MDedge Endocrinology

TOPLINE:

A national study in Israel demonstrates the feasibility and diagnostic benefits of rapid trio genome sequencing in critically ill neonates.

METHODOLOGY:

• Researchers conducted a prospective, multicenter cohort study from October 2021 to December 2022, involving all Israeli medical genetics institutes and neonatal intensive care units.
• A total of 130 critically ill neonates suspected of having a genetic disorder were enrolled, with rapid genome sequencing results expected within 10 days.

TAKEAWAY:

• Rapid trio genome sequencing diagnosed 50% of the neonates with disease-causing variants, including 12 chromosomal and 52 monogenic conditions.
• Another 11% had variants of unknown significance that were suspected to be disease-causing, and 1% had a novel gene suspected of causing disease.
• The mean turnaround time for the rapid reports was 7 days, demonstrating the feasibility of implementing rapid genome sequencing in a national healthcare setting, the researchers said.
• Genomic testing led to a change in clinical management for 22% of the neonates, which shows the clinical utility of this approach to diagnosis, they said.

IN PRACTICE:

Genetic testing may identify patients who are candidates for precision medical treatment and inform family planning, which is “critical for families with a severely affected or deceased child,” the study authors wrote.

SOURCE:

The corresponding author for the study was Daphna Marom, MD, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. It was published online on February 22, 2024, in JAMA Network Open.

LIMITATIONS:

The study’s reliance on voluntary participation may have introduced referral bias, potentially affecting the diagnostic rates. The long-term impact of diagnosis on survival, growth, and development remains to be evaluated. Bioinformatics tools have limitations, as shown by the missed detection of maternal uniparental disomy in one case of a hypotonic infant with Prader-Willi syndrome, the researchers noted. Clinical judgment is still essential, they said.

DISCLOSURES:

The study was sponsored by a collaboration between the Israeli Ministry of Health, Illumina, and the Genomics Center at the Tel Aviv Sourasky Medical Center. Illumina provided reagents, bioinformatics tools, and editorial assistance. Study authors disclosed financial ties to Illumina.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

A national study in Israel demonstrates the feasibility and diagnostic benefits of rapid trio genome sequencing in critically ill neonates.

METHODOLOGY:

• Researchers conducted a prospective, multicenter cohort study from October 2021 to December 2022, involving all Israeli medical genetics institutes and neonatal intensive care units.
• A total of 130 critically ill neonates suspected of having a genetic disorder were enrolled, with rapid genome sequencing results expected within 10 days.

TAKEAWAY:

• Rapid trio genome sequencing diagnosed 50% of the neonates with disease-causing variants, including 12 chromosomal and 52 monogenic conditions.
• Another 11% had variants of unknown significance that were suspected to be disease-causing, and 1% had a novel gene suspected of causing disease.
• The mean turnaround time for the rapid reports was 7 days, demonstrating the feasibility of implementing rapid genome sequencing in a national healthcare setting, the researchers said.
• Genomic testing led to a change in clinical management for 22% of the neonates, which shows the clinical utility of this approach to diagnosis, they said.

IN PRACTICE:

Genetic testing may identify patients who are candidates for precision medical treatment and inform family planning, which is “critical for families with a severely affected or deceased child,” the study authors wrote.

SOURCE:

The corresponding author for the study was Daphna Marom, MD, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. It was published online on February 22, 2024, in JAMA Network Open.

LIMITATIONS:

The study’s reliance on voluntary participation may have introduced referral bias, potentially affecting the diagnostic rates. The long-term impact of diagnosis on survival, growth, and development remains to be evaluated. Bioinformatics tools have limitations, as shown by the missed detection of maternal uniparental disomy in one case of a hypotonic infant with Prader-Willi syndrome, the researchers noted. Clinical judgment is still essential, they said.

DISCLOSURES:

The study was sponsored by a collaboration between the Israeli Ministry of Health, Illumina, and the Genomics Center at the Tel Aviv Sourasky Medical Center. Illumina provided reagents, bioinformatics tools, and editorial assistance. Study authors disclosed financial ties to Illumina.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

TOPLINE:

A national study in Israel demonstrates the feasibility and diagnostic benefits of rapid trio genome sequencing in critically ill neonates.

METHODOLOGY:

• Researchers conducted a prospective, multicenter cohort study from October 2021 to December 2022, involving all Israeli medical genetics institutes and neonatal intensive care units.
• A total of 130 critically ill neonates suspected of having a genetic disorder were enrolled, with rapid genome sequencing results expected within 10 days.

TAKEAWAY:

• Rapid trio genome sequencing diagnosed 50% of the neonates with disease-causing variants, including 12 chromosomal and 52 monogenic conditions.
• Another 11% had variants of unknown significance that were suspected to be disease-causing, and 1% had a novel gene suspected of causing disease.
• The mean turnaround time for the rapid reports was 7 days, demonstrating the feasibility of implementing rapid genome sequencing in a national healthcare setting, the researchers said.
• Genomic testing led to a change in clinical management for 22% of the neonates, which shows the clinical utility of this approach to diagnosis, they said.

IN PRACTICE:

Genetic testing may identify patients who are candidates for precision medical treatment and inform family planning, which is “critical for families with a severely affected or deceased child,” the study authors wrote.

SOURCE:

The corresponding author for the study was Daphna Marom, MD, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. It was published online on February 22, 2024, in JAMA Network Open.

LIMITATIONS:

The study’s reliance on voluntary participation may have introduced referral bias, potentially affecting the diagnostic rates. The long-term impact of diagnosis on survival, growth, and development remains to be evaluated. Bioinformatics tools have limitations, as shown by the missed detection of maternal uniparental disomy in one case of a hypotonic infant with Prader-Willi syndrome, the researchers noted. Clinical judgment is still essential, they said.

DISCLOSURES:

The study was sponsored by a collaboration between the Israeli Ministry of Health, Illumina, and the Genomics Center at the Tel Aviv Sourasky Medical Center. Illumina provided reagents, bioinformatics tools, and editorial assistance. Study authors disclosed financial ties to Illumina.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.

A version of this article appeared on Medscape.com.

As a front-line treatment for type 2 diabetes, metformin is among the most widely prescribed drugs in the United States. In 2021 alone, clinicians wrote more than 91 million orders for the medication — up from 40 million 2004.

But is metformin just getting started? Emerging evidence suggests the drug may be effective for a much broader range of conditions beyond managing high blood glucose, including various cancers, obesity, liver disease, cardiovascular, neurodegenerative, and renal diseases. As the evidence for diverse uses accumulates, many trials have launched, with researchers looking to expand metformin’s indications and validate or explore new directions.

Metformin’s long history as a pharmaceutical includes an herbal ancestry, recognition in 1918 for its ability to lower blood glucose, being cast aside because of toxicity fears in the 1930s, rediscovery and synthesis in Europe in the 1940s, the first reported use for diabetes in 1957, and approval in the United States in 1994.

The drug has maintained its place as the preferred first-line treatment for type 2 diabetes since 2011, when it was first included in the World Health Organization’s essential medicines list.

“The focus hitherto has been primarily on its insulin sensitization effects,” Akshay Jain, MD, a clinical and research endocrinologist at TLC Diabetes and Endocrinology, in Surrey, British Columbia, Canada, told this news organization.

“The recent surge of renewed interest is in part related to its postulated effects on multiple other receptors,” he said. “In my mind, the metformin data on coronary artery disease reduction and cancer-protective effects have come farther along than other disease states.”

Cardiovascular Outcomes

Gregory G. Schwartz, MD, PhD, chief of the cardiology section at Rocky Mountain Regional VA Medical Center and professor of medicine at the University of Colorado School of Medicine in Aurora, is leading the VA-IMPACT trial. Despite metformin’s long history and widespread use, he said his study is the first placebo-controlled cardiovascular outcomes trial of the drug.

Launched in 2023, the study tests the hypothesis that metformin reduces the risk for death or nonfatal ischemic cardiovascular events in patients with prediabetes and established coronary, cerebrovascular, or peripheral artery disease, Dr. Schwartz said. The trial is being conducted at roughly 40 VA medical centers, with a planned enrollment of 7410 patients. The estimated completion date is March 2029.

“The principal mechanism of action of metformin is through activation of AMP [adenosine monophosphate]–activated protein kinase, a central pathway in metabolic regulation, cell protection, and survival,” Dr. Schwartz explained. “Experimental data have demonstrated attenuated development of atherosclerosis, reduced myocardial infarct size, improved endothelial function, and antiarrhythmic actions — none of those dependent on the presence of diabetes.”

Dr. Schwartz and his colleagues decided to test their hypothesis in people with prediabetes, rather than diabetes, to create a “true placebo-controlled comparison,” he said.

“If patients with type 2 diabetes had been chosen, there would be potential for confounding because a placebo group would require more treatment with other active antihyperglycemic medications to achieve the same degree of glycemic control as a metformin group,” Dr. Schwartz said.

“If proven efficacious in the VA-IMPACT trial, metformin could provide an inexpensive, generally safe, and well-tolerated approach to reduce cardiovascular morbidity and mortality in a large segment of the population,” Dr. Schwartz added. “Perhaps the old dog can learn some new tricks.”

Other recruiting trials looking at cardiovascular-related outcomes include Met-PEF, LIMIT, and Metformin as an Adjunctive Therapy to Catheter Ablation in Atrial Fibrillation.

Reducing Cancer Risks

Sai Yendamuri, MD, chair of the Department of Thoracic Surgery and director of the Thoracic Surgery Laboratory at Roswell Park Comprehensive Cancer Center in Buffalo, New York, is leading a phase 2 trial exploring whether metformin can prevent lung cancer in people with overweight or obesity who are at a high risk for the malignancy.

The study, which has accrued about 60% of its estimated enrollment, also will assess whether metformin can reprogram participants’ immune systems, with a view toward reducing the activity of regulatory T cells that are linked to development of tumors.

“In our preclinical and retrospective clinical data, we found that metformin had anticancer effects but only if the patients were overweight,” Dr. Yendamuri said. “In mice, we find that obesity increases regulatory T-cell function, which suppresses the immune system of the lungs. This effect is reversed by metformin.” The team is conducting the current study to examine if this happens in patients, as well. Results are expected next year.

Research is underway in other tumor types, including oral and endometrial, and brain cancers.

Preventing Alzheimer’s Disease

Cognitive function — or at least delaying its erosion — represents another front for metformin. José A. Luchsinger, MD, MPH, vice-chair for clinical and epidemiological research and director of the section on geriatrics, gerontology, and aging at Columbia University Irving Medical Center in New York City, is heading a phase 2/3 randomized controlled trial assessing the ability of the drug to prevent Alzheimer›s disease.

The study investigators hope to enroll 326 men and women aged 55-90 years with early and late mild cognitive impairment, overweight or obesity, and no diabetes.

“The hypothesis is that improving insulin and glucose levels can lead to lowering the risk of Alzheimer’s disease,” Dr. Luchsinger said. Recruitment should be complete by the end of 2024 and results are expected in late 2026.

Similar studies are underway in Europe and Asia.

Other areas of investigation, while tantalizing, are mostly in early stages, although bolstered by preclinical and mechanistic studies. The authors of a recent review on the potential mechanisms of action of metformin and existing evidence of the drug›s effectiveness — or lack thereof — in treating diseases other than diabetes, wrote: “Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an antihyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct antiviral actions.”

Off-Label Uses

Metformin currently is approved by the US Food and Drug Administration only for the treatment of type 2 diabetes, although it is also the only antidiabetic medication for prediabetes currently recommended by the American Diabetes Association.

Some studies currently are looking at its use in a variety of off-label indications, including obesity, gestational diabetes, weight gain from antipsychotics, and polycystic ovary syndrome.

For the most part, metformin is considered a safe drug, but it is not risk-free, Dr. Jain cautioned.

“Although it would certainly be helpful to see if this inexpensive medication that’s universally available can help in disease states, one shouldn’t overlook the potential risk of adverse effects, such as gastrointestinal, potential vitamin B12 deficiency, blunting of skeletal muscle development and the rare risk of lactic acidosis in those with kidney impairment,” he said.

“Similarly, with recent reports of the carcinogenic potential of certain formulations of long-acting metformin that contained NDMA [N-nitrosodimethylamine], it would be imperative that these kinks are removed before we incorporate metformin as the gift that keeps giving.”

Dr. Jain reported financial relationships with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk. Dr. Yendamuri disclosed serving on the scientific advisory board member of Karkinos Healthcare and research funding from Lumeda for the metformin study. Dr. Luchsinger reported receiving donated metformin and matching placebo from EMD Serono, a subsidiary of Merck, for the MAP study. Dr. Schwartz received research support from the US Department of Veterans Affairs as National Chair of the VA-IMPACT trial.
 

A version of this article appeared on Medscape.com.

As a front-line treatment for type 2 diabetes, metformin is among the most widely prescribed drugs in the United States. In 2021 alone, clinicians wrote more than 91 million orders for the medication — up from 40 million 2004.

But is metformin just getting started? Emerging evidence suggests the drug may be effective for a much broader range of conditions beyond managing high blood glucose, including various cancers, obesity, liver disease, cardiovascular, neurodegenerative, and renal diseases. As the evidence for diverse uses accumulates, many trials have launched, with researchers looking to expand metformin’s indications and validate or explore new directions.

Metformin’s long history as a pharmaceutical includes an herbal ancestry, recognition in 1918 for its ability to lower blood glucose, being cast aside because of toxicity fears in the 1930s, rediscovery and synthesis in Europe in the 1940s, the first reported use for diabetes in 1957, and approval in the United States in 1994.

The drug has maintained its place as the preferred first-line treatment for type 2 diabetes since 2011, when it was first included in the World Health Organization’s essential medicines list.

“The focus hitherto has been primarily on its insulin sensitization effects,” Akshay Jain, MD, a clinical and research endocrinologist at TLC Diabetes and Endocrinology, in Surrey, British Columbia, Canada, told this news organization.

“The recent surge of renewed interest is in part related to its postulated effects on multiple other receptors,” he said. “In my mind, the metformin data on coronary artery disease reduction and cancer-protective effects have come farther along than other disease states.”

Cardiovascular Outcomes

Gregory G. Schwartz, MD, PhD, chief of the cardiology section at Rocky Mountain Regional VA Medical Center and professor of medicine at the University of Colorado School of Medicine in Aurora, is leading the VA-IMPACT trial. Despite metformin’s long history and widespread use, he said his study is the first placebo-controlled cardiovascular outcomes trial of the drug.

Launched in 2023, the study tests the hypothesis that metformin reduces the risk for death or nonfatal ischemic cardiovascular events in patients with prediabetes and established coronary, cerebrovascular, or peripheral artery disease, Dr. Schwartz said. The trial is being conducted at roughly 40 VA medical centers, with a planned enrollment of 7410 patients. The estimated completion date is March 2029.

“The principal mechanism of action of metformin is through activation of AMP [adenosine monophosphate]–activated protein kinase, a central pathway in metabolic regulation, cell protection, and survival,” Dr. Schwartz explained. “Experimental data have demonstrated attenuated development of atherosclerosis, reduced myocardial infarct size, improved endothelial function, and antiarrhythmic actions — none of those dependent on the presence of diabetes.”

Dr. Schwartz and his colleagues decided to test their hypothesis in people with prediabetes, rather than diabetes, to create a “true placebo-controlled comparison,” he said.

“If patients with type 2 diabetes had been chosen, there would be potential for confounding because a placebo group would require more treatment with other active antihyperglycemic medications to achieve the same degree of glycemic control as a metformin group,” Dr. Schwartz said.

“If proven efficacious in the VA-IMPACT trial, metformin could provide an inexpensive, generally safe, and well-tolerated approach to reduce cardiovascular morbidity and mortality in a large segment of the population,” Dr. Schwartz added. “Perhaps the old dog can learn some new tricks.”

Other recruiting trials looking at cardiovascular-related outcomes include Met-PEF, LIMIT, and Metformin as an Adjunctive Therapy to Catheter Ablation in Atrial Fibrillation.

Reducing Cancer Risks

Sai Yendamuri, MD, chair of the Department of Thoracic Surgery and director of the Thoracic Surgery Laboratory at Roswell Park Comprehensive Cancer Center in Buffalo, New York, is leading a phase 2 trial exploring whether metformin can prevent lung cancer in people with overweight or obesity who are at a high risk for the malignancy.

The study, which has accrued about 60% of its estimated enrollment, also will assess whether metformin can reprogram participants’ immune systems, with a view toward reducing the activity of regulatory T cells that are linked to development of tumors.

“In our preclinical and retrospective clinical data, we found that metformin had anticancer effects but only if the patients were overweight,” Dr. Yendamuri said. “In mice, we find that obesity increases regulatory T-cell function, which suppresses the immune system of the lungs. This effect is reversed by metformin.” The team is conducting the current study to examine if this happens in patients, as well. Results are expected next year.

Research is underway in other tumor types, including oral and endometrial, and brain cancers.

Preventing Alzheimer’s Disease

Cognitive function — or at least delaying its erosion — represents another front for metformin. José A. Luchsinger, MD, MPH, vice-chair for clinical and epidemiological research and director of the section on geriatrics, gerontology, and aging at Columbia University Irving Medical Center in New York City, is heading a phase 2/3 randomized controlled trial assessing the ability of the drug to prevent Alzheimer›s disease.

The study investigators hope to enroll 326 men and women aged 55-90 years with early and late mild cognitive impairment, overweight or obesity, and no diabetes.

“The hypothesis is that improving insulin and glucose levels can lead to lowering the risk of Alzheimer’s disease,” Dr. Luchsinger said. Recruitment should be complete by the end of 2024 and results are expected in late 2026.

Similar studies are underway in Europe and Asia.

Other areas of investigation, while tantalizing, are mostly in early stages, although bolstered by preclinical and mechanistic studies. The authors of a recent review on the potential mechanisms of action of metformin and existing evidence of the drug›s effectiveness — or lack thereof — in treating diseases other than diabetes, wrote: “Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an antihyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct antiviral actions.”

Off-Label Uses

Metformin currently is approved by the US Food and Drug Administration only for the treatment of type 2 diabetes, although it is also the only antidiabetic medication for prediabetes currently recommended by the American Diabetes Association.

Some studies currently are looking at its use in a variety of off-label indications, including obesity, gestational diabetes, weight gain from antipsychotics, and polycystic ovary syndrome.

For the most part, metformin is considered a safe drug, but it is not risk-free, Dr. Jain cautioned.

“Although it would certainly be helpful to see if this inexpensive medication that’s universally available can help in disease states, one shouldn’t overlook the potential risk of adverse effects, such as gastrointestinal, potential vitamin B12 deficiency, blunting of skeletal muscle development and the rare risk of lactic acidosis in those with kidney impairment,” he said.

“Similarly, with recent reports of the carcinogenic potential of certain formulations of long-acting metformin that contained NDMA [N-nitrosodimethylamine], it would be imperative that these kinks are removed before we incorporate metformin as the gift that keeps giving.”

Dr. Jain reported financial relationships with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk. Dr. Yendamuri disclosed serving on the scientific advisory board member of Karkinos Healthcare and research funding from Lumeda for the metformin study. Dr. Luchsinger reported receiving donated metformin and matching placebo from EMD Serono, a subsidiary of Merck, for the MAP study. Dr. Schwartz received research support from the US Department of Veterans Affairs as National Chair of the VA-IMPACT trial.
 

A version of this article appeared on Medscape.com.

As a front-line treatment for type 2 diabetes, metformin is among the most widely prescribed drugs in the United States. In 2021 alone, clinicians wrote more than 91 million orders for the medication — up from 40 million 2004.

But is metformin just getting started? Emerging evidence suggests the drug may be effective for a much broader range of conditions beyond managing high blood glucose, including various cancers, obesity, liver disease, cardiovascular, neurodegenerative, and renal diseases. As the evidence for diverse uses accumulates, many trials have launched, with researchers looking to expand metformin’s indications and validate or explore new directions.

Metformin’s long history as a pharmaceutical includes an herbal ancestry, recognition in 1918 for its ability to lower blood glucose, being cast aside because of toxicity fears in the 1930s, rediscovery and synthesis in Europe in the 1940s, the first reported use for diabetes in 1957, and approval in the United States in 1994.

The drug has maintained its place as the preferred first-line treatment for type 2 diabetes since 2011, when it was first included in the World Health Organization’s essential medicines list.

“The focus hitherto has been primarily on its insulin sensitization effects,” Akshay Jain, MD, a clinical and research endocrinologist at TLC Diabetes and Endocrinology, in Surrey, British Columbia, Canada, told this news organization.

“The recent surge of renewed interest is in part related to its postulated effects on multiple other receptors,” he said. “In my mind, the metformin data on coronary artery disease reduction and cancer-protective effects have come farther along than other disease states.”

Cardiovascular Outcomes

Gregory G. Schwartz, MD, PhD, chief of the cardiology section at Rocky Mountain Regional VA Medical Center and professor of medicine at the University of Colorado School of Medicine in Aurora, is leading the VA-IMPACT trial. Despite metformin’s long history and widespread use, he said his study is the first placebo-controlled cardiovascular outcomes trial of the drug.

Launched in 2023, the study tests the hypothesis that metformin reduces the risk for death or nonfatal ischemic cardiovascular events in patients with prediabetes and established coronary, cerebrovascular, or peripheral artery disease, Dr. Schwartz said. The trial is being conducted at roughly 40 VA medical centers, with a planned enrollment of 7410 patients. The estimated completion date is March 2029.

“The principal mechanism of action of metformin is through activation of AMP [adenosine monophosphate]–activated protein kinase, a central pathway in metabolic regulation, cell protection, and survival,” Dr. Schwartz explained. “Experimental data have demonstrated attenuated development of atherosclerosis, reduced myocardial infarct size, improved endothelial function, and antiarrhythmic actions — none of those dependent on the presence of diabetes.”

Dr. Schwartz and his colleagues decided to test their hypothesis in people with prediabetes, rather than diabetes, to create a “true placebo-controlled comparison,” he said.

“If patients with type 2 diabetes had been chosen, there would be potential for confounding because a placebo group would require more treatment with other active antihyperglycemic medications to achieve the same degree of glycemic control as a metformin group,” Dr. Schwartz said.

“If proven efficacious in the VA-IMPACT trial, metformin could provide an inexpensive, generally safe, and well-tolerated approach to reduce cardiovascular morbidity and mortality in a large segment of the population,” Dr. Schwartz added. “Perhaps the old dog can learn some new tricks.”

Other recruiting trials looking at cardiovascular-related outcomes include Met-PEF, LIMIT, and Metformin as an Adjunctive Therapy to Catheter Ablation in Atrial Fibrillation.

Reducing Cancer Risks

Sai Yendamuri, MD, chair of the Department of Thoracic Surgery and director of the Thoracic Surgery Laboratory at Roswell Park Comprehensive Cancer Center in Buffalo, New York, is leading a phase 2 trial exploring whether metformin can prevent lung cancer in people with overweight or obesity who are at a high risk for the malignancy.

The study, which has accrued about 60% of its estimated enrollment, also will assess whether metformin can reprogram participants’ immune systems, with a view toward reducing the activity of regulatory T cells that are linked to development of tumors.

“In our preclinical and retrospective clinical data, we found that metformin had anticancer effects but only if the patients were overweight,” Dr. Yendamuri said. “In mice, we find that obesity increases regulatory T-cell function, which suppresses the immune system of the lungs. This effect is reversed by metformin.” The team is conducting the current study to examine if this happens in patients, as well. Results are expected next year.

Research is underway in other tumor types, including oral and endometrial, and brain cancers.

Preventing Alzheimer’s Disease

Cognitive function — or at least delaying its erosion — represents another front for metformin. José A. Luchsinger, MD, MPH, vice-chair for clinical and epidemiological research and director of the section on geriatrics, gerontology, and aging at Columbia University Irving Medical Center in New York City, is heading a phase 2/3 randomized controlled trial assessing the ability of the drug to prevent Alzheimer›s disease.

The study investigators hope to enroll 326 men and women aged 55-90 years with early and late mild cognitive impairment, overweight or obesity, and no diabetes.

“The hypothesis is that improving insulin and glucose levels can lead to lowering the risk of Alzheimer’s disease,” Dr. Luchsinger said. Recruitment should be complete by the end of 2024 and results are expected in late 2026.

Similar studies are underway in Europe and Asia.

Other areas of investigation, while tantalizing, are mostly in early stages, although bolstered by preclinical and mechanistic studies. The authors of a recent review on the potential mechanisms of action of metformin and existing evidence of the drug›s effectiveness — or lack thereof — in treating diseases other than diabetes, wrote: “Collectively, these data raise the question: Is metformin a drug for all diseases? It remains unclear as to whether all of these putative beneficial effects are secondary to its actions as an antihyperglycemic and insulin-sensitizing drug, or result from other cellular actions, including inhibition of mTOR (mammalian target for rapamycin), or direct antiviral actions.”

Off-Label Uses

Metformin currently is approved by the US Food and Drug Administration only for the treatment of type 2 diabetes, although it is also the only antidiabetic medication for prediabetes currently recommended by the American Diabetes Association.

Some studies currently are looking at its use in a variety of off-label indications, including obesity, gestational diabetes, weight gain from antipsychotics, and polycystic ovary syndrome.

For the most part, metformin is considered a safe drug, but it is not risk-free, Dr. Jain cautioned.

“Although it would certainly be helpful to see if this inexpensive medication that’s universally available can help in disease states, one shouldn’t overlook the potential risk of adverse effects, such as gastrointestinal, potential vitamin B12 deficiency, blunting of skeletal muscle development and the rare risk of lactic acidosis in those with kidney impairment,” he said.

“Similarly, with recent reports of the carcinogenic potential of certain formulations of long-acting metformin that contained NDMA [N-nitrosodimethylamine], it would be imperative that these kinks are removed before we incorporate metformin as the gift that keeps giving.”

Dr. Jain reported financial relationships with Abbott, Amgen, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Medtronic, Merck, and Novo Nordisk. Dr. Yendamuri disclosed serving on the scientific advisory board member of Karkinos Healthcare and research funding from Lumeda for the metformin study. Dr. Luchsinger reported receiving donated metformin and matching placebo from EMD Serono, a subsidiary of Merck, for the MAP study. Dr. Schwartz received research support from the US Department of Veterans Affairs as National Chair of the VA-IMPACT trial.
 

A version of this article appeared on Medscape.com.

Bariatric surgery appears to decrease the risk for some cancers, but it may increase the risk for others, particularly colorectal cancer (CRC), according to a synthesis of current evidence.

“There has been a recent burst of studies examining the association between bariatric surgery and the longitudinal risks of developing cancer,” corresponding author Zhi Ven Fong, MD, MPH, DrPH, surgical oncologist, Mayo Clinic Arizona, Phoenix, said in an interview. “However, there has not been a rigorous and critical analysis of the data published to date.”

In evaluating research showing an association between bariatric surgery and longitudinal cancer risk, the investigators found that the quality of the studies and their findings are “heterogeneous and might be susceptible to bias,” Dr. Fong said.

Bariatric surgery appears to have the strongest and most consistent association with the reduction of breast, ovarian, and endometrial cancer risk, first author Pei-Wen Lim, MD, MS, bariatric surgeon at Mayo Clinic Arizona, Phoenix, told this news organization. “However, there have been concerning signals from preclinical and epidemiological studies that bariatric surgery may be associated with a higher risk of developing colorectal cancers,” she added.

The authors cautioned against certain changes in clinical management.

“First, cancer surveillance frequency should not be altered after bariatric surgery because of any assumed reduction in longitudinal cancer risk, and surveillance strategy should mirror that of an average-risk individual,” they wrote. “Secondly, the indications for bariatric surgery should not be expanded for the purpose of cancer-risk mitigation.”

The review was published online in JAMA Surgery.
 

Protection Against Hormone-Related Cancers

The authors pointed to several studies that appear to support the association between bariatric surgery and decreased risk for hormone-related cancers.

Among them is an observational study of 6781 patients in Canada that showed a significant reduction in breast cancer risk at a median follow-up of 5 years in those who had bariatric surgery vs those who did not (P = .01).

The largest study to date on risk for hormone-related cancer after bariatric surgery was conducted using New York State data for 302,883 women.

It showed a lower rate of breast, endometrial, and ovarian cancers after bariatric surgery (hazard ratio [HR], 0.78; P < .001), with Roux-en-Y gastric bypass conferring the greatest benefit compared with laparoscopic sleeve gastrectomy (HR, 0.66; P = .006) and laparoscopic adjustable gastric banding (HR, 0.83; P = .006).

Beyond the shared mechanisms explaining obesity and cancer risk, a proposed explanation for the strong, consistent association between bariatric surgery and hormone-sensitive cancers is the role obesity-related changes in estrogen stimulation play in development of such cancers, the authors noted.
 

Association With GI Cancers

The association between bariatric surgery and development of esophageal, gastric, liver, and pancreas cancers is less clear. The data are heterogeneous, with studies showing either no association or decreased longitudinal incidence, the authors reported.

The data are also mixed when it comes to CRC. Epidemiological studies have demonstrated decreased longitudinal incidence of colon and rectal cancer after bariatric surgery; however, two studies have suggested an increased CRC risk after bariatric surgery, the authors noted.

A 15-year study from England that matched 8794 patients with obesity who underwent bariatric surgery with 8794 patients with obesity who did not have the surgery showed that gastric bypass (but not gastric banding or sleeve gastrectomy) was associated with a greater than twofold increased risk of developing colon and rectal cancer (odds ratio, 2.63).

These findings were corroborated in a Swedish cohort study with more than 10 years of follow-up data.

One potential explanation for the heterogeneous findings is that “present studies do not discriminate the sub-types of colon and rectal cancer, with bariatric surgery possibly increasing the incidence of colitis-associated cancers but not hereditary cancers,” the authors wrote.

“The mechanism by which gastric bypass may increase the risk of colorectal cancer is through changes in the gut’s microbiome. These changes in gut flora may triumph the protective effect of weight loss on the development of colorectal cancers,” Dr. Fong said.

Prospective studies are necessary to better delineate CRC risk after bariatric surgery, the authors wrote.
 

Benefits Outweigh Risk

“Ultimately, it has been proven that bariatric surgery saves lives by improving the metabolic profile of patients with obesity through reduction in cardiovascular risk factors such as hypertension, diabetes, and nonalcoholic fatty liver disease,” Dr. Lim said.

“If patients qualify for bariatric surgery on the basis of their BMI or comorbidities, they should pursue it for its metabolic benefits, but perhaps consider timely or closer-interval screening colonoscopies to monitor for potential colorectal cancer development,” Dr. Lim added.

When asked to comment on the review, Marina Kurian, MD, president, American Society for Metabolic and Bariatric Surgery, also pointed to the advantages of bariatric surgery in reducing major adverse cardiovascular events and improving hypertension, hyperlipidemia, and diabetes.

Bariatric surgery reduces many types of cancers, although the data specific to CRC risk with bariatric surgery are mixed, she added.

“The jury is still out,” said Dr. Kurian, clinical professor of surgery at NYU Langone Health in New York, who was not involved in the review. “There are papers and meta-analyses that show benefit even in colorectal cancer, but then there are a couple of papers out there that suggest a risk that seems to be specific to men.

“It could just be a numbers game, where we may not have enough data. We need more granular data that will help address these nuances and really determine what is the actual risk,” Dr. Kurian said. “But overall, for cancer, bariatric surgery is a win.”

This research had no specific funding. Dr. Fong and Dr. Lim had no relevant disclosures. Dr. Kurian disclosed relationships with Allergan, Allurion, CineMed, CSATS, Ezisurg Medical, Hernon, Johnson & Johnson, Medtronic, Novo, Stryker, and Vivus.
 

A version of this article appeared on Medscape.com.

Bariatric surgery appears to decrease the risk for some cancers, but it may increase the risk for others, particularly colorectal cancer (CRC), according to a synthesis of current evidence.

“There has been a recent burst of studies examining the association between bariatric surgery and the longitudinal risks of developing cancer,” corresponding author Zhi Ven Fong, MD, MPH, DrPH, surgical oncologist, Mayo Clinic Arizona, Phoenix, said in an interview. “However, there has not been a rigorous and critical analysis of the data published to date.”

In evaluating research showing an association between bariatric surgery and longitudinal cancer risk, the investigators found that the quality of the studies and their findings are “heterogeneous and might be susceptible to bias,” Dr. Fong said.

Bariatric surgery appears to have the strongest and most consistent association with the reduction of breast, ovarian, and endometrial cancer risk, first author Pei-Wen Lim, MD, MS, bariatric surgeon at Mayo Clinic Arizona, Phoenix, told this news organization. “However, there have been concerning signals from preclinical and epidemiological studies that bariatric surgery may be associated with a higher risk of developing colorectal cancers,” she added.

The authors cautioned against certain changes in clinical management.

“First, cancer surveillance frequency should not be altered after bariatric surgery because of any assumed reduction in longitudinal cancer risk, and surveillance strategy should mirror that of an average-risk individual,” they wrote. “Secondly, the indications for bariatric surgery should not be expanded for the purpose of cancer-risk mitigation.”

The review was published online in JAMA Surgery.
 

Protection Against Hormone-Related Cancers

The authors pointed to several studies that appear to support the association between bariatric surgery and decreased risk for hormone-related cancers.

Among them is an observational study of 6781 patients in Canada that showed a significant reduction in breast cancer risk at a median follow-up of 5 years in those who had bariatric surgery vs those who did not (P = .01).

The largest study to date on risk for hormone-related cancer after bariatric surgery was conducted using New York State data for 302,883 women.

It showed a lower rate of breast, endometrial, and ovarian cancers after bariatric surgery (hazard ratio [HR], 0.78; P < .001), with Roux-en-Y gastric bypass conferring the greatest benefit compared with laparoscopic sleeve gastrectomy (HR, 0.66; P = .006) and laparoscopic adjustable gastric banding (HR, 0.83; P = .006).

Beyond the shared mechanisms explaining obesity and cancer risk, a proposed explanation for the strong, consistent association between bariatric surgery and hormone-sensitive cancers is the role obesity-related changes in estrogen stimulation play in development of such cancers, the authors noted.
 

Association With GI Cancers

The association between bariatric surgery and development of esophageal, gastric, liver, and pancreas cancers is less clear. The data are heterogeneous, with studies showing either no association or decreased longitudinal incidence, the authors reported.

The data are also mixed when it comes to CRC. Epidemiological studies have demonstrated decreased longitudinal incidence of colon and rectal cancer after bariatric surgery; however, two studies have suggested an increased CRC risk after bariatric surgery, the authors noted.

A 15-year study from England that matched 8794 patients with obesity who underwent bariatric surgery with 8794 patients with obesity who did not have the surgery showed that gastric bypass (but not gastric banding or sleeve gastrectomy) was associated with a greater than twofold increased risk of developing colon and rectal cancer (odds ratio, 2.63).

These findings were corroborated in a Swedish cohort study with more than 10 years of follow-up data.

One potential explanation for the heterogeneous findings is that “present studies do not discriminate the sub-types of colon and rectal cancer, with bariatric surgery possibly increasing the incidence of colitis-associated cancers but not hereditary cancers,” the authors wrote.

“The mechanism by which gastric bypass may increase the risk of colorectal cancer is through changes in the gut’s microbiome. These changes in gut flora may triumph the protective effect of weight loss on the development of colorectal cancers,” Dr. Fong said.

Prospective studies are necessary to better delineate CRC risk after bariatric surgery, the authors wrote.
 

Benefits Outweigh Risk

“Ultimately, it has been proven that bariatric surgery saves lives by improving the metabolic profile of patients with obesity through reduction in cardiovascular risk factors such as hypertension, diabetes, and nonalcoholic fatty liver disease,” Dr. Lim said.

“If patients qualify for bariatric surgery on the basis of their BMI or comorbidities, they should pursue it for its metabolic benefits, but perhaps consider timely or closer-interval screening colonoscopies to monitor for potential colorectal cancer development,” Dr. Lim added.

When asked to comment on the review, Marina Kurian, MD, president, American Society for Metabolic and Bariatric Surgery, also pointed to the advantages of bariatric surgery in reducing major adverse cardiovascular events and improving hypertension, hyperlipidemia, and diabetes.

Bariatric surgery reduces many types of cancers, although the data specific to CRC risk with bariatric surgery are mixed, she added.

“The jury is still out,” said Dr. Kurian, clinical professor of surgery at NYU Langone Health in New York, who was not involved in the review. “There are papers and meta-analyses that show benefit even in colorectal cancer, but then there are a couple of papers out there that suggest a risk that seems to be specific to men.

“It could just be a numbers game, where we may not have enough data. We need more granular data that will help address these nuances and really determine what is the actual risk,” Dr. Kurian said. “But overall, for cancer, bariatric surgery is a win.”

This research had no specific funding. Dr. Fong and Dr. Lim had no relevant disclosures. Dr. Kurian disclosed relationships with Allergan, Allurion, CineMed, CSATS, Ezisurg Medical, Hernon, Johnson & Johnson, Medtronic, Novo, Stryker, and Vivus.
 

A version of this article appeared on Medscape.com.

Bariatric surgery appears to decrease the risk for some cancers, but it may increase the risk for others, particularly colorectal cancer (CRC), according to a synthesis of current evidence.

“There has been a recent burst of studies examining the association between bariatric surgery and the longitudinal risks of developing cancer,” corresponding author Zhi Ven Fong, MD, MPH, DrPH, surgical oncologist, Mayo Clinic Arizona, Phoenix, said in an interview. “However, there has not been a rigorous and critical analysis of the data published to date.”

In evaluating research showing an association between bariatric surgery and longitudinal cancer risk, the investigators found that the quality of the studies and their findings are “heterogeneous and might be susceptible to bias,” Dr. Fong said.

Bariatric surgery appears to have the strongest and most consistent association with the reduction of breast, ovarian, and endometrial cancer risk, first author Pei-Wen Lim, MD, MS, bariatric surgeon at Mayo Clinic Arizona, Phoenix, told this news organization. “However, there have been concerning signals from preclinical and epidemiological studies that bariatric surgery may be associated with a higher risk of developing colorectal cancers,” she added.

The authors cautioned against certain changes in clinical management.

“First, cancer surveillance frequency should not be altered after bariatric surgery because of any assumed reduction in longitudinal cancer risk, and surveillance strategy should mirror that of an average-risk individual,” they wrote. “Secondly, the indications for bariatric surgery should not be expanded for the purpose of cancer-risk mitigation.”

The review was published online in JAMA Surgery.
 

Protection Against Hormone-Related Cancers

The authors pointed to several studies that appear to support the association between bariatric surgery and decreased risk for hormone-related cancers.

Among them is an observational study of 6781 patients in Canada that showed a significant reduction in breast cancer risk at a median follow-up of 5 years in those who had bariatric surgery vs those who did not (P = .01).

The largest study to date on risk for hormone-related cancer after bariatric surgery was conducted using New York State data for 302,883 women.

It showed a lower rate of breast, endometrial, and ovarian cancers after bariatric surgery (hazard ratio [HR], 0.78; P < .001), with Roux-en-Y gastric bypass conferring the greatest benefit compared with laparoscopic sleeve gastrectomy (HR, 0.66; P = .006) and laparoscopic adjustable gastric banding (HR, 0.83; P = .006).

Beyond the shared mechanisms explaining obesity and cancer risk, a proposed explanation for the strong, consistent association between bariatric surgery and hormone-sensitive cancers is the role obesity-related changes in estrogen stimulation play in development of such cancers, the authors noted.
 

Association With GI Cancers

The association between bariatric surgery and development of esophageal, gastric, liver, and pancreas cancers is less clear. The data are heterogeneous, with studies showing either no association or decreased longitudinal incidence, the authors reported.

The data are also mixed when it comes to CRC. Epidemiological studies have demonstrated decreased longitudinal incidence of colon and rectal cancer after bariatric surgery; however, two studies have suggested an increased CRC risk after bariatric surgery, the authors noted.

A 15-year study from England that matched 8794 patients with obesity who underwent bariatric surgery with 8794 patients with obesity who did not have the surgery showed that gastric bypass (but not gastric banding or sleeve gastrectomy) was associated with a greater than twofold increased risk of developing colon and rectal cancer (odds ratio, 2.63).

These findings were corroborated in a Swedish cohort study with more than 10 years of follow-up data.

One potential explanation for the heterogeneous findings is that “present studies do not discriminate the sub-types of colon and rectal cancer, with bariatric surgery possibly increasing the incidence of colitis-associated cancers but not hereditary cancers,” the authors wrote.

“The mechanism by which gastric bypass may increase the risk of colorectal cancer is through changes in the gut’s microbiome. These changes in gut flora may triumph the protective effect of weight loss on the development of colorectal cancers,” Dr. Fong said.

Prospective studies are necessary to better delineate CRC risk after bariatric surgery, the authors wrote.
 

Benefits Outweigh Risk

“Ultimately, it has been proven that bariatric surgery saves lives by improving the metabolic profile of patients with obesity through reduction in cardiovascular risk factors such as hypertension, diabetes, and nonalcoholic fatty liver disease,” Dr. Lim said.

“If patients qualify for bariatric surgery on the basis of their BMI or comorbidities, they should pursue it for its metabolic benefits, but perhaps consider timely or closer-interval screening colonoscopies to monitor for potential colorectal cancer development,” Dr. Lim added.

When asked to comment on the review, Marina Kurian, MD, president, American Society for Metabolic and Bariatric Surgery, also pointed to the advantages of bariatric surgery in reducing major adverse cardiovascular events and improving hypertension, hyperlipidemia, and diabetes.

Bariatric surgery reduces many types of cancers, although the data specific to CRC risk with bariatric surgery are mixed, she added.

“The jury is still out,” said Dr. Kurian, clinical professor of surgery at NYU Langone Health in New York, who was not involved in the review. “There are papers and meta-analyses that show benefit even in colorectal cancer, but then there are a couple of papers out there that suggest a risk that seems to be specific to men.

“It could just be a numbers game, where we may not have enough data. We need more granular data that will help address these nuances and really determine what is the actual risk,” Dr. Kurian said. “But overall, for cancer, bariatric surgery is a win.”

This research had no specific funding. Dr. Fong and Dr. Lim had no relevant disclosures. Dr. Kurian disclosed relationships with Allergan, Allurion, CineMed, CSATS, Ezisurg Medical, Hernon, Johnson & Johnson, Medtronic, Novo, Stryker, and Vivus.
 

A version of this article appeared on Medscape.com.

TOPLINE:

A diet with a low glycemic index (GI) had protective effects against diabetes and other chronic diseases similar to those of a diet high in fiber and whole grains.

METHODOLOGY:

• A 2019 Lancet report from the World Health Organization promoted fiber and whole grains to manage type 2 diabetes, cardiovascular disease, and cancer but rejected GI as a relevant dietary factor to prevent chronic diseases.
• This meta-analysis assessed the evidence of how GI and glycemic load are associated with four main outcomes and did the same for diets high in fiber and whole grain.
• Researchers identified 10 large prospective cohort studies (each including ≥ 100,000 participants) that assessed associations of GI, glycemic load, and fiber and whole grains with the outcomes of interest.
• The mean age was 56 years, and the mean follow-up duration was 12.6 years.
• The primary outcomes were incidence of type 2 diabetes, cardiovascular diseases and its components, diabetes-related cancers, and all-cause mortality.

TAKEAWAY:

• Compared with low-GI diets, high-GI diets were associated with an increased risk for:
• Type 2 diabetes (relative risk [RR], 1.27; P < .0001)
• Total cardiovascular disease (RR, 1.15; P < .0001)
• Diabetes-related cancers (RR, 1.05; P = .0001)
• All-cause mortality (RR, 1.08; P < .0001), statistically significant in women only.
• Foods with high glycemic load were associated with an increased risk for incident type 2 diabetes (RR, 1.15; P < .0001) and total cardiovascular disease (RR, 1.15; P < .0001) than foods with a low glycemic load.
• A diet high in fiber and whole grains reduced the risk for all four outcomes, with the association being similar to that observed for low-GI diet.

IN PRACTICE:

“These findings justify the combination of GI with fiber and whole grains in dietary recommendations to reduce the risk of diabetes and related chronic diseases,” the authors wrote.

SOURCE:

This study was led by David J.A. Jenkins, MD, Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Ontario, Canada, and published online in The Lancet Diabetes & Endocrinology.

LIMITATIONS:

The lack of evaluation or absence of positive effects in some analyses may have led to a paucity of reported studies for some outcomes. Moreover, the findings for some outcomes may have had limited robustness because of a small difference in RR. Furthermore, only one or two cohorts were included to compare most disease outcomes related to GI with fiber and wholegrain exposure.

DISCLOSURES:

This study was funded by Banting and Best and the Karuna Foundation. The authors declared receiving research grants, payments, honoraria, and travel support from and having other ties with food and beverage growers, processors and manufacturers, as well as with foundations, chronic disease advocacy and research groups, professional societies, government organizations, and other sources.

A version of this article appeared on Medscape.com.

TOPLINE:

A diet with a low glycemic index (GI) had protective effects against diabetes and other chronic diseases similar to those of a diet high in fiber and whole grains.

METHODOLOGY:

• A 2019 Lancet report from the World Health Organization promoted fiber and whole grains to manage type 2 diabetes, cardiovascular disease, and cancer but rejected GI as a relevant dietary factor to prevent chronic diseases.
• This meta-analysis assessed the evidence of how GI and glycemic load are associated with four main outcomes and did the same for diets high in fiber and whole grain.
• Researchers identified 10 large prospective cohort studies (each including ≥ 100,000 participants) that assessed associations of GI, glycemic load, and fiber and whole grains with the outcomes of interest.
• The mean age was 56 years, and the mean follow-up duration was 12.6 years.
• The primary outcomes were incidence of type 2 diabetes, cardiovascular diseases and its components, diabetes-related cancers, and all-cause mortality.

TAKEAWAY:

• Compared with low-GI diets, high-GI diets were associated with an increased risk for:
• Type 2 diabetes (relative risk [RR], 1.27; P < .0001)
• Total cardiovascular disease (RR, 1.15; P < .0001)
• Diabetes-related cancers (RR, 1.05; P = .0001)
• All-cause mortality (RR, 1.08; P < .0001), statistically significant in women only.
• Foods with high glycemic load were associated with an increased risk for incident type 2 diabetes (RR, 1.15; P < .0001) and total cardiovascular disease (RR, 1.15; P < .0001) than foods with a low glycemic load.
• A diet high in fiber and whole grains reduced the risk for all four outcomes, with the association being similar to that observed for low-GI diet.

IN PRACTICE:

“These findings justify the combination of GI with fiber and whole grains in dietary recommendations to reduce the risk of diabetes and related chronic diseases,” the authors wrote.

SOURCE:

This study was led by David J.A. Jenkins, MD, Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Ontario, Canada, and published online in The Lancet Diabetes & Endocrinology.

LIMITATIONS:

The lack of evaluation or absence of positive effects in some analyses may have led to a paucity of reported studies for some outcomes. Moreover, the findings for some outcomes may have had limited robustness because of a small difference in RR. Furthermore, only one or two cohorts were included to compare most disease outcomes related to GI with fiber and wholegrain exposure.

DISCLOSURES:

This study was funded by Banting and Best and the Karuna Foundation. The authors declared receiving research grants, payments, honoraria, and travel support from and having other ties with food and beverage growers, processors and manufacturers, as well as with foundations, chronic disease advocacy and research groups, professional societies, government organizations, and other sources.

A version of this article appeared on Medscape.com.

TOPLINE:

A diet with a low glycemic index (GI) had protective effects against diabetes and other chronic diseases similar to those of a diet high in fiber and whole grains.

METHODOLOGY:

• A 2019 Lancet report from the World Health Organization promoted fiber and whole grains to manage type 2 diabetes, cardiovascular disease, and cancer but rejected GI as a relevant dietary factor to prevent chronic diseases.
• This meta-analysis assessed the evidence of how GI and glycemic load are associated with four main outcomes and did the same for diets high in fiber and whole grain.
• Researchers identified 10 large prospective cohort studies (each including ≥ 100,000 participants) that assessed associations of GI, glycemic load, and fiber and whole grains with the outcomes of interest.
• The mean age was 56 years, and the mean follow-up duration was 12.6 years.
• The primary outcomes were incidence of type 2 diabetes, cardiovascular diseases and its components, diabetes-related cancers, and all-cause mortality.

TAKEAWAY:

• Compared with low-GI diets, high-GI diets were associated with an increased risk for:
• Type 2 diabetes (relative risk [RR], 1.27; P < .0001)
• Total cardiovascular disease (RR, 1.15; P < .0001)
• Diabetes-related cancers (RR, 1.05; P = .0001)
• All-cause mortality (RR, 1.08; P < .0001), statistically significant in women only.
• Foods with high glycemic load were associated with an increased risk for incident type 2 diabetes (RR, 1.15; P < .0001) and total cardiovascular disease (RR, 1.15; P < .0001) than foods with a low glycemic load.
• A diet high in fiber and whole grains reduced the risk for all four outcomes, with the association being similar to that observed for low-GI diet.

IN PRACTICE:

“These findings justify the combination of GI with fiber and whole grains in dietary recommendations to reduce the risk of diabetes and related chronic diseases,” the authors wrote.

SOURCE:

This study was led by David J.A. Jenkins, MD, Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Ontario, Canada, and published online in The Lancet Diabetes & Endocrinology.

LIMITATIONS:

The lack of evaluation or absence of positive effects in some analyses may have led to a paucity of reported studies for some outcomes. Moreover, the findings for some outcomes may have had limited robustness because of a small difference in RR. Furthermore, only one or two cohorts were included to compare most disease outcomes related to GI with fiber and wholegrain exposure.

DISCLOSURES:

This study was funded by Banting and Best and the Karuna Foundation. The authors declared receiving research grants, payments, honoraria, and travel support from and having other ties with food and beverage growers, processors and manufacturers, as well as with foundations, chronic disease advocacy and research groups, professional societies, government organizations, and other sources.

A version of this article appeared on Medscape.com.

The explosion of interest in glucagon-like peptide 1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, has raised questions about what therapeutic effects this class of medication might have beyond their current indications for type 2 diabetes and obesity. 

Recent clinical trials have recently identified benefits from GLP-1 agents for the heart, liver, and kidneys, but the current evidence base is murkier regarding how the drugs may affect male fertility. 

Experts say the connection between GLP-1 RAs and improved male fertility makes sense biologically. For starters, overweight and obesity are strongly associated with male infertility in several overlapping ways. Obesity can disrupt hormones linked to fertility, increase the risk for defective sperm, adversely affect semen quality, and even make sexual intercourse more difficult due to obesity’s link to erectile dysfunction. As a result, GLP-1 RAs should at least in theory boost male fertility in men who take the drugs to lose weight. 

But animal studies and a handful of small trials and observational data point to the potential for GLP-1 RAs to improve male fertility in other ways.

A recent narrative review on GLP-1 RAs and male reproductive health, published in the journal Medicina in December 2023, surveyed the potential of the drugs for male infertility and offered reason for optimism. 

Hossein Sadeghi-Nejad, MD, director of urology at NYU Langone Health, New York, and a coauthor of the article, said that one reason he and his colleagues conducted their analysis was the known association between weight loss and an increase in testosterone.

“Most of the animal studies that are out there show that this class of drugs does affect testosterone levels,” Dr. Sadeghi-Nejad said; they wanted to better understand what other evidence showed about GLP-1 agonists and other fertility factors. 
 

Link Between Obesity and Fertility

The recent paper first reviews the well-established link between obesity and poorer fertility outcomes. 

“Certainly, obesity poses a significant societal problem with substantial impacts on both overall health and economic aspects,” senior author Ranjith Ramasamy, MD, associate professor of urology and director of the reproductive urology Fellowship program at the University of Miami’s Miller School of Medicine, told this news organization. “The escalating global obesity rates raise concerns, especially in the field of male infertility, where excessive body fat induces intrinsic hormonal changes leading to alterations, eventually, in semen parameters.”

The authors noted that obesity has been linked in the research to worse assisted reproductive technology (ART) outcomes and to subfecundity, taking more than 12 months to achieve pregnancy. They also referenced a systematic review that found men with obesity were more likely to have lower sperm counts and less viable sperm.

“From our standpoint, I think the key point was to raise awareness about the fact that obesity, because of the aromatization of testosterone to estradiol [from excess adipose tissue], will affect the hormonal axis and the availability of testosterone and, therefore, indirectly affects spermatogenesis,” Dr. Sadeghi-Nejad said. 

Obesity is also linked to lower levels of inhibin B, which stimulates testosterone secretion in Sertoli cells, which, when combined with the proinflammatory state of obesity, “results in a less favorable environment for sperm production,” he said. Finally, the link between obesity and poorer sexual function further inhibits fertility potential, he added. 

Until recently, the primary treatments for obesity in men experiencing fertility problems have been lifestyle modifications or surgical interventions. But the recent approval of GLP-1 RA drugs for obesity present an additional option depending on how these drugs affect other fertility parameters. 
 

Direct or Indirect Effects?

Most of the available evidence on GLP-RAs and sperm parameters comes from preclinical research. One of the few clinical trials, published last year in the Journal of Clinical Medicine, investigated the effects of liraglutide in men with metabolic hypogonadism, a body mass index between (BMI) 30 and 40, and severe erectile dysfunction. 

Among the 110 men enrolled in the study, only the 35 participants who said that they were not seeking fatherhood received liraglutide. After 4 months of treatment, these men had significantly improved semen concentration, motility, and morphology than did those wanting to conceive who received conventional fertility treatment. Erectile dysfunction was also more improved in the liraglutide group, according to the researchers. 

Though this study demonstrated the potential for liraglutide to treat metabolic hypogonadism, the men in that group also had greater weight loss and BMI reduction than the other participants. The review cited several other studies — albeit small ones — in which weight loss was associated with improvements in sperm parameters, including one randomized controlled trial in which one group lost weight with liraglutide and the other with lifestyle modifications; both groups showed increases in the concentration and number of sperm. 

One of the key questions requiring further research, then, is whether GLP-1 agents have direct effects on male fertility independent of a reduction in obesity. The randomized controlled trials comparing liraglutide and lifestyle modifications failed to find additional effects on semen in the men taking liraglutide; however, the study had only 56 participants, and results from liraglutide cannot be generalized to potential effects of semaglutide or tirzepatide, Dr. Sadeghi-Nejad said.

“Determining the relative contributions of weight loss versus direct drug actions on fertility outcomes remains challenging without robust data,” Dr. Ramasamy said. “While acknowledged that diet and physical activity positively impact fertility, confirming the synergistic role of GLP-1 receptor agonists requires evidence from well-designed randomized clinical trials.” 

Rodent studies suggest that GLP-1 RAs may independently affect testicular function because GLP-1 receptors exist in Sertoli and Leydig cells of the testes. In one study, for example, obese mice who received the GLP-1 agonist exenatide for 8 weeks had “improved sperm motility, DNA integrity, and decreased expression of pro-inflammatory cytokines,” the authors of the review reported. But the precise mechanisms aren’t well understood. 

“We know that there are GLP-1 receptors in the reproductive tract, but the extent of the downstream effect of stimulating those receptors, I don’t think we know well,” said John P. Lindsey II, MD, MEng, assistant professor of urology at University of California San Francisco Health. 

Other hormonal effects of GLP-1 agonists, such as stimulating insulin production and better regulating blood glucose levels, are better understood, said Raevti Bole, MD, a urologist at Cleveland Clinic, in Ohio, but still other effects of the drugs may not yet be identified.

“I think the really big unknown is whether these types of drugs have effects that are not hormonal on male fertility and what those effects are, and how those affect sperm,” Dr. Bole said. “For example, we know that these drugs slow gastric emptying. Is it possible that slow gastric emptying affects some of the nutrients that you absorb, and that could affect fertility?” Similarly, she said, it’s not clear whether GLP-1 agonists would have any effects on the thyroid that could then affect fertility. 
 

Effects on Offspring

Another open question about GLP-1 RAs and male fertility is their potential effects on the offspring, said Sriram Machineni, MBBS, associate professor of endocrinology at the Albert Einstein College of Medicine in New York City. The clinical trials involving the drugs for treating type 2 diabetes and obesity required both men and women to use contraception. If sperm contributing to a pregnancy are exposed to a GLP-1 agent, “we don’t know what the consequences could be,” Dr. Machineni said. “Just increasing the fertility of the man is not enough. We need to make sure it’s safe long-term for the fetus.”

Dr. Bole also pointed out the need for understanding potential effects in the fetus.

“We know that there are epigenetic changes that can happen to sperm that are influenced by the lifestyle and the physical health and environment of the parent,” Dr. Bole said. “So how could these drugs potentially affect those epigenetic changes that then potentially are passed on to the offspring? We don’t know that.” 

An ideal source for that data would be a cohort registry of people who are taking the medication and then cause a pregnancy. “They have a registry for pregnant women,” Dr. Machineni said, “but we need something similar for men.”

Dr. Sadeghi-Nejad said that he and his coauthors are working on developing a registry for men who take GLP-1 RAs that would enable long-term tracking of multiple andrologic outcomes, including fertility and sexual dysfunction. Such a registry could theoretically be useful in tracking pregnancy and offspring outcomes as well. 
 

Too Soon for Prescribing

Additional options for treating fertility in men with obesity would be welcome. Current treatments include the selective estrogen receptor modulator (SERM) clomiphene citrate and the aromatase inhibitor anastrozole. But these have their drawbacks, Dr. Sadeghi-Nejad pointed out; in the overweight population in particular, they “are not necessarily ideal,” he said.

“Although both are viable treatments for enhancing hormonal balance and semen parameters, clomiphene citrate has rare but documented side effects, including thromboembolism, gastrointestinal distress and occasional weight gain in men,” Dr. Sadeghi-Nejad and his colleagues wrote. “Furthermore, despite clomiphene citrate’s association with significant increases in sperm concentration, it is not universally effective, with a meta-analysis indicating a significant increase in sperm concentration in approximately 60% of men.” 

For men who have obesity and oligospermia but normal levels of testosterone and estradiol, “conventional pharmaceutical approaches like clomiphene may not be suitable,” the authors wrote. 

Still, GLP-1 RAs may have a role to play for this population. 

“I think it is within the wheelhouse of a reproductive urologist to consider those types of medications,” Dr. Lindsey said. For example, for a patient who has overweight or obesity, “does it make sense to think about doing clomiphene therapy, which we often do for someone who has low testosterone, in conjunction [with a GLP-1 agonist]? Maybe there’s a kind of an additive effect of having both on board.”

Dr. Ramasamy similarly noted that GLP-1 agonists cannot replace SERMs but may work “synergistically” with them.

“Despite the established popularity of GLP-1 receptor agonists, there may be some reluctance among urologists and fertility specialists to prescribe them, with some others advocating for their use to enhance semen parameters,” Dr. Ramasamy said. “However, robust scientific evidence is still lacking, necessitating caution and a wait for more substantial data.”

Even if GLP-1 RAs prove to have therapeutic benefit for fertility, considerations such as availability and cost may affect prescribing. 

“We do currently have safe and effective drugs that we use for male fertility, and those are generally nowhere near as expensive,” Dr. Bole said. “When we start talking about another drug that we can add, we have to think about the efficacy and the potential side effect but also, is this affordable for patients?” 

Eventually, once more evidence become available, all of the urologists who spoke with this news organization said that they expect discussion about the possible therapeutic utility of GLP-1 agonists to make its way into clinical guidelines.

“Obesity is such a huge impediment for fertility in the modern environment,” Dr. Machineni said. “We will have to clarify the use of these agents, so I think this will be a part of the guidelines some point, but I think we need more information.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the American Cancer Society. The review authors and other quoted physicians reported no disclosures. Dr. Machineni has consulted for Novo Nordisk and Lilly and has conducted clinical trials with semaglutide and tirzepatide for those companies. 
 

A version of this article appeared on Medscape.com.

The explosion of interest in glucagon-like peptide 1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, has raised questions about what therapeutic effects this class of medication might have beyond their current indications for type 2 diabetes and obesity. 

Recent clinical trials have recently identified benefits from GLP-1 agents for the heart, liver, and kidneys, but the current evidence base is murkier regarding how the drugs may affect male fertility. 

Experts say the connection between GLP-1 RAs and improved male fertility makes sense biologically. For starters, overweight and obesity are strongly associated with male infertility in several overlapping ways. Obesity can disrupt hormones linked to fertility, increase the risk for defective sperm, adversely affect semen quality, and even make sexual intercourse more difficult due to obesity’s link to erectile dysfunction. As a result, GLP-1 RAs should at least in theory boost male fertility in men who take the drugs to lose weight. 

But animal studies and a handful of small trials and observational data point to the potential for GLP-1 RAs to improve male fertility in other ways.

A recent narrative review on GLP-1 RAs and male reproductive health, published in the journal Medicina in December 2023, surveyed the potential of the drugs for male infertility and offered reason for optimism. 

Hossein Sadeghi-Nejad, MD, director of urology at NYU Langone Health, New York, and a coauthor of the article, said that one reason he and his colleagues conducted their analysis was the known association between weight loss and an increase in testosterone.

“Most of the animal studies that are out there show that this class of drugs does affect testosterone levels,” Dr. Sadeghi-Nejad said; they wanted to better understand what other evidence showed about GLP-1 agonists and other fertility factors. 
 

Link Between Obesity and Fertility

The recent paper first reviews the well-established link between obesity and poorer fertility outcomes. 

“Certainly, obesity poses a significant societal problem with substantial impacts on both overall health and economic aspects,” senior author Ranjith Ramasamy, MD, associate professor of urology and director of the reproductive urology Fellowship program at the University of Miami’s Miller School of Medicine, told this news organization. “The escalating global obesity rates raise concerns, especially in the field of male infertility, where excessive body fat induces intrinsic hormonal changes leading to alterations, eventually, in semen parameters.”

The authors noted that obesity has been linked in the research to worse assisted reproductive technology (ART) outcomes and to subfecundity, taking more than 12 months to achieve pregnancy. They also referenced a systematic review that found men with obesity were more likely to have lower sperm counts and less viable sperm.

“From our standpoint, I think the key point was to raise awareness about the fact that obesity, because of the aromatization of testosterone to estradiol [from excess adipose tissue], will affect the hormonal axis and the availability of testosterone and, therefore, indirectly affects spermatogenesis,” Dr. Sadeghi-Nejad said. 

Obesity is also linked to lower levels of inhibin B, which stimulates testosterone secretion in Sertoli cells, which, when combined with the proinflammatory state of obesity, “results in a less favorable environment for sperm production,” he said. Finally, the link between obesity and poorer sexual function further inhibits fertility potential, he added. 

Until recently, the primary treatments for obesity in men experiencing fertility problems have been lifestyle modifications or surgical interventions. But the recent approval of GLP-1 RA drugs for obesity present an additional option depending on how these drugs affect other fertility parameters. 
 

Direct or Indirect Effects?

Most of the available evidence on GLP-RAs and sperm parameters comes from preclinical research. One of the few clinical trials, published last year in the Journal of Clinical Medicine, investigated the effects of liraglutide in men with metabolic hypogonadism, a body mass index between (BMI) 30 and 40, and severe erectile dysfunction. 

Among the 110 men enrolled in the study, only the 35 participants who said that they were not seeking fatherhood received liraglutide. After 4 months of treatment, these men had significantly improved semen concentration, motility, and morphology than did those wanting to conceive who received conventional fertility treatment. Erectile dysfunction was also more improved in the liraglutide group, according to the researchers. 

Though this study demonstrated the potential for liraglutide to treat metabolic hypogonadism, the men in that group also had greater weight loss and BMI reduction than the other participants. The review cited several other studies — albeit small ones — in which weight loss was associated with improvements in sperm parameters, including one randomized controlled trial in which one group lost weight with liraglutide and the other with lifestyle modifications; both groups showed increases in the concentration and number of sperm. 

One of the key questions requiring further research, then, is whether GLP-1 agents have direct effects on male fertility independent of a reduction in obesity. The randomized controlled trials comparing liraglutide and lifestyle modifications failed to find additional effects on semen in the men taking liraglutide; however, the study had only 56 participants, and results from liraglutide cannot be generalized to potential effects of semaglutide or tirzepatide, Dr. Sadeghi-Nejad said.

“Determining the relative contributions of weight loss versus direct drug actions on fertility outcomes remains challenging without robust data,” Dr. Ramasamy said. “While acknowledged that diet and physical activity positively impact fertility, confirming the synergistic role of GLP-1 receptor agonists requires evidence from well-designed randomized clinical trials.” 

Rodent studies suggest that GLP-1 RAs may independently affect testicular function because GLP-1 receptors exist in Sertoli and Leydig cells of the testes. In one study, for example, obese mice who received the GLP-1 agonist exenatide for 8 weeks had “improved sperm motility, DNA integrity, and decreased expression of pro-inflammatory cytokines,” the authors of the review reported. But the precise mechanisms aren’t well understood. 

“We know that there are GLP-1 receptors in the reproductive tract, but the extent of the downstream effect of stimulating those receptors, I don’t think we know well,” said John P. Lindsey II, MD, MEng, assistant professor of urology at University of California San Francisco Health. 

Other hormonal effects of GLP-1 agonists, such as stimulating insulin production and better regulating blood glucose levels, are better understood, said Raevti Bole, MD, a urologist at Cleveland Clinic, in Ohio, but still other effects of the drugs may not yet be identified.

“I think the really big unknown is whether these types of drugs have effects that are not hormonal on male fertility and what those effects are, and how those affect sperm,” Dr. Bole said. “For example, we know that these drugs slow gastric emptying. Is it possible that slow gastric emptying affects some of the nutrients that you absorb, and that could affect fertility?” Similarly, she said, it’s not clear whether GLP-1 agonists would have any effects on the thyroid that could then affect fertility. 
 

Effects on Offspring

Another open question about GLP-1 RAs and male fertility is their potential effects on the offspring, said Sriram Machineni, MBBS, associate professor of endocrinology at the Albert Einstein College of Medicine in New York City. The clinical trials involving the drugs for treating type 2 diabetes and obesity required both men and women to use contraception. If sperm contributing to a pregnancy are exposed to a GLP-1 agent, “we don’t know what the consequences could be,” Dr. Machineni said. “Just increasing the fertility of the man is not enough. We need to make sure it’s safe long-term for the fetus.”

Dr. Bole also pointed out the need for understanding potential effects in the fetus.

“We know that there are epigenetic changes that can happen to sperm that are influenced by the lifestyle and the physical health and environment of the parent,” Dr. Bole said. “So how could these drugs potentially affect those epigenetic changes that then potentially are passed on to the offspring? We don’t know that.” 

An ideal source for that data would be a cohort registry of people who are taking the medication and then cause a pregnancy. “They have a registry for pregnant women,” Dr. Machineni said, “but we need something similar for men.”

Dr. Sadeghi-Nejad said that he and his coauthors are working on developing a registry for men who take GLP-1 RAs that would enable long-term tracking of multiple andrologic outcomes, including fertility and sexual dysfunction. Such a registry could theoretically be useful in tracking pregnancy and offspring outcomes as well. 
 

Too Soon for Prescribing

Additional options for treating fertility in men with obesity would be welcome. Current treatments include the selective estrogen receptor modulator (SERM) clomiphene citrate and the aromatase inhibitor anastrozole. But these have their drawbacks, Dr. Sadeghi-Nejad pointed out; in the overweight population in particular, they “are not necessarily ideal,” he said.

“Although both are viable treatments for enhancing hormonal balance and semen parameters, clomiphene citrate has rare but documented side effects, including thromboembolism, gastrointestinal distress and occasional weight gain in men,” Dr. Sadeghi-Nejad and his colleagues wrote. “Furthermore, despite clomiphene citrate’s association with significant increases in sperm concentration, it is not universally effective, with a meta-analysis indicating a significant increase in sperm concentration in approximately 60% of men.” 

For men who have obesity and oligospermia but normal levels of testosterone and estradiol, “conventional pharmaceutical approaches like clomiphene may not be suitable,” the authors wrote. 

Still, GLP-1 RAs may have a role to play for this population. 

“I think it is within the wheelhouse of a reproductive urologist to consider those types of medications,” Dr. Lindsey said. For example, for a patient who has overweight or obesity, “does it make sense to think about doing clomiphene therapy, which we often do for someone who has low testosterone, in conjunction [with a GLP-1 agonist]? Maybe there’s a kind of an additive effect of having both on board.”

Dr. Ramasamy similarly noted that GLP-1 agonists cannot replace SERMs but may work “synergistically” with them.

“Despite the established popularity of GLP-1 receptor agonists, there may be some reluctance among urologists and fertility specialists to prescribe them, with some others advocating for their use to enhance semen parameters,” Dr. Ramasamy said. “However, robust scientific evidence is still lacking, necessitating caution and a wait for more substantial data.”

Even if GLP-1 RAs prove to have therapeutic benefit for fertility, considerations such as availability and cost may affect prescribing. 

“We do currently have safe and effective drugs that we use for male fertility, and those are generally nowhere near as expensive,” Dr. Bole said. “When we start talking about another drug that we can add, we have to think about the efficacy and the potential side effect but also, is this affordable for patients?” 

Eventually, once more evidence become available, all of the urologists who spoke with this news organization said that they expect discussion about the possible therapeutic utility of GLP-1 agonists to make its way into clinical guidelines.

“Obesity is such a huge impediment for fertility in the modern environment,” Dr. Machineni said. “We will have to clarify the use of these agents, so I think this will be a part of the guidelines some point, but I think we need more information.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the American Cancer Society. The review authors and other quoted physicians reported no disclosures. Dr. Machineni has consulted for Novo Nordisk and Lilly and has conducted clinical trials with semaglutide and tirzepatide for those companies. 
 

A version of this article appeared on Medscape.com.

The explosion of interest in glucagon-like peptide 1 receptor agonists (GLP-1 RAs), such as semaglutide and tirzepatide, has raised questions about what therapeutic effects this class of medication might have beyond their current indications for type 2 diabetes and obesity. 

Recent clinical trials have recently identified benefits from GLP-1 agents for the heart, liver, and kidneys, but the current evidence base is murkier regarding how the drugs may affect male fertility. 

Experts say the connection between GLP-1 RAs and improved male fertility makes sense biologically. For starters, overweight and obesity are strongly associated with male infertility in several overlapping ways. Obesity can disrupt hormones linked to fertility, increase the risk for defective sperm, adversely affect semen quality, and even make sexual intercourse more difficult due to obesity’s link to erectile dysfunction. As a result, GLP-1 RAs should at least in theory boost male fertility in men who take the drugs to lose weight. 

But animal studies and a handful of small trials and observational data point to the potential for GLP-1 RAs to improve male fertility in other ways.

A recent narrative review on GLP-1 RAs and male reproductive health, published in the journal Medicina in December 2023, surveyed the potential of the drugs for male infertility and offered reason for optimism. 

Hossein Sadeghi-Nejad, MD, director of urology at NYU Langone Health, New York, and a coauthor of the article, said that one reason he and his colleagues conducted their analysis was the known association between weight loss and an increase in testosterone.

“Most of the animal studies that are out there show that this class of drugs does affect testosterone levels,” Dr. Sadeghi-Nejad said; they wanted to better understand what other evidence showed about GLP-1 agonists and other fertility factors. 
 

Link Between Obesity and Fertility

The recent paper first reviews the well-established link between obesity and poorer fertility outcomes. 

“Certainly, obesity poses a significant societal problem with substantial impacts on both overall health and economic aspects,” senior author Ranjith Ramasamy, MD, associate professor of urology and director of the reproductive urology Fellowship program at the University of Miami’s Miller School of Medicine, told this news organization. “The escalating global obesity rates raise concerns, especially in the field of male infertility, where excessive body fat induces intrinsic hormonal changes leading to alterations, eventually, in semen parameters.”

The authors noted that obesity has been linked in the research to worse assisted reproductive technology (ART) outcomes and to subfecundity, taking more than 12 months to achieve pregnancy. They also referenced a systematic review that found men with obesity were more likely to have lower sperm counts and less viable sperm.

“From our standpoint, I think the key point was to raise awareness about the fact that obesity, because of the aromatization of testosterone to estradiol [from excess adipose tissue], will affect the hormonal axis and the availability of testosterone and, therefore, indirectly affects spermatogenesis,” Dr. Sadeghi-Nejad said. 

Obesity is also linked to lower levels of inhibin B, which stimulates testosterone secretion in Sertoli cells, which, when combined with the proinflammatory state of obesity, “results in a less favorable environment for sperm production,” he said. Finally, the link between obesity and poorer sexual function further inhibits fertility potential, he added. 

Until recently, the primary treatments for obesity in men experiencing fertility problems have been lifestyle modifications or surgical interventions. But the recent approval of GLP-1 RA drugs for obesity present an additional option depending on how these drugs affect other fertility parameters. 
 

Direct or Indirect Effects?

Most of the available evidence on GLP-RAs and sperm parameters comes from preclinical research. One of the few clinical trials, published last year in the Journal of Clinical Medicine, investigated the effects of liraglutide in men with metabolic hypogonadism, a body mass index between (BMI) 30 and 40, and severe erectile dysfunction. 

Among the 110 men enrolled in the study, only the 35 participants who said that they were not seeking fatherhood received liraglutide. After 4 months of treatment, these men had significantly improved semen concentration, motility, and morphology than did those wanting to conceive who received conventional fertility treatment. Erectile dysfunction was also more improved in the liraglutide group, according to the researchers. 

Though this study demonstrated the potential for liraglutide to treat metabolic hypogonadism, the men in that group also had greater weight loss and BMI reduction than the other participants. The review cited several other studies — albeit small ones — in which weight loss was associated with improvements in sperm parameters, including one randomized controlled trial in which one group lost weight with liraglutide and the other with lifestyle modifications; both groups showed increases in the concentration and number of sperm. 

One of the key questions requiring further research, then, is whether GLP-1 agents have direct effects on male fertility independent of a reduction in obesity. The randomized controlled trials comparing liraglutide and lifestyle modifications failed to find additional effects on semen in the men taking liraglutide; however, the study had only 56 participants, and results from liraglutide cannot be generalized to potential effects of semaglutide or tirzepatide, Dr. Sadeghi-Nejad said.

“Determining the relative contributions of weight loss versus direct drug actions on fertility outcomes remains challenging without robust data,” Dr. Ramasamy said. “While acknowledged that diet and physical activity positively impact fertility, confirming the synergistic role of GLP-1 receptor agonists requires evidence from well-designed randomized clinical trials.” 

Rodent studies suggest that GLP-1 RAs may independently affect testicular function because GLP-1 receptors exist in Sertoli and Leydig cells of the testes. In one study, for example, obese mice who received the GLP-1 agonist exenatide for 8 weeks had “improved sperm motility, DNA integrity, and decreased expression of pro-inflammatory cytokines,” the authors of the review reported. But the precise mechanisms aren’t well understood. 

“We know that there are GLP-1 receptors in the reproductive tract, but the extent of the downstream effect of stimulating those receptors, I don’t think we know well,” said John P. Lindsey II, MD, MEng, assistant professor of urology at University of California San Francisco Health. 

Other hormonal effects of GLP-1 agonists, such as stimulating insulin production and better regulating blood glucose levels, are better understood, said Raevti Bole, MD, a urologist at Cleveland Clinic, in Ohio, but still other effects of the drugs may not yet be identified.

“I think the really big unknown is whether these types of drugs have effects that are not hormonal on male fertility and what those effects are, and how those affect sperm,” Dr. Bole said. “For example, we know that these drugs slow gastric emptying. Is it possible that slow gastric emptying affects some of the nutrients that you absorb, and that could affect fertility?” Similarly, she said, it’s not clear whether GLP-1 agonists would have any effects on the thyroid that could then affect fertility. 
 

Effects on Offspring

Another open question about GLP-1 RAs and male fertility is their potential effects on the offspring, said Sriram Machineni, MBBS, associate professor of endocrinology at the Albert Einstein College of Medicine in New York City. The clinical trials involving the drugs for treating type 2 diabetes and obesity required both men and women to use contraception. If sperm contributing to a pregnancy are exposed to a GLP-1 agent, “we don’t know what the consequences could be,” Dr. Machineni said. “Just increasing the fertility of the man is not enough. We need to make sure it’s safe long-term for the fetus.”

Dr. Bole also pointed out the need for understanding potential effects in the fetus.

“We know that there are epigenetic changes that can happen to sperm that are influenced by the lifestyle and the physical health and environment of the parent,” Dr. Bole said. “So how could these drugs potentially affect those epigenetic changes that then potentially are passed on to the offspring? We don’t know that.” 

An ideal source for that data would be a cohort registry of people who are taking the medication and then cause a pregnancy. “They have a registry for pregnant women,” Dr. Machineni said, “but we need something similar for men.”

Dr. Sadeghi-Nejad said that he and his coauthors are working on developing a registry for men who take GLP-1 RAs that would enable long-term tracking of multiple andrologic outcomes, including fertility and sexual dysfunction. Such a registry could theoretically be useful in tracking pregnancy and offspring outcomes as well. 
 

Too Soon for Prescribing

Additional options for treating fertility in men with obesity would be welcome. Current treatments include the selective estrogen receptor modulator (SERM) clomiphene citrate and the aromatase inhibitor anastrozole. But these have their drawbacks, Dr. Sadeghi-Nejad pointed out; in the overweight population in particular, they “are not necessarily ideal,” he said.

“Although both are viable treatments for enhancing hormonal balance and semen parameters, clomiphene citrate has rare but documented side effects, including thromboembolism, gastrointestinal distress and occasional weight gain in men,” Dr. Sadeghi-Nejad and his colleagues wrote. “Furthermore, despite clomiphene citrate’s association with significant increases in sperm concentration, it is not universally effective, with a meta-analysis indicating a significant increase in sperm concentration in approximately 60% of men.” 

For men who have obesity and oligospermia but normal levels of testosterone and estradiol, “conventional pharmaceutical approaches like clomiphene may not be suitable,” the authors wrote. 

Still, GLP-1 RAs may have a role to play for this population. 

“I think it is within the wheelhouse of a reproductive urologist to consider those types of medications,” Dr. Lindsey said. For example, for a patient who has overweight or obesity, “does it make sense to think about doing clomiphene therapy, which we often do for someone who has low testosterone, in conjunction [with a GLP-1 agonist]? Maybe there’s a kind of an additive effect of having both on board.”

Dr. Ramasamy similarly noted that GLP-1 agonists cannot replace SERMs but may work “synergistically” with them.

“Despite the established popularity of GLP-1 receptor agonists, there may be some reluctance among urologists and fertility specialists to prescribe them, with some others advocating for their use to enhance semen parameters,” Dr. Ramasamy said. “However, robust scientific evidence is still lacking, necessitating caution and a wait for more substantial data.”

Even if GLP-1 RAs prove to have therapeutic benefit for fertility, considerations such as availability and cost may affect prescribing. 

“We do currently have safe and effective drugs that we use for male fertility, and those are generally nowhere near as expensive,” Dr. Bole said. “When we start talking about another drug that we can add, we have to think about the efficacy and the potential side effect but also, is this affordable for patients?” 

Eventually, once more evidence become available, all of the urologists who spoke with this news organization said that they expect discussion about the possible therapeutic utility of GLP-1 agonists to make its way into clinical guidelines.

“Obesity is such a huge impediment for fertility in the modern environment,” Dr. Machineni said. “We will have to clarify the use of these agents, so I think this will be a part of the guidelines some point, but I think we need more information.”

The research was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the American Cancer Society. The review authors and other quoted physicians reported no disclosures. Dr. Machineni has consulted for Novo Nordisk and Lilly and has conducted clinical trials with semaglutide and tirzepatide for those companies. 
 

A version of this article appeared on Medscape.com.

Injectable weight loss drugs like Wegovy, Saxenda, and Zepbound have been getting all the glory lately, but they’re not for everyone. If the inconvenience or cost of weight-loss drugs isn’t for you, another approach may be boosting your gut microbiome.

So how does one do that, and how does it work?

“There are a lot of different factors naturally in weight gain and weight loss, so the gut microbiome is certainly not the only thing,” said Chris Damman, MD, a gastroenterologist at the University of Washington. He studies how food and the microbiome affect your health. “With that caveat, it probably is playing an important role.”
 

Trillions of Microbes

The idea that your gut is home to an enormous range of tiny organisms — microbes — has existed for more than 100 years, but only in the 21st century have scientists had the ability to delve into specifics. 

We now know you want a robust assortment of microbes in your gut, especially in the lower gut, your colon. They feast on fiber from the food you eat and turn it into substances your body needs. Those substances send signals all over your body.

If you don’t have enough microbes or have too many of the wrong kinds, it influences those signals, which can lead to health problems. Over the last 20 years, research has linked problems in the gut microbiome to a wide variety of conditions, including inflammatory bowel disease, autoimmune diseases like rheumatoid arthritis, metabolic ones like diabetes, and cardiovascular disease, asthma, and even autism.

Thanks to these efforts, we know a lot about the interactions between your gut and the rest of your body, but we don’t know exactly how many things happen — whether some teeny critters within your microbiome cause the issues or vice versa.

“That’s the problem with so much of the microbiome stuff,” said Elizabeth Hohmann, MD, a physician investigator at the Massachusetts General Research Institute. “Olympic athletes have a better gut microbiome than most people. Well, sure they do — because they’re paying attention to their diet, they’re getting enough rest. Correlation does not causation make.”
 

The American Diet Messes With Your Gut

If you’re a typical American, you eat a lot of ultra-processed foods — manufactured with a long ingredients list that includes additives or preservatives. According to one study, those foods make up 73% of our food supply. That can have a serious impact on gut health.

“When you process a food and mill it, it turns a whole food into tiny particles,” Dr. Damman said. “That makes the food highly digestible. But if you eat a stalk of broccoli, a large amount of that broccoli in the form of fiber and other things will make its way to your lower gut, where it will feed microbes.”

With heavily processed foods, on the other hand, most of it gets digested before it can reach your lower gut, which leaves your microbes without the energy they need to survive.

Rosa Krajmalnik-Brown, PhD, is director of the Biodesign Center for Health Through Microbiomes at Arizona State University. Her lab has done research into how microbes use the undigested food that reaches your gut. She describes the problem with processed foods this way:

“Think about a Coke. When you drink it, all the sugar goes to your bloodstream, and the microbes in your gut don’t even know you’ve had it. Instead of drinking a Coke, if you eat an apple or something with fiber, some will go to you and some to the microbes. You’re feeding them, giving them energy.”
 

Weight and Your Gut Microbiome

The link between gut health and body weight has received a lot of attention. Research has shown, for example, that people with obesity have less diversity in their gut microbiome, and certain specific bacteria have been linked to obesity. In animal studies, transplanting gut microbes from obese mice to “germ-free” mice led those GF mice to gain weight. This suggests excess weight is, in fact, caused by certain microbes, but to date there’s scant evidence that the same is true with humans.

Dr. Krajmalnik-Brown’s group did an experiment in which they had people follow two different diets for 23 days each, with a break in between. Both provided similar amounts of calories and macronutrients each day but via different foods. The study’s typical Western menu featured processed foods — think grape juice, sandwiches made with deli turkey and white bread, and spaghetti with jarred sauce and ground beef. The other menu, what researchers called a “microbiome enhancer diet,” included foods like whole fruit, veggie sandwiches on multigrain buns, and steak with a side of whole wheat spaghetti.

While the study wasn’t designed for weight loss, an interesting thing happened when researchers analyzed participants’ bowel movements.

“We found that when you feed subjects a diet designed to provide more energy to the microbes and not to the [body], our subjects lost a little weight,” Dr. Krajmalnik-Brown said. “It looks like by feeding your microbes, it seems to make people healthier and potentially even lose a little.”

Another possible mechanism involves the same hormone that powers those injectable weight loss drugs. The lower part of your gut makes hormones that tell the entire gut to slow down and also help orchestrate metabolism and appetite. Among them is GLP-1. The drugs use a synthetic version, semaglutide or tirzepatide, to trigger the same effect.

According to Dr. Damman, you can stimulate your gut to make those helpful hormones with the food you eat — by giving your microbes the right fuel.
 

Eat to Feed Your Microbes

The foods you eat can affect your gut microbiome and so your weight. But don’t go looking for that one perfect ingredient, experts warn.

“Oftentimes we get this micro-focus, is this a good food or a bad food?” warned Katie Chapmon, a registered dietitian whose practice focuses on gut health. “You just want to make sure your microbiome is robust and healthy, so it communicates that your body is running, you’ve got it.”

Instead, try to give your body more of the kinds of food research has shown can feed your microbiome, many of which are plant-based. “Those are the things that are largely taken out during processing,” Dr. Damman said. He calls them the “Four Fs”:

Fiber: When you eat fiber-rich foods like fruits, vegetables, whole grains, nuts, and beans, your body can’t digest the fiber while it’s in the upper parts of your GI tract. It passes through to your lower gut, where healthy bacteria ferment it. That produces short-chain fatty acids, which send signals throughout your body, including ones related to appetite and feeling full.

Phenols: Phenolic compounds are antioxidants that give plant-based foods their color — when you talk about eating the rainbow, you’re talking about phenols. The microbes in your gut feed on them, too. “My goal for a meal is five distinct colors on the plate,” Ms. Chapmon said. “That rounds out the bases for the different polyphenols.”

Fermented foods: You can get a different kind of health benefit by eating food that’s already fermented — like sauerkraut, kimchi, kefir, yogurt, miso, tempeh, and kombucha. Fermentation can make the phenols in foods more accessible to your body. Plus, each mouthful introduces good bacteria into your body, some of which make it down to your gut. The bacteria that are already there feed on these new strains, which helps to increase the diversity of your microbiome.

Healthy fats: Here, it’s not so much about feeding the good bacteria in your microbiome. Dr. Damman says that omega-3 fatty acids, found in fatty fish, canola oil, some nuts, and other foods, decrease inflammation in the lining of your gut. Plus, healthy fat sources like extra-virgin olive oil and avocados are full of phenols.

Eating for gut health isn’t a magic bullet in terms of weight loss. But the benefits of a healthy gut go far beyond shedding a few pounds.

“I think we need to strive for health, not weight loss.” Dr. Krajmalnik-Brown said. “Keep your gut healthy and your microbes healthy, and that should eventually lead to a healthy weight. You’ll make your microbes happy, and your microbes do a lot for your health.”

A version of this article appeared on WebMD.com.

Injectable weight loss drugs like Wegovy, Saxenda, and Zepbound have been getting all the glory lately, but they’re not for everyone. If the inconvenience or cost of weight-loss drugs isn’t for you, another approach may be boosting your gut microbiome.

So how does one do that, and how does it work?

“There are a lot of different factors naturally in weight gain and weight loss, so the gut microbiome is certainly not the only thing,” said Chris Damman, MD, a gastroenterologist at the University of Washington. He studies how food and the microbiome affect your health. “With that caveat, it probably is playing an important role.”
 

Trillions of Microbes

The idea that your gut is home to an enormous range of tiny organisms — microbes — has existed for more than 100 years, but only in the 21st century have scientists had the ability to delve into specifics. 

We now know you want a robust assortment of microbes in your gut, especially in the lower gut, your colon. They feast on fiber from the food you eat and turn it into substances your body needs. Those substances send signals all over your body.

If you don’t have enough microbes or have too many of the wrong kinds, it influences those signals, which can lead to health problems. Over the last 20 years, research has linked problems in the gut microbiome to a wide variety of conditions, including inflammatory bowel disease, autoimmune diseases like rheumatoid arthritis, metabolic ones like diabetes, and cardiovascular disease, asthma, and even autism.

Thanks to these efforts, we know a lot about the interactions between your gut and the rest of your body, but we don’t know exactly how many things happen — whether some teeny critters within your microbiome cause the issues or vice versa.

“That’s the problem with so much of the microbiome stuff,” said Elizabeth Hohmann, MD, a physician investigator at the Massachusetts General Research Institute. “Olympic athletes have a better gut microbiome than most people. Well, sure they do — because they’re paying attention to their diet, they’re getting enough rest. Correlation does not causation make.”
 

The American Diet Messes With Your Gut

If you’re a typical American, you eat a lot of ultra-processed foods — manufactured with a long ingredients list that includes additives or preservatives. According to one study, those foods make up 73% of our food supply. That can have a serious impact on gut health.

“When you process a food and mill it, it turns a whole food into tiny particles,” Dr. Damman said. “That makes the food highly digestible. But if you eat a stalk of broccoli, a large amount of that broccoli in the form of fiber and other things will make its way to your lower gut, where it will feed microbes.”

With heavily processed foods, on the other hand, most of it gets digested before it can reach your lower gut, which leaves your microbes without the energy they need to survive.

Rosa Krajmalnik-Brown, PhD, is director of the Biodesign Center for Health Through Microbiomes at Arizona State University. Her lab has done research into how microbes use the undigested food that reaches your gut. She describes the problem with processed foods this way:

“Think about a Coke. When you drink it, all the sugar goes to your bloodstream, and the microbes in your gut don’t even know you’ve had it. Instead of drinking a Coke, if you eat an apple or something with fiber, some will go to you and some to the microbes. You’re feeding them, giving them energy.”
 

Weight and Your Gut Microbiome

The link between gut health and body weight has received a lot of attention. Research has shown, for example, that people with obesity have less diversity in their gut microbiome, and certain specific bacteria have been linked to obesity. In animal studies, transplanting gut microbes from obese mice to “germ-free” mice led those GF mice to gain weight. This suggests excess weight is, in fact, caused by certain microbes, but to date there’s scant evidence that the same is true with humans.

Dr. Krajmalnik-Brown’s group did an experiment in which they had people follow two different diets for 23 days each, with a break in between. Both provided similar amounts of calories and macronutrients each day but via different foods. The study’s typical Western menu featured processed foods — think grape juice, sandwiches made with deli turkey and white bread, and spaghetti with jarred sauce and ground beef. The other menu, what researchers called a “microbiome enhancer diet,” included foods like whole fruit, veggie sandwiches on multigrain buns, and steak with a side of whole wheat spaghetti.

While the study wasn’t designed for weight loss, an interesting thing happened when researchers analyzed participants’ bowel movements.

“We found that when you feed subjects a diet designed to provide more energy to the microbes and not to the [body], our subjects lost a little weight,” Dr. Krajmalnik-Brown said. “It looks like by feeding your microbes, it seems to make people healthier and potentially even lose a little.”

Another possible mechanism involves the same hormone that powers those injectable weight loss drugs. The lower part of your gut makes hormones that tell the entire gut to slow down and also help orchestrate metabolism and appetite. Among them is GLP-1. The drugs use a synthetic version, semaglutide or tirzepatide, to trigger the same effect.

According to Dr. Damman, you can stimulate your gut to make those helpful hormones with the food you eat — by giving your microbes the right fuel.
 

Eat to Feed Your Microbes

The foods you eat can affect your gut microbiome and so your weight. But don’t go looking for that one perfect ingredient, experts warn.

“Oftentimes we get this micro-focus, is this a good food or a bad food?” warned Katie Chapmon, a registered dietitian whose practice focuses on gut health. “You just want to make sure your microbiome is robust and healthy, so it communicates that your body is running, you’ve got it.”

Instead, try to give your body more of the kinds of food research has shown can feed your microbiome, many of which are plant-based. “Those are the things that are largely taken out during processing,” Dr. Damman said. He calls them the “Four Fs”:

Fiber: When you eat fiber-rich foods like fruits, vegetables, whole grains, nuts, and beans, your body can’t digest the fiber while it’s in the upper parts of your GI tract. It passes through to your lower gut, where healthy bacteria ferment it. That produces short-chain fatty acids, which send signals throughout your body, including ones related to appetite and feeling full.

Phenols: Phenolic compounds are antioxidants that give plant-based foods their color — when you talk about eating the rainbow, you’re talking about phenols. The microbes in your gut feed on them, too. “My goal for a meal is five distinct colors on the plate,” Ms. Chapmon said. “That rounds out the bases for the different polyphenols.”

Fermented foods: You can get a different kind of health benefit by eating food that’s already fermented — like sauerkraut, kimchi, kefir, yogurt, miso, tempeh, and kombucha. Fermentation can make the phenols in foods more accessible to your body. Plus, each mouthful introduces good bacteria into your body, some of which make it down to your gut. The bacteria that are already there feed on these new strains, which helps to increase the diversity of your microbiome.

Healthy fats: Here, it’s not so much about feeding the good bacteria in your microbiome. Dr. Damman says that omega-3 fatty acids, found in fatty fish, canola oil, some nuts, and other foods, decrease inflammation in the lining of your gut. Plus, healthy fat sources like extra-virgin olive oil and avocados are full of phenols.

Eating for gut health isn’t a magic bullet in terms of weight loss. But the benefits of a healthy gut go far beyond shedding a few pounds.

“I think we need to strive for health, not weight loss.” Dr. Krajmalnik-Brown said. “Keep your gut healthy and your microbes healthy, and that should eventually lead to a healthy weight. You’ll make your microbes happy, and your microbes do a lot for your health.”

A version of this article appeared on WebMD.com.

Injectable weight loss drugs like Wegovy, Saxenda, and Zepbound have been getting all the glory lately, but they’re not for everyone. If the inconvenience or cost of weight-loss drugs isn’t for you, another approach may be boosting your gut microbiome.

So how does one do that, and how does it work?

“There are a lot of different factors naturally in weight gain and weight loss, so the gut microbiome is certainly not the only thing,” said Chris Damman, MD, a gastroenterologist at the University of Washington. He studies how food and the microbiome affect your health. “With that caveat, it probably is playing an important role.”
 

Trillions of Microbes

The idea that your gut is home to an enormous range of tiny organisms — microbes — has existed for more than 100 years, but only in the 21st century have scientists had the ability to delve into specifics. 

We now know you want a robust assortment of microbes in your gut, especially in the lower gut, your colon. They feast on fiber from the food you eat and turn it into substances your body needs. Those substances send signals all over your body.

If you don’t have enough microbes or have too many of the wrong kinds, it influences those signals, which can lead to health problems. Over the last 20 years, research has linked problems in the gut microbiome to a wide variety of conditions, including inflammatory bowel disease, autoimmune diseases like rheumatoid arthritis, metabolic ones like diabetes, and cardiovascular disease, asthma, and even autism.

Thanks to these efforts, we know a lot about the interactions between your gut and the rest of your body, but we don’t know exactly how many things happen — whether some teeny critters within your microbiome cause the issues or vice versa.

“That’s the problem with so much of the microbiome stuff,” said Elizabeth Hohmann, MD, a physician investigator at the Massachusetts General Research Institute. “Olympic athletes have a better gut microbiome than most people. Well, sure they do — because they’re paying attention to their diet, they’re getting enough rest. Correlation does not causation make.”
 

The American Diet Messes With Your Gut

If you’re a typical American, you eat a lot of ultra-processed foods — manufactured with a long ingredients list that includes additives or preservatives. According to one study, those foods make up 73% of our food supply. That can have a serious impact on gut health.

“When you process a food and mill it, it turns a whole food into tiny particles,” Dr. Damman said. “That makes the food highly digestible. But if you eat a stalk of broccoli, a large amount of that broccoli in the form of fiber and other things will make its way to your lower gut, where it will feed microbes.”

With heavily processed foods, on the other hand, most of it gets digested before it can reach your lower gut, which leaves your microbes without the energy they need to survive.

Rosa Krajmalnik-Brown, PhD, is director of the Biodesign Center for Health Through Microbiomes at Arizona State University. Her lab has done research into how microbes use the undigested food that reaches your gut. She describes the problem with processed foods this way:

“Think about a Coke. When you drink it, all the sugar goes to your bloodstream, and the microbes in your gut don’t even know you’ve had it. Instead of drinking a Coke, if you eat an apple or something with fiber, some will go to you and some to the microbes. You’re feeding them, giving them energy.”
 

Weight and Your Gut Microbiome

The link between gut health and body weight has received a lot of attention. Research has shown, for example, that people with obesity have less diversity in their gut microbiome, and certain specific bacteria have been linked to obesity. In animal studies, transplanting gut microbes from obese mice to “germ-free” mice led those GF mice to gain weight. This suggests excess weight is, in fact, caused by certain microbes, but to date there’s scant evidence that the same is true with humans.

Dr. Krajmalnik-Brown’s group did an experiment in which they had people follow two different diets for 23 days each, with a break in between. Both provided similar amounts of calories and macronutrients each day but via different foods. The study’s typical Western menu featured processed foods — think grape juice, sandwiches made with deli turkey and white bread, and spaghetti with jarred sauce and ground beef. The other menu, what researchers called a “microbiome enhancer diet,” included foods like whole fruit, veggie sandwiches on multigrain buns, and steak with a side of whole wheat spaghetti.

While the study wasn’t designed for weight loss, an interesting thing happened when researchers analyzed participants’ bowel movements.

“We found that when you feed subjects a diet designed to provide more energy to the microbes and not to the [body], our subjects lost a little weight,” Dr. Krajmalnik-Brown said. “It looks like by feeding your microbes, it seems to make people healthier and potentially even lose a little.”

Another possible mechanism involves the same hormone that powers those injectable weight loss drugs. The lower part of your gut makes hormones that tell the entire gut to slow down and also help orchestrate metabolism and appetite. Among them is GLP-1. The drugs use a synthetic version, semaglutide or tirzepatide, to trigger the same effect.

According to Dr. Damman, you can stimulate your gut to make those helpful hormones with the food you eat — by giving your microbes the right fuel.
 

Eat to Feed Your Microbes

The foods you eat can affect your gut microbiome and so your weight. But don’t go looking for that one perfect ingredient, experts warn.

“Oftentimes we get this micro-focus, is this a good food or a bad food?” warned Katie Chapmon, a registered dietitian whose practice focuses on gut health. “You just want to make sure your microbiome is robust and healthy, so it communicates that your body is running, you’ve got it.”

Instead, try to give your body more of the kinds of food research has shown can feed your microbiome, many of which are plant-based. “Those are the things that are largely taken out during processing,” Dr. Damman said. He calls them the “Four Fs”:

Fiber: When you eat fiber-rich foods like fruits, vegetables, whole grains, nuts, and beans, your body can’t digest the fiber while it’s in the upper parts of your GI tract. It passes through to your lower gut, where healthy bacteria ferment it. That produces short-chain fatty acids, which send signals throughout your body, including ones related to appetite and feeling full.

Phenols: Phenolic compounds are antioxidants that give plant-based foods their color — when you talk about eating the rainbow, you’re talking about phenols. The microbes in your gut feed on them, too. “My goal for a meal is five distinct colors on the plate,” Ms. Chapmon said. “That rounds out the bases for the different polyphenols.”

Fermented foods: You can get a different kind of health benefit by eating food that’s already fermented — like sauerkraut, kimchi, kefir, yogurt, miso, tempeh, and kombucha. Fermentation can make the phenols in foods more accessible to your body. Plus, each mouthful introduces good bacteria into your body, some of which make it down to your gut. The bacteria that are already there feed on these new strains, which helps to increase the diversity of your microbiome.

Healthy fats: Here, it’s not so much about feeding the good bacteria in your microbiome. Dr. Damman says that omega-3 fatty acids, found in fatty fish, canola oil, some nuts, and other foods, decrease inflammation in the lining of your gut. Plus, healthy fat sources like extra-virgin olive oil and avocados are full of phenols.

Eating for gut health isn’t a magic bullet in terms of weight loss. But the benefits of a healthy gut go far beyond shedding a few pounds.

“I think we need to strive for health, not weight loss.” Dr. Krajmalnik-Brown said. “Keep your gut healthy and your microbes healthy, and that should eventually lead to a healthy weight. You’ll make your microbes happy, and your microbes do a lot for your health.”

A version of this article appeared on WebMD.com.

Many patients with obesity blame weight gain on their metabolism. The reality is that metabolism can be blamed for weight regain after people try to lose weight! As we age, our metabolism does slow down; sometimes we think it stops working.

Metabolism, or resting energy expenditure, is directly related to how much muscle mass we have. As we age, we lose muscle, which is called sarcopenia.

What happens to our metabolism when we try to lose weight? Let’s first discuss what metabolism is.
 

What Is Metabolism?

Metabolism refers to the chemical reactions in the body’s cells that convert food into energy for sustaining life, cellular processes, and as storage for a rainy day.

Total energy expenditure (TEE) is broken down into resting energy expenditure (REE), thermic effect of food (TEF), and nonresting expenditure (NREE) or physical activity, and is made up of: TEE = 60% REE + 10% TEF + 30% NREE.

An elegant study performed by Dr. Rudy Leibel explored the effects of weight loss or weight gain on metabolism in 23 lean and 18 patients with obesity who were placed in a metabolic chamber. Weight loss of 10% or 20% body weight led to a decrease in TEE roughly equal to about 300 kcal/d, and an increase in body weight of 10% caused an increase in TEE of about 500 kcal/d. These changes led to the patient reverting to the prior weight (before weight loss or gain). In other words, Dr. Leibel postulated a feedback mechanism for the effect of fat mass decrease or increase on energy metabolism. The feedback mechanism or signal from fat was subsequently found to be leptin.

In a later study, Dr. Leibel and colleagues investigated the effects of body fat mass change on TEE and found that a 10% reduction in weight caused a decrease of TEE by 21%, comprising a decrease in NREE of 37.5% and a decrease in REE of 11.6%.

Therefore, the biggest change in TEE comes from NREE or exercise energy expenditure. The 35% variance in NEE change was accounted for by a decrease in muscle work efficiency in generating 10 watts or low levels of work such as walking.

In other words, when persons with obesity or lean persons lose weight, the efficiency of muscle at low levels of work increases such that one burns less energy when walking than one normally would. This helps conserve energy and tends to cause the body to go back to the higher weight.
 

So, How Can One Change Metabolism?

Let’s say one did lose weight and wants to counteract this TEE loss and increased muscle efficiency at low levels of work.

To counteract this effect, one should increase muscle work beyond low level so that more energy is expended. Another way would be to increase muscle mass so that there is more muscle that can do work.

This is exactly how metabolism can be altered or increased. What can be changed most readily, and what we have the most power over in our bodies, is the NREE.

To do this, muscles need anabolic power — the power to heal and build muscle mass. Anabolic power comes from eating healthy protein sources such as lean chicken, fish, beef, and eggs as well as dry beans, tofu, and dairy products.. It seems that older adults (> 60 years) need more protein than younger adults to build muscle mass, due to the body’s natural aging process which leads to sarcopenia. How much more? Studies show between 1.2 and 1.5 g/kg of body weight per day, whereas younger persons need 0.80 g/kg.

Developing sarcopenia with age involves muscle losing the ability to use protein and amino acids to rebuild injured tissue.

Let’s put this in perspective for treating obesity.

Obesity is brought on by the body’s defense of a higher body weight by interaction with the environment of highly processed foods that work on the reward pathway, leading to weight gain and resistance to satiety. Weight loss via diet, exercise, and medications works, but this weight loss is also accompanied by a decrease in TEE.

Weight loss is primarily fat mass loss, but depending on the degree of protein intake and muscle resistance training, 20%-50% of the total weight loss is muscle mass loss. Therefore, higher-protein diets and resistance exercise can be useful in preserving muscle mass and counteracting the decrease in TEE, maintaining energy expenditure. In older patients, an additional factor is the muscle’s lack of ability to use protein as an anabolic agent to protect muscle mass and thus the need for higher protein loads to do this.

All in all, can doctors help patients boost their metabolism, especially as they lose weight and maintain that loss? Yes — through protein intake and resistance exercise training.

Here are some tips to help your patients get cardio and resistance exercise into their routine.

First find out whether your patient prefers a social exercise interaction or solo training. If social, then the gym or classes such as cycling or boot camps at those gyms may work for them, especially if they can go with a friend. If solo is better, than a gym in the home might work. Peloton bikes are expensive but the interaction is all on the website!

A personal trainer may help motivate the patient if they know someone is waiting for them.

Let’s hit the gym!

Another note: There are agents in the obesity treatment pipeline that purport to change body composition while helping patients lose weight. Some of these agents are myostatin antagonists and antibodies that inhibit the activity of myostatin to break down muscle. These agents have been found to build muscle mass, but whether the quality of the muscle mass leads to an increase in muscle strength or functionality remains controversial. The next frontier in obesity treatment will be about decreasing fat mass and increasing muscle mass while making sure that increased muscle mass leads to improved functionality.

In the meantime, aside from new agents on the horizon, the best and healthiest way to keep metabolism on the up and up is to eat healthy lean proteins and exercise. How much exercise? The recommendation is 30-60 minutes of moderate to vigorous physical activity at least 5 days per week; plus 20 minutes of resistance exercise training 2-3 days per week for upper- and lower-extremity and core strength.

Again, let’s hit the gym!
 

Dr. Apovian is in the department of medicine, and codirector, Center for Weight Management and Wellness, Section of Endocrinology, Diabetes, and Hypertension, at Brigham and Women’s Hospital, Harvard Medical School, Boston. She disclosed ties with Altimmune, Cowen and Company, Currax Pharmaceuticals, EPG Communication Holdings, Gelesis, Srl, L-Nutra, and NeuroBo Pharmaceuticals, and Novo Nordisk. She received research grant from the National Institutes of Health, Patient-Centered Outcomes Research Institute, and GI Dynamics.

A version of this article appeared on Medscape.com.

Many patients with obesity blame weight gain on their metabolism. The reality is that metabolism can be blamed for weight regain after people try to lose weight! As we age, our metabolism does slow down; sometimes we think it stops working.

Metabolism, or resting energy expenditure, is directly related to how much muscle mass we have. As we age, we lose muscle, which is called sarcopenia.

What happens to our metabolism when we try to lose weight? Let’s first discuss what metabolism is.
 

What Is Metabolism?

Metabolism refers to the chemical reactions in the body’s cells that convert food into energy for sustaining life, cellular processes, and as storage for a rainy day.

Total energy expenditure (TEE) is broken down into resting energy expenditure (REE), thermic effect of food (TEF), and nonresting expenditure (NREE) or physical activity, and is made up of: TEE = 60% REE + 10% TEF + 30% NREE.

An elegant study performed by Dr. Rudy Leibel explored the effects of weight loss or weight gain on metabolism in 23 lean and 18 patients with obesity who were placed in a metabolic chamber. Weight loss of 10% or 20% body weight led to a decrease in TEE roughly equal to about 300 kcal/d, and an increase in body weight of 10% caused an increase in TEE of about 500 kcal/d. These changes led to the patient reverting to the prior weight (before weight loss or gain). In other words, Dr. Leibel postulated a feedback mechanism for the effect of fat mass decrease or increase on energy metabolism. The feedback mechanism or signal from fat was subsequently found to be leptin.

In a later study, Dr. Leibel and colleagues investigated the effects of body fat mass change on TEE and found that a 10% reduction in weight caused a decrease of TEE by 21%, comprising a decrease in NREE of 37.5% and a decrease in REE of 11.6%.

Therefore, the biggest change in TEE comes from NREE or exercise energy expenditure. The 35% variance in NEE change was accounted for by a decrease in muscle work efficiency in generating 10 watts or low levels of work such as walking.

In other words, when persons with obesity or lean persons lose weight, the efficiency of muscle at low levels of work increases such that one burns less energy when walking than one normally would. This helps conserve energy and tends to cause the body to go back to the higher weight.
 

So, How Can One Change Metabolism?

Let’s say one did lose weight and wants to counteract this TEE loss and increased muscle efficiency at low levels of work.

To counteract this effect, one should increase muscle work beyond low level so that more energy is expended. Another way would be to increase muscle mass so that there is more muscle that can do work.

This is exactly how metabolism can be altered or increased. What can be changed most readily, and what we have the most power over in our bodies, is the NREE.

To do this, muscles need anabolic power — the power to heal and build muscle mass. Anabolic power comes from eating healthy protein sources such as lean chicken, fish, beef, and eggs as well as dry beans, tofu, and dairy products.. It seems that older adults (> 60 years) need more protein than younger adults to build muscle mass, due to the body’s natural aging process which leads to sarcopenia. How much more? Studies show between 1.2 and 1.5 g/kg of body weight per day, whereas younger persons need 0.80 g/kg.

Developing sarcopenia with age involves muscle losing the ability to use protein and amino acids to rebuild injured tissue.

Let’s put this in perspective for treating obesity.

Obesity is brought on by the body’s defense of a higher body weight by interaction with the environment of highly processed foods that work on the reward pathway, leading to weight gain and resistance to satiety. Weight loss via diet, exercise, and medications works, but this weight loss is also accompanied by a decrease in TEE.

Weight loss is primarily fat mass loss, but depending on the degree of protein intake and muscle resistance training, 20%-50% of the total weight loss is muscle mass loss. Therefore, higher-protein diets and resistance exercise can be useful in preserving muscle mass and counteracting the decrease in TEE, maintaining energy expenditure. In older patients, an additional factor is the muscle’s lack of ability to use protein as an anabolic agent to protect muscle mass and thus the need for higher protein loads to do this.

All in all, can doctors help patients boost their metabolism, especially as they lose weight and maintain that loss? Yes — through protein intake and resistance exercise training.

Here are some tips to help your patients get cardio and resistance exercise into their routine.

First find out whether your patient prefers a social exercise interaction or solo training. If social, then the gym or classes such as cycling or boot camps at those gyms may work for them, especially if they can go with a friend. If solo is better, than a gym in the home might work. Peloton bikes are expensive but the interaction is all on the website!

A personal trainer may help motivate the patient if they know someone is waiting for them.

Let’s hit the gym!

Another note: There are agents in the obesity treatment pipeline that purport to change body composition while helping patients lose weight. Some of these agents are myostatin antagonists and antibodies that inhibit the activity of myostatin to break down muscle. These agents have been found to build muscle mass, but whether the quality of the muscle mass leads to an increase in muscle strength or functionality remains controversial. The next frontier in obesity treatment will be about decreasing fat mass and increasing muscle mass while making sure that increased muscle mass leads to improved functionality.

In the meantime, aside from new agents on the horizon, the best and healthiest way to keep metabolism on the up and up is to eat healthy lean proteins and exercise. How much exercise? The recommendation is 30-60 minutes of moderate to vigorous physical activity at least 5 days per week; plus 20 minutes of resistance exercise training 2-3 days per week for upper- and lower-extremity and core strength.

Again, let’s hit the gym!
 

Dr. Apovian is in the department of medicine, and codirector, Center for Weight Management and Wellness, Section of Endocrinology, Diabetes, and Hypertension, at Brigham and Women’s Hospital, Harvard Medical School, Boston. She disclosed ties with Altimmune, Cowen and Company, Currax Pharmaceuticals, EPG Communication Holdings, Gelesis, Srl, L-Nutra, and NeuroBo Pharmaceuticals, and Novo Nordisk. She received research grant from the National Institutes of Health, Patient-Centered Outcomes Research Institute, and GI Dynamics.

A version of this article appeared on Medscape.com.

Many patients with obesity blame weight gain on their metabolism. The reality is that metabolism can be blamed for weight regain after people try to lose weight! As we age, our metabolism does slow down; sometimes we think it stops working.

Metabolism, or resting energy expenditure, is directly related to how much muscle mass we have. As we age, we lose muscle, which is called sarcopenia.

What happens to our metabolism when we try to lose weight? Let’s first discuss what metabolism is.
 

What Is Metabolism?

Metabolism refers to the chemical reactions in the body’s cells that convert food into energy for sustaining life, cellular processes, and as storage for a rainy day.

Total energy expenditure (TEE) is broken down into resting energy expenditure (REE), thermic effect of food (TEF), and nonresting expenditure (NREE) or physical activity, and is made up of: TEE = 60% REE + 10% TEF + 30% NREE.

An elegant study performed by Dr. Rudy Leibel explored the effects of weight loss or weight gain on metabolism in 23 lean and 18 patients with obesity who were placed in a metabolic chamber. Weight loss of 10% or 20% body weight led to a decrease in TEE roughly equal to about 300 kcal/d, and an increase in body weight of 10% caused an increase in TEE of about 500 kcal/d. These changes led to the patient reverting to the prior weight (before weight loss or gain). In other words, Dr. Leibel postulated a feedback mechanism for the effect of fat mass decrease or increase on energy metabolism. The feedback mechanism or signal from fat was subsequently found to be leptin.

In a later study, Dr. Leibel and colleagues investigated the effects of body fat mass change on TEE and found that a 10% reduction in weight caused a decrease of TEE by 21%, comprising a decrease in NREE of 37.5% and a decrease in REE of 11.6%.

Therefore, the biggest change in TEE comes from NREE or exercise energy expenditure. The 35% variance in NEE change was accounted for by a decrease in muscle work efficiency in generating 10 watts or low levels of work such as walking.

In other words, when persons with obesity or lean persons lose weight, the efficiency of muscle at low levels of work increases such that one burns less energy when walking than one normally would. This helps conserve energy and tends to cause the body to go back to the higher weight.
 

So, How Can One Change Metabolism?

Let’s say one did lose weight and wants to counteract this TEE loss and increased muscle efficiency at low levels of work.

To counteract this effect, one should increase muscle work beyond low level so that more energy is expended. Another way would be to increase muscle mass so that there is more muscle that can do work.

This is exactly how metabolism can be altered or increased. What can be changed most readily, and what we have the most power over in our bodies, is the NREE.

To do this, muscles need anabolic power — the power to heal and build muscle mass. Anabolic power comes from eating healthy protein sources such as lean chicken, fish, beef, and eggs as well as dry beans, tofu, and dairy products.. It seems that older adults (> 60 years) need more protein than younger adults to build muscle mass, due to the body’s natural aging process which leads to sarcopenia. How much more? Studies show between 1.2 and 1.5 g/kg of body weight per day, whereas younger persons need 0.80 g/kg.

Developing sarcopenia with age involves muscle losing the ability to use protein and amino acids to rebuild injured tissue.

Let’s put this in perspective for treating obesity.

Obesity is brought on by the body’s defense of a higher body weight by interaction with the environment of highly processed foods that work on the reward pathway, leading to weight gain and resistance to satiety. Weight loss via diet, exercise, and medications works, but this weight loss is also accompanied by a decrease in TEE.

Weight loss is primarily fat mass loss, but depending on the degree of protein intake and muscle resistance training, 20%-50% of the total weight loss is muscle mass loss. Therefore, higher-protein diets and resistance exercise can be useful in preserving muscle mass and counteracting the decrease in TEE, maintaining energy expenditure. In older patients, an additional factor is the muscle’s lack of ability to use protein as an anabolic agent to protect muscle mass and thus the need for higher protein loads to do this.

All in all, can doctors help patients boost their metabolism, especially as they lose weight and maintain that loss? Yes — through protein intake and resistance exercise training.

Here are some tips to help your patients get cardio and resistance exercise into their routine.

First find out whether your patient prefers a social exercise interaction or solo training. If social, then the gym or classes such as cycling or boot camps at those gyms may work for them, especially if they can go with a friend. If solo is better, than a gym in the home might work. Peloton bikes are expensive but the interaction is all on the website!

A personal trainer may help motivate the patient if they know someone is waiting for them.

Let’s hit the gym!

Another note: There are agents in the obesity treatment pipeline that purport to change body composition while helping patients lose weight. Some of these agents are myostatin antagonists and antibodies that inhibit the activity of myostatin to break down muscle. These agents have been found to build muscle mass, but whether the quality of the muscle mass leads to an increase in muscle strength or functionality remains controversial. The next frontier in obesity treatment will be about decreasing fat mass and increasing muscle mass while making sure that increased muscle mass leads to improved functionality.

In the meantime, aside from new agents on the horizon, the best and healthiest way to keep metabolism on the up and up is to eat healthy lean proteins and exercise. How much exercise? The recommendation is 30-60 minutes of moderate to vigorous physical activity at least 5 days per week; plus 20 minutes of resistance exercise training 2-3 days per week for upper- and lower-extremity and core strength.

Again, let’s hit the gym!
 

Dr. Apovian is in the department of medicine, and codirector, Center for Weight Management and Wellness, Section of Endocrinology, Diabetes, and Hypertension, at Brigham and Women’s Hospital, Harvard Medical School, Boston. She disclosed ties with Altimmune, Cowen and Company, Currax Pharmaceuticals, EPG Communication Holdings, Gelesis, Srl, L-Nutra, and NeuroBo Pharmaceuticals, and Novo Nordisk. She received research grant from the National Institutes of Health, Patient-Centered Outcomes Research Institute, and GI Dynamics.

A version of this article appeared on Medscape.com.

Communicating bad news to patients is one of the most stressful and challenging clinical tasks for any physician, regardless of his or her specialty. Delivering bad news to a patient or their close relative is demanding because the information provided during the dialogue can substantially alter the person’s perspective on life. This task is more frequent for physicians caring for oncology patients and can also affect the physician’s emotional state.

The manner in which bad news is communicated plays a significant role in the psychological burden on the patient, and various communication techniques and guidelines have been developed to enable physicians to perform this difficult task effectively.

Revealing bad news in person whenever possible, to address the emotional responses of patients or relatives, is part of the prevailing expert recommendations. However, it has been acknowledged that in certain situations, communicating bad news over the phone is more feasible.

Since the beginning of the COVID-19 pandemic, the disclosure of bad news over the phone has become a necessary substitute for in-person visits and an integral part of clinical practice worldwide. It remains to be clarified what the real psychological impact on patients and their closest relatives is when delivering bad news over the phone compared with delivering it in person.

Right and Wrong Ways

The most popular guideline for communicating bad news is SPIKES, a six-phase protocol with a special application for cancer patients. It is used in various countries (eg, the United States, France, and Germany) as a guide for this sensitive practice and for training in communication skills in this context. The SPIKES acronym refers to the following six recommended steps for delivering bad news:

• Setting: Set up the conversation.
• Perception: Assess the patient’s perception.
• Invitation: Ask the patient what he or she would like to know.
• Knowledge: Provide the patient with knowledge and information, breaking it down into small parts.
• Emotions: Acknowledge and empathetically address the patient’s emotions.
• Strategy and Summary: Summarize and define a medical action plan.

The lesson from SPIKES is that when a person experiences strong emotions, it is difficult to continue discussing anything, and they will struggle to hear anything. Allowing for silence is fundamental. In addition, empathy allows the patient to express his or her feelings and concerns, as well as provide support. The aim is not to argue but to allow the expression of emotions without criticism. However, these recommendations are primarily based on expert opinion and less on empirical evidence, due to the difficulty of studies in assessing patient outcomes in various phases of these protocols.

A recent study analyzed the differences in psychological distress between patients who received bad news over the phone vs those who received it in person. The study was a systematic review and meta-analysis.

The investigators examined 5944 studies, including 11 qualitative analysis studies, nine meta-analyses, and four randomized controlled trials.

In a set of studies ranging from moderate to good quality, no difference in psychological distress was found when bad news was disclosed over the phone compared with in person, regarding anxiety, depression, and posttraumatic stress disorder.

There was no average difference in patient satisfaction levels when bad news was delivered over the phone compared with in person. The risk for dissatisfaction was similar between groups.

Clinical Practice Guidelines

The demand for telemedicine, including the disclosure of bad news, is growing despite the limited knowledge of potential adverse effects. The results of existing studies suggest that the mode of disclosure may play a secondary role, and the manner in which bad news is communicated may be more important.

Therefore, it is paramount to prepare patients or their families for the possibility of receiving bad news well in advance and, during the conversation, to ensure first and foremost that they are in an appropriate environment. The structure and content of the conversation may be relevant, and adhering to dedicated communication strategies can be a wise choice for the physician and the interlocutor.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Communicating bad news to patients is one of the most stressful and challenging clinical tasks for any physician, regardless of his or her specialty. Delivering bad news to a patient or their close relative is demanding because the information provided during the dialogue can substantially alter the person’s perspective on life. This task is more frequent for physicians caring for oncology patients and can also affect the physician’s emotional state.

The manner in which bad news is communicated plays a significant role in the psychological burden on the patient, and various communication techniques and guidelines have been developed to enable physicians to perform this difficult task effectively.

Revealing bad news in person whenever possible, to address the emotional responses of patients or relatives, is part of the prevailing expert recommendations. However, it has been acknowledged that in certain situations, communicating bad news over the phone is more feasible.

Since the beginning of the COVID-19 pandemic, the disclosure of bad news over the phone has become a necessary substitute for in-person visits and an integral part of clinical practice worldwide. It remains to be clarified what the real psychological impact on patients and their closest relatives is when delivering bad news over the phone compared with delivering it in person.

Right and Wrong Ways

The most popular guideline for communicating bad news is SPIKES, a six-phase protocol with a special application for cancer patients. It is used in various countries (eg, the United States, France, and Germany) as a guide for this sensitive practice and for training in communication skills in this context. The SPIKES acronym refers to the following six recommended steps for delivering bad news:

• Setting: Set up the conversation.
• Perception: Assess the patient’s perception.
• Invitation: Ask the patient what he or she would like to know.
• Knowledge: Provide the patient with knowledge and information, breaking it down into small parts.
• Emotions: Acknowledge and empathetically address the patient’s emotions.
• Strategy and Summary: Summarize and define a medical action plan.

The lesson from SPIKES is that when a person experiences strong emotions, it is difficult to continue discussing anything, and they will struggle to hear anything. Allowing for silence is fundamental. In addition, empathy allows the patient to express his or her feelings and concerns, as well as provide support. The aim is not to argue but to allow the expression of emotions without criticism. However, these recommendations are primarily based on expert opinion and less on empirical evidence, due to the difficulty of studies in assessing patient outcomes in various phases of these protocols.

A recent study analyzed the differences in psychological distress between patients who received bad news over the phone vs those who received it in person. The study was a systematic review and meta-analysis.

The investigators examined 5944 studies, including 11 qualitative analysis studies, nine meta-analyses, and four randomized controlled trials.

In a set of studies ranging from moderate to good quality, no difference in psychological distress was found when bad news was disclosed over the phone compared with in person, regarding anxiety, depression, and posttraumatic stress disorder.

There was no average difference in patient satisfaction levels when bad news was delivered over the phone compared with in person. The risk for dissatisfaction was similar between groups.

Clinical Practice Guidelines

The demand for telemedicine, including the disclosure of bad news, is growing despite the limited knowledge of potential adverse effects. The results of existing studies suggest that the mode of disclosure may play a secondary role, and the manner in which bad news is communicated may be more important.

Therefore, it is paramount to prepare patients or their families for the possibility of receiving bad news well in advance and, during the conversation, to ensure first and foremost that they are in an appropriate environment. The structure and content of the conversation may be relevant, and adhering to dedicated communication strategies can be a wise choice for the physician and the interlocutor.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Communicating bad news to patients is one of the most stressful and challenging clinical tasks for any physician, regardless of his or her specialty. Delivering bad news to a patient or their close relative is demanding because the information provided during the dialogue can substantially alter the person’s perspective on life. This task is more frequent for physicians caring for oncology patients and can also affect the physician’s emotional state.

The manner in which bad news is communicated plays a significant role in the psychological burden on the patient, and various communication techniques and guidelines have been developed to enable physicians to perform this difficult task effectively.

Revealing bad news in person whenever possible, to address the emotional responses of patients or relatives, is part of the prevailing expert recommendations. However, it has been acknowledged that in certain situations, communicating bad news over the phone is more feasible.

Since the beginning of the COVID-19 pandemic, the disclosure of bad news over the phone has become a necessary substitute for in-person visits and an integral part of clinical practice worldwide. It remains to be clarified what the real psychological impact on patients and their closest relatives is when delivering bad news over the phone compared with delivering it in person.

Right and Wrong Ways

The most popular guideline for communicating bad news is SPIKES, a six-phase protocol with a special application for cancer patients. It is used in various countries (eg, the United States, France, and Germany) as a guide for this sensitive practice and for training in communication skills in this context. The SPIKES acronym refers to the following six recommended steps for delivering bad news:

• Setting: Set up the conversation.
• Perception: Assess the patient’s perception.
• Invitation: Ask the patient what he or she would like to know.
• Knowledge: Provide the patient with knowledge and information, breaking it down into small parts.
• Emotions: Acknowledge and empathetically address the patient’s emotions.
• Strategy and Summary: Summarize and define a medical action plan.

The lesson from SPIKES is that when a person experiences strong emotions, it is difficult to continue discussing anything, and they will struggle to hear anything. Allowing for silence is fundamental. In addition, empathy allows the patient to express his or her feelings and concerns, as well as provide support. The aim is not to argue but to allow the expression of emotions without criticism. However, these recommendations are primarily based on expert opinion and less on empirical evidence, due to the difficulty of studies in assessing patient outcomes in various phases of these protocols.

A recent study analyzed the differences in psychological distress between patients who received bad news over the phone vs those who received it in person. The study was a systematic review and meta-analysis.

The investigators examined 5944 studies, including 11 qualitative analysis studies, nine meta-analyses, and four randomized controlled trials.

In a set of studies ranging from moderate to good quality, no difference in psychological distress was found when bad news was disclosed over the phone compared with in person, regarding anxiety, depression, and posttraumatic stress disorder.

There was no average difference in patient satisfaction levels when bad news was delivered over the phone compared with in person. The risk for dissatisfaction was similar between groups.

Clinical Practice Guidelines

The demand for telemedicine, including the disclosure of bad news, is growing despite the limited knowledge of potential adverse effects. The results of existing studies suggest that the mode of disclosure may play a secondary role, and the manner in which bad news is communicated may be more important.

Therefore, it is paramount to prepare patients or their families for the possibility of receiving bad news well in advance and, during the conversation, to ensure first and foremost that they are in an appropriate environment. The structure and content of the conversation may be relevant, and adhering to dedicated communication strategies can be a wise choice for the physician and the interlocutor.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Campaigners for greater transparency in medical science have reiterated calls for more to be done to avoid “medical research waste” after an investigation found that results from more than a fifth of clinical trials across five Nordic countries have never been made public.

A study found that results from 475 clinical trials in Denmark, Iceland, Finland, Norway, and Sweden — involving almost 84,000 participants — were never made public in any form.

Nonpublication of clinical trial results wastes public money, harms patients, and undermines public health, the researchers said. 

There is already a well-defined ethical responsibility to publish trial results. Article 36 of the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects states that “researchers have a duty to make publicly available the results of their research on human subjects,” and World Health Organization best practice protocols call for results to be uploaded onto trial registries within 12 months of trial completion.
 

Research Waste Is a ‘Pervasive Problem’

So, how and why do so many trials end up gathering dust in a drawer? The latest study, published February 5 as a preprint, evaluated the reporting outcomes of 2113 clinical trials at medical universities and university hospitals in Nordic countries between 2016 and 2019. It found that across the five countries, 22% of all clinical trial results had not been shared. Furthermore, only 27% of all trial results were made public, either on registries or in journals, within 12 months. Even 2 years after trials ended, only around half of results (51.7%) had been put into the public domain.

The authors concluded that missing and delayed results from academically-led clinical trials was a “pervasive problem” in Nordic countries and that institutions, funding bodies, and policymakers needed to ensure that regulations around reporting results were adhered to so that important findings are not lost.

Study first author, Gustav Nilsonne, MD, PHD, from the Department of Clinical Neuroscience at the Karolinska Institutet, Sweden, told this news organization: “Most people I talk to — most colleagues who are clinical scientists — tend to think that the main reason is that negative results are not as interesting to publish and therefore they get lower priority, and they get published later and sometimes not at all.”

Experts stressed that the problem is not confined to Nordic countries and that wasted medical research persists elsewhere in Europe and remains a global problem. For instance, a report published in the Journal of Clinical Epidemiology found that 30% of German trials completed between 2014 and 2017 remained unpublished 5 years after completion.
 

The Case for Laws, Monitoring, and Fines

Till Bruckner, PHD, from TranspariMED, which campaigns to end evidence distortion in medicine, told this news organization: “What is needed to comprehensively fix the problem is a national legal requirement to make all trial results public, coupled with effective monitoring, and followed by sanctions in the rare cases where institutions refuse to comply.” 

Dr. Nilsonne added: “We have argued that the sponsors need to take greater responsibility, but also that there needs to be somebody whose job it is to monitor clinical trials reporting. It shouldn’t have to be that we do this as researchers on a shoestring with no dedicated resources. It should be somebody’s job.”

Since January 31, 2023, all initial clinical trial applications in the European Union must be submitted through the EU Clinical Trials Information System. Dr. Bruckner said that “the picture is not yet clear” in Europe, as the first trial results under the system are not expected until later this year. Even then, enforcement lies with regulators in individual countries. And while Denmark has already indicated it will enforce the regulations, he warned that other countries “might turn a blind eye.”

He pointed out that existing laws don’t apply to all types of trials. “That means that for many trials, nobody is legally responsible for ensuring that results are made public, and no government agency has any oversight or mandate,” he said.

Outside the EU, the United Kingdom has helped lead the way through the NHS Health Research Authority (HRA), which registers trials run in the country. One year after a trial has been completed, the HRA checks to see if the results have been uploaded to the registry and issues reminders if they haven’t.

In an update of its work in January, the authority said that compliance had hovered at just below 90% between 2018 and 2021 but that it was working to increase this to 100% by working with stakeholders across the research sector.

Dr. Nilsonne considers the UK system of central registration and follow-up an attractive option. “I would love to see something along those lines in other countries too,” he said.
 

‘Rampant Noncompliance’ in the United States

In the United States, a requirement to make trial results public is backed by law. Despite this, there’s evidence of “rampant noncompliance” and minimal government action, according to Megan Curtin from Universities Allied for Essential Medicines (UAEM), which has been tracking the issue in the United States and working to push universities and others to make their findings available.

The US Food and Drug Administration (FDA) shares responsibility with the National Institutes of Health for enforcement of clinical trial results reporting, but the UAEM says nearly 4000 trials are currently out of compliance with reporting requirements. In January last year, the UAEM copublished a report with the National Center for Health Research and TranspariMED, which found that 3627 American children participated in clinical trials whose results remain unreported.

The FDA can levy a fine of up to $10,000 USD for a violation of the law, but UAEM said that, as of January 2023, the FDA had sent only 92 preliminary notices of noncompliance and four notices of noncompliance. “A clear difference between the EU field of clinical trial operation and US clinical trials is that there are clear laws for reporting within 12 months, which can be enforced, but they’re not being enforced by the FDA,” Ms. Curtin told this news organization.

The UAEM is pushing the FDA to issue a minimum of 250 preliminary notices of noncompliance each year to noncompliant trial sponsors.

Dr. Nilsonne said: “I do believe we have a great responsibility to the patients that do contribute. We need to make sure that the harms and risks that a clinical trial entails are really balanced by knowledge gain, and if the results are never reported, then we can’t have a knowledge gain.”
 

A version of this article appeared on Medscape.com.

Campaigners for greater transparency in medical science have reiterated calls for more to be done to avoid “medical research waste” after an investigation found that results from more than a fifth of clinical trials across five Nordic countries have never been made public.

A study found that results from 475 clinical trials in Denmark, Iceland, Finland, Norway, and Sweden — involving almost 84,000 participants — were never made public in any form.

Nonpublication of clinical trial results wastes public money, harms patients, and undermines public health, the researchers said. 

There is already a well-defined ethical responsibility to publish trial results. Article 36 of the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects states that “researchers have a duty to make publicly available the results of their research on human subjects,” and World Health Organization best practice protocols call for results to be uploaded onto trial registries within 12 months of trial completion.
 

Research Waste Is a ‘Pervasive Problem’

So, how and why do so many trials end up gathering dust in a drawer? The latest study, published February 5 as a preprint, evaluated the reporting outcomes of 2113 clinical trials at medical universities and university hospitals in Nordic countries between 2016 and 2019. It found that across the five countries, 22% of all clinical trial results had not been shared. Furthermore, only 27% of all trial results were made public, either on registries or in journals, within 12 months. Even 2 years after trials ended, only around half of results (51.7%) had been put into the public domain.

The authors concluded that missing and delayed results from academically-led clinical trials was a “pervasive problem” in Nordic countries and that institutions, funding bodies, and policymakers needed to ensure that regulations around reporting results were adhered to so that important findings are not lost.

Study first author, Gustav Nilsonne, MD, PHD, from the Department of Clinical Neuroscience at the Karolinska Institutet, Sweden, told this news organization: “Most people I talk to — most colleagues who are clinical scientists — tend to think that the main reason is that negative results are not as interesting to publish and therefore they get lower priority, and they get published later and sometimes not at all.”

Experts stressed that the problem is not confined to Nordic countries and that wasted medical research persists elsewhere in Europe and remains a global problem. For instance, a report published in the Journal of Clinical Epidemiology found that 30% of German trials completed between 2014 and 2017 remained unpublished 5 years after completion.
 

The Case for Laws, Monitoring, and Fines

Till Bruckner, PHD, from TranspariMED, which campaigns to end evidence distortion in medicine, told this news organization: “What is needed to comprehensively fix the problem is a national legal requirement to make all trial results public, coupled with effective monitoring, and followed by sanctions in the rare cases where institutions refuse to comply.” 

Dr. Nilsonne added: “We have argued that the sponsors need to take greater responsibility, but also that there needs to be somebody whose job it is to monitor clinical trials reporting. It shouldn’t have to be that we do this as researchers on a shoestring with no dedicated resources. It should be somebody’s job.”

Since January 31, 2023, all initial clinical trial applications in the European Union must be submitted through the EU Clinical Trials Information System. Dr. Bruckner said that “the picture is not yet clear” in Europe, as the first trial results under the system are not expected until later this year. Even then, enforcement lies with regulators in individual countries. And while Denmark has already indicated it will enforce the regulations, he warned that other countries “might turn a blind eye.”

He pointed out that existing laws don’t apply to all types of trials. “That means that for many trials, nobody is legally responsible for ensuring that results are made public, and no government agency has any oversight or mandate,” he said.

Outside the EU, the United Kingdom has helped lead the way through the NHS Health Research Authority (HRA), which registers trials run in the country. One year after a trial has been completed, the HRA checks to see if the results have been uploaded to the registry and issues reminders if they haven’t.

In an update of its work in January, the authority said that compliance had hovered at just below 90% between 2018 and 2021 but that it was working to increase this to 100% by working with stakeholders across the research sector.

Dr. Nilsonne considers the UK system of central registration and follow-up an attractive option. “I would love to see something along those lines in other countries too,” he said.
 

‘Rampant Noncompliance’ in the United States

In the United States, a requirement to make trial results public is backed by law. Despite this, there’s evidence of “rampant noncompliance” and minimal government action, according to Megan Curtin from Universities Allied for Essential Medicines (UAEM), which has been tracking the issue in the United States and working to push universities and others to make their findings available.

The US Food and Drug Administration (FDA) shares responsibility with the National Institutes of Health for enforcement of clinical trial results reporting, but the UAEM says nearly 4000 trials are currently out of compliance with reporting requirements. In January last year, the UAEM copublished a report with the National Center for Health Research and TranspariMED, which found that 3627 American children participated in clinical trials whose results remain unreported.

The FDA can levy a fine of up to $10,000 USD for a violation of the law, but UAEM said that, as of January 2023, the FDA had sent only 92 preliminary notices of noncompliance and four notices of noncompliance. “A clear difference between the EU field of clinical trial operation and US clinical trials is that there are clear laws for reporting within 12 months, which can be enforced, but they’re not being enforced by the FDA,” Ms. Curtin told this news organization.

The UAEM is pushing the FDA to issue a minimum of 250 preliminary notices of noncompliance each year to noncompliant trial sponsors.

Dr. Nilsonne said: “I do believe we have a great responsibility to the patients that do contribute. We need to make sure that the harms and risks that a clinical trial entails are really balanced by knowledge gain, and if the results are never reported, then we can’t have a knowledge gain.”
 

A version of this article appeared on Medscape.com.

Campaigners for greater transparency in medical science have reiterated calls for more to be done to avoid “medical research waste” after an investigation found that results from more than a fifth of clinical trials across five Nordic countries have never been made public.

A study found that results from 475 clinical trials in Denmark, Iceland, Finland, Norway, and Sweden — involving almost 84,000 participants — were never made public in any form.

Nonpublication of clinical trial results wastes public money, harms patients, and undermines public health, the researchers said. 

There is already a well-defined ethical responsibility to publish trial results. Article 36 of the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects states that “researchers have a duty to make publicly available the results of their research on human subjects,” and World Health Organization best practice protocols call for results to be uploaded onto trial registries within 12 months of trial completion.
 

Research Waste Is a ‘Pervasive Problem’

So, how and why do so many trials end up gathering dust in a drawer? The latest study, published February 5 as a preprint, evaluated the reporting outcomes of 2113 clinical trials at medical universities and university hospitals in Nordic countries between 2016 and 2019. It found that across the five countries, 22% of all clinical trial results had not been shared. Furthermore, only 27% of all trial results were made public, either on registries or in journals, within 12 months. Even 2 years after trials ended, only around half of results (51.7%) had been put into the public domain.

The authors concluded that missing and delayed results from academically-led clinical trials was a “pervasive problem” in Nordic countries and that institutions, funding bodies, and policymakers needed to ensure that regulations around reporting results were adhered to so that important findings are not lost.

Study first author, Gustav Nilsonne, MD, PHD, from the Department of Clinical Neuroscience at the Karolinska Institutet, Sweden, told this news organization: “Most people I talk to — most colleagues who are clinical scientists — tend to think that the main reason is that negative results are not as interesting to publish and therefore they get lower priority, and they get published later and sometimes not at all.”

Experts stressed that the problem is not confined to Nordic countries and that wasted medical research persists elsewhere in Europe and remains a global problem. For instance, a report published in the Journal of Clinical Epidemiology found that 30% of German trials completed between 2014 and 2017 remained unpublished 5 years after completion.
 

The Case for Laws, Monitoring, and Fines

Till Bruckner, PHD, from TranspariMED, which campaigns to end evidence distortion in medicine, told this news organization: “What is needed to comprehensively fix the problem is a national legal requirement to make all trial results public, coupled with effective monitoring, and followed by sanctions in the rare cases where institutions refuse to comply.” 

Dr. Nilsonne added: “We have argued that the sponsors need to take greater responsibility, but also that there needs to be somebody whose job it is to monitor clinical trials reporting. It shouldn’t have to be that we do this as researchers on a shoestring with no dedicated resources. It should be somebody’s job.”

Since January 31, 2023, all initial clinical trial applications in the European Union must be submitted through the EU Clinical Trials Information System. Dr. Bruckner said that “the picture is not yet clear” in Europe, as the first trial results under the system are not expected until later this year. Even then, enforcement lies with regulators in individual countries. And while Denmark has already indicated it will enforce the regulations, he warned that other countries “might turn a blind eye.”

He pointed out that existing laws don’t apply to all types of trials. “That means that for many trials, nobody is legally responsible for ensuring that results are made public, and no government agency has any oversight or mandate,” he said.

Outside the EU, the United Kingdom has helped lead the way through the NHS Health Research Authority (HRA), which registers trials run in the country. One year after a trial has been completed, the HRA checks to see if the results have been uploaded to the registry and issues reminders if they haven’t.

In an update of its work in January, the authority said that compliance had hovered at just below 90% between 2018 and 2021 but that it was working to increase this to 100% by working with stakeholders across the research sector.

Dr. Nilsonne considers the UK system of central registration and follow-up an attractive option. “I would love to see something along those lines in other countries too,” he said.
 

‘Rampant Noncompliance’ in the United States

In the United States, a requirement to make trial results public is backed by law. Despite this, there’s evidence of “rampant noncompliance” and minimal government action, according to Megan Curtin from Universities Allied for Essential Medicines (UAEM), which has been tracking the issue in the United States and working to push universities and others to make their findings available.

The US Food and Drug Administration (FDA) shares responsibility with the National Institutes of Health for enforcement of clinical trial results reporting, but the UAEM says nearly 4000 trials are currently out of compliance with reporting requirements. In January last year, the UAEM copublished a report with the National Center for Health Research and TranspariMED, which found that 3627 American children participated in clinical trials whose results remain unreported.

The FDA can levy a fine of up to $10,000 USD for a violation of the law, but UAEM said that, as of January 2023, the FDA had sent only 92 preliminary notices of noncompliance and four notices of noncompliance. “A clear difference between the EU field of clinical trial operation and US clinical trials is that there are clear laws for reporting within 12 months, which can be enforced, but they’re not being enforced by the FDA,” Ms. Curtin told this news organization.

The UAEM is pushing the FDA to issue a minimum of 250 preliminary notices of noncompliance each year to noncompliant trial sponsors.

Dr. Nilsonne said: “I do believe we have a great responsibility to the patients that do contribute. We need to make sure that the harms and risks that a clinical trial entails are really balanced by knowledge gain, and if the results are never reported, then we can’t have a knowledge gain.”
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.

Patients with Cushing disease have an increased risk for new-onset autoimmune disease in the 3 years after surgical remission, according to a new retrospective study published on February 20 in Annals of Internal Medicine.

Outcomes for patients with Cushing disease were compared against those with nonfunctioning pituitary adenomas (NFPAs). New-onset autoimmune disease occurred in 10.4% with Cushing disease and 1.6% among patients with NFPA (hazard ratio, 7.80; 95% CI, 2.88-21.10).

“Understanding and recognizing new and recurrent autoimmune disease in this setting is important to avoid misclassifying such patients with glucocorticoid withdrawal syndrome, which could result in failure to treat underlying autoimmune disease, as well as erroneous diagnosis of steroid withdrawal cases,” wrote Dennis Delasi Nyanyo of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues.

Given the general population’s annual incidence of major autoimmune diseases, estimated at about 100 cases per 100,000 people, and the 3-year incidence of 10.4% found in this study’s cohort, “our findings suggest that Cushing disease remission may trigger development of autoimmune disease,” the authors wrote.
 

Monitor Patients With Family History of Autoimmune Disease?

The study results were not necessarily surprising to Anthony P. Heaney, MD, PhD, an endocrinologist and professor of medicine at the University of California, Los Angeles, because past research has raised similar questions. The authors’ suggestion that the rapid postsurgical drop in cortisol that occurs as a result of treating Cushing disease becomes some sort of autoimmune trigger is interesting but remains speculative, Dr. Heaney pointed out.

If future evidence supports that possibility, “it would suggest, in terms of managing those patients in the postoperative setting, that there may be some merit to giving them higher concentrations of glucocorticoids for a short period of time,” Dr. Heaney said, thereby bringing their levels down more gradually rather than taking them off a cliff, in a sense. Or, if more evidence bears out the authors’ hypothesis, another approach might be treating patients with medicine to bring down the cortisol before surgery, though there are challenges to that approach, Dr. Heaney said.

At the same time, those who developed new autoimmune disease remain a small subset of patients with Cushing disease, so such approaches may become only potentially appropriate to consider in patients with risk factors, such as a family history of autoimmune disease.

The researchers conducted a retrospective chart review of adult patients who underwent transsphenoidal surgery for either Cushing disease or NFPA at Massachusetts General Hospital between 2005 and 2019.

The study involved 194 patients with Cushing disease who had postsurgical remission and at least one follow-up visit with a pituitary expert and 92 patients with NFPA who were matched to patients with Cushing disease based on age and sex. The authors regarded autoimmune disease diagnosed within 36 months of the surgery to be temporally associated with Cushing disease remission. Among the autoimmune diseases considered were “rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, autoimmune thyroiditis, celiac disease, psoriasis, vitiligo, autoimmune neuropathy, multiple sclerosis, myasthenia gravis, and ulcerative colitis.”

Patients differed in average body mass index and tumor size, but family history of autoimmune disease was similar in both groups. Average BMI was 34.5 in the Cushing group and 29.5 in the NFPA group. Average tumor size was 5.7 mm in the Cushing group and 21.3 mm in the NFPA group.

Before surgery, 2.9% of patients with Cushing disease and 15.4% of patients with NFPA had central hypothyroidism, and 8% in the Cushing group and 56.8% in the NFPA group had hyperprolactinemia. Central adrenal insufficiency occurred in 11% with NFPA and in all with Cushing disease, by definition.

After surgery, 93.8% in the Cushing group and 16.5% in the NFPA group had adrenal insufficiency. In addition, patients with Cushing disease had lower postsurgical nadir serum cortisol levels (63.8 nmol/L) than those with NFPA (282.3 nmol/L).

Of the 17 patients with Cushing disease — all women — who developed autoimmune disease within 3 years, 6 had a personal history of autoimmune disease and 7 had a family history of it. In addition, 41.2% of them had adrenal insufficiency when they developed the new autoimmune disease. Among the diseases were six autoimmune thyroiditis cases, three Sjögren syndrome cases, and two autoimmune seronegative spondyloarthropathy.

Dr. Heaney said he found it interesting that more than half of the new autoimmune diseases in patients with Cushing disease were related to the thyroid. “In this kind of setting, where you have a patient who has been producing too much steroid over a period of time and then you take that away, it’s almost like you release a brake on the TSH [thyroid-stimulating hormone],” Dr. Heaney said. “So, there’s probably some rebound in TSH that occurs, and that could be driving the thyroiditis, to some extent, that we see in these patients.”

Only one patient with NFPA developed new-onset autoimmune disease, a woman who developed Graves disease 22 months after surgery. When the researchers excluded patients in both groups with central hypothyroidism, new-onset autoimmune disease was still significantly higher (11.4%) in the Cushing group than in the NFPA group (1.9%; HR, 7.02; 95% CI, 2.54-19.39).
 

Could Postoperative Adrenal Insufficiency Contribute to Risk?

Within the Cushing cohort, those who developed autoimmune disease had a lower BMI (31.8 vs 34.8) and larger tumor size (7.2 vs 5.6 mm) than those who didn’t develop new autoimmune disease. Patients who developed autoimmune disease also had a lower baseline urine free cortisol ratio (2.7 vs 6.3) before surgery and more family history of autoimmune disease (41.2% vs 20.9%) than those who didn’t develop one.

“The higher prevalence of adrenal insufficiency and the lower nadir serum cortisol levels in the Cushing disease group suggest that the postoperative adrenal insufficiency in the Cushing disease group might have contributed to autoimmune disease pathogenesis,” the authors wrote. “This finding is clinically significant because cortisol plays a pivotal role in modulating the immune system.”

Most postoperative management among patients with Cushing disease was similar, with all but one patient receiving 0.5 or 1 mg daily dexamethasone within the first week after surgery. (The one outlier received 5 mg daily prednisone.) However, fewer patients who developed autoimmune disease (17.6%) received supraphysiologic doses of glucocorticoid — equivalent to at least 25 mg hydrocortisone — compared with patients who didn’t develop autoimmune disease (41.8%).

“Although the daily average hydrocortisone equivalent replacement doses within the first month and during long-term follow-up were within the physiologic range in both subgroups, patients with Cushing disease who had autoimmune disease received slightly lower doses of glucocorticoid replacement within the first month after surgery,” the authors reported. “The immediate postoperative period might be a critical window where supraphysiologic glucocorticoids seem to be protective with regard to development of autoimmune disease,” they wrote, though they acknowledged the study’s retrospective design as a limitation in drawing that conclusion.

At the least, they suggested that new symptoms in patients with Cushing disease, particularly those with a family history of autoimmune disease, should prompt investigation of potential autoimmune disease.

Recordati Rare Diseases funded the study. The research was also conducted with support from Harvard Catalyst (the Harvard Clinical and Translational Science Center) as well as financial contributions from Harvard University and its affiliated academic healthcare centers. One author reported holding stocks in Pfizer and Amgen, and another reported receiving consulting fees from Corcept. Dr. Heaney reported receiving institutional grants for trials from Corcept, Ascendis, Crinetics, and Sparrow Pharm; serving on the advisory board for Xeris, Recordati, Corcept, Novo Nordisk, Lundbeck, and Crinetics; and serving as a speaker for Chiesi, Novo Nordisk, and Corcept.
 

A version of this article appeared on Medscape.com.