary outcome of 4.01, whereas those with a moderate risk score had a hazard ratio of 2.39 (P < .001 for both).

For the individual outcome of heart failure hospitalization, the effect was even greater. A high-risk score was associated with a hazard ratio vs. a low-risk score of 6.04 (P < .001), whereas patients with a moderate risk score had a hazard ratio of 2.45 (P = .04).

The researchers also reported that, between baseline and year 1, concentrations of all four biomarkers rose from 6% to 29% in the placebo group, but from 3% to just 10% in those treated with canagliflozin.

“It was reassuring to discover that canagliflozin helped reduce risks the most in people with the highest chances for complications,” said Dr. Januzzi.

The CREDENCE trial and the current analysis were funded by Janssen Research & Development LLC. NT-proBNP, hs-cTnT, GDF-15, and IGFBP7 reagents were provided by Roche Diagnostics. Dr. Januzzi is funded in part by the Hutter Family Professorship. Dr. Januzzi declared relationships with Imbria Pharmaceuticals, Jana Care, Abbott, Applied Therapeutics, HeartFlow, Innolife, Roche Diagnostics, Beckman, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck, Novartis, Pfizer, Siemens, Abbott, AbbVie, CVRx, Intercept, and Takeda.


 

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

Acute liver failure (ALF), a rare life-threatening condition, is potentially reversible if recognized and treated early, according to the latest guidelines from the American College of Gastroenterology.

The guidelines emphasize the need for timely transfer to a transplant center for patients who are at risk for poor outcomes.

“We wanted to produce an updated set of ALF guidelines for general gastroenterologists,” said lead author Alexandra Shingina, MD, MSc, Vanderbilt University Medical Center, Nashville, Tenn.

The aim was to “provide a comprehensive review of early evaluation and management of these patients,” she added.

The new guidelines build on previous guidelines produced by the American Association for the Study of Liver Diseases in 2011. The guidelines were published in the American Journal of Gastroenterology.

In 2017, the American Gastroenterological Association issued guidelines specific to the diagnosis and management of acute liver failure.

Siddharth Singh, MD, a gastroenterologist with UC San Diego Health and an author of the AGA guidelines, said the new guidelines will help inform the treatment of ALF. “It is encouraging to see the recent ACG guidelines building on prior guidelines published by the AGA in 2017,” he said.

ALF is typically defined as severe liver impairment and rapid clinical deterioration that, with few exceptions, “occurs in patients with no pre-existing liver disease,” the authors write. It is critical to distinguish ALF from the more common acutely decompensated cirrhosis or acute on chronic liver failure, the guidelines note, because their management differs significantly.

“ALF has a multitude of etiologies and a variety of clinical presentations that can affect virtually every organ system,” the authors write.

The cause of ALF is an essential indicator for prognosis and treatment strategy, especially for liver transplantation. For example, hyperacute ALF is predominantly seen in the setting of viral hepatitis A and E, acetaminophen toxicity, and ischemic injury, they note. Although the hyperacute subtype “carries a high risk for cerebral edema, it has the best prognosis without transplantation,” compared with other forms of ALF.

Before liver transplants, nearly 80% of patients with ALF died from the condition. In the past 20 years, 1- and 5-year survival rates from liver transplants are about 80% and 75%, respectively.

The authors emphasize that it is “imperative for clinicians to recognize ALF early ... because initiation of treatment and transplant considerations could be life-saving.”
 

Notable new recommendations

To develop the new guidelines, a writing group was assembled that included hepatology experts across a range of practice settings and different stages of their clinical and research careers.

They conducted a literature search of the MEDLINE, EMBASE, and Cochrane Library databases for relevant studies published in English up to January 2022, focusing on the highest quality of evidence, where available. Owing to a lack of solid data, the recommendations are based predominantly on expert opinion, the authors note.

ALF “is a rare entity. Literature reporting on outcomes is sparse and limited to retrospective cases series, with almost no randomized controlled trials available,” Dr. Shingina said.

She and her colleagues developed the recommendations to cover all aspects of ALF management, from initial diagnosis through to system- and etiology-specific management of ALF and liver transplantation.

“One of the new recommendations is the early use of CRRT [continuous renal replacement therapy] in patients with ALF and grade 2 encephalopathy, even in the absence of conventional RRT indications,” Dr. Shingina said.

“Although the evidence is limited, we felt that it was an important point in the multidisciplinary management of complex ALF patients, which can potentially save lives by reducing cerebral edema and allowing for more time if a liver transplant is not readily available,” she said.

She also highlighted a recommendation supporting intravenous N-acetylcysteine use in patients with acetaminophen-induced ALF and pointed out that the routine use of intracranial pressure monitors is no longer recommended “given the lack of literature on improved outcomes.”

Dr. Shingina emphasized that living donor liver transplantation can be considered in patients with ALF who are listed as status 1A priority for transplantation in experienced centers, when deceased donor liver transplantation is not readily available, as can ABO-incompatible grafts in patients who are rapidly declining.

The authors also present a timeline of ALF presentation and investigations.

During the first 2-4 hours after presentation at the emergency department, the patient should undergo initial stabilization and investigations, with a transfer to the ICU for those with grade 2 or higher hepatic encephalopathy. The transplant center should also be contacted during this period, the authors write.

After transfer to the ICU or a transplant center and during hours 4-12 After the initial presentation, patients should undergo intensive monitoring.

Psychiatry, social work, and hepatobiliary surgery consults should also be undertaken to determine the patient’s transplant eligibility, and if eligible, they should be put on a list.

Those who are ineligible for transplant or who show improvements should subsequently receive supportive management.

Overall, Dr. Shingina said that risk stratification and contact with a transplant center for potential transfer is of “utmost importance” for general gastroenterologists working in the community.

She said that either the Kings College Criteria or Model for End-Stage Liver Disease score can be used for prognostication, with a MELD score of 25 indicating worse outcomes.

“These are the patients who would benefit from early transfer to the nearest transplant center,” Dr. Shingina said.
 

Guidelines valuable, offer ‘concrete advice’

Approached for comment, Michael P. Curry, MD, Beth Israel Deaconess Medical Center, Boston, welcomed the guidelines, saying they are “very well written.”

He said there have been “a lot of changes in the field” since the 2011 guidelines. The current recommendations “provide concrete advice to all physicians on the appropriate assessment of patients with ALF,” he said.

Dr. Curry singled out the new recommendation on the early use of CRRT in patients with encephalopathy. He agreed on the need for gastroenterologists outside of transplant centers to make contact for potential transfer early.

“These are not patients who should, or could, be managed in a small community hospital or in a program that does not have a transplant center with which they work in close collaboration,” he said.

“So, identifying patients who are at highest risk of progressing is really important,” he said.

Dr. Curry hopes the guidelines will be shared widely by colleagues, but he is concerned that they are “not going to make it to some of these intensive care units in community, non-tertiary care centers.”

Nikolaos Pyrsopoulos, MD, PhD, MBA, Rutgers New Jersey Medical School, Newark, said the guidelines offer a “very comprehensive review of the literature.”

He said they are also a “very thorough evaluation of the quality of the evidence-based publications.”

It was “about time” that there was a set of guidelines of this quality, he added.

As for the recommendations, Dr. Pyrsopoulos believes that they will be “really valuable for the general gastroenterologist practicing in the community,” as well as for pathologists, to help them evaluate patients with ALF “as soon as possible, and in a standardized manner.”

He also emphasized the need for the rapid transfer of patients for transplant “when they are still lucid ... so we have the opportunity to discuss with and evaluate the patient.” This can be problematic in those who have been intubated and in patients with hepatic encephalopathy because they “become really confused.”

“The window of opportunity is closing very rapidly in some of these patients ... and morbidity and mortality is really pretty high” he said, so the transplant centers “appreciate when the referral is made to them earlier.”

No funding declared. No relevant financial relationships declared.

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

Acute liver failure (ALF), a rare life-threatening condition, is potentially reversible if recognized and treated early, according to the latest guidelines from the American College of Gastroenterology.

The guidelines emphasize the need for timely transfer to a transplant center for patients who are at risk for poor outcomes.

“We wanted to produce an updated set of ALF guidelines for general gastroenterologists,” said lead author Alexandra Shingina, MD, MSc, Vanderbilt University Medical Center, Nashville, Tenn.

The aim was to “provide a comprehensive review of early evaluation and management of these patients,” she added.

The new guidelines build on previous guidelines produced by the American Association for the Study of Liver Diseases in 2011. The guidelines were published in the American Journal of Gastroenterology.

In 2017, the American Gastroenterological Association issued guidelines specific to the diagnosis and management of acute liver failure.

Siddharth Singh, MD, a gastroenterologist with UC San Diego Health and an author of the AGA guidelines, said the new guidelines will help inform the treatment of ALF. “It is encouraging to see the recent ACG guidelines building on prior guidelines published by the AGA in 2017,” he said.

ALF is typically defined as severe liver impairment and rapid clinical deterioration that, with few exceptions, “occurs in patients with no pre-existing liver disease,” the authors write. It is critical to distinguish ALF from the more common acutely decompensated cirrhosis or acute on chronic liver failure, the guidelines note, because their management differs significantly.

“ALF has a multitude of etiologies and a variety of clinical presentations that can affect virtually every organ system,” the authors write.

The cause of ALF is an essential indicator for prognosis and treatment strategy, especially for liver transplantation. For example, hyperacute ALF is predominantly seen in the setting of viral hepatitis A and E, acetaminophen toxicity, and ischemic injury, they note. Although the hyperacute subtype “carries a high risk for cerebral edema, it has the best prognosis without transplantation,” compared with other forms of ALF.

Before liver transplants, nearly 80% of patients with ALF died from the condition. In the past 20 years, 1- and 5-year survival rates from liver transplants are about 80% and 75%, respectively.

The authors emphasize that it is “imperative for clinicians to recognize ALF early ... because initiation of treatment and transplant considerations could be life-saving.”
 

Notable new recommendations

To develop the new guidelines, a writing group was assembled that included hepatology experts across a range of practice settings and different stages of their clinical and research careers.

They conducted a literature search of the MEDLINE, EMBASE, and Cochrane Library databases for relevant studies published in English up to January 2022, focusing on the highest quality of evidence, where available. Owing to a lack of solid data, the recommendations are based predominantly on expert opinion, the authors note.

ALF “is a rare entity. Literature reporting on outcomes is sparse and limited to retrospective cases series, with almost no randomized controlled trials available,” Dr. Shingina said.

She and her colleagues developed the recommendations to cover all aspects of ALF management, from initial diagnosis through to system- and etiology-specific management of ALF and liver transplantation.

“One of the new recommendations is the early use of CRRT [continuous renal replacement therapy] in patients with ALF and grade 2 encephalopathy, even in the absence of conventional RRT indications,” Dr. Shingina said.

“Although the evidence is limited, we felt that it was an important point in the multidisciplinary management of complex ALF patients, which can potentially save lives by reducing cerebral edema and allowing for more time if a liver transplant is not readily available,” she said.

She also highlighted a recommendation supporting intravenous N-acetylcysteine use in patients with acetaminophen-induced ALF and pointed out that the routine use of intracranial pressure monitors is no longer recommended “given the lack of literature on improved outcomes.”

Dr. Shingina emphasized that living donor liver transplantation can be considered in patients with ALF who are listed as status 1A priority for transplantation in experienced centers, when deceased donor liver transplantation is not readily available, as can ABO-incompatible grafts in patients who are rapidly declining.

The authors also present a timeline of ALF presentation and investigations.

During the first 2-4 hours after presentation at the emergency department, the patient should undergo initial stabilization and investigations, with a transfer to the ICU for those with grade 2 or higher hepatic encephalopathy. The transplant center should also be contacted during this period, the authors write.

After transfer to the ICU or a transplant center and during hours 4-12 After the initial presentation, patients should undergo intensive monitoring.

Psychiatry, social work, and hepatobiliary surgery consults should also be undertaken to determine the patient’s transplant eligibility, and if eligible, they should be put on a list.

Those who are ineligible for transplant or who show improvements should subsequently receive supportive management.

Overall, Dr. Shingina said that risk stratification and contact with a transplant center for potential transfer is of “utmost importance” for general gastroenterologists working in the community.

She said that either the Kings College Criteria or Model for End-Stage Liver Disease score can be used for prognostication, with a MELD score of 25 indicating worse outcomes.

“These are the patients who would benefit from early transfer to the nearest transplant center,” Dr. Shingina said.
 

Guidelines valuable, offer ‘concrete advice’

Approached for comment, Michael P. Curry, MD, Beth Israel Deaconess Medical Center, Boston, welcomed the guidelines, saying they are “very well written.”

He said there have been “a lot of changes in the field” since the 2011 guidelines. The current recommendations “provide concrete advice to all physicians on the appropriate assessment of patients with ALF,” he said.

Dr. Curry singled out the new recommendation on the early use of CRRT in patients with encephalopathy. He agreed on the need for gastroenterologists outside of transplant centers to make contact for potential transfer early.

“These are not patients who should, or could, be managed in a small community hospital or in a program that does not have a transplant center with which they work in close collaboration,” he said.

“So, identifying patients who are at highest risk of progressing is really important,” he said.

Dr. Curry hopes the guidelines will be shared widely by colleagues, but he is concerned that they are “not going to make it to some of these intensive care units in community, non-tertiary care centers.”

Nikolaos Pyrsopoulos, MD, PhD, MBA, Rutgers New Jersey Medical School, Newark, said the guidelines offer a “very comprehensive review of the literature.”

He said they are also a “very thorough evaluation of the quality of the evidence-based publications.”

It was “about time” that there was a set of guidelines of this quality, he added.

As for the recommendations, Dr. Pyrsopoulos believes that they will be “really valuable for the general gastroenterologist practicing in the community,” as well as for pathologists, to help them evaluate patients with ALF “as soon as possible, and in a standardized manner.”

He also emphasized the need for the rapid transfer of patients for transplant “when they are still lucid ... so we have the opportunity to discuss with and evaluate the patient.” This can be problematic in those who have been intubated and in patients with hepatic encephalopathy because they “become really confused.”

“The window of opportunity is closing very rapidly in some of these patients ... and morbidity and mortality is really pretty high” he said, so the transplant centers “appreciate when the referral is made to them earlier.”

No funding declared. No relevant financial relationships declared.

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

Acute liver failure (ALF), a rare life-threatening condition, is potentially reversible if recognized and treated early, according to the latest guidelines from the American College of Gastroenterology.

The guidelines emphasize the need for timely transfer to a transplant center for patients who are at risk for poor outcomes.

“We wanted to produce an updated set of ALF guidelines for general gastroenterologists,” said lead author Alexandra Shingina, MD, MSc, Vanderbilt University Medical Center, Nashville, Tenn.

The aim was to “provide a comprehensive review of early evaluation and management of these patients,” she added.

The new guidelines build on previous guidelines produced by the American Association for the Study of Liver Diseases in 2011. The guidelines were published in the American Journal of Gastroenterology.

In 2017, the American Gastroenterological Association issued guidelines specific to the diagnosis and management of acute liver failure.

Siddharth Singh, MD, a gastroenterologist with UC San Diego Health and an author of the AGA guidelines, said the new guidelines will help inform the treatment of ALF. “It is encouraging to see the recent ACG guidelines building on prior guidelines published by the AGA in 2017,” he said.

ALF is typically defined as severe liver impairment and rapid clinical deterioration that, with few exceptions, “occurs in patients with no pre-existing liver disease,” the authors write. It is critical to distinguish ALF from the more common acutely decompensated cirrhosis or acute on chronic liver failure, the guidelines note, because their management differs significantly.

“ALF has a multitude of etiologies and a variety of clinical presentations that can affect virtually every organ system,” the authors write.

The cause of ALF is an essential indicator for prognosis and treatment strategy, especially for liver transplantation. For example, hyperacute ALF is predominantly seen in the setting of viral hepatitis A and E, acetaminophen toxicity, and ischemic injury, they note. Although the hyperacute subtype “carries a high risk for cerebral edema, it has the best prognosis without transplantation,” compared with other forms of ALF.

Before liver transplants, nearly 80% of patients with ALF died from the condition. In the past 20 years, 1- and 5-year survival rates from liver transplants are about 80% and 75%, respectively.

The authors emphasize that it is “imperative for clinicians to recognize ALF early ... because initiation of treatment and transplant considerations could be life-saving.”
 

Notable new recommendations

To develop the new guidelines, a writing group was assembled that included hepatology experts across a range of practice settings and different stages of their clinical and research careers.

They conducted a literature search of the MEDLINE, EMBASE, and Cochrane Library databases for relevant studies published in English up to January 2022, focusing on the highest quality of evidence, where available. Owing to a lack of solid data, the recommendations are based predominantly on expert opinion, the authors note.

ALF “is a rare entity. Literature reporting on outcomes is sparse and limited to retrospective cases series, with almost no randomized controlled trials available,” Dr. Shingina said.

She and her colleagues developed the recommendations to cover all aspects of ALF management, from initial diagnosis through to system- and etiology-specific management of ALF and liver transplantation.

“One of the new recommendations is the early use of CRRT [continuous renal replacement therapy] in patients with ALF and grade 2 encephalopathy, even in the absence of conventional RRT indications,” Dr. Shingina said.

“Although the evidence is limited, we felt that it was an important point in the multidisciplinary management of complex ALF patients, which can potentially save lives by reducing cerebral edema and allowing for more time if a liver transplant is not readily available,” she said.

She also highlighted a recommendation supporting intravenous N-acetylcysteine use in patients with acetaminophen-induced ALF and pointed out that the routine use of intracranial pressure monitors is no longer recommended “given the lack of literature on improved outcomes.”

Dr. Shingina emphasized that living donor liver transplantation can be considered in patients with ALF who are listed as status 1A priority for transplantation in experienced centers, when deceased donor liver transplantation is not readily available, as can ABO-incompatible grafts in patients who are rapidly declining.

The authors also present a timeline of ALF presentation and investigations.

During the first 2-4 hours after presentation at the emergency department, the patient should undergo initial stabilization and investigations, with a transfer to the ICU for those with grade 2 or higher hepatic encephalopathy. The transplant center should also be contacted during this period, the authors write.

After transfer to the ICU or a transplant center and during hours 4-12 After the initial presentation, patients should undergo intensive monitoring.

Psychiatry, social work, and hepatobiliary surgery consults should also be undertaken to determine the patient’s transplant eligibility, and if eligible, they should be put on a list.

Those who are ineligible for transplant or who show improvements should subsequently receive supportive management.

Overall, Dr. Shingina said that risk stratification and contact with a transplant center for potential transfer is of “utmost importance” for general gastroenterologists working in the community.

She said that either the Kings College Criteria or Model for End-Stage Liver Disease score can be used for prognostication, with a MELD score of 25 indicating worse outcomes.

“These are the patients who would benefit from early transfer to the nearest transplant center,” Dr. Shingina said.
 

Guidelines valuable, offer ‘concrete advice’

Approached for comment, Michael P. Curry, MD, Beth Israel Deaconess Medical Center, Boston, welcomed the guidelines, saying they are “very well written.”

He said there have been “a lot of changes in the field” since the 2011 guidelines. The current recommendations “provide concrete advice to all physicians on the appropriate assessment of patients with ALF,” he said.

Dr. Curry singled out the new recommendation on the early use of CRRT in patients with encephalopathy. He agreed on the need for gastroenterologists outside of transplant centers to make contact for potential transfer early.

“These are not patients who should, or could, be managed in a small community hospital or in a program that does not have a transplant center with which they work in close collaboration,” he said.

“So, identifying patients who are at highest risk of progressing is really important,” he said.

Dr. Curry hopes the guidelines will be shared widely by colleagues, but he is concerned that they are “not going to make it to some of these intensive care units in community, non-tertiary care centers.”

Nikolaos Pyrsopoulos, MD, PhD, MBA, Rutgers New Jersey Medical School, Newark, said the guidelines offer a “very comprehensive review of the literature.”

He said they are also a “very thorough evaluation of the quality of the evidence-based publications.”

It was “about time” that there was a set of guidelines of this quality, he added.

As for the recommendations, Dr. Pyrsopoulos believes that they will be “really valuable for the general gastroenterologist practicing in the community,” as well as for pathologists, to help them evaluate patients with ALF “as soon as possible, and in a standardized manner.”

He also emphasized the need for the rapid transfer of patients for transplant “when they are still lucid ... so we have the opportunity to discuss with and evaluate the patient.” This can be problematic in those who have been intubated and in patients with hepatic encephalopathy because they “become really confused.”

“The window of opportunity is closing very rapidly in some of these patients ... and morbidity and mortality is really pretty high” he said, so the transplant centers “appreciate when the referral is made to them earlier.”

No funding declared. No relevant financial relationships declared.

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