Endocrinology

Children with growth hormone deficiency (GHD) have differences in gut microbiota and microbial metabolites from both individuals with idiopathic short stature (ISS) and healthy controls, suggesting an interaction with growth hormone levels, said Chinese researchers.

The research, published recently in Pediatric Research, involved more than 80 children and showed that those with GHD had alterations in microbial populations that have been linked to longevity, as well as a microbial and metabolite signature that allowed accurate discrimination from ISS.

“These findings provide novel insights into potential early diagnosis and innovative treatment alternatives, such as fecal microbiota transplantation, for short stature with varying growth hormone levels,” the authors wrote.

Andrew Dauber, MD, MMSc, chief of endocrinology, Children’s National Hospital, Washington, who was not involved in the study, said that while this is “a really interesting area of research,” he expressed “hesitancy about getting too excited about this data yet.”

“One of the problems is how you define growth hormone deficiency,” as it is “not a black and white diagnosis,” and the etiology and child’s growth trajectory also need to be considered, Dr. Dauber told said.

He explained: “The problem is that, when you rely on the growth hormone stimulation test alone, there’s so many false positives and so much overlap between patients with true growth hormone deficiency and those without. And I think that this article fell prey to that.”

He added: “It would be really, really interesting and helpful to have a microbiome signature that allows you to distinguish between true growth hormone deficiency and patients with idiopathic short stature.”

“But you have to make sure that your groups are very well defined for this study to be really valid. And that’s one of my concerns here.”

Dr. Dauber continued: “Now, that being said, they did find some associations that correlated with growth hormone peak levels,” some which replicate previous findings, “so I do think that there are kernels of important findings here.”
 

‘Tease Out Influences’ to Isolate the Interaction

He pointed out that there are “many factors that influence the microbiome,” such as the use of antibiotics, diet, age, and geographic location. Therefore, a study that could truly tease out all these influences and isolate the interaction with growth hormone levels would need to be “very thoughtfully designed.”

A number of factors contribute to short stature, lead author Lan Li, MD, Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China, and colleagues.

These include genetic factors, environmental factors, and conditions such as being small for gestational age at birth, familial short stature, and chronic systemic diseases, as well as GHD and ISS.

Recent animal studies have suggested that there may be a bidirectional relationship between the gut microbiota and the growth hormone/insulin-like growth factor 1 axis, and it has been shown that individuals with GHD have significant alterations in their gut microbiota compared with healthy controls.

To investigate, they studied 36 children diagnosed with GHD, 32 with ISS, and 16 age- and sex-matched healthy controls, all of whom were recruited between February 2019 and June 2021 from the Pediatric Endocrinology Department of The Second Affiliated Hospital of Wenzhou Medical University.

Fecal samples obtained from the children underwent microbiome analysis using 16S ribosomal RNA gene sequencing, alongside nuclear MRI analysis of the metabolome, or the entire complement of small molecules in the samples.

Patients with GHD had a significantly higher body mass index than those with ISS (P < .05), and their peak growth hormone level was significantly lower (P < .001). Patients with GHD also had significantly higher total cholesterol and low-density lipoprotein cholesterol levels than patients with ISS (P < .05).

The team reports that the alpha diversity of the fecal microbiome, which measures the microbial diversity within a fecal sample, was similar between the three groups.

However, there was significant variation between the groups in the beta diversity, which quantifies the similarity or dissimilarity between two samples, and allows the overall taxonomic or functional diversity pattern to be linked to environmental features.

Compared with the healthy control group, the abundance of Pelomonas, Rodentibacter, and Rothia was significantly decreased in GHD and patients with ISS, while the abundance of Prevotellaceae_NK3B31_group was increased in the two patient groups, particularly in those with GHD.

In addition, the researchers found a decreased Firmicutes/Bacteroidota (F/B) ratio in participants with short stature, particularly in the GHD group. They noted that “emerging evidence suggests the F/B ratio may play a role in longevity.”

Nocardioides was substantially more common in the ISS group vs both patients with GHD and healthy controls, while Fusobacterium mortiferum was characteristic of GHD. The team suggests this “may serve as a critical intestinal factor contributing to the short stature observed in GHD.”

The metabolome analysis revealed that glucose, pyruvate, and pyrimidine metabolism may also play a significant role in distinguishing between patients with GHD and ISS and healthy control groups.

Finally, the team demonstrated that a panel combining 13 microbiome and metabolome markers was able to discriminate between GHD and ISS at an area under the receiver operating characteristic curve of 0.945, with a sensitivity of 87% and a specificity of 91%.

The study was supported by grants from the National Natural Science Foundation of China and Wenzhou Science and Technology Bureau in China. No relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

Children with growth hormone deficiency (GHD) have differences in gut microbiota and microbial metabolites from both individuals with idiopathic short stature (ISS) and healthy controls, suggesting an interaction with growth hormone levels, said Chinese researchers.

The research, published recently in Pediatric Research, involved more than 80 children and showed that those with GHD had alterations in microbial populations that have been linked to longevity, as well as a microbial and metabolite signature that allowed accurate discrimination from ISS.

“These findings provide novel insights into potential early diagnosis and innovative treatment alternatives, such as fecal microbiota transplantation, for short stature with varying growth hormone levels,” the authors wrote.

Andrew Dauber, MD, MMSc, chief of endocrinology, Children’s National Hospital, Washington, who was not involved in the study, said that while this is “a really interesting area of research,” he expressed “hesitancy about getting too excited about this data yet.”

“One of the problems is how you define growth hormone deficiency,” as it is “not a black and white diagnosis,” and the etiology and child’s growth trajectory also need to be considered, Dr. Dauber told said.

He explained: “The problem is that, when you rely on the growth hormone stimulation test alone, there’s so many false positives and so much overlap between patients with true growth hormone deficiency and those without. And I think that this article fell prey to that.”

He added: “It would be really, really interesting and helpful to have a microbiome signature that allows you to distinguish between true growth hormone deficiency and patients with idiopathic short stature.”

“But you have to make sure that your groups are very well defined for this study to be really valid. And that’s one of my concerns here.”

Dr. Dauber continued: “Now, that being said, they did find some associations that correlated with growth hormone peak levels,” some which replicate previous findings, “so I do think that there are kernels of important findings here.”
 

‘Tease Out Influences’ to Isolate the Interaction

He pointed out that there are “many factors that influence the microbiome,” such as the use of antibiotics, diet, age, and geographic location. Therefore, a study that could truly tease out all these influences and isolate the interaction with growth hormone levels would need to be “very thoughtfully designed.”

A number of factors contribute to short stature, lead author Lan Li, MD, Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China, and colleagues.

These include genetic factors, environmental factors, and conditions such as being small for gestational age at birth, familial short stature, and chronic systemic diseases, as well as GHD and ISS.

Recent animal studies have suggested that there may be a bidirectional relationship between the gut microbiota and the growth hormone/insulin-like growth factor 1 axis, and it has been shown that individuals with GHD have significant alterations in their gut microbiota compared with healthy controls.

To investigate, they studied 36 children diagnosed with GHD, 32 with ISS, and 16 age- and sex-matched healthy controls, all of whom were recruited between February 2019 and June 2021 from the Pediatric Endocrinology Department of The Second Affiliated Hospital of Wenzhou Medical University.

Fecal samples obtained from the children underwent microbiome analysis using 16S ribosomal RNA gene sequencing, alongside nuclear MRI analysis of the metabolome, or the entire complement of small molecules in the samples.

Patients with GHD had a significantly higher body mass index than those with ISS (P < .05), and their peak growth hormone level was significantly lower (P < .001). Patients with GHD also had significantly higher total cholesterol and low-density lipoprotein cholesterol levels than patients with ISS (P < .05).

The team reports that the alpha diversity of the fecal microbiome, which measures the microbial diversity within a fecal sample, was similar between the three groups.

However, there was significant variation between the groups in the beta diversity, which quantifies the similarity or dissimilarity between two samples, and allows the overall taxonomic or functional diversity pattern to be linked to environmental features.

Compared with the healthy control group, the abundance of Pelomonas, Rodentibacter, and Rothia was significantly decreased in GHD and patients with ISS, while the abundance of Prevotellaceae_NK3B31_group was increased in the two patient groups, particularly in those with GHD.

In addition, the researchers found a decreased Firmicutes/Bacteroidota (F/B) ratio in participants with short stature, particularly in the GHD group. They noted that “emerging evidence suggests the F/B ratio may play a role in longevity.”

Nocardioides was substantially more common in the ISS group vs both patients with GHD and healthy controls, while Fusobacterium mortiferum was characteristic of GHD. The team suggests this “may serve as a critical intestinal factor contributing to the short stature observed in GHD.”

The metabolome analysis revealed that glucose, pyruvate, and pyrimidine metabolism may also play a significant role in distinguishing between patients with GHD and ISS and healthy control groups.

Finally, the team demonstrated that a panel combining 13 microbiome and metabolome markers was able to discriminate between GHD and ISS at an area under the receiver operating characteristic curve of 0.945, with a sensitivity of 87% and a specificity of 91%.

The study was supported by grants from the National Natural Science Foundation of China and Wenzhou Science and Technology Bureau in China. No relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

Children with growth hormone deficiency (GHD) have differences in gut microbiota and microbial metabolites from both individuals with idiopathic short stature (ISS) and healthy controls, suggesting an interaction with growth hormone levels, said Chinese researchers.

The research, published recently in Pediatric Research, involved more than 80 children and showed that those with GHD had alterations in microbial populations that have been linked to longevity, as well as a microbial and metabolite signature that allowed accurate discrimination from ISS.

“These findings provide novel insights into potential early diagnosis and innovative treatment alternatives, such as fecal microbiota transplantation, for short stature with varying growth hormone levels,” the authors wrote.

Andrew Dauber, MD, MMSc, chief of endocrinology, Children’s National Hospital, Washington, who was not involved in the study, said that while this is “a really interesting area of research,” he expressed “hesitancy about getting too excited about this data yet.”

“One of the problems is how you define growth hormone deficiency,” as it is “not a black and white diagnosis,” and the etiology and child’s growth trajectory also need to be considered, Dr. Dauber told said.

He explained: “The problem is that, when you rely on the growth hormone stimulation test alone, there’s so many false positives and so much overlap between patients with true growth hormone deficiency and those without. And I think that this article fell prey to that.”

He added: “It would be really, really interesting and helpful to have a microbiome signature that allows you to distinguish between true growth hormone deficiency and patients with idiopathic short stature.”

“But you have to make sure that your groups are very well defined for this study to be really valid. And that’s one of my concerns here.”

Dr. Dauber continued: “Now, that being said, they did find some associations that correlated with growth hormone peak levels,” some which replicate previous findings, “so I do think that there are kernels of important findings here.”
 

‘Tease Out Influences’ to Isolate the Interaction

He pointed out that there are “many factors that influence the microbiome,” such as the use of antibiotics, diet, age, and geographic location. Therefore, a study that could truly tease out all these influences and isolate the interaction with growth hormone levels would need to be “very thoughtfully designed.”

A number of factors contribute to short stature, lead author Lan Li, MD, Department of Radiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China, and colleagues.

These include genetic factors, environmental factors, and conditions such as being small for gestational age at birth, familial short stature, and chronic systemic diseases, as well as GHD and ISS.

Recent animal studies have suggested that there may be a bidirectional relationship between the gut microbiota and the growth hormone/insulin-like growth factor 1 axis, and it has been shown that individuals with GHD have significant alterations in their gut microbiota compared with healthy controls.

To investigate, they studied 36 children diagnosed with GHD, 32 with ISS, and 16 age- and sex-matched healthy controls, all of whom were recruited between February 2019 and June 2021 from the Pediatric Endocrinology Department of The Second Affiliated Hospital of Wenzhou Medical University.

Fecal samples obtained from the children underwent microbiome analysis using 16S ribosomal RNA gene sequencing, alongside nuclear MRI analysis of the metabolome, or the entire complement of small molecules in the samples.

Patients with GHD had a significantly higher body mass index than those with ISS (P < .05), and their peak growth hormone level was significantly lower (P < .001). Patients with GHD also had significantly higher total cholesterol and low-density lipoprotein cholesterol levels than patients with ISS (P < .05).

The team reports that the alpha diversity of the fecal microbiome, which measures the microbial diversity within a fecal sample, was similar between the three groups.

However, there was significant variation between the groups in the beta diversity, which quantifies the similarity or dissimilarity between two samples, and allows the overall taxonomic or functional diversity pattern to be linked to environmental features.

Compared with the healthy control group, the abundance of Pelomonas, Rodentibacter, and Rothia was significantly decreased in GHD and patients with ISS, while the abundance of Prevotellaceae_NK3B31_group was increased in the two patient groups, particularly in those with GHD.

In addition, the researchers found a decreased Firmicutes/Bacteroidota (F/B) ratio in participants with short stature, particularly in the GHD group. They noted that “emerging evidence suggests the F/B ratio may play a role in longevity.”

Nocardioides was substantially more common in the ISS group vs both patients with GHD and healthy controls, while Fusobacterium mortiferum was characteristic of GHD. The team suggests this “may serve as a critical intestinal factor contributing to the short stature observed in GHD.”

The metabolome analysis revealed that glucose, pyruvate, and pyrimidine metabolism may also play a significant role in distinguishing between patients with GHD and ISS and healthy control groups.

Finally, the team demonstrated that a panel combining 13 microbiome and metabolome markers was able to discriminate between GHD and ISS at an area under the receiver operating characteristic curve of 0.945, with a sensitivity of 87% and a specificity of 91%.

The study was supported by grants from the National Natural Science Foundation of China and Wenzhou Science and Technology Bureau in China. No relevant financial relationships were declared.
 

A version of this article appeared on Medscape.com.

With all the excitement about GLP-1 agonists, I get many questions from providers about which antiobesity drug they should prescribe. I’ll tell you the methods that I use to determine which drug is best for which patient.

Of course, we want to make sure that we’re treating the right condition. If the patient has type 2 diabetes, we tend to give them medication that is indicated for type 2 diabetes. Many GLP-1 agonists are available in a diabetes version and a chronic weight management or obesity version. If a patient has diabetes and obesity, they can receive either one. If a patient has only diabetes but not obesity, they should be prescribed the diabetes version. For obesity without diabetes, we tend to stick with the drugs that are indicated for chronic weight management.

Let’s go through them.

Exenatide. In chronological order of approval, the first GLP-1 drug that was used for diabetes dates back to exenatide (Bydureon). Bydureon had a partner called Byetta (also exenatide), both of which are still on the market but infrequently used. Some patients reported that these medications were inconvenient because they required twice-daily injections and caused painful injection-site nodules.

Diabetes drugs in more common use include liraglutide (Victoza) for type 2 diabetes. It is a daily injection and has various doses. We always start low and increase with tolerance and desired effect for A1c.

Liraglutide. Victoza has an antiobesity counterpart called Saxenda. The Saxenda pen looks very similar to the Victoza pen. It is a daily GLP-1 agonist for chronic weight management. The SCALE trial demonstrated 8%-12% weight loss with Saxenda.

Those are the daily injections: Victoza for diabetes and Saxenda for weight loss.

Our patients are very excited about the advent of weekly injections for diabetes and weight management. Ozempic is very popular. It is a weekly GLP-1 agonist for type 2 diabetes. Many patients come in asking for Ozempic, and we must make sure that we’re moving them in the right direction depending on their condition.

Semaglutide. Ozempic has a few different doses. It is a weekly injection and has been found to be quite efficacious for treating diabetes. The drug’s weight loss counterpart is called Wegovy, which comes in a different pen. Both forms contain the compound semaglutide. While all of these GLP-1 agonists are indicated to treat type 2 diabetes or for weight management, Wegovy has a special indication that none of the others have. In March 2024, Wegovy acquired an indication to decrease cardiac risk in those with a BMI ≥ 27 and a previous cardiac history. This will really change the accessibility of this medication because patients with heart conditions who are on Medicare are expected to have access to Wegovy.

Tirzepatide. Another weekly injection for treatment of type 2 diabetes is called Mounjaro. Its counterpart for weight management is called Zepbound, which was found to have about 20.9% weight loss over 72 weeks. These medications have similar side effects in differing degrees, but the most-often reported are nausea, stool changes, abdominal pain, and reflux. There are some other potential side effects; I recommend that you read the individual prescribing information available for each drug to have more clarity about that.

It is important that we stay on label for using the GLP-1 receptor agonists, for many reasons. One, it increases our patients’ accessibility to the right medication for them, and we can also make sure that we’re treating the patient with the right drug according to the clinical trials. When the clinical trials are done, the study populations demonstrate safety and efficacy for that population. But if we’re prescribing a GLP-1 for a different population, it is considered off-label use.
 

Dr. Lofton, an obesity medicine specialist, is clinical associate professor of surgery and medicine at NYU Grossman School of Medicine, and director of the medical weight management program at NYU Langone Weight Management Center, New York. She disclosed ties to Novo Nordisk and Eli Lilly. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.

With all the excitement about GLP-1 agonists, I get many questions from providers about which antiobesity drug they should prescribe. I’ll tell you the methods that I use to determine which drug is best for which patient.

Of course, we want to make sure that we’re treating the right condition. If the patient has type 2 diabetes, we tend to give them medication that is indicated for type 2 diabetes. Many GLP-1 agonists are available in a diabetes version and a chronic weight management or obesity version. If a patient has diabetes and obesity, they can receive either one. If a patient has only diabetes but not obesity, they should be prescribed the diabetes version. For obesity without diabetes, we tend to stick with the drugs that are indicated for chronic weight management.

Let’s go through them.

Exenatide. In chronological order of approval, the first GLP-1 drug that was used for diabetes dates back to exenatide (Bydureon). Bydureon had a partner called Byetta (also exenatide), both of which are still on the market but infrequently used. Some patients reported that these medications were inconvenient because they required twice-daily injections and caused painful injection-site nodules.

Diabetes drugs in more common use include liraglutide (Victoza) for type 2 diabetes. It is a daily injection and has various doses. We always start low and increase with tolerance and desired effect for A1c.

Liraglutide. Victoza has an antiobesity counterpart called Saxenda. The Saxenda pen looks very similar to the Victoza pen. It is a daily GLP-1 agonist for chronic weight management. The SCALE trial demonstrated 8%-12% weight loss with Saxenda.

Those are the daily injections: Victoza for diabetes and Saxenda for weight loss.

Our patients are very excited about the advent of weekly injections for diabetes and weight management. Ozempic is very popular. It is a weekly GLP-1 agonist for type 2 diabetes. Many patients come in asking for Ozempic, and we must make sure that we’re moving them in the right direction depending on their condition.

Semaglutide. Ozempic has a few different doses. It is a weekly injection and has been found to be quite efficacious for treating diabetes. The drug’s weight loss counterpart is called Wegovy, which comes in a different pen. Both forms contain the compound semaglutide. While all of these GLP-1 agonists are indicated to treat type 2 diabetes or for weight management, Wegovy has a special indication that none of the others have. In March 2024, Wegovy acquired an indication to decrease cardiac risk in those with a BMI ≥ 27 and a previous cardiac history. This will really change the accessibility of this medication because patients with heart conditions who are on Medicare are expected to have access to Wegovy.

Tirzepatide. Another weekly injection for treatment of type 2 diabetes is called Mounjaro. Its counterpart for weight management is called Zepbound, which was found to have about 20.9% weight loss over 72 weeks. These medications have similar side effects in differing degrees, but the most-often reported are nausea, stool changes, abdominal pain, and reflux. There are some other potential side effects; I recommend that you read the individual prescribing information available for each drug to have more clarity about that.

It is important that we stay on label for using the GLP-1 receptor agonists, for many reasons. One, it increases our patients’ accessibility to the right medication for them, and we can also make sure that we’re treating the patient with the right drug according to the clinical trials. When the clinical trials are done, the study populations demonstrate safety and efficacy for that population. But if we’re prescribing a GLP-1 for a different population, it is considered off-label use.
 

Dr. Lofton, an obesity medicine specialist, is clinical associate professor of surgery and medicine at NYU Grossman School of Medicine, and director of the medical weight management program at NYU Langone Weight Management Center, New York. She disclosed ties to Novo Nordisk and Eli Lilly. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.

With all the excitement about GLP-1 agonists, I get many questions from providers about which antiobesity drug they should prescribe. I’ll tell you the methods that I use to determine which drug is best for which patient.

Of course, we want to make sure that we’re treating the right condition. If the patient has type 2 diabetes, we tend to give them medication that is indicated for type 2 diabetes. Many GLP-1 agonists are available in a diabetes version and a chronic weight management or obesity version. If a patient has diabetes and obesity, they can receive either one. If a patient has only diabetes but not obesity, they should be prescribed the diabetes version. For obesity without diabetes, we tend to stick with the drugs that are indicated for chronic weight management.

Let’s go through them.

Exenatide. In chronological order of approval, the first GLP-1 drug that was used for diabetes dates back to exenatide (Bydureon). Bydureon had a partner called Byetta (also exenatide), both of which are still on the market but infrequently used. Some patients reported that these medications were inconvenient because they required twice-daily injections and caused painful injection-site nodules.

Diabetes drugs in more common use include liraglutide (Victoza) for type 2 diabetes. It is a daily injection and has various doses. We always start low and increase with tolerance and desired effect for A1c.

Liraglutide. Victoza has an antiobesity counterpart called Saxenda. The Saxenda pen looks very similar to the Victoza pen. It is a daily GLP-1 agonist for chronic weight management. The SCALE trial demonstrated 8%-12% weight loss with Saxenda.

Those are the daily injections: Victoza for diabetes and Saxenda for weight loss.

Our patients are very excited about the advent of weekly injections for diabetes and weight management. Ozempic is very popular. It is a weekly GLP-1 agonist for type 2 diabetes. Many patients come in asking for Ozempic, and we must make sure that we’re moving them in the right direction depending on their condition.

Semaglutide. Ozempic has a few different doses. It is a weekly injection and has been found to be quite efficacious for treating diabetes. The drug’s weight loss counterpart is called Wegovy, which comes in a different pen. Both forms contain the compound semaglutide. While all of these GLP-1 agonists are indicated to treat type 2 diabetes or for weight management, Wegovy has a special indication that none of the others have. In March 2024, Wegovy acquired an indication to decrease cardiac risk in those with a BMI ≥ 27 and a previous cardiac history. This will really change the accessibility of this medication because patients with heart conditions who are on Medicare are expected to have access to Wegovy.

Tirzepatide. Another weekly injection for treatment of type 2 diabetes is called Mounjaro. Its counterpart for weight management is called Zepbound, which was found to have about 20.9% weight loss over 72 weeks. These medications have similar side effects in differing degrees, but the most-often reported are nausea, stool changes, abdominal pain, and reflux. There are some other potential side effects; I recommend that you read the individual prescribing information available for each drug to have more clarity about that.

It is important that we stay on label for using the GLP-1 receptor agonists, for many reasons. One, it increases our patients’ accessibility to the right medication for them, and we can also make sure that we’re treating the patient with the right drug according to the clinical trials. When the clinical trials are done, the study populations demonstrate safety and efficacy for that population. But if we’re prescribing a GLP-1 for a different population, it is considered off-label use.
 

Dr. Lofton, an obesity medicine specialist, is clinical associate professor of surgery and medicine at NYU Grossman School of Medicine, and director of the medical weight management program at NYU Langone Weight Management Center, New York. She disclosed ties to Novo Nordisk and Eli Lilly. This transcript has been edited for clarity.

A version of this article appeared on Medscape.com.

Recent headlines scream that we have an obesity problem and that carbs are the culprit for the problem. That leads me to ask: How did we get to blaming carbs as the enemy in the war against obesity?

First, a quick review of the history of diet and macronutrient content.

A long time ago, prehistoric humans foraged and hunted for food. Protein and fat were procured from animal meat, which was very important for encephalization, or evolutionary increase in the complexity or relative size of the brain. Most of the requirements for protein and iron were satisfied by hunting and eating land animals as well as consuming marine life that washed up on shore.

Carbohydrates in the form of plant foods served as the only sources of energy available to prehistoric hunter-gatherers, which offset the high protein content of the rest of their diet. These were only available during spring and summer.

Then, about 10,000 years ago, plant and animal agriculture began, and humans saw a permanent shift in the macronutrient content of our daily intake so that it was more consistent and stable. Initially, the nutrient characteristic changes were subtle, going from wild food to cultivated food with the Agricultural Revolution in the mid-17th century. Then, it changed even more rapidly less than 200 years ago with the Industrial Revolution, resulting in semiprocessed and ultraprocessed foods.

This change in food intake altered human physiology, with major changes in our digestive, immune, and neural physiology and an increase in chronic disease prevalence. The last 50 years has seen an increase in obesity in the United States, along with increases in chronic disease such as type 2 diabetes, which leads cardiovascular disease and certain cancers. 
 

Back to Carbohydrates: Do We Need Them? How Much? What Kind?

The increase in the macronutrient content of the food we eat containing saturated fat and refined carbohydrates and sugars represents a major change and is arguably the smoking gun of the obesity epidemic. Unfortunately, ultraprocessed foods have become a staple of the standard American or Western diet. 

Ultraprocessed foods such as cakes, cookies, crackers, sugary breakfast cereals, pizza, potato chips, soft drinks, and ice cream are eons away from our prehistoric diet of wild game, nuts, fruits, and berries, at which time, our digestive immune and nervous systems evolved. The pace at which ultraprocessed foods have entered our diet outpaces the time necessary for adaptation of our digestive systems and genes to these foods. They are indeed pathogenic in this context. 

So when was the time when humans consumed an “optimal” diet? This is hard to say because during the time of brain evolution, we needed protein and iron and succumbed to infections and trauma. In the early 1900s, we continued to succumb to infection until the discovery of antibiotics. Soon thereafter, industrialization and processed foods led to weight gain and the chronic diseases of the cardiovascular system and type 2 diabetes. 

Carbohydrates provide calories and fiber and some micronutrients, which are needed for energy, metabolism, and bowel and immune health. But how much do we need? 

Currently in the United States, the percentage of total food energy derived from the three major macronutrients is: carbohydrates, 51.8%; fat, 32.8%; and protein, 15.4%. Current advice for a healthy diet to lower risk for cardiovascular disease is to limit fat intake to 30% of total energy, protein to 15%, and to increase complex carbohydrates to 55%-60% of total energy. But we also need to qualify this in terms of the quality of the macronutrient, particularly carbohydrates. 

In addition to the quality, the macronutrient content of the diet has varied considerably from our prehistoric times when dietary protein intakes were high at 19%-35% of energy at the expense of carbohydrate (22%-40% of energy). 

If our genes haven’t kept up with industrialization, then why do we need so many carbohydrates to equate to 55%-60% of energy? Is it possible that we are confusing what is available with what we actually need? What do I mean by this?

We certainly have changed the landscape of the world due to agriculture, which has allowed us to procreate and feed ourselves, and certainly, industrialization has increased the availability of accessible cheap food. Protein in the form of meat, fish, and fowl are harder to get in industrialized nations as are fruits and vegetables. These macronutrients were the foods of our ancestors. It may be that a healthy diet is considered the one that is available. 

For instance, the Mediterranean diet is somewhat higher in fat content, 40%-50% fat (mostly mono and unsaturated), and similar in protein content but lower in carbohydrate content than the typical Western diet. The Dietary Approaches to Stop Hypertension (DASH) diet is lower in fat at 25% total calories, is higher in carbohydrates at 55%, and is lower in protein, but this diet was generated in the United States, therefore it is more Western. 

We need high-quality protein for organ and muscle function, high-quality unsaturated and monounsaturated fats for brain function and cellular functions, and high-quality complex carbohydrates for energy and gut health as well as micronutrients for many cellular functions. A ketogenic diet is not sustainable in the long-term for these reasons: chiefly the need for some carbohydrates for gut health and micronutrients. 

How much carbohydrate content is needed should take into consideration energy expenditure as well as micronutrients and fiber intake. Protein and fat can contribute to energy production but not as readily as carbohydrates that can quickly restore glycogen in the muscle and liver. What’s interesting is that our ancestors were able to hunt and run away from danger with the small amounts of carbohydrates from plants and berries plus the protein and fat intake from animals and fish — but the Olympics weren’t a thing then!

It may be another 200,000 years before our genes catch up to ultraprocessed foods and the simple carbohydrates and sugars contained in these products. Evidence suggests that ultraprocessed foods cause inflammation in organs like the liver, adipose tissue, the heart, and even the brain. In the brain, this inflammation may be what’s causing us to defend a higher body weight set point in this environment of easily obtained highly palatable ultraprocessed foods. 

Let’s not wait until our genes catch up and our bodies tolerate junk food without disease progression. It could be like waiting for Godot!

Dr. Apovian is professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, Massachusetts. She disclosed ties to Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, and L-Nutra.

A version of this article appeared on Medscape.com.

Recent headlines scream that we have an obesity problem and that carbs are the culprit for the problem. That leads me to ask: How did we get to blaming carbs as the enemy in the war against obesity?

First, a quick review of the history of diet and macronutrient content.

A long time ago, prehistoric humans foraged and hunted for food. Protein and fat were procured from animal meat, which was very important for encephalization, or evolutionary increase in the complexity or relative size of the brain. Most of the requirements for protein and iron were satisfied by hunting and eating land animals as well as consuming marine life that washed up on shore.

Carbohydrates in the form of plant foods served as the only sources of energy available to prehistoric hunter-gatherers, which offset the high protein content of the rest of their diet. These were only available during spring and summer.

Then, about 10,000 years ago, plant and animal agriculture began, and humans saw a permanent shift in the macronutrient content of our daily intake so that it was more consistent and stable. Initially, the nutrient characteristic changes were subtle, going from wild food to cultivated food with the Agricultural Revolution in the mid-17th century. Then, it changed even more rapidly less than 200 years ago with the Industrial Revolution, resulting in semiprocessed and ultraprocessed foods.

This change in food intake altered human physiology, with major changes in our digestive, immune, and neural physiology and an increase in chronic disease prevalence. The last 50 years has seen an increase in obesity in the United States, along with increases in chronic disease such as type 2 diabetes, which leads cardiovascular disease and certain cancers. 
 

Back to Carbohydrates: Do We Need Them? How Much? What Kind?

The increase in the macronutrient content of the food we eat containing saturated fat and refined carbohydrates and sugars represents a major change and is arguably the smoking gun of the obesity epidemic. Unfortunately, ultraprocessed foods have become a staple of the standard American or Western diet. 

Ultraprocessed foods such as cakes, cookies, crackers, sugary breakfast cereals, pizza, potato chips, soft drinks, and ice cream are eons away from our prehistoric diet of wild game, nuts, fruits, and berries, at which time, our digestive immune and nervous systems evolved. The pace at which ultraprocessed foods have entered our diet outpaces the time necessary for adaptation of our digestive systems and genes to these foods. They are indeed pathogenic in this context. 

So when was the time when humans consumed an “optimal” diet? This is hard to say because during the time of brain evolution, we needed protein and iron and succumbed to infections and trauma. In the early 1900s, we continued to succumb to infection until the discovery of antibiotics. Soon thereafter, industrialization and processed foods led to weight gain and the chronic diseases of the cardiovascular system and type 2 diabetes. 

Carbohydrates provide calories and fiber and some micronutrients, which are needed for energy, metabolism, and bowel and immune health. But how much do we need? 

Currently in the United States, the percentage of total food energy derived from the three major macronutrients is: carbohydrates, 51.8%; fat, 32.8%; and protein, 15.4%. Current advice for a healthy diet to lower risk for cardiovascular disease is to limit fat intake to 30% of total energy, protein to 15%, and to increase complex carbohydrates to 55%-60% of total energy. But we also need to qualify this in terms of the quality of the macronutrient, particularly carbohydrates. 

In addition to the quality, the macronutrient content of the diet has varied considerably from our prehistoric times when dietary protein intakes were high at 19%-35% of energy at the expense of carbohydrate (22%-40% of energy). 

If our genes haven’t kept up with industrialization, then why do we need so many carbohydrates to equate to 55%-60% of energy? Is it possible that we are confusing what is available with what we actually need? What do I mean by this?

We certainly have changed the landscape of the world due to agriculture, which has allowed us to procreate and feed ourselves, and certainly, industrialization has increased the availability of accessible cheap food. Protein in the form of meat, fish, and fowl are harder to get in industrialized nations as are fruits and vegetables. These macronutrients were the foods of our ancestors. It may be that a healthy diet is considered the one that is available. 

For instance, the Mediterranean diet is somewhat higher in fat content, 40%-50% fat (mostly mono and unsaturated), and similar in protein content but lower in carbohydrate content than the typical Western diet. The Dietary Approaches to Stop Hypertension (DASH) diet is lower in fat at 25% total calories, is higher in carbohydrates at 55%, and is lower in protein, but this diet was generated in the United States, therefore it is more Western. 

We need high-quality protein for organ and muscle function, high-quality unsaturated and monounsaturated fats for brain function and cellular functions, and high-quality complex carbohydrates for energy and gut health as well as micronutrients for many cellular functions. A ketogenic diet is not sustainable in the long-term for these reasons: chiefly the need for some carbohydrates for gut health and micronutrients. 

How much carbohydrate content is needed should take into consideration energy expenditure as well as micronutrients and fiber intake. Protein and fat can contribute to energy production but not as readily as carbohydrates that can quickly restore glycogen in the muscle and liver. What’s interesting is that our ancestors were able to hunt and run away from danger with the small amounts of carbohydrates from plants and berries plus the protein and fat intake from animals and fish — but the Olympics weren’t a thing then!

It may be another 200,000 years before our genes catch up to ultraprocessed foods and the simple carbohydrates and sugars contained in these products. Evidence suggests that ultraprocessed foods cause inflammation in organs like the liver, adipose tissue, the heart, and even the brain. In the brain, this inflammation may be what’s causing us to defend a higher body weight set point in this environment of easily obtained highly palatable ultraprocessed foods. 

Let’s not wait until our genes catch up and our bodies tolerate junk food without disease progression. It could be like waiting for Godot!

Dr. Apovian is professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, Massachusetts. She disclosed ties to Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, and L-Nutra.

A version of this article appeared on Medscape.com.

Recent headlines scream that we have an obesity problem and that carbs are the culprit for the problem. That leads me to ask: How did we get to blaming carbs as the enemy in the war against obesity?

First, a quick review of the history of diet and macronutrient content.

A long time ago, prehistoric humans foraged and hunted for food. Protein and fat were procured from animal meat, which was very important for encephalization, or evolutionary increase in the complexity or relative size of the brain. Most of the requirements for protein and iron were satisfied by hunting and eating land animals as well as consuming marine life that washed up on shore.

Carbohydrates in the form of plant foods served as the only sources of energy available to prehistoric hunter-gatherers, which offset the high protein content of the rest of their diet. These were only available during spring and summer.

Then, about 10,000 years ago, plant and animal agriculture began, and humans saw a permanent shift in the macronutrient content of our daily intake so that it was more consistent and stable. Initially, the nutrient characteristic changes were subtle, going from wild food to cultivated food with the Agricultural Revolution in the mid-17th century. Then, it changed even more rapidly less than 200 years ago with the Industrial Revolution, resulting in semiprocessed and ultraprocessed foods.

This change in food intake altered human physiology, with major changes in our digestive, immune, and neural physiology and an increase in chronic disease prevalence. The last 50 years has seen an increase in obesity in the United States, along with increases in chronic disease such as type 2 diabetes, which leads cardiovascular disease and certain cancers. 
 

Back to Carbohydrates: Do We Need Them? How Much? What Kind?

The increase in the macronutrient content of the food we eat containing saturated fat and refined carbohydrates and sugars represents a major change and is arguably the smoking gun of the obesity epidemic. Unfortunately, ultraprocessed foods have become a staple of the standard American or Western diet. 

Ultraprocessed foods such as cakes, cookies, crackers, sugary breakfast cereals, pizza, potato chips, soft drinks, and ice cream are eons away from our prehistoric diet of wild game, nuts, fruits, and berries, at which time, our digestive immune and nervous systems evolved. The pace at which ultraprocessed foods have entered our diet outpaces the time necessary for adaptation of our digestive systems and genes to these foods. They are indeed pathogenic in this context. 

So when was the time when humans consumed an “optimal” diet? This is hard to say because during the time of brain evolution, we needed protein and iron and succumbed to infections and trauma. In the early 1900s, we continued to succumb to infection until the discovery of antibiotics. Soon thereafter, industrialization and processed foods led to weight gain and the chronic diseases of the cardiovascular system and type 2 diabetes. 

Carbohydrates provide calories and fiber and some micronutrients, which are needed for energy, metabolism, and bowel and immune health. But how much do we need? 

Currently in the United States, the percentage of total food energy derived from the three major macronutrients is: carbohydrates, 51.8%; fat, 32.8%; and protein, 15.4%. Current advice for a healthy diet to lower risk for cardiovascular disease is to limit fat intake to 30% of total energy, protein to 15%, and to increase complex carbohydrates to 55%-60% of total energy. But we also need to qualify this in terms of the quality of the macronutrient, particularly carbohydrates. 

In addition to the quality, the macronutrient content of the diet has varied considerably from our prehistoric times when dietary protein intakes were high at 19%-35% of energy at the expense of carbohydrate (22%-40% of energy). 

If our genes haven’t kept up with industrialization, then why do we need so many carbohydrates to equate to 55%-60% of energy? Is it possible that we are confusing what is available with what we actually need? What do I mean by this?

We certainly have changed the landscape of the world due to agriculture, which has allowed us to procreate and feed ourselves, and certainly, industrialization has increased the availability of accessible cheap food. Protein in the form of meat, fish, and fowl are harder to get in industrialized nations as are fruits and vegetables. These macronutrients were the foods of our ancestors. It may be that a healthy diet is considered the one that is available. 

For instance, the Mediterranean diet is somewhat higher in fat content, 40%-50% fat (mostly mono and unsaturated), and similar in protein content but lower in carbohydrate content than the typical Western diet. The Dietary Approaches to Stop Hypertension (DASH) diet is lower in fat at 25% total calories, is higher in carbohydrates at 55%, and is lower in protein, but this diet was generated in the United States, therefore it is more Western. 

We need high-quality protein for organ and muscle function, high-quality unsaturated and monounsaturated fats for brain function and cellular functions, and high-quality complex carbohydrates for energy and gut health as well as micronutrients for many cellular functions. A ketogenic diet is not sustainable in the long-term for these reasons: chiefly the need for some carbohydrates for gut health and micronutrients. 

How much carbohydrate content is needed should take into consideration energy expenditure as well as micronutrients and fiber intake. Protein and fat can contribute to energy production but not as readily as carbohydrates that can quickly restore glycogen in the muscle and liver. What’s interesting is that our ancestors were able to hunt and run away from danger with the small amounts of carbohydrates from plants and berries plus the protein and fat intake from animals and fish — but the Olympics weren’t a thing then!

It may be another 200,000 years before our genes catch up to ultraprocessed foods and the simple carbohydrates and sugars contained in these products. Evidence suggests that ultraprocessed foods cause inflammation in organs like the liver, adipose tissue, the heart, and even the brain. In the brain, this inflammation may be what’s causing us to defend a higher body weight set point in this environment of easily obtained highly palatable ultraprocessed foods. 

Let’s not wait until our genes catch up and our bodies tolerate junk food without disease progression. It could be like waiting for Godot!

Dr. Apovian is professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, Boston, Massachusetts. She disclosed ties to Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, and L-Nutra.

A version of this article appeared on Medscape.com.

LONDON — Weight loss, glycemic control, fatty liver, and the need for insulin all showed improvement in patients with both refractory type 2 diabetes and obesity after a gut liner known as EndoBarrier (RESET, Morphic Medical, United States) was implanted for 1 year, showed data.

Two years after the liner’s removal, 80% of patients continued to show significant improvement, while 20% returned to baseline.

Presenting results at the Diabetes UK Professional Conference (DUKPC) 2024, the researchers, led by Bob Ryder, MD, FRCP, from the Department of Diabetes, Birmingham City Hospital, Birmingham, England, aimed to assess the safety and efficacy of EndoBarrier, as well as maintenance of efficacy 24 months after the device removal.

“We think EndoBarrier finds its place between the end of all the earlier measures and the possible option of bariatric surgery, and these data show that it can lead to tremendous weight loss and improvement in A1c,” Dr. Ryder said in an interview.

Commenting on how most patients had responded to use of the device, Dr. Ryder said, “People with obesity are often very unhappy and have tried everything over many years to no effect; however, this gut liner provided the opportunity to shift out of this state, and they often become so happy with the result they were determined to stick with it and continue with a healthier lifestyle including much more exercise.”
 

Convenient, Reversible Procedure

Ninety consecutive patients from Birmingham, all with longstanding, poorly controlled, type 2 diabetes and obesity, underwent the implantation procedure, and 60 of these attended follow-up visits 2 years post implantation.

Unlike permanent and more invasive weight loss surgeries, the EndoBarrier device is reversible and fitted with a straightforward procedure.

The thin impermeable sleeve is inserted via an approximate 1-hour endoscopy, enabling the patient to return home the same day. It lines the first 60 cm of the small intestine. Digested food passes through it without absorption and then makes contact with pancreatic and bile juices at the other end. This triggers a change in the metabolism of glucose and nutrients through modulating gut hormones and gut bacteria, as well as disrupting bile flow.

“Because the food bypasses the small intestine, the first time the food is encountered is in an area where it is not normally found, and this causes a reaction where signals are sent to the brain to stop eating,” explained Dr. Ryder.

Due to a license for 1 year of use, the gut liner was removed after a year via a 30-minute endoscopy procedure.
 

Over Half Maintained Full Improvement 2 Years Post Removal

A total of 60/90 (66%) attended follow-up visits and comprised the data presented. Mean age was 51.2 years, 47% were men, 50% were White, mean body mass index (BMI) was 41.5 kg/m², and mean A1c was 9.3%. Duration of type 2 diabetes was a median of 11 years, and 60% were taking insulin.

Patients followed dietary requirements for the initial phase after implantation. “During the first week, they followed a liquid diet, then during week 2 — mushy food, and then they were told to chew it really well to avoid blockage,” said Dr. Ryder.

Mean weight loss on removal of the liner (at 12 months post implantation) was 16.7 kg (P < .001), while BMI dropped by mean 6 kg/m², A1c dropped by a mean of 1.8%, and mean systolic blood pressure by 10.9 mm Hg.

Just over half (32/60, 53%) showed maintenance of fully sustained improvement 2 years after removal of the liner — defined as no significant difference after 2 years between weight loss (mean, 96-97 kg) and similarly for A1c improvement (7.6%-7.4%).

Sixteen of 60 (27%) showed partially sustained improvement over the 2 years of follow-up, with BMI increasing from a mean of 116.8 kg to 128.6 kg and A1c increasing from 7.5% to 8.4%. While 20% (12/60) returned to baseline.

Of the 36/60 people using insulin prior to EndoBarrier treatment, 10 (27.8%) were no longer using insulin at 2 years post removal.

Thirteen of 90 (14%) had early removal of the gut liner due to gastrointestinal hemorrhage (five), liver abscess (two), other abscess (one), and gastrointestinal symptoms (five), but they all made a full recovery; after removal, most experienced benefit despite the adverse event, reported Dr. Ryder.

Sarah Davies, MBBCh, a GP at Woodlands Medical Centre, Cardiff, Wales, agreed that EndoBarrier might be a viable option for patients struggling with obesity. “As GPs, we are the first port of call for these patients. It’s very novel, I hadn’t heard of it before. I like how it’s a noninvasive way for my patients to lose weight and maintain that even after EndoBarrier has been removed.”

Outcomes are being monitored in an ongoing global registry to help determine if EndoBarrier is a safe and effective treatment for individuals with type 2 diabetes and obesity. Dr. Ryder noted that a similar study with 3 years of follow-up showed similar results. Further results will be presented by Dr. Ryder at the upcoming meeting of the American Diabetes Association.

EndoBarrier is currently not approved in the United States. It is awaiting United Kingdom and European CE mark, which the manufacturer hope will be granted this summer. The license will be for patients with BMI of 35-50 kg/m².
 

A version of this article appeared on Medscape.com.

LONDON — Weight loss, glycemic control, fatty liver, and the need for insulin all showed improvement in patients with both refractory type 2 diabetes and obesity after a gut liner known as EndoBarrier (RESET, Morphic Medical, United States) was implanted for 1 year, showed data.

Two years after the liner’s removal, 80% of patients continued to show significant improvement, while 20% returned to baseline.

Presenting results at the Diabetes UK Professional Conference (DUKPC) 2024, the researchers, led by Bob Ryder, MD, FRCP, from the Department of Diabetes, Birmingham City Hospital, Birmingham, England, aimed to assess the safety and efficacy of EndoBarrier, as well as maintenance of efficacy 24 months after the device removal.

“We think EndoBarrier finds its place between the end of all the earlier measures and the possible option of bariatric surgery, and these data show that it can lead to tremendous weight loss and improvement in A1c,” Dr. Ryder said in an interview.

Commenting on how most patients had responded to use of the device, Dr. Ryder said, “People with obesity are often very unhappy and have tried everything over many years to no effect; however, this gut liner provided the opportunity to shift out of this state, and they often become so happy with the result they were determined to stick with it and continue with a healthier lifestyle including much more exercise.”
 

Convenient, Reversible Procedure

Ninety consecutive patients from Birmingham, all with longstanding, poorly controlled, type 2 diabetes and obesity, underwent the implantation procedure, and 60 of these attended follow-up visits 2 years post implantation.

Unlike permanent and more invasive weight loss surgeries, the EndoBarrier device is reversible and fitted with a straightforward procedure.

The thin impermeable sleeve is inserted via an approximate 1-hour endoscopy, enabling the patient to return home the same day. It lines the first 60 cm of the small intestine. Digested food passes through it without absorption and then makes contact with pancreatic and bile juices at the other end. This triggers a change in the metabolism of glucose and nutrients through modulating gut hormones and gut bacteria, as well as disrupting bile flow.

“Because the food bypasses the small intestine, the first time the food is encountered is in an area where it is not normally found, and this causes a reaction where signals are sent to the brain to stop eating,” explained Dr. Ryder.

Due to a license for 1 year of use, the gut liner was removed after a year via a 30-minute endoscopy procedure.
 

Over Half Maintained Full Improvement 2 Years Post Removal

A total of 60/90 (66%) attended follow-up visits and comprised the data presented. Mean age was 51.2 years, 47% were men, 50% were White, mean body mass index (BMI) was 41.5 kg/m², and mean A1c was 9.3%. Duration of type 2 diabetes was a median of 11 years, and 60% were taking insulin.

Patients followed dietary requirements for the initial phase after implantation. “During the first week, they followed a liquid diet, then during week 2 — mushy food, and then they were told to chew it really well to avoid blockage,” said Dr. Ryder.

Mean weight loss on removal of the liner (at 12 months post implantation) was 16.7 kg (P < .001), while BMI dropped by mean 6 kg/m², A1c dropped by a mean of 1.8%, and mean systolic blood pressure by 10.9 mm Hg.

Just over half (32/60, 53%) showed maintenance of fully sustained improvement 2 years after removal of the liner — defined as no significant difference after 2 years between weight loss (mean, 96-97 kg) and similarly for A1c improvement (7.6%-7.4%).

Sixteen of 60 (27%) showed partially sustained improvement over the 2 years of follow-up, with BMI increasing from a mean of 116.8 kg to 128.6 kg and A1c increasing from 7.5% to 8.4%. While 20% (12/60) returned to baseline.

Of the 36/60 people using insulin prior to EndoBarrier treatment, 10 (27.8%) were no longer using insulin at 2 years post removal.

Thirteen of 90 (14%) had early removal of the gut liner due to gastrointestinal hemorrhage (five), liver abscess (two), other abscess (one), and gastrointestinal symptoms (five), but they all made a full recovery; after removal, most experienced benefit despite the adverse event, reported Dr. Ryder.

Sarah Davies, MBBCh, a GP at Woodlands Medical Centre, Cardiff, Wales, agreed that EndoBarrier might be a viable option for patients struggling with obesity. “As GPs, we are the first port of call for these patients. It’s very novel, I hadn’t heard of it before. I like how it’s a noninvasive way for my patients to lose weight and maintain that even after EndoBarrier has been removed.”

Outcomes are being monitored in an ongoing global registry to help determine if EndoBarrier is a safe and effective treatment for individuals with type 2 diabetes and obesity. Dr. Ryder noted that a similar study with 3 years of follow-up showed similar results. Further results will be presented by Dr. Ryder at the upcoming meeting of the American Diabetes Association.

EndoBarrier is currently not approved in the United States. It is awaiting United Kingdom and European CE mark, which the manufacturer hope will be granted this summer. The license will be for patients with BMI of 35-50 kg/m².
 

A version of this article appeared on Medscape.com.

LONDON — Weight loss, glycemic control, fatty liver, and the need for insulin all showed improvement in patients with both refractory type 2 diabetes and obesity after a gut liner known as EndoBarrier (RESET, Morphic Medical, United States) was implanted for 1 year, showed data.

Two years after the liner’s removal, 80% of patients continued to show significant improvement, while 20% returned to baseline.

Presenting results at the Diabetes UK Professional Conference (DUKPC) 2024, the researchers, led by Bob Ryder, MD, FRCP, from the Department of Diabetes, Birmingham City Hospital, Birmingham, England, aimed to assess the safety and efficacy of EndoBarrier, as well as maintenance of efficacy 24 months after the device removal.

“We think EndoBarrier finds its place between the end of all the earlier measures and the possible option of bariatric surgery, and these data show that it can lead to tremendous weight loss and improvement in A1c,” Dr. Ryder said in an interview.

Commenting on how most patients had responded to use of the device, Dr. Ryder said, “People with obesity are often very unhappy and have tried everything over many years to no effect; however, this gut liner provided the opportunity to shift out of this state, and they often become so happy with the result they were determined to stick with it and continue with a healthier lifestyle including much more exercise.”
 

Convenient, Reversible Procedure

Ninety consecutive patients from Birmingham, all with longstanding, poorly controlled, type 2 diabetes and obesity, underwent the implantation procedure, and 60 of these attended follow-up visits 2 years post implantation.

Unlike permanent and more invasive weight loss surgeries, the EndoBarrier device is reversible and fitted with a straightforward procedure.

The thin impermeable sleeve is inserted via an approximate 1-hour endoscopy, enabling the patient to return home the same day. It lines the first 60 cm of the small intestine. Digested food passes through it without absorption and then makes contact with pancreatic and bile juices at the other end. This triggers a change in the metabolism of glucose and nutrients through modulating gut hormones and gut bacteria, as well as disrupting bile flow.

“Because the food bypasses the small intestine, the first time the food is encountered is in an area where it is not normally found, and this causes a reaction where signals are sent to the brain to stop eating,” explained Dr. Ryder.

Due to a license for 1 year of use, the gut liner was removed after a year via a 30-minute endoscopy procedure.
 

Over Half Maintained Full Improvement 2 Years Post Removal

A total of 60/90 (66%) attended follow-up visits and comprised the data presented. Mean age was 51.2 years, 47% were men, 50% were White, mean body mass index (BMI) was 41.5 kg/m², and mean A1c was 9.3%. Duration of type 2 diabetes was a median of 11 years, and 60% were taking insulin.

Patients followed dietary requirements for the initial phase after implantation. “During the first week, they followed a liquid diet, then during week 2 — mushy food, and then they were told to chew it really well to avoid blockage,” said Dr. Ryder.

Mean weight loss on removal of the liner (at 12 months post implantation) was 16.7 kg (P < .001), while BMI dropped by mean 6 kg/m², A1c dropped by a mean of 1.8%, and mean systolic blood pressure by 10.9 mm Hg.

Just over half (32/60, 53%) showed maintenance of fully sustained improvement 2 years after removal of the liner — defined as no significant difference after 2 years between weight loss (mean, 96-97 kg) and similarly for A1c improvement (7.6%-7.4%).

Sixteen of 60 (27%) showed partially sustained improvement over the 2 years of follow-up, with BMI increasing from a mean of 116.8 kg to 128.6 kg and A1c increasing from 7.5% to 8.4%. While 20% (12/60) returned to baseline.

Of the 36/60 people using insulin prior to EndoBarrier treatment, 10 (27.8%) were no longer using insulin at 2 years post removal.

Thirteen of 90 (14%) had early removal of the gut liner due to gastrointestinal hemorrhage (five), liver abscess (two), other abscess (one), and gastrointestinal symptoms (five), but they all made a full recovery; after removal, most experienced benefit despite the adverse event, reported Dr. Ryder.

Sarah Davies, MBBCh, a GP at Woodlands Medical Centre, Cardiff, Wales, agreed that EndoBarrier might be a viable option for patients struggling with obesity. “As GPs, we are the first port of call for these patients. It’s very novel, I hadn’t heard of it before. I like how it’s a noninvasive way for my patients to lose weight and maintain that even after EndoBarrier has been removed.”

Outcomes are being monitored in an ongoing global registry to help determine if EndoBarrier is a safe and effective treatment for individuals with type 2 diabetes and obesity. Dr. Ryder noted that a similar study with 3 years of follow-up showed similar results. Further results will be presented by Dr. Ryder at the upcoming meeting of the American Diabetes Association.

EndoBarrier is currently not approved in the United States. It is awaiting United Kingdom and European CE mark, which the manufacturer hope will be granted this summer. The license will be for patients with BMI of 35-50 kg/m².
 

A version of this article appeared on Medscape.com.

TOPLINE:

Biscuits reformulated with the sweeteners and sweetness enhancers (S&SEs) neotame and stevia rebaudioside M (StRebM) yield appetite responses similar to those of sucrose-sweetened ones but decrease post-meal insulin and glucose levels in adults with overweight or obesity.

METHODOLOGY:

• In 2023, the World Health Organization issued a conditional recommendation that S&SE should not be used for weight control, apparently due to a lack of evidence for a clear benefit and weak evidence linking S&SE intake with excess weight and poorer health outcomes.
• This randomized crossover trial, conducted in England and France between 2021 and 2022, evaluated the acute (1 day) and repeated (daily for 2 weeks) effects of S&SEs vs sucrose in solid food on appetite and endocrine responses in adults with overweight or obesity.
• Overall, 53 adults (33 women, 20 men; aged 18-60 years) with overweight or obesity consumed biscuits with fruit filling containing either sucrose or reformulated with the S&SEs StRebM or neotame, daily for three 2-week intervention periods separated by a washout period of 14-21 days.
• Participants were required to fast for 12 hours before attending a laboratory session at the beginning (day 1) and end (day 14) of each consumption period.
• The primary endpoint was the composite appetite score, while secondary endpoints included food preferences, postprandial glucose and insulin response, and other satiety-related peptides, such as ghrelin, glucagon-like peptide 1, and pancreatic polypeptide.

TAKEAWAY:

• The composite appetite scores were comparable between the sucrose, StRebM, and neotame groups, with lower appetite suppression observed on day 14 than on day 1 for all three formulations.
• Neotame (P < .001) and StRebM (P < .001) lowered postprandial insulin levels compared with sucrose, while glucose levels saw a decline only with StRebM (and not with neotame) compared with sucrose (P < .05).
• The S&SEs had no effect on satiety levels, as any acute or repeated exposures to StRebM or neotame vs sucrose did not affect the ghrelin and glucagon-like peptide-1 responses.
• Gastrointestinal issues were more frequently reported in the neotame and StRebM groups than in the sucrose group.

IN PRACTICE:

“There is no detrimental impact of replacing sugar with S&SE in these endpoints,” the authors wrote. “Additionally, glucose and insulin responses were blunted after acute and repeated consumption of S&SE-reformulated biscuits, which may confer a benefit for blood glucose control, for example, in individuals at risk of developing type 2 diabetes.”

SOURCE:

This study was led by Catherine Gibbons, School of Psychology, Faculty of Medicine and Health, University of Leeds, England. It was published online in eBioMedicine.

LIMITATIONS:

The reformulated products required the addition of polyol bulking agents (8% maltitol and 8% sorbitol) to match the biscuits in sensory qualities as closely as possible. Gastrointestinal symptoms (initial bloating and flatulence) in the neotame and StRebM formulations may be due to the polyols, classed as low-digestible carbohydrates.

DISCLOSURES:

This study received funding from a European Union Horizon 2020 program, SWEET (Sweeteners and sweetness enhancers: Impact on health, obesity, safety, and sustainability). The authors reported receiving funding and honoraria from the food and beverage industry and trade groups from various entities.

A version of this article appeared on Medscape.com.

TOPLINE:

Biscuits reformulated with the sweeteners and sweetness enhancers (S&SEs) neotame and stevia rebaudioside M (StRebM) yield appetite responses similar to those of sucrose-sweetened ones but decrease post-meal insulin and glucose levels in adults with overweight or obesity.

METHODOLOGY:

• In 2023, the World Health Organization issued a conditional recommendation that S&SE should not be used for weight control, apparently due to a lack of evidence for a clear benefit and weak evidence linking S&SE intake with excess weight and poorer health outcomes.
• This randomized crossover trial, conducted in England and France between 2021 and 2022, evaluated the acute (1 day) and repeated (daily for 2 weeks) effects of S&SEs vs sucrose in solid food on appetite and endocrine responses in adults with overweight or obesity.
• Overall, 53 adults (33 women, 20 men; aged 18-60 years) with overweight or obesity consumed biscuits with fruit filling containing either sucrose or reformulated with the S&SEs StRebM or neotame, daily for three 2-week intervention periods separated by a washout period of 14-21 days.
• Participants were required to fast for 12 hours before attending a laboratory session at the beginning (day 1) and end (day 14) of each consumption period.
• The primary endpoint was the composite appetite score, while secondary endpoints included food preferences, postprandial glucose and insulin response, and other satiety-related peptides, such as ghrelin, glucagon-like peptide 1, and pancreatic polypeptide.

TAKEAWAY:

• The composite appetite scores were comparable between the sucrose, StRebM, and neotame groups, with lower appetite suppression observed on day 14 than on day 1 for all three formulations.
• Neotame (P < .001) and StRebM (P < .001) lowered postprandial insulin levels compared with sucrose, while glucose levels saw a decline only with StRebM (and not with neotame) compared with sucrose (P < .05).
• The S&SEs had no effect on satiety levels, as any acute or repeated exposures to StRebM or neotame vs sucrose did not affect the ghrelin and glucagon-like peptide-1 responses.
• Gastrointestinal issues were more frequently reported in the neotame and StRebM groups than in the sucrose group.

IN PRACTICE:

“There is no detrimental impact of replacing sugar with S&SE in these endpoints,” the authors wrote. “Additionally, glucose and insulin responses were blunted after acute and repeated consumption of S&SE-reformulated biscuits, which may confer a benefit for blood glucose control, for example, in individuals at risk of developing type 2 diabetes.”

SOURCE:

This study was led by Catherine Gibbons, School of Psychology, Faculty of Medicine and Health, University of Leeds, England. It was published online in eBioMedicine.

LIMITATIONS:

The reformulated products required the addition of polyol bulking agents (8% maltitol and 8% sorbitol) to match the biscuits in sensory qualities as closely as possible. Gastrointestinal symptoms (initial bloating and flatulence) in the neotame and StRebM formulations may be due to the polyols, classed as low-digestible carbohydrates.

DISCLOSURES:

This study received funding from a European Union Horizon 2020 program, SWEET (Sweeteners and sweetness enhancers: Impact on health, obesity, safety, and sustainability). The authors reported receiving funding and honoraria from the food and beverage industry and trade groups from various entities.

A version of this article appeared on Medscape.com.

TOPLINE:

Biscuits reformulated with the sweeteners and sweetness enhancers (S&SEs) neotame and stevia rebaudioside M (StRebM) yield appetite responses similar to those of sucrose-sweetened ones but decrease post-meal insulin and glucose levels in adults with overweight or obesity.

METHODOLOGY:

• In 2023, the World Health Organization issued a conditional recommendation that S&SE should not be used for weight control, apparently due to a lack of evidence for a clear benefit and weak evidence linking S&SE intake with excess weight and poorer health outcomes.
• This randomized crossover trial, conducted in England and France between 2021 and 2022, evaluated the acute (1 day) and repeated (daily for 2 weeks) effects of S&SEs vs sucrose in solid food on appetite and endocrine responses in adults with overweight or obesity.
• Overall, 53 adults (33 women, 20 men; aged 18-60 years) with overweight or obesity consumed biscuits with fruit filling containing either sucrose or reformulated with the S&SEs StRebM or neotame, daily for three 2-week intervention periods separated by a washout period of 14-21 days.
• Participants were required to fast for 12 hours before attending a laboratory session at the beginning (day 1) and end (day 14) of each consumption period.
• The primary endpoint was the composite appetite score, while secondary endpoints included food preferences, postprandial glucose and insulin response, and other satiety-related peptides, such as ghrelin, glucagon-like peptide 1, and pancreatic polypeptide.

TAKEAWAY:

• The composite appetite scores were comparable between the sucrose, StRebM, and neotame groups, with lower appetite suppression observed on day 14 than on day 1 for all three formulations.
• Neotame (P < .001) and StRebM (P < .001) lowered postprandial insulin levels compared with sucrose, while glucose levels saw a decline only with StRebM (and not with neotame) compared with sucrose (P < .05).
• The S&SEs had no effect on satiety levels, as any acute or repeated exposures to StRebM or neotame vs sucrose did not affect the ghrelin and glucagon-like peptide-1 responses.
• Gastrointestinal issues were more frequently reported in the neotame and StRebM groups than in the sucrose group.

IN PRACTICE:

“There is no detrimental impact of replacing sugar with S&SE in these endpoints,” the authors wrote. “Additionally, glucose and insulin responses were blunted after acute and repeated consumption of S&SE-reformulated biscuits, which may confer a benefit for blood glucose control, for example, in individuals at risk of developing type 2 diabetes.”

SOURCE:

This study was led by Catherine Gibbons, School of Psychology, Faculty of Medicine and Health, University of Leeds, England. It was published online in eBioMedicine.

LIMITATIONS:

The reformulated products required the addition of polyol bulking agents (8% maltitol and 8% sorbitol) to match the biscuits in sensory qualities as closely as possible. Gastrointestinal symptoms (initial bloating and flatulence) in the neotame and StRebM formulations may be due to the polyols, classed as low-digestible carbohydrates.

DISCLOSURES:

This study received funding from a European Union Horizon 2020 program, SWEET (Sweeteners and sweetness enhancers: Impact on health, obesity, safety, and sustainability). The authors reported receiving funding and honoraria from the food and beverage industry and trade groups from various entities.

A version of this article appeared on Medscape.com.

TOPLINE:

No significant association was found between the use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and thyroid cancer over nearly 4 years.

METHODOLOGY:

• A cohort study using data from nationwide registers in Denmark, Norway, and Sweden between 2007 and 2021 included 145,410 patients who initiated GLP-1 RAs and 291,667 propensity score-matched patients initiating dipeptidyl peptidase 4 (DPP4) inhibitors as active comparators.
• Additional analysis included 111,744 who initiated GLP-1 RAs and 148,179 patients initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors.
• Overall, mean follow-up time was 3.9 years, with 25% followed for more than 6 years.

TAKEAWAY:

• The most common individual GLP-1 RAs were liraglutide (57.3%) and semaglutide (32.9%).
• During follow-up, there were 76 incident thyroid cancer cases among GLP-1 RA users and 184 cases in DPP4 inhibitor users, giving incidence rates per 10,000 of 1.33 and 1.46, respectively, a nonsignificant difference (hazard ratio [HR], 0.93; 95% CI, 0.66-1.31).
• Papillary thyroid cancer was the most common thyroid cancer subtype, followed by follicular and medullary, with no significant increases in risk with GLP-1 RAs by cancer type, although the numbers were small.
• In the SGLT2 inhibitor comparison, there was also no significantly increased thyroid cancer risk for GLP-1 RAs (HR, 1.16; 95% CI, 0.65-2.05).

IN PRACTICE:

“Given the upper limit of the confidence interval, the findings are incompatible with more than a 31% increased relative risk of thyroid cancer. In absolute terms, this translates to no more than 0.36 excess cases per 10 000 person-years, a figure that should be interpreted against the background incidence of 1.46 per 10,000 person-years among the comparator group in the study populations.”

SOURCE:

This study was conducted by Björn Pasternak, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues. It was published online on April 10, 2024, in The BMJ.

LIMITATIONS:

Relatively short follow-up for cancer risk. Risk by individual GLP-1 RA not analyzed. Small event numbers. Observational, with potential for residual confounding and time-release bias.

DISCLOSURES:

The study was supported by grants from the Swedish Cancer Society and the Swedish Research Council. Dr. Pasternak was supported by a consolidator investigator grant from Karolinska Institutet. Some of the coauthors had industry disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

No significant association was found between the use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and thyroid cancer over nearly 4 years.

METHODOLOGY:

• A cohort study using data from nationwide registers in Denmark, Norway, and Sweden between 2007 and 2021 included 145,410 patients who initiated GLP-1 RAs and 291,667 propensity score-matched patients initiating dipeptidyl peptidase 4 (DPP4) inhibitors as active comparators.
• Additional analysis included 111,744 who initiated GLP-1 RAs and 148,179 patients initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors.
• Overall, mean follow-up time was 3.9 years, with 25% followed for more than 6 years.

TAKEAWAY:

• The most common individual GLP-1 RAs were liraglutide (57.3%) and semaglutide (32.9%).
• During follow-up, there were 76 incident thyroid cancer cases among GLP-1 RA users and 184 cases in DPP4 inhibitor users, giving incidence rates per 10,000 of 1.33 and 1.46, respectively, a nonsignificant difference (hazard ratio [HR], 0.93; 95% CI, 0.66-1.31).
• Papillary thyroid cancer was the most common thyroid cancer subtype, followed by follicular and medullary, with no significant increases in risk with GLP-1 RAs by cancer type, although the numbers were small.
• In the SGLT2 inhibitor comparison, there was also no significantly increased thyroid cancer risk for GLP-1 RAs (HR, 1.16; 95% CI, 0.65-2.05).

IN PRACTICE:

“Given the upper limit of the confidence interval, the findings are incompatible with more than a 31% increased relative risk of thyroid cancer. In absolute terms, this translates to no more than 0.36 excess cases per 10 000 person-years, a figure that should be interpreted against the background incidence of 1.46 per 10,000 person-years among the comparator group in the study populations.”

SOURCE:

This study was conducted by Björn Pasternak, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues. It was published online on April 10, 2024, in The BMJ.

LIMITATIONS:

Relatively short follow-up for cancer risk. Risk by individual GLP-1 RA not analyzed. Small event numbers. Observational, with potential for residual confounding and time-release bias.

DISCLOSURES:

The study was supported by grants from the Swedish Cancer Society and the Swedish Research Council. Dr. Pasternak was supported by a consolidator investigator grant from Karolinska Institutet. Some of the coauthors had industry disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

No significant association was found between the use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and thyroid cancer over nearly 4 years.

METHODOLOGY:

• A cohort study using data from nationwide registers in Denmark, Norway, and Sweden between 2007 and 2021 included 145,410 patients who initiated GLP-1 RAs and 291,667 propensity score-matched patients initiating dipeptidyl peptidase 4 (DPP4) inhibitors as active comparators.
• Additional analysis included 111,744 who initiated GLP-1 RAs and 148,179 patients initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors.
• Overall, mean follow-up time was 3.9 years, with 25% followed for more than 6 years.

TAKEAWAY:

• The most common individual GLP-1 RAs were liraglutide (57.3%) and semaglutide (32.9%).
• During follow-up, there were 76 incident thyroid cancer cases among GLP-1 RA users and 184 cases in DPP4 inhibitor users, giving incidence rates per 10,000 of 1.33 and 1.46, respectively, a nonsignificant difference (hazard ratio [HR], 0.93; 95% CI, 0.66-1.31).
• Papillary thyroid cancer was the most common thyroid cancer subtype, followed by follicular and medullary, with no significant increases in risk with GLP-1 RAs by cancer type, although the numbers were small.
• In the SGLT2 inhibitor comparison, there was also no significantly increased thyroid cancer risk for GLP-1 RAs (HR, 1.16; 95% CI, 0.65-2.05).

IN PRACTICE:

“Given the upper limit of the confidence interval, the findings are incompatible with more than a 31% increased relative risk of thyroid cancer. In absolute terms, this translates to no more than 0.36 excess cases per 10 000 person-years, a figure that should be interpreted against the background incidence of 1.46 per 10,000 person-years among the comparator group in the study populations.”

SOURCE:

This study was conducted by Björn Pasternak, MD, PhD, of the Karolinska Institutet, Stockholm, and colleagues. It was published online on April 10, 2024, in The BMJ.

LIMITATIONS:

Relatively short follow-up for cancer risk. Risk by individual GLP-1 RA not analyzed. Small event numbers. Observational, with potential for residual confounding and time-release bias.

DISCLOSURES:

The study was supported by grants from the Swedish Cancer Society and the Swedish Research Council. Dr. Pasternak was supported by a consolidator investigator grant from Karolinska Institutet. Some of the coauthors had industry disclosures.

A version of this article appeared on Medscape.com.

TOPLINE:

A review of 22 articles found a higher incidence of “altered skin sensations” and alopecia in individuals receiving oral semaglutide than in those receiving placebo.

METHODOLOGY:

• The Food and Drug Administration’s  has not received reports of semaglutide-related safety events, and few studies have characterized skin findings associated with oral or subcutaneous semaglutide, a glucagon-like peptide 1 agonist used to treat obesity and type 2 diabetes.
• In this scoping review, researchers included 22 articles (15 clinical trials, six case reports, and one retrospective cohort study), published through January 2024, of patients receiving either semaglutide or a placebo or comparator, which included reports of semaglutide-associated adverse dermatologic events in 255 participants.

TAKEAWAY:

• Patients who received 50 mg oral semaglutide weekly reported a higher incidence of altered skin sensations, such as dysesthesia (1.8% vs 0%), hyperesthesia (1.2% vs 0%), skin pain (2.4% vs 0%), paresthesia (2.7% vs 0%), and sensitive skin (2.7% vs 0%), than those receiving placebo or comparator.
• Reports of alopecia (6.9% vs 0.3%) were higher in patients who received 50 mg oral semaglutide weekly than in those on placebo, but only 0.2% of patients on 2.4 mg of subcutaneous semaglutide reported alopecia vs 0.5% of those on placebo.
• Unspecified dermatologic reactions (4.1% vs 1.5%) were reported in more patients on subcutaneous semaglutide than those on a placebo or comparator. Several case reports described isolated cases of severe skin-related adverse effects, such as bullous pemphigoid, eosinophilic fasciitis, and leukocytoclastic vasculitis.
• On the contrary, injection site reactions (3.5% vs 6.7%) were less common in patients on subcutaneous semaglutide compared with in those on a placebo or comparator.

IN PRACTICE:

“Variations in dosage and administration routes could influence the types and severity of skin findings, underscoring the need for additional research,” the authors wrote.

SOURCE:

Megan M. Tran, BS, from the Warren Alpert Medical School, Brown University, Providence, Rhode Island, led this study, which was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study could not adjust for confounding factors and could not establish a direct causal association between semaglutide and the adverse reactions reported.

DISCLOSURES:

This study did not report any funding sources. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A review of 22 articles found a higher incidence of “altered skin sensations” and alopecia in individuals receiving oral semaglutide than in those receiving placebo.

METHODOLOGY:

• The Food and Drug Administration’s  has not received reports of semaglutide-related safety events, and few studies have characterized skin findings associated with oral or subcutaneous semaglutide, a glucagon-like peptide 1 agonist used to treat obesity and type 2 diabetes.
• In this scoping review, researchers included 22 articles (15 clinical trials, six case reports, and one retrospective cohort study), published through January 2024, of patients receiving either semaglutide or a placebo or comparator, which included reports of semaglutide-associated adverse dermatologic events in 255 participants.

TAKEAWAY:

• Patients who received 50 mg oral semaglutide weekly reported a higher incidence of altered skin sensations, such as dysesthesia (1.8% vs 0%), hyperesthesia (1.2% vs 0%), skin pain (2.4% vs 0%), paresthesia (2.7% vs 0%), and sensitive skin (2.7% vs 0%), than those receiving placebo or comparator.
• Reports of alopecia (6.9% vs 0.3%) were higher in patients who received 50 mg oral semaglutide weekly than in those on placebo, but only 0.2% of patients on 2.4 mg of subcutaneous semaglutide reported alopecia vs 0.5% of those on placebo.
• Unspecified dermatologic reactions (4.1% vs 1.5%) were reported in more patients on subcutaneous semaglutide than those on a placebo or comparator. Several case reports described isolated cases of severe skin-related adverse effects, such as bullous pemphigoid, eosinophilic fasciitis, and leukocytoclastic vasculitis.
• On the contrary, injection site reactions (3.5% vs 6.7%) were less common in patients on subcutaneous semaglutide compared with in those on a placebo or comparator.

IN PRACTICE:

“Variations in dosage and administration routes could influence the types and severity of skin findings, underscoring the need for additional research,” the authors wrote.

SOURCE:

Megan M. Tran, BS, from the Warren Alpert Medical School, Brown University, Providence, Rhode Island, led this study, which was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study could not adjust for confounding factors and could not establish a direct causal association between semaglutide and the adverse reactions reported.

DISCLOSURES:

This study did not report any funding sources. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

A review of 22 articles found a higher incidence of “altered skin sensations” and alopecia in individuals receiving oral semaglutide than in those receiving placebo.

METHODOLOGY:

• The Food and Drug Administration’s  has not received reports of semaglutide-related safety events, and few studies have characterized skin findings associated with oral or subcutaneous semaglutide, a glucagon-like peptide 1 agonist used to treat obesity and type 2 diabetes.
• In this scoping review, researchers included 22 articles (15 clinical trials, six case reports, and one retrospective cohort study), published through January 2024, of patients receiving either semaglutide or a placebo or comparator, which included reports of semaglutide-associated adverse dermatologic events in 255 participants.

TAKEAWAY:

• Patients who received 50 mg oral semaglutide weekly reported a higher incidence of altered skin sensations, such as dysesthesia (1.8% vs 0%), hyperesthesia (1.2% vs 0%), skin pain (2.4% vs 0%), paresthesia (2.7% vs 0%), and sensitive skin (2.7% vs 0%), than those receiving placebo or comparator.
• Reports of alopecia (6.9% vs 0.3%) were higher in patients who received 50 mg oral semaglutide weekly than in those on placebo, but only 0.2% of patients on 2.4 mg of subcutaneous semaglutide reported alopecia vs 0.5% of those on placebo.
• Unspecified dermatologic reactions (4.1% vs 1.5%) were reported in more patients on subcutaneous semaglutide than those on a placebo or comparator. Several case reports described isolated cases of severe skin-related adverse effects, such as bullous pemphigoid, eosinophilic fasciitis, and leukocytoclastic vasculitis.
• On the contrary, injection site reactions (3.5% vs 6.7%) were less common in patients on subcutaneous semaglutide compared with in those on a placebo or comparator.

IN PRACTICE:

“Variations in dosage and administration routes could influence the types and severity of skin findings, underscoring the need for additional research,” the authors wrote.

SOURCE:

Megan M. Tran, BS, from the Warren Alpert Medical School, Brown University, Providence, Rhode Island, led this study, which was published online in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study could not adjust for confounding factors and could not establish a direct causal association between semaglutide and the adverse reactions reported.

DISCLOSURES:

This study did not report any funding sources. The authors declared no conflicts of interest.

A version of this article appeared on Medscape.com.

Fractures, particularly hip and spine fractures, are a major cause of mortality and morbidity among older individuals. The term “osteoporosis” indicates increased porosity of bones resulting in low bone density; increased bone fragility; and an increased risk for fracture, often with minimal trauma.

During the adolescent years, bone accrues at a rapid rate, and optimal bone accrual during this time is essential to attain optimal peak bone mass, typically achieved in the third decade of life. Bone mass then stays stable until the 40s-50s, after which it starts to decline. One’s peak bone mass sets the stage for both immediate and future bone health. Individuals with lower peak bone mass tend to have less optimal bone health throughout their lives, and this becomes particularly problematic in older men and in the postmenopausal years for women.

The best strategy to optimize bone health is to prevent osteoporosis from occurring in the first place. This requires attention to factors that contribute to optimal bone health. One’s genes have a major impact on bone density and are currently not modifiable.

Modifiable factors include mechanical loading of bones through exercise activity, maintaining a normal body weight, and ensuring adequate intake of micronutrients (including calcium and vitamin D) and macronutrients. Medications such as glucocorticoids that have deleterious effects on bones should be limited as far as possible. Endocrine, gastrointestinal, renal, and rheumatologic conditions and others, such as cancer, which are known to be associated with reduced bone density and increased fracture risk, should be managed appropriately.

A deficiency of the gonadal hormones (estrogen and testosterone) and high blood concentrations of cortisol are particularly deleterious to bone. Hormone replacement therapy in those with gonadal hormone deficiency and strategies to reduce cortisol levels in those with hypercortisolemia are essential to prevent osteoporosis and also improve bone density over time. The same applies to management of conditions such as anorexia nervosa, relative energy deficiency in sports, inflammatory bowel disease, celiac disease, cystic fibrosis, chronic kidney disease, and chronic arthritis.

Once osteoporosis has developed, depending on the cause, these strategies may not be sufficient to completely reverse the condition, and pharmacologic therapy may be necessary to improve bone density and reduce fracture risk. This is particularly an issue with postmenopausal women and older men. In these individuals, medications that increase bone formation or reduce bone loss may be necessary.

Medications that reduce bone loss include bisphosphonates and denosumab; these are also called “antiresorptive medications” because they reduce bone resorption by cells called osteoclasts. Bisphosphonates include alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid, and these medications have direct effects on osteoclasts, reducing their activity. Some bisphosphonates, such as alendronate and risedronate, are taken orally (daily, weekly, or monthly, depending on the medication and its strength), whereas others, such as pamidronate and zoledronic acid, are administered intravenously: every 3-4 months for pamidronate and every 6-12 months for zoledronic acid. Ibandronate is available both orally and intravenously.

Denosumab is a medication that inhibits the action of receptor activator of nuclear factor-kappa ligand 1 (RANKL), which otherwise increases osteoclast activity. It is administered as a subcutaneous injection every 6 months to treat osteoporosis. One concern with denosumab is a rapid increase in bone loss after its discontinuation.

Medications that increase bone formation are called bone anabolics and include teriparatide, abaloparatide, and romosozumab. Teriparatide is a synthetic form of parathyroid hormone (recombinant PTH1-34) administered daily for up to 2 years. Abaloparatide is a synthetic analog of parathyroid hormone–related peptide (PTHrP), which is also administered daily as a subcutaneous injection. Romosozumab inhibits sclerostin (a substance that otherwise reduces bone formation and increases bone resorption) and is administered as a subcutaneous injection once a month. Effects of these medications tend to be lost after they are discontinued.

In 2019, the Endocrine Society published guidelines for managing postmenopausal osteoporosis. The guidelines recommend lifestyle modifications, including attention to diet, calcium and vitamin D supplements, and weight-bearing exercise for all postmenopausal women. They also recommend assessing fracture risk using country-specific existing models.

Guidelines vary depending on whether fracture risk is low, moderate, or high. Patients at low risk are followed and reassessed every 2-4 years for fracture risk. Those at moderate risk may be followed similarly or prescribed bisphosphonates. Those at high risk are prescribed an antiresorptive, such as a bisphosphonate or denosumab, or a bone anabolic, such as teriparatide or abaloparatide (for up to 2 years) or romosozumab (for a year), with calcium and vitamin D and are reassessed at defined intervals for fracture risk; subsequent management then depends on the assessed fracture risk.

People who are on a bone anabolic should typically follow this with an antiresorptive medication to maintain the gains achieved with the former after that medication is discontinued. Patients who discontinue denosumab should be switched to bisphosphonates to prevent the increase in bone loss that typically occurs.

In postmenopausal women who are intolerant to or inappropriate for use of these medications, guidelines vary depending on age (younger or older than 60 years) and presence or absence of vasomotor symptoms (such as hot flashes). Options could include the use of calcium and vitamin D supplements; hormone replacement therapy with estrogen with or without a progestin; or selective estrogen receptor modulators (such as raloxifene or bazedoxifene), tibolone, or calcitonin.

It’s important to recognize that all pharmacologic therapy carries the risk for adverse events, and it’s essential to take the necessary steps to prevent, monitor for, and manage any adverse effects that may develop.

Managing osteoporosis in older men could include the use of bone anabolics and/or antiresorptives. In younger individuals, use of pharmacologic therapy is less common but sometimes necessary, particularly when bone density is very low and associated with a problematic fracture history — for example, in those with genetic conditions such as osteogenesis imperfecta. Furthermore, the occurrence of vertebral compression fractures often requires bisphosphonate treatment regardless of bone density, particularly in patients on chronic glucocorticoid therapy.

Preventing osteoporosis is best managed by paying attention to lifestyle; optimizing nutrition and calcium and vitamin D intake; and managing conditions and limiting the use of medications that reduce bone density.

However, in certain patients, these measures are not enough, and pharmacologic therapy with bone anabolics or antiresorptives may be necessary to improve bone density and reduce fracture risk.

Dr. Misra, of the University of Virginia and UVA Health Children’s Hospital, Charlottesville, disclosed ties with AbbVie, Sanofi, and Ipsen.
 

A version of this article appeared on Medscape.com.

Fractures, particularly hip and spine fractures, are a major cause of mortality and morbidity among older individuals. The term “osteoporosis” indicates increased porosity of bones resulting in low bone density; increased bone fragility; and an increased risk for fracture, often with minimal trauma.

During the adolescent years, bone accrues at a rapid rate, and optimal bone accrual during this time is essential to attain optimal peak bone mass, typically achieved in the third decade of life. Bone mass then stays stable until the 40s-50s, after which it starts to decline. One’s peak bone mass sets the stage for both immediate and future bone health. Individuals with lower peak bone mass tend to have less optimal bone health throughout their lives, and this becomes particularly problematic in older men and in the postmenopausal years for women.

The best strategy to optimize bone health is to prevent osteoporosis from occurring in the first place. This requires attention to factors that contribute to optimal bone health. One’s genes have a major impact on bone density and are currently not modifiable.

Modifiable factors include mechanical loading of bones through exercise activity, maintaining a normal body weight, and ensuring adequate intake of micronutrients (including calcium and vitamin D) and macronutrients. Medications such as glucocorticoids that have deleterious effects on bones should be limited as far as possible. Endocrine, gastrointestinal, renal, and rheumatologic conditions and others, such as cancer, which are known to be associated with reduced bone density and increased fracture risk, should be managed appropriately.

A deficiency of the gonadal hormones (estrogen and testosterone) and high blood concentrations of cortisol are particularly deleterious to bone. Hormone replacement therapy in those with gonadal hormone deficiency and strategies to reduce cortisol levels in those with hypercortisolemia are essential to prevent osteoporosis and also improve bone density over time. The same applies to management of conditions such as anorexia nervosa, relative energy deficiency in sports, inflammatory bowel disease, celiac disease, cystic fibrosis, chronic kidney disease, and chronic arthritis.

Once osteoporosis has developed, depending on the cause, these strategies may not be sufficient to completely reverse the condition, and pharmacologic therapy may be necessary to improve bone density and reduce fracture risk. This is particularly an issue with postmenopausal women and older men. In these individuals, medications that increase bone formation or reduce bone loss may be necessary.

Medications that reduce bone loss include bisphosphonates and denosumab; these are also called “antiresorptive medications” because they reduce bone resorption by cells called osteoclasts. Bisphosphonates include alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid, and these medications have direct effects on osteoclasts, reducing their activity. Some bisphosphonates, such as alendronate and risedronate, are taken orally (daily, weekly, or monthly, depending on the medication and its strength), whereas others, such as pamidronate and zoledronic acid, are administered intravenously: every 3-4 months for pamidronate and every 6-12 months for zoledronic acid. Ibandronate is available both orally and intravenously.

Denosumab is a medication that inhibits the action of receptor activator of nuclear factor-kappa ligand 1 (RANKL), which otherwise increases osteoclast activity. It is administered as a subcutaneous injection every 6 months to treat osteoporosis. One concern with denosumab is a rapid increase in bone loss after its discontinuation.

Medications that increase bone formation are called bone anabolics and include teriparatide, abaloparatide, and romosozumab. Teriparatide is a synthetic form of parathyroid hormone (recombinant PTH1-34) administered daily for up to 2 years. Abaloparatide is a synthetic analog of parathyroid hormone–related peptide (PTHrP), which is also administered daily as a subcutaneous injection. Romosozumab inhibits sclerostin (a substance that otherwise reduces bone formation and increases bone resorption) and is administered as a subcutaneous injection once a month. Effects of these medications tend to be lost after they are discontinued.

In 2019, the Endocrine Society published guidelines for managing postmenopausal osteoporosis. The guidelines recommend lifestyle modifications, including attention to diet, calcium and vitamin D supplements, and weight-bearing exercise for all postmenopausal women. They also recommend assessing fracture risk using country-specific existing models.

Guidelines vary depending on whether fracture risk is low, moderate, or high. Patients at low risk are followed and reassessed every 2-4 years for fracture risk. Those at moderate risk may be followed similarly or prescribed bisphosphonates. Those at high risk are prescribed an antiresorptive, such as a bisphosphonate or denosumab, or a bone anabolic, such as teriparatide or abaloparatide (for up to 2 years) or romosozumab (for a year), with calcium and vitamin D and are reassessed at defined intervals for fracture risk; subsequent management then depends on the assessed fracture risk.

People who are on a bone anabolic should typically follow this with an antiresorptive medication to maintain the gains achieved with the former after that medication is discontinued. Patients who discontinue denosumab should be switched to bisphosphonates to prevent the increase in bone loss that typically occurs.

In postmenopausal women who are intolerant to or inappropriate for use of these medications, guidelines vary depending on age (younger or older than 60 years) and presence or absence of vasomotor symptoms (such as hot flashes). Options could include the use of calcium and vitamin D supplements; hormone replacement therapy with estrogen with or without a progestin; or selective estrogen receptor modulators (such as raloxifene or bazedoxifene), tibolone, or calcitonin.

It’s important to recognize that all pharmacologic therapy carries the risk for adverse events, and it’s essential to take the necessary steps to prevent, monitor for, and manage any adverse effects that may develop.

Managing osteoporosis in older men could include the use of bone anabolics and/or antiresorptives. In younger individuals, use of pharmacologic therapy is less common but sometimes necessary, particularly when bone density is very low and associated with a problematic fracture history — for example, in those with genetic conditions such as osteogenesis imperfecta. Furthermore, the occurrence of vertebral compression fractures often requires bisphosphonate treatment regardless of bone density, particularly in patients on chronic glucocorticoid therapy.

Preventing osteoporosis is best managed by paying attention to lifestyle; optimizing nutrition and calcium and vitamin D intake; and managing conditions and limiting the use of medications that reduce bone density.

However, in certain patients, these measures are not enough, and pharmacologic therapy with bone anabolics or antiresorptives may be necessary to improve bone density and reduce fracture risk.

Dr. Misra, of the University of Virginia and UVA Health Children’s Hospital, Charlottesville, disclosed ties with AbbVie, Sanofi, and Ipsen.
 

A version of this article appeared on Medscape.com.

Fractures, particularly hip and spine fractures, are a major cause of mortality and morbidity among older individuals. The term “osteoporosis” indicates increased porosity of bones resulting in low bone density; increased bone fragility; and an increased risk for fracture, often with minimal trauma.

During the adolescent years, bone accrues at a rapid rate, and optimal bone accrual during this time is essential to attain optimal peak bone mass, typically achieved in the third decade of life. Bone mass then stays stable until the 40s-50s, after which it starts to decline. One’s peak bone mass sets the stage for both immediate and future bone health. Individuals with lower peak bone mass tend to have less optimal bone health throughout their lives, and this becomes particularly problematic in older men and in the postmenopausal years for women.

The best strategy to optimize bone health is to prevent osteoporosis from occurring in the first place. This requires attention to factors that contribute to optimal bone health. One’s genes have a major impact on bone density and are currently not modifiable.

Modifiable factors include mechanical loading of bones through exercise activity, maintaining a normal body weight, and ensuring adequate intake of micronutrients (including calcium and vitamin D) and macronutrients. Medications such as glucocorticoids that have deleterious effects on bones should be limited as far as possible. Endocrine, gastrointestinal, renal, and rheumatologic conditions and others, such as cancer, which are known to be associated with reduced bone density and increased fracture risk, should be managed appropriately.

A deficiency of the gonadal hormones (estrogen and testosterone) and high blood concentrations of cortisol are particularly deleterious to bone. Hormone replacement therapy in those with gonadal hormone deficiency and strategies to reduce cortisol levels in those with hypercortisolemia are essential to prevent osteoporosis and also improve bone density over time. The same applies to management of conditions such as anorexia nervosa, relative energy deficiency in sports, inflammatory bowel disease, celiac disease, cystic fibrosis, chronic kidney disease, and chronic arthritis.

Once osteoporosis has developed, depending on the cause, these strategies may not be sufficient to completely reverse the condition, and pharmacologic therapy may be necessary to improve bone density and reduce fracture risk. This is particularly an issue with postmenopausal women and older men. In these individuals, medications that increase bone formation or reduce bone loss may be necessary.

Medications that reduce bone loss include bisphosphonates and denosumab; these are also called “antiresorptive medications” because they reduce bone resorption by cells called osteoclasts. Bisphosphonates include alendronate, risedronate, ibandronate, pamidronate, and zoledronic acid, and these medications have direct effects on osteoclasts, reducing their activity. Some bisphosphonates, such as alendronate and risedronate, are taken orally (daily, weekly, or monthly, depending on the medication and its strength), whereas others, such as pamidronate and zoledronic acid, are administered intravenously: every 3-4 months for pamidronate and every 6-12 months for zoledronic acid. Ibandronate is available both orally and intravenously.

Denosumab is a medication that inhibits the action of receptor activator of nuclear factor-kappa ligand 1 (RANKL), which otherwise increases osteoclast activity. It is administered as a subcutaneous injection every 6 months to treat osteoporosis. One concern with denosumab is a rapid increase in bone loss after its discontinuation.

Medications that increase bone formation are called bone anabolics and include teriparatide, abaloparatide, and romosozumab. Teriparatide is a synthetic form of parathyroid hormone (recombinant PTH1-34) administered daily for up to 2 years. Abaloparatide is a synthetic analog of parathyroid hormone–related peptide (PTHrP), which is also administered daily as a subcutaneous injection. Romosozumab inhibits sclerostin (a substance that otherwise reduces bone formation and increases bone resorption) and is administered as a subcutaneous injection once a month. Effects of these medications tend to be lost after they are discontinued.

In 2019, the Endocrine Society published guidelines for managing postmenopausal osteoporosis. The guidelines recommend lifestyle modifications, including attention to diet, calcium and vitamin D supplements, and weight-bearing exercise for all postmenopausal women. They also recommend assessing fracture risk using country-specific existing models.

Guidelines vary depending on whether fracture risk is low, moderate, or high. Patients at low risk are followed and reassessed every 2-4 years for fracture risk. Those at moderate risk may be followed similarly or prescribed bisphosphonates. Those at high risk are prescribed an antiresorptive, such as a bisphosphonate or denosumab, or a bone anabolic, such as teriparatide or abaloparatide (for up to 2 years) or romosozumab (for a year), with calcium and vitamin D and are reassessed at defined intervals for fracture risk; subsequent management then depends on the assessed fracture risk.

People who are on a bone anabolic should typically follow this with an antiresorptive medication to maintain the gains achieved with the former after that medication is discontinued. Patients who discontinue denosumab should be switched to bisphosphonates to prevent the increase in bone loss that typically occurs.

In postmenopausal women who are intolerant to or inappropriate for use of these medications, guidelines vary depending on age (younger or older than 60 years) and presence or absence of vasomotor symptoms (such as hot flashes). Options could include the use of calcium and vitamin D supplements; hormone replacement therapy with estrogen with or without a progestin; or selective estrogen receptor modulators (such as raloxifene or bazedoxifene), tibolone, or calcitonin.

It’s important to recognize that all pharmacologic therapy carries the risk for adverse events, and it’s essential to take the necessary steps to prevent, monitor for, and manage any adverse effects that may develop.

Managing osteoporosis in older men could include the use of bone anabolics and/or antiresorptives. In younger individuals, use of pharmacologic therapy is less common but sometimes necessary, particularly when bone density is very low and associated with a problematic fracture history — for example, in those with genetic conditions such as osteogenesis imperfecta. Furthermore, the occurrence of vertebral compression fractures often requires bisphosphonate treatment regardless of bone density, particularly in patients on chronic glucocorticoid therapy.

Preventing osteoporosis is best managed by paying attention to lifestyle; optimizing nutrition and calcium and vitamin D intake; and managing conditions and limiting the use of medications that reduce bone density.

However, in certain patients, these measures are not enough, and pharmacologic therapy with bone anabolics or antiresorptives may be necessary to improve bone density and reduce fracture risk.

Dr. Misra, of the University of Virginia and UVA Health Children’s Hospital, Charlottesville, disclosed ties with AbbVie, Sanofi, and Ipsen.
 

A version of this article appeared on Medscape.com.

Stefan Bornstein, MD, PhD, professor, made it clear during a press conference at the 67th Congress of the German Society of Endocrinology (DGE) that there is more than one interaction between them. Nowadays, one can almost speak of an “endocrine virology and even of the virome as an additional, hormonally metabolically active gland,” said Dr. Bornstein, who will receive the Berthold Medal from the DGE in 2024.

Many questions remain unanswered: “We need a better understanding of the interaction of hormone systems with infectious agents — from basics to therapeutic applications,” emphasized the director of the Medical Clinic and Polyclinic III and the Center for Internal Medicine at the Carl Gustav Carus University Hospital, Dresden, Germany.

If infectious diseases could trigger diabetes and other metabolic diseases, this means that “through vaccination programs, we may be able to prevent the occurrence of common metabolic diseases such as diabetes,” said Dr. Bornstein. He highlighted that many people who experienced severe COVID-19 during the pandemic, or died from it, exhibited diabetes or a pre-metabolic syndrome.

“SARS-CoV-2 has utilized an endocrine signaling pathway to invade our cells and cause damage in the organ systems and inflammation,” said Dr. Bornstein. Conversely, it is now known that infections with coronaviruses or other infectious agents like influenza can significantly worsen metabolic status, diabetes, and other endocrine diseases.
 

SARS-CoV-2 Infects the Beta Cells

Data from the COVID-19 pandemic showed that the likelihood of developing type 1 diabetes significantly increases with a SARS-CoV-2 infection. Researchers led by Dr. Bornstein demonstrated in 2021 that SARS-CoV-2 can infect the insulin-producing cells of the organ. They examined pancreatic tissue from 20 patients who died from COVID-19 using immunofluorescence, immunohistochemistry, RNA in situ hybridization, and electron microscopy.

They found viral SARS-CoV-2 infiltration of the beta cells in all patients. In 11 patients with COVID-19, the expression of ACE2, TMPRSS, and other receptors and factors like DPP4, HMBG1, and NRP1 that can facilitate virus entry was examined. They found that even in the absence of manifest newly onset diabetes, necroptotic cell death, immune cell infiltration, and SARS-CoV-2 infection of the pancreas beta cells can contribute to varying degrees of metabolic disturbance in patients with COVID-19.

In a report published in October 2020, Tim Hollstein, MD, from the Institute for Diabetology and Clinical Metabolic Research at UKSH in Kiel, Germany, and colleagues described the case of a 19-year-old man who developed symptoms of insulin-dependent diabetes after a SARS-CoV-2 infection, without the presence of autoantibodies typical for type 1 diabetes.

The man presented to the emergency department with diabetic ketoacidosis, a C-peptide level of 0.62 µg/L, a blood glucose concentration of 30.6 mmol/L (552 mg/dL), and an A1c level of 16.8%. The patient’s history revealed a probable SARS-CoV-2 infection 5-7 weeks before admission, based on a positive antibody test against SARS-CoV-2.
 

Some Viruses Produce Insulin-Like Proteins

Recent studies have shown that some viruses can produce insulin-like proteins or hormones that interfere with the metabolism of the affected organism, reported Dr. Bornstein. In addition to metabolic regulation, these “viral hormones” also seem to influence cell turnover and cell death.

Dr. Bornstein pointed out that antiviral medications can delay the onset of type 1 diabetes by preserving the function of insulin-producing beta cells. It has also been shown that conventional medications used to treat hormonal disorders can reduce the susceptibility of the organism to infections — such as antidiabetic preparations like DPP-4 inhibitors or metformin.

In a review published in 2023, Nikolaos Perakakis, MD, professor, research group leader at the Paul Langerhans Institute Dresden, Dresden, Germany, Dr. Bornstein, and colleagues discussed scientific evidence for a close mutual dependence between various virus infections and metabolic diseases. They discussed how viruses can lead to the development or progression of metabolic diseases and vice versa and how metabolic diseases can increase the severity of a virus infection.
 

Viruses Favor Metabolic Diseases...

Viruses can favor metabolic diseases by, for example, influencing the regulation of cell survival and specific signaling pathways relevant for cell death, proliferation, or dedifferentiation in important endocrine and metabolic organs. Viruses are also capable of controlling cellular glucose metabolism by modulating glucose transporters, altering glucose uptake, regulating signaling pathways, and stimulating glycolysis in infected cells.

Due to the destruction of beta cells, enteroviruses, but also the mumps virus, parainfluenza virus, or human herpes virus 6, are associated with the development of diabetes. The timing of infection often precedes or coincides with the peak of development of islet autoantibodies. The fact that only a small proportion of patients actually develop type 1 diabetes suggests that genetic background, and likely the timing of infection, play an important role.
 

...And Metabolic Diseases Influence the Course of Infection

Infection with hepatitis C virus (HCV), on the other hand, is associated with an increased risk for type 2 diabetes, with the risk being higher for older individuals with a family history of diabetes. The negative effects of HCV on glucose balance are mainly attributed to increased insulin resistance in the liver. HCV reduces hepatic glucose uptake by downregulating the expression of glucose transporters and additionally impairs insulin signal transduction by inhibiting the PI3K/Akt signaling pathway.

People with obesity, diabetes, or insulin resistance show significant changes in the innate and adaptive functions of the immune system. Regarding the innate immune system, impaired chemotaxis and phagocytosis of neutrophils have been observed in patients with type 2 diabetes.

In the case of obesity, the number of natural killer T cells in adipose tissue decreases, whereas B cells accumulate in adipose tissue and secrete more proinflammatory cytokines. Longitudinal multiomics analyses of various biopsies from individuals with insulin resistance showed a delayed immune response to respiratory virus infections compared with individuals with normal insulin sensitivity.

This story was translated from Medscape Germany 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.

Stefan Bornstein, MD, PhD, professor, made it clear during a press conference at the 67th Congress of the German Society of Endocrinology (DGE) that there is more than one interaction between them. Nowadays, one can almost speak of an “endocrine virology and even of the virome as an additional, hormonally metabolically active gland,” said Dr. Bornstein, who will receive the Berthold Medal from the DGE in 2024.

Many questions remain unanswered: “We need a better understanding of the interaction of hormone systems with infectious agents — from basics to therapeutic applications,” emphasized the director of the Medical Clinic and Polyclinic III and the Center for Internal Medicine at the Carl Gustav Carus University Hospital, Dresden, Germany.

If infectious diseases could trigger diabetes and other metabolic diseases, this means that “through vaccination programs, we may be able to prevent the occurrence of common metabolic diseases such as diabetes,” said Dr. Bornstein. He highlighted that many people who experienced severe COVID-19 during the pandemic, or died from it, exhibited diabetes or a pre-metabolic syndrome.

“SARS-CoV-2 has utilized an endocrine signaling pathway to invade our cells and cause damage in the organ systems and inflammation,” said Dr. Bornstein. Conversely, it is now known that infections with coronaviruses or other infectious agents like influenza can significantly worsen metabolic status, diabetes, and other endocrine diseases.
 

SARS-CoV-2 Infects the Beta Cells

Data from the COVID-19 pandemic showed that the likelihood of developing type 1 diabetes significantly increases with a SARS-CoV-2 infection. Researchers led by Dr. Bornstein demonstrated in 2021 that SARS-CoV-2 can infect the insulin-producing cells of the organ. They examined pancreatic tissue from 20 patients who died from COVID-19 using immunofluorescence, immunohistochemistry, RNA in situ hybridization, and electron microscopy.

They found viral SARS-CoV-2 infiltration of the beta cells in all patients. In 11 patients with COVID-19, the expression of ACE2, TMPRSS, and other receptors and factors like DPP4, HMBG1, and NRP1 that can facilitate virus entry was examined. They found that even in the absence of manifest newly onset diabetes, necroptotic cell death, immune cell infiltration, and SARS-CoV-2 infection of the pancreas beta cells can contribute to varying degrees of metabolic disturbance in patients with COVID-19.

In a report published in October 2020, Tim Hollstein, MD, from the Institute for Diabetology and Clinical Metabolic Research at UKSH in Kiel, Germany, and colleagues described the case of a 19-year-old man who developed symptoms of insulin-dependent diabetes after a SARS-CoV-2 infection, without the presence of autoantibodies typical for type 1 diabetes.

The man presented to the emergency department with diabetic ketoacidosis, a C-peptide level of 0.62 µg/L, a blood glucose concentration of 30.6 mmol/L (552 mg/dL), and an A1c level of 16.8%. The patient’s history revealed a probable SARS-CoV-2 infection 5-7 weeks before admission, based on a positive antibody test against SARS-CoV-2.
 

Some Viruses Produce Insulin-Like Proteins

Recent studies have shown that some viruses can produce insulin-like proteins or hormones that interfere with the metabolism of the affected organism, reported Dr. Bornstein. In addition to metabolic regulation, these “viral hormones” also seem to influence cell turnover and cell death.

Dr. Bornstein pointed out that antiviral medications can delay the onset of type 1 diabetes by preserving the function of insulin-producing beta cells. It has also been shown that conventional medications used to treat hormonal disorders can reduce the susceptibility of the organism to infections — such as antidiabetic preparations like DPP-4 inhibitors or metformin.

In a review published in 2023, Nikolaos Perakakis, MD, professor, research group leader at the Paul Langerhans Institute Dresden, Dresden, Germany, Dr. Bornstein, and colleagues discussed scientific evidence for a close mutual dependence between various virus infections and metabolic diseases. They discussed how viruses can lead to the development or progression of metabolic diseases and vice versa and how metabolic diseases can increase the severity of a virus infection.
 

Viruses Favor Metabolic Diseases...

Viruses can favor metabolic diseases by, for example, influencing the regulation of cell survival and specific signaling pathways relevant for cell death, proliferation, or dedifferentiation in important endocrine and metabolic organs. Viruses are also capable of controlling cellular glucose metabolism by modulating glucose transporters, altering glucose uptake, regulating signaling pathways, and stimulating glycolysis in infected cells.

Due to the destruction of beta cells, enteroviruses, but also the mumps virus, parainfluenza virus, or human herpes virus 6, are associated with the development of diabetes. The timing of infection often precedes or coincides with the peak of development of islet autoantibodies. The fact that only a small proportion of patients actually develop type 1 diabetes suggests that genetic background, and likely the timing of infection, play an important role.
 

...And Metabolic Diseases Influence the Course of Infection

Infection with hepatitis C virus (HCV), on the other hand, is associated with an increased risk for type 2 diabetes, with the risk being higher for older individuals with a family history of diabetes. The negative effects of HCV on glucose balance are mainly attributed to increased insulin resistance in the liver. HCV reduces hepatic glucose uptake by downregulating the expression of glucose transporters and additionally impairs insulin signal transduction by inhibiting the PI3K/Akt signaling pathway.

People with obesity, diabetes, or insulin resistance show significant changes in the innate and adaptive functions of the immune system. Regarding the innate immune system, impaired chemotaxis and phagocytosis of neutrophils have been observed in patients with type 2 diabetes.

In the case of obesity, the number of natural killer T cells in adipose tissue decreases, whereas B cells accumulate in adipose tissue and secrete more proinflammatory cytokines. Longitudinal multiomics analyses of various biopsies from individuals with insulin resistance showed a delayed immune response to respiratory virus infections compared with individuals with normal insulin sensitivity.

This story was translated from Medscape Germany 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.

Stefan Bornstein, MD, PhD, professor, made it clear during a press conference at the 67th Congress of the German Society of Endocrinology (DGE) that there is more than one interaction between them. Nowadays, one can almost speak of an “endocrine virology and even of the virome as an additional, hormonally metabolically active gland,” said Dr. Bornstein, who will receive the Berthold Medal from the DGE in 2024.

Many questions remain unanswered: “We need a better understanding of the interaction of hormone systems with infectious agents — from basics to therapeutic applications,” emphasized the director of the Medical Clinic and Polyclinic III and the Center for Internal Medicine at the Carl Gustav Carus University Hospital, Dresden, Germany.

If infectious diseases could trigger diabetes and other metabolic diseases, this means that “through vaccination programs, we may be able to prevent the occurrence of common metabolic diseases such as diabetes,” said Dr. Bornstein. He highlighted that many people who experienced severe COVID-19 during the pandemic, or died from it, exhibited diabetes or a pre-metabolic syndrome.

“SARS-CoV-2 has utilized an endocrine signaling pathway to invade our cells and cause damage in the organ systems and inflammation,” said Dr. Bornstein. Conversely, it is now known that infections with coronaviruses or other infectious agents like influenza can significantly worsen metabolic status, diabetes, and other endocrine diseases.
 

SARS-CoV-2 Infects the Beta Cells

Data from the COVID-19 pandemic showed that the likelihood of developing type 1 diabetes significantly increases with a SARS-CoV-2 infection. Researchers led by Dr. Bornstein demonstrated in 2021 that SARS-CoV-2 can infect the insulin-producing cells of the organ. They examined pancreatic tissue from 20 patients who died from COVID-19 using immunofluorescence, immunohistochemistry, RNA in situ hybridization, and electron microscopy.

They found viral SARS-CoV-2 infiltration of the beta cells in all patients. In 11 patients with COVID-19, the expression of ACE2, TMPRSS, and other receptors and factors like DPP4, HMBG1, and NRP1 that can facilitate virus entry was examined. They found that even in the absence of manifest newly onset diabetes, necroptotic cell death, immune cell infiltration, and SARS-CoV-2 infection of the pancreas beta cells can contribute to varying degrees of metabolic disturbance in patients with COVID-19.

In a report published in October 2020, Tim Hollstein, MD, from the Institute for Diabetology and Clinical Metabolic Research at UKSH in Kiel, Germany, and colleagues described the case of a 19-year-old man who developed symptoms of insulin-dependent diabetes after a SARS-CoV-2 infection, without the presence of autoantibodies typical for type 1 diabetes.

The man presented to the emergency department with diabetic ketoacidosis, a C-peptide level of 0.62 µg/L, a blood glucose concentration of 30.6 mmol/L (552 mg/dL), and an A1c level of 16.8%. The patient’s history revealed a probable SARS-CoV-2 infection 5-7 weeks before admission, based on a positive antibody test against SARS-CoV-2.
 

Some Viruses Produce Insulin-Like Proteins

Recent studies have shown that some viruses can produce insulin-like proteins or hormones that interfere with the metabolism of the affected organism, reported Dr. Bornstein. In addition to metabolic regulation, these “viral hormones” also seem to influence cell turnover and cell death.

Dr. Bornstein pointed out that antiviral medications can delay the onset of type 1 diabetes by preserving the function of insulin-producing beta cells. It has also been shown that conventional medications used to treat hormonal disorders can reduce the susceptibility of the organism to infections — such as antidiabetic preparations like DPP-4 inhibitors or metformin.

In a review published in 2023, Nikolaos Perakakis, MD, professor, research group leader at the Paul Langerhans Institute Dresden, Dresden, Germany, Dr. Bornstein, and colleagues discussed scientific evidence for a close mutual dependence between various virus infections and metabolic diseases. They discussed how viruses can lead to the development or progression of metabolic diseases and vice versa and how metabolic diseases can increase the severity of a virus infection.
 

Viruses Favor Metabolic Diseases...

Viruses can favor metabolic diseases by, for example, influencing the regulation of cell survival and specific signaling pathways relevant for cell death, proliferation, or dedifferentiation in important endocrine and metabolic organs. Viruses are also capable of controlling cellular glucose metabolism by modulating glucose transporters, altering glucose uptake, regulating signaling pathways, and stimulating glycolysis in infected cells.

Due to the destruction of beta cells, enteroviruses, but also the mumps virus, parainfluenza virus, or human herpes virus 6, are associated with the development of diabetes. The timing of infection often precedes or coincides with the peak of development of islet autoantibodies. The fact that only a small proportion of patients actually develop type 1 diabetes suggests that genetic background, and likely the timing of infection, play an important role.
 

...And Metabolic Diseases Influence the Course of Infection

Infection with hepatitis C virus (HCV), on the other hand, is associated with an increased risk for type 2 diabetes, with the risk being higher for older individuals with a family history of diabetes. The negative effects of HCV on glucose balance are mainly attributed to increased insulin resistance in the liver. HCV reduces hepatic glucose uptake by downregulating the expression of glucose transporters and additionally impairs insulin signal transduction by inhibiting the PI3K/Akt signaling pathway.

People with obesity, diabetes, or insulin resistance show significant changes in the innate and adaptive functions of the immune system. Regarding the innate immune system, impaired chemotaxis and phagocytosis of neutrophils have been observed in patients with type 2 diabetes.

In the case of obesity, the number of natural killer T cells in adipose tissue decreases, whereas B cells accumulate in adipose tissue and secrete more proinflammatory cytokines. Longitudinal multiomics analyses of various biopsies from individuals with insulin resistance showed a delayed immune response to respiratory virus infections compared with individuals with normal insulin sensitivity.

This story was translated from Medscape Germany 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.

Some doctors may be scratching their heads over a new analysis reporting that combined calcium and vitamin D (CaD) supplements appear to be associated with a slight 6% increase in cardiovascular (CVD) mortality, a slight 7% decrease in cancer risk, and no effect on osteoporotic fracture in postmenopausal women.

The study, in Annals of Internal Medicine, found no effect of supplementation on all-cause mortality.

The findings emerged from an analysis of more than 20 years’ follow-up data on a randomized trial in postmenopausal women conducted as part of the Women’s Health Initiative (WHI).

Cynthia A. Thomson, PhD, RD, first author and cancer prevention scientist at the Arizona Cancer Center and a professor of health promotion sciences at the University of Arizona in Tucson said the findings recommend individualized assessment of the need for supplements for older women as they consider them in hopes of preventing fractures.

Thomson_Cynthia_AZ_web.jpg

Study Details

The investigators conducted postintervention follow-up of the WHI’s 7-year multicenter randomized intervention trial of CaD vs placebo.

Since existing evidence of long-term health outcomes was limited, the trial, begun in 1999 and closed in 2005, enrolled 36,282 postmenopausal women (mean age 62) with no history of breast or colorectal cancer. They were randomly assigned 1:1 to supplementation with 1000 mg of calcium carbonate (400 mg elemental calcium) plus 400 IU of vitamin D3 daily or placebo, taken twice daily in half doses.

Study outcomes were incidence of CRC, total and invasive breast cancer; disease-specific and all-cause mortality; total CVD; and hip fracture measured through December 2020, with analyses stratified by personal supplement usage.

Cancer. CaD was associated with reduced incident total cancer, CRC, and invasive breast cancer — notably among participants not taking CaD before randomization. Cancer incidence estimates varied widely, the authors noted, when stratified by supplement use before randomization. Noting that CaD seemed to have more cancer-related impact in those without prior supplementation, the authors suggested supplementation may affect cancer biology primarily by augmenting nutrient insufficiency.

An estimated 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years: 1817 vs 1943 deaths (hazard ratio, 0.93; 95% CI, 0.87-0.99).

CVD. An estimated 6% increase in CVD mortality was seen in the CaD group: 2621 vs 2420 deaths (HR, 1.06; 95% CI, 1.01-1.12). Pretrial supplement users were found to be at higher CVD risk.

Hip fracture. No effect on hip fracture risk was measured, but the authors cautioned that hip fracture and CVD outcomes were available only for a subset of participants, and the effects of calcium alone vs vitamin D alone vs the combination could not be disentangled.

In a small subgroup analysis, some CaD users were seen to respond in terms of bone mineral density but since only 4 of the study’s 40 sites collected such information, the study was underpowered to examine the effect. ”Many other studies, however, show a response to supplementation in women who already have bone mineral deficits,” Dr. Thomson said.
 

The Calcification Question

One of the possible mechanisms of harm is that high-dose calcium supplements can increase the rate of blood coagulation and promote vascular calcification, said Emma Laing, PhD, RD, director of dietetics at the University of Georgia in Athens and a spokesperson for the Chicago-based Academy of Nutrition and Dietetics.

Laing_Emma_GA_web.jpg

“Other factors that should be considered when determining a patient’s CVD risk are race, genetic predisposition, medical and social history, response to stress, and lifestyle behaviors, as well as the length of time supplements have been consumed,” added Dr. Laing, who was not involved in the WHI analysis.

“We asked ourselves if CaD supplements might contribute to calcification of the coronary arteries, since some believe this to be the case, although the literature is mixed,” said Dr. Thomson.

“So we did a shorter ancillary study in a small sample of several hundred [women] to see if there was any increase in calcification” and no difference was seen on imaging across the two arms. “However, women who were already on supplements before entering the study seemed to be at higher CVD risk,” she said.

Added study coauthor JoAnn E. Manson, MD, DrPH, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of women’s health at Harvard Medical School, both in Boston: “With no increase or decrease in coronary artery calcium at the end of the trial, we don’t believe starting or continuing calcium/vitamin D supplements should require screening for coronary artery disease.”

Manson_JoAnn_E_BOSTON_web.jpg

Vitamin D Supplementation

As for vitamin D only supplementation, an updated meta-analysis including more than 83,000 individuals showed that it confers no cardiovascular protection and is therefore not indicated for this purpose.
 

Practice Considerations

Offering an outsider’s perspective, Sarah G. Candler, MD, MPH, an internist in Houston specializing in primary care for older high-risk adults, said: “Unfortunately, this latest study continues the trend of creating more questions than answers. If the adverse outcome of CVD death is a result of supplementation, it is unclear if this is due to the vitamin D, the calcium, or both. And it is unclear if this is dose dependent, time dependent, or due to concurrent risk factors unique to certain populations.

Candler_Sarah_TX_web.jpg

“It is recommended that patients at risk of osteoporosis based on age, sex, medications, and lifestyle be screened for osteoporosis and treated accordingly, including supplementation with CaD,” Dr. Candler said. “It remains unclear whether supplementation with CaD in the absence of osteoporosis and osteopenia is net beneficial or harmful, and at this time I would not recommend it to my patients.” 

Added Dr. Manson: “The very small increase seen in cardiovascular mortality wouldn’t be a reason to discontinue supplementation among women who have been advised by their healthcare providers to take these supplements for bone health or other purposes.

“Among those at usual risk of fracture, we recommend trying to obtain adequate calcium and vitamin D from food sources first and to use supplements only for the purpose of filling gaps in intake,” Dr. Manson continued. Overall, the findings support the national recommended dietary allowances for daily calcium intake of 1200 mg and daily vitamin D intake of 600-800 IU among postmenopausal women for maintenance of bone health, she said.

While a 2022 study found that vitamin D supplementation alone did not prevent fractures in healthy adults, other research has shown that a calcium/vitamin D combination is more likely to protect the skeleton.

“Patients at risk for fractures will probably benefit from calcium and/or vitamin D supplementation if they do not meet dietary intake requirements, have malabsorption syndromes, are taking medications that affect nutrient absorption, or if they are older and not regularly exposed to sunlight,” said Dr. Laing. “A combination of biochemical, imaging, functional, and dietary intake data can help determine if a supplement is warranted.”

She stressed that additional research is needed in more diverse populations before changing practice guidelines. “However, doctors should continue to weigh the risks and benefits of prescribing supplements for each patient.”

The WHI program is funded by the National Heart, Lung, and Blood Institute. Dr. Thomson disclosed no competing interests. Dr. Manson reported a relationship with Mars Edge. Multiple authors reported grant support from government funding agencies. The outside commentators had no relevant competing interests to disclose.

Some doctors may be scratching their heads over a new analysis reporting that combined calcium and vitamin D (CaD) supplements appear to be associated with a slight 6% increase in cardiovascular (CVD) mortality, a slight 7% decrease in cancer risk, and no effect on osteoporotic fracture in postmenopausal women.

The study, in Annals of Internal Medicine, found no effect of supplementation on all-cause mortality.

The findings emerged from an analysis of more than 20 years’ follow-up data on a randomized trial in postmenopausal women conducted as part of the Women’s Health Initiative (WHI).

Cynthia A. Thomson, PhD, RD, first author and cancer prevention scientist at the Arizona Cancer Center and a professor of health promotion sciences at the University of Arizona in Tucson said the findings recommend individualized assessment of the need for supplements for older women as they consider them in hopes of preventing fractures.

Thomson_Cynthia_AZ_web.jpg

Study Details

The investigators conducted postintervention follow-up of the WHI’s 7-year multicenter randomized intervention trial of CaD vs placebo.

Since existing evidence of long-term health outcomes was limited, the trial, begun in 1999 and closed in 2005, enrolled 36,282 postmenopausal women (mean age 62) with no history of breast or colorectal cancer. They were randomly assigned 1:1 to supplementation with 1000 mg of calcium carbonate (400 mg elemental calcium) plus 400 IU of vitamin D3 daily or placebo, taken twice daily in half doses.

Study outcomes were incidence of CRC, total and invasive breast cancer; disease-specific and all-cause mortality; total CVD; and hip fracture measured through December 2020, with analyses stratified by personal supplement usage.

Cancer. CaD was associated with reduced incident total cancer, CRC, and invasive breast cancer — notably among participants not taking CaD before randomization. Cancer incidence estimates varied widely, the authors noted, when stratified by supplement use before randomization. Noting that CaD seemed to have more cancer-related impact in those without prior supplementation, the authors suggested supplementation may affect cancer biology primarily by augmenting nutrient insufficiency.

An estimated 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years: 1817 vs 1943 deaths (hazard ratio, 0.93; 95% CI, 0.87-0.99).

CVD. An estimated 6% increase in CVD mortality was seen in the CaD group: 2621 vs 2420 deaths (HR, 1.06; 95% CI, 1.01-1.12). Pretrial supplement users were found to be at higher CVD risk.

Hip fracture. No effect on hip fracture risk was measured, but the authors cautioned that hip fracture and CVD outcomes were available only for a subset of participants, and the effects of calcium alone vs vitamin D alone vs the combination could not be disentangled.

In a small subgroup analysis, some CaD users were seen to respond in terms of bone mineral density but since only 4 of the study’s 40 sites collected such information, the study was underpowered to examine the effect. ”Many other studies, however, show a response to supplementation in women who already have bone mineral deficits,” Dr. Thomson said.
 

The Calcification Question

One of the possible mechanisms of harm is that high-dose calcium supplements can increase the rate of blood coagulation and promote vascular calcification, said Emma Laing, PhD, RD, director of dietetics at the University of Georgia in Athens and a spokesperson for the Chicago-based Academy of Nutrition and Dietetics.

Laing_Emma_GA_web.jpg

“Other factors that should be considered when determining a patient’s CVD risk are race, genetic predisposition, medical and social history, response to stress, and lifestyle behaviors, as well as the length of time supplements have been consumed,” added Dr. Laing, who was not involved in the WHI analysis.

“We asked ourselves if CaD supplements might contribute to calcification of the coronary arteries, since some believe this to be the case, although the literature is mixed,” said Dr. Thomson.

“So we did a shorter ancillary study in a small sample of several hundred [women] to see if there was any increase in calcification” and no difference was seen on imaging across the two arms. “However, women who were already on supplements before entering the study seemed to be at higher CVD risk,” she said.

Added study coauthor JoAnn E. Manson, MD, DrPH, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of women’s health at Harvard Medical School, both in Boston: “With no increase or decrease in coronary artery calcium at the end of the trial, we don’t believe starting or continuing calcium/vitamin D supplements should require screening for coronary artery disease.”

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Vitamin D Supplementation

As for vitamin D only supplementation, an updated meta-analysis including more than 83,000 individuals showed that it confers no cardiovascular protection and is therefore not indicated for this purpose.
 

Practice Considerations

Offering an outsider’s perspective, Sarah G. Candler, MD, MPH, an internist in Houston specializing in primary care for older high-risk adults, said: “Unfortunately, this latest study continues the trend of creating more questions than answers. If the adverse outcome of CVD death is a result of supplementation, it is unclear if this is due to the vitamin D, the calcium, or both. And it is unclear if this is dose dependent, time dependent, or due to concurrent risk factors unique to certain populations.

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“It is recommended that patients at risk of osteoporosis based on age, sex, medications, and lifestyle be screened for osteoporosis and treated accordingly, including supplementation with CaD,” Dr. Candler said. “It remains unclear whether supplementation with CaD in the absence of osteoporosis and osteopenia is net beneficial or harmful, and at this time I would not recommend it to my patients.” 

Added Dr. Manson: “The very small increase seen in cardiovascular mortality wouldn’t be a reason to discontinue supplementation among women who have been advised by their healthcare providers to take these supplements for bone health or other purposes.

“Among those at usual risk of fracture, we recommend trying to obtain adequate calcium and vitamin D from food sources first and to use supplements only for the purpose of filling gaps in intake,” Dr. Manson continued. Overall, the findings support the national recommended dietary allowances for daily calcium intake of 1200 mg and daily vitamin D intake of 600-800 IU among postmenopausal women for maintenance of bone health, she said.

While a 2022 study found that vitamin D supplementation alone did not prevent fractures in healthy adults, other research has shown that a calcium/vitamin D combination is more likely to protect the skeleton.

“Patients at risk for fractures will probably benefit from calcium and/or vitamin D supplementation if they do not meet dietary intake requirements, have malabsorption syndromes, are taking medications that affect nutrient absorption, or if they are older and not regularly exposed to sunlight,” said Dr. Laing. “A combination of biochemical, imaging, functional, and dietary intake data can help determine if a supplement is warranted.”

She stressed that additional research is needed in more diverse populations before changing practice guidelines. “However, doctors should continue to weigh the risks and benefits of prescribing supplements for each patient.”

The WHI program is funded by the National Heart, Lung, and Blood Institute. Dr. Thomson disclosed no competing interests. Dr. Manson reported a relationship with Mars Edge. Multiple authors reported grant support from government funding agencies. The outside commentators had no relevant competing interests to disclose.

Some doctors may be scratching their heads over a new analysis reporting that combined calcium and vitamin D (CaD) supplements appear to be associated with a slight 6% increase in cardiovascular (CVD) mortality, a slight 7% decrease in cancer risk, and no effect on osteoporotic fracture in postmenopausal women.

The study, in Annals of Internal Medicine, found no effect of supplementation on all-cause mortality.

The findings emerged from an analysis of more than 20 years’ follow-up data on a randomized trial in postmenopausal women conducted as part of the Women’s Health Initiative (WHI).

Cynthia A. Thomson, PhD, RD, first author and cancer prevention scientist at the Arizona Cancer Center and a professor of health promotion sciences at the University of Arizona in Tucson said the findings recommend individualized assessment of the need for supplements for older women as they consider them in hopes of preventing fractures.

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Study Details

The investigators conducted postintervention follow-up of the WHI’s 7-year multicenter randomized intervention trial of CaD vs placebo.

Since existing evidence of long-term health outcomes was limited, the trial, begun in 1999 and closed in 2005, enrolled 36,282 postmenopausal women (mean age 62) with no history of breast or colorectal cancer. They were randomly assigned 1:1 to supplementation with 1000 mg of calcium carbonate (400 mg elemental calcium) plus 400 IU of vitamin D3 daily or placebo, taken twice daily in half doses.

Study outcomes were incidence of CRC, total and invasive breast cancer; disease-specific and all-cause mortality; total CVD; and hip fracture measured through December 2020, with analyses stratified by personal supplement usage.

Cancer. CaD was associated with reduced incident total cancer, CRC, and invasive breast cancer — notably among participants not taking CaD before randomization. Cancer incidence estimates varied widely, the authors noted, when stratified by supplement use before randomization. Noting that CaD seemed to have more cancer-related impact in those without prior supplementation, the authors suggested supplementation may affect cancer biology primarily by augmenting nutrient insufficiency.

An estimated 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years: 1817 vs 1943 deaths (hazard ratio, 0.93; 95% CI, 0.87-0.99).

CVD. An estimated 6% increase in CVD mortality was seen in the CaD group: 2621 vs 2420 deaths (HR, 1.06; 95% CI, 1.01-1.12). Pretrial supplement users were found to be at higher CVD risk.

Hip fracture. No effect on hip fracture risk was measured, but the authors cautioned that hip fracture and CVD outcomes were available only for a subset of participants, and the effects of calcium alone vs vitamin D alone vs the combination could not be disentangled.

In a small subgroup analysis, some CaD users were seen to respond in terms of bone mineral density but since only 4 of the study’s 40 sites collected such information, the study was underpowered to examine the effect. ”Many other studies, however, show a response to supplementation in women who already have bone mineral deficits,” Dr. Thomson said.
 

The Calcification Question

One of the possible mechanisms of harm is that high-dose calcium supplements can increase the rate of blood coagulation and promote vascular calcification, said Emma Laing, PhD, RD, director of dietetics at the University of Georgia in Athens and a spokesperson for the Chicago-based Academy of Nutrition and Dietetics.

Laing_Emma_GA_web.jpg

“Other factors that should be considered when determining a patient’s CVD risk are race, genetic predisposition, medical and social history, response to stress, and lifestyle behaviors, as well as the length of time supplements have been consumed,” added Dr. Laing, who was not involved in the WHI analysis.

“We asked ourselves if CaD supplements might contribute to calcification of the coronary arteries, since some believe this to be the case, although the literature is mixed,” said Dr. Thomson.

“So we did a shorter ancillary study in a small sample of several hundred [women] to see if there was any increase in calcification” and no difference was seen on imaging across the two arms. “However, women who were already on supplements before entering the study seemed to be at higher CVD risk,” she said.

Added study coauthor JoAnn E. Manson, MD, DrPH, chief of the division of preventive medicine at Brigham and Women’s Hospital and professor of women’s health at Harvard Medical School, both in Boston: “With no increase or decrease in coronary artery calcium at the end of the trial, we don’t believe starting or continuing calcium/vitamin D supplements should require screening for coronary artery disease.”

Manson_JoAnn_E_BOSTON_web.jpg

Vitamin D Supplementation

As for vitamin D only supplementation, an updated meta-analysis including more than 83,000 individuals showed that it confers no cardiovascular protection and is therefore not indicated for this purpose.
 

Practice Considerations

Offering an outsider’s perspective, Sarah G. Candler, MD, MPH, an internist in Houston specializing in primary care for older high-risk adults, said: “Unfortunately, this latest study continues the trend of creating more questions than answers. If the adverse outcome of CVD death is a result of supplementation, it is unclear if this is due to the vitamin D, the calcium, or both. And it is unclear if this is dose dependent, time dependent, or due to concurrent risk factors unique to certain populations.

Candler_Sarah_TX_web.jpg

“It is recommended that patients at risk of osteoporosis based on age, sex, medications, and lifestyle be screened for osteoporosis and treated accordingly, including supplementation with CaD,” Dr. Candler said. “It remains unclear whether supplementation with CaD in the absence of osteoporosis and osteopenia is net beneficial or harmful, and at this time I would not recommend it to my patients.” 

Added Dr. Manson: “The very small increase seen in cardiovascular mortality wouldn’t be a reason to discontinue supplementation among women who have been advised by their healthcare providers to take these supplements for bone health or other purposes.

“Among those at usual risk of fracture, we recommend trying to obtain adequate calcium and vitamin D from food sources first and to use supplements only for the purpose of filling gaps in intake,” Dr. Manson continued. Overall, the findings support the national recommended dietary allowances for daily calcium intake of 1200 mg and daily vitamin D intake of 600-800 IU among postmenopausal women for maintenance of bone health, she said.

While a 2022 study found that vitamin D supplementation alone did not prevent fractures in healthy adults, other research has shown that a calcium/vitamin D combination is more likely to protect the skeleton.

“Patients at risk for fractures will probably benefit from calcium and/or vitamin D supplementation if they do not meet dietary intake requirements, have malabsorption syndromes, are taking medications that affect nutrient absorption, or if they are older and not regularly exposed to sunlight,” said Dr. Laing. “A combination of biochemical, imaging, functional, and dietary intake data can help determine if a supplement is warranted.”

She stressed that additional research is needed in more diverse populations before changing practice guidelines. “However, doctors should continue to weigh the risks and benefits of prescribing supplements for each patient.”

The WHI program is funded by the National Heart, Lung, and Blood Institute. Dr. Thomson disclosed no competing interests. Dr. Manson reported a relationship with Mars Edge. Multiple authors reported grant support from government funding agencies. The outside commentators had no relevant competing interests to disclose.