Ultra-Processed Doesn’t Always Mean Bad — Here’s How to Tell

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Thu, 09/12/2024 - 14:56

 

You may have been warned that ultra-processed foods can wreak havoc on your health. But not all of them are created equal. 

A new study out of The Lancet Regional Health – Americas looked at different types of ultra-processed foods and found that some were even linked with lower risks of cardiovascular diseasecoronary heart disease, and stroke

“Avoiding all ultra-processed foods is not practical for most people,” said Dariush Mozaffarian, MD, a cardiologist, public health scientist, and director of the Food is Medicine Institute at Tufts University in Boston, Massachusetts. “So, it is helpful to start to understand, within the category of all processing, what food might be more or less harmful.”

Researchers analyzed food questionnaires from three large groups of US adults, with most people in their review being White and female. The study found that sugary and artificially sweetened drinks, along with processed meats, were linked to a greater risk of cardiovascular disease and coronary heart disease. But cereals, savory snacks, and yogurt and dairy-based desserts were linked to a lower risk of these diseases. Ultra-processed cereals and breads were also linked to a lower stroke risk. 
 

The Truth About Processed Meat

Studies show that cured, salted, or smoked meats are linked to certain cancers.

“We know that sugar-sweetened beverages are associated with metabolic derangement for things like higher glucose levels, insulin resistance, visceral obesityprediabetesdiabetes, and higher triglycerides,” said Ashish Sarraju, MD, a cardiologist with the Cleveland Clinic in Ohio. “Added sugars associated with all of those things are in turn risk factors for heart disease.” Sugar-sweetened beverages are often very high in sugar, artificial colors, and other additives, and almost “nothing beneficial” in terms of ingredients, Dr. Mozaffarian said. “They’re also consumed in very high doses, very quickly.”

Processed meats have 400% higher levels of salt, compared with unprocessed meats, said Dr. Mozaffarian. They also contain high levels of added nitrates, which are a carcinogen that could also affect the heart and blood vessels. Certain ultra-processed foods, such as bacon, are often fried at sky-high temperatures, which can trigger inflammatory compounds. 

“If you put together the inflammatory effects, the salt, and the nitrates, this is a package of food that can really build to cause harm,” said Dr. Mozaffarian. The World Health Organization has also classified processed meats (bacon, ham, salami) as a group one carcinogen, he noted.

“Processed meats are typically high in saturated fats, sodium, and preservatives, which can increase blood pressure, promote inflammation, and negatively affect cholesterol levels, leading to a higher risk of coronary heart disease, said Joseph A. Daibes, DO, an interventional cardiologist at Lenox Hill Hospital, New York City. “The study underscores the importance of limiting these types of foods to reduce cardiovascular risk.”

But considering that breakfast cereals – albeit highly processed – are a top source of whole grains for Americans, it makes sense that they are linked with lower risk of heart disease, said Dr. Mozaffarian. 

“They have fiber, bran, whole grains, and they also have sugar, and additives,” he said. “But on average, putting all those things together, this study suggested that the net effect is beneficial. That doesn’t mean they couldn’t be more beneficial if we made them less processed, but they don’t seem to have harm.”

The active probiotics and fermentation in yogurt can make it a healthy snack of choice, as there has been more and more research showing that fermented foods with probiotics are good for heart health and work against metabolic disease, or a cluster of conditions that can increase the risk of stroke, heart disease, and type 2 diabetes, Dr. Mozaffarian said.

Savory snacks, cereals, and yogurt and dairy-based desserts may also be less calorie dense than sugary beverages and processed meats, said Dr. Daibes. 

“Additionally, the type of fat used in savory snacks and the presence of probiotics in yogurt may have neutral or even positive effects on heart health, as opposed to the harmful fats and additives found in many ultra-processed foods,” he said.
 

How Ultra-Processed Foods Can Harm Your Health 

There are “clear and concerning links” between eating ultra-processed foods and getting heart disease, according to Dr. Daibes. “In real-life clinical practice, it’s a rather clear and straightforward relationship – the patients who tend to have poorer diets, with more ultra-processed and nutrient-barren foods, tend to have worse health outcomes, both cardiovascular and otherwise.”

Processing foods is centered on breaking down the natural structures of foods, as well as the loss of their natural nutrients, Dr. Mozaffarian explained. When you include the word “ultra,” this refers to putting in industrial additives.

“I think refined starches (such as wheat, corn, and rice) and sugars are some of the biggest harms because it leads to a big spike in blood glucose,” Dr. Mozaffarian said. “But also, those refined starches and sugars are digested so quickly in the stomach and small intestine that you starve your gut bacteria in your large intestines.” 

Many “good-for-you ingredients,” such as fermentable fibers and bio-active compounds, are found in unprocessed, whole foods like fruits, vegetables, nuts, beans, and seeds, noted Dr. Mozaffarian. High levels of salt in ultra-processed foods are another cause for concern, as are other additives such as artificial flavorings, sweeteners, and thickeners. 
 

Opting for Whole Foods

There may be people looking to eat cleaner, unprocessed foods, but high cost and a lack of access to them could create challenges. Dr. Sarraju advises his patients to simply do their best to eat foods in their whole-ingredient form and avoid prepackaged foods as much as possible.

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

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You may have been warned that ultra-processed foods can wreak havoc on your health. But not all of them are created equal. 

A new study out of The Lancet Regional Health – Americas looked at different types of ultra-processed foods and found that some were even linked with lower risks of cardiovascular diseasecoronary heart disease, and stroke

“Avoiding all ultra-processed foods is not practical for most people,” said Dariush Mozaffarian, MD, a cardiologist, public health scientist, and director of the Food is Medicine Institute at Tufts University in Boston, Massachusetts. “So, it is helpful to start to understand, within the category of all processing, what food might be more or less harmful.”

Researchers analyzed food questionnaires from three large groups of US adults, with most people in their review being White and female. The study found that sugary and artificially sweetened drinks, along with processed meats, were linked to a greater risk of cardiovascular disease and coronary heart disease. But cereals, savory snacks, and yogurt and dairy-based desserts were linked to a lower risk of these diseases. Ultra-processed cereals and breads were also linked to a lower stroke risk. 
 

The Truth About Processed Meat

Studies show that cured, salted, or smoked meats are linked to certain cancers.

“We know that sugar-sweetened beverages are associated with metabolic derangement for things like higher glucose levels, insulin resistance, visceral obesityprediabetesdiabetes, and higher triglycerides,” said Ashish Sarraju, MD, a cardiologist with the Cleveland Clinic in Ohio. “Added sugars associated with all of those things are in turn risk factors for heart disease.” Sugar-sweetened beverages are often very high in sugar, artificial colors, and other additives, and almost “nothing beneficial” in terms of ingredients, Dr. Mozaffarian said. “They’re also consumed in very high doses, very quickly.”

Processed meats have 400% higher levels of salt, compared with unprocessed meats, said Dr. Mozaffarian. They also contain high levels of added nitrates, which are a carcinogen that could also affect the heart and blood vessels. Certain ultra-processed foods, such as bacon, are often fried at sky-high temperatures, which can trigger inflammatory compounds. 

“If you put together the inflammatory effects, the salt, and the nitrates, this is a package of food that can really build to cause harm,” said Dr. Mozaffarian. The World Health Organization has also classified processed meats (bacon, ham, salami) as a group one carcinogen, he noted.

“Processed meats are typically high in saturated fats, sodium, and preservatives, which can increase blood pressure, promote inflammation, and negatively affect cholesterol levels, leading to a higher risk of coronary heart disease, said Joseph A. Daibes, DO, an interventional cardiologist at Lenox Hill Hospital, New York City. “The study underscores the importance of limiting these types of foods to reduce cardiovascular risk.”

But considering that breakfast cereals – albeit highly processed – are a top source of whole grains for Americans, it makes sense that they are linked with lower risk of heart disease, said Dr. Mozaffarian. 

“They have fiber, bran, whole grains, and they also have sugar, and additives,” he said. “But on average, putting all those things together, this study suggested that the net effect is beneficial. That doesn’t mean they couldn’t be more beneficial if we made them less processed, but they don’t seem to have harm.”

The active probiotics and fermentation in yogurt can make it a healthy snack of choice, as there has been more and more research showing that fermented foods with probiotics are good for heart health and work against metabolic disease, or a cluster of conditions that can increase the risk of stroke, heart disease, and type 2 diabetes, Dr. Mozaffarian said.

Savory snacks, cereals, and yogurt and dairy-based desserts may also be less calorie dense than sugary beverages and processed meats, said Dr. Daibes. 

“Additionally, the type of fat used in savory snacks and the presence of probiotics in yogurt may have neutral or even positive effects on heart health, as opposed to the harmful fats and additives found in many ultra-processed foods,” he said.
 

How Ultra-Processed Foods Can Harm Your Health 

There are “clear and concerning links” between eating ultra-processed foods and getting heart disease, according to Dr. Daibes. “In real-life clinical practice, it’s a rather clear and straightforward relationship – the patients who tend to have poorer diets, with more ultra-processed and nutrient-barren foods, tend to have worse health outcomes, both cardiovascular and otherwise.”

Processing foods is centered on breaking down the natural structures of foods, as well as the loss of their natural nutrients, Dr. Mozaffarian explained. When you include the word “ultra,” this refers to putting in industrial additives.

“I think refined starches (such as wheat, corn, and rice) and sugars are some of the biggest harms because it leads to a big spike in blood glucose,” Dr. Mozaffarian said. “But also, those refined starches and sugars are digested so quickly in the stomach and small intestine that you starve your gut bacteria in your large intestines.” 

Many “good-for-you ingredients,” such as fermentable fibers and bio-active compounds, are found in unprocessed, whole foods like fruits, vegetables, nuts, beans, and seeds, noted Dr. Mozaffarian. High levels of salt in ultra-processed foods are another cause for concern, as are other additives such as artificial flavorings, sweeteners, and thickeners. 
 

Opting for Whole Foods

There may be people looking to eat cleaner, unprocessed foods, but high cost and a lack of access to them could create challenges. Dr. Sarraju advises his patients to simply do their best to eat foods in their whole-ingredient form and avoid prepackaged foods as much as possible.

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

 

You may have been warned that ultra-processed foods can wreak havoc on your health. But not all of them are created equal. 

A new study out of The Lancet Regional Health – Americas looked at different types of ultra-processed foods and found that some were even linked with lower risks of cardiovascular diseasecoronary heart disease, and stroke

“Avoiding all ultra-processed foods is not practical for most people,” said Dariush Mozaffarian, MD, a cardiologist, public health scientist, and director of the Food is Medicine Institute at Tufts University in Boston, Massachusetts. “So, it is helpful to start to understand, within the category of all processing, what food might be more or less harmful.”

Researchers analyzed food questionnaires from three large groups of US adults, with most people in their review being White and female. The study found that sugary and artificially sweetened drinks, along with processed meats, were linked to a greater risk of cardiovascular disease and coronary heart disease. But cereals, savory snacks, and yogurt and dairy-based desserts were linked to a lower risk of these diseases. Ultra-processed cereals and breads were also linked to a lower stroke risk. 
 

The Truth About Processed Meat

Studies show that cured, salted, or smoked meats are linked to certain cancers.

“We know that sugar-sweetened beverages are associated with metabolic derangement for things like higher glucose levels, insulin resistance, visceral obesityprediabetesdiabetes, and higher triglycerides,” said Ashish Sarraju, MD, a cardiologist with the Cleveland Clinic in Ohio. “Added sugars associated with all of those things are in turn risk factors for heart disease.” Sugar-sweetened beverages are often very high in sugar, artificial colors, and other additives, and almost “nothing beneficial” in terms of ingredients, Dr. Mozaffarian said. “They’re also consumed in very high doses, very quickly.”

Processed meats have 400% higher levels of salt, compared with unprocessed meats, said Dr. Mozaffarian. They also contain high levels of added nitrates, which are a carcinogen that could also affect the heart and blood vessels. Certain ultra-processed foods, such as bacon, are often fried at sky-high temperatures, which can trigger inflammatory compounds. 

“If you put together the inflammatory effects, the salt, and the nitrates, this is a package of food that can really build to cause harm,” said Dr. Mozaffarian. The World Health Organization has also classified processed meats (bacon, ham, salami) as a group one carcinogen, he noted.

“Processed meats are typically high in saturated fats, sodium, and preservatives, which can increase blood pressure, promote inflammation, and negatively affect cholesterol levels, leading to a higher risk of coronary heart disease, said Joseph A. Daibes, DO, an interventional cardiologist at Lenox Hill Hospital, New York City. “The study underscores the importance of limiting these types of foods to reduce cardiovascular risk.”

But considering that breakfast cereals – albeit highly processed – are a top source of whole grains for Americans, it makes sense that they are linked with lower risk of heart disease, said Dr. Mozaffarian. 

“They have fiber, bran, whole grains, and they also have sugar, and additives,” he said. “But on average, putting all those things together, this study suggested that the net effect is beneficial. That doesn’t mean they couldn’t be more beneficial if we made them less processed, but they don’t seem to have harm.”

The active probiotics and fermentation in yogurt can make it a healthy snack of choice, as there has been more and more research showing that fermented foods with probiotics are good for heart health and work against metabolic disease, or a cluster of conditions that can increase the risk of stroke, heart disease, and type 2 diabetes, Dr. Mozaffarian said.

Savory snacks, cereals, and yogurt and dairy-based desserts may also be less calorie dense than sugary beverages and processed meats, said Dr. Daibes. 

“Additionally, the type of fat used in savory snacks and the presence of probiotics in yogurt may have neutral or even positive effects on heart health, as opposed to the harmful fats and additives found in many ultra-processed foods,” he said.
 

How Ultra-Processed Foods Can Harm Your Health 

There are “clear and concerning links” between eating ultra-processed foods and getting heart disease, according to Dr. Daibes. “In real-life clinical practice, it’s a rather clear and straightforward relationship – the patients who tend to have poorer diets, with more ultra-processed and nutrient-barren foods, tend to have worse health outcomes, both cardiovascular and otherwise.”

Processing foods is centered on breaking down the natural structures of foods, as well as the loss of their natural nutrients, Dr. Mozaffarian explained. When you include the word “ultra,” this refers to putting in industrial additives.

“I think refined starches (such as wheat, corn, and rice) and sugars are some of the biggest harms because it leads to a big spike in blood glucose,” Dr. Mozaffarian said. “But also, those refined starches and sugars are digested so quickly in the stomach and small intestine that you starve your gut bacteria in your large intestines.” 

Many “good-for-you ingredients,” such as fermentable fibers and bio-active compounds, are found in unprocessed, whole foods like fruits, vegetables, nuts, beans, and seeds, noted Dr. Mozaffarian. High levels of salt in ultra-processed foods are another cause for concern, as are other additives such as artificial flavorings, sweeteners, and thickeners. 
 

Opting for Whole Foods

There may be people looking to eat cleaner, unprocessed foods, but high cost and a lack of access to them could create challenges. Dr. Sarraju advises his patients to simply do their best to eat foods in their whole-ingredient form and avoid prepackaged foods as much as possible.

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

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FROM THE LANCET REGIONAL HEALTH AMERICAS

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Beyond Weight Loss, Limited Bariatric Surgery Benefits in Older Adults

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Thu, 09/12/2024 - 12:53

 

TOPLINE:

For older adults with obesity, bariatric surgery does not appear to significantly reduce the risk for obesity-related cancer and cardiovascular disease (CVD), as it does in younger adults.

METHODOLOGY:

  • Bariatric surgery has been shown to decrease the risk for obesity-related cancer and CVD but is typically reserved for patients aged < 60 years. Whether the same holds for patients who undergo surgery at older ages is unclear.
  • Researchers analyzed nationwide data from three countries (Denmark, Finland, and Sweden) to compare patients with no history of cancer or CVD and age ≥ 60 years who underwent bariatric surgery against matched controls who received nonoperative treatment for obesity.
  • The main outcome was obesity-related cancer, defined as a composite outcome of breast, endometrial, esophageal, colorectal, and kidney cancer. The secondary outcome was CVD, defined as a composite of myocardial infarction, ischemic stroke, and cerebral hemorrhage.
  • Analyses were adjusted for diabetes, hypertension, peripheral vascular disease, chronic obstructive pulmonary disease, kidney disease, and frailty.

TAKEAWAY:

  • Of the 15,300 patients (66.4% women) included, 2550 underwent bariatric surgery (including gastric bypass in 1930) and 12,750 matched controls received nonoperative treatment for obesity.
  • During a median 5.8 years of follow-up, 658 (4.3%) people developed obesity-related cancer and 1436 (9.4%) developed CVD.
  • Bariatric surgery in adults aged ≥ 60 years was not associated with a reduced risk for obesity-related cancer (hazard ratio [HR], 0.81) or CVD (HR, 0.86) compared with matched nonoperative controls.
  • Bariatric surgery appeared to be associated with a decreased risk for obesity-related cancer in women (HR, 0.76).
  • There was a decreased risk for both obesity-related cancer (HR, 0.74) and CVD (HR, 0.82) in patients who underwent gastric bypass.

IN PRACTICE:

“The findings from this study suggest a limited role of bariatric surgery in older patients for the prevention of obesity-related cancer or cardiovascular disease,” the authors wrote, noting that this “may be explained by the poorer weight loss and resolution of comorbidities observed in patients who underwent surgery at an older age.”

SOURCE:

The study, with first author Peter Gerber, MD, PhD, Department of Surgery, Capio St Göran’s Hospital, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

Data on smoking status and body mass index were not available. The observational design limited the ability to draw causal inferences. The null association between bariatric surgery and outcomes may be due to limited power.

DISCLOSURES:

The study was funded by the Swedish Society of Medicine. The authors reported no conflicts of interest.

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

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TOPLINE:

For older adults with obesity, bariatric surgery does not appear to significantly reduce the risk for obesity-related cancer and cardiovascular disease (CVD), as it does in younger adults.

METHODOLOGY:

  • Bariatric surgery has been shown to decrease the risk for obesity-related cancer and CVD but is typically reserved for patients aged < 60 years. Whether the same holds for patients who undergo surgery at older ages is unclear.
  • Researchers analyzed nationwide data from three countries (Denmark, Finland, and Sweden) to compare patients with no history of cancer or CVD and age ≥ 60 years who underwent bariatric surgery against matched controls who received nonoperative treatment for obesity.
  • The main outcome was obesity-related cancer, defined as a composite outcome of breast, endometrial, esophageal, colorectal, and kidney cancer. The secondary outcome was CVD, defined as a composite of myocardial infarction, ischemic stroke, and cerebral hemorrhage.
  • Analyses were adjusted for diabetes, hypertension, peripheral vascular disease, chronic obstructive pulmonary disease, kidney disease, and frailty.

TAKEAWAY:

  • Of the 15,300 patients (66.4% women) included, 2550 underwent bariatric surgery (including gastric bypass in 1930) and 12,750 matched controls received nonoperative treatment for obesity.
  • During a median 5.8 years of follow-up, 658 (4.3%) people developed obesity-related cancer and 1436 (9.4%) developed CVD.
  • Bariatric surgery in adults aged ≥ 60 years was not associated with a reduced risk for obesity-related cancer (hazard ratio [HR], 0.81) or CVD (HR, 0.86) compared with matched nonoperative controls.
  • Bariatric surgery appeared to be associated with a decreased risk for obesity-related cancer in women (HR, 0.76).
  • There was a decreased risk for both obesity-related cancer (HR, 0.74) and CVD (HR, 0.82) in patients who underwent gastric bypass.

IN PRACTICE:

“The findings from this study suggest a limited role of bariatric surgery in older patients for the prevention of obesity-related cancer or cardiovascular disease,” the authors wrote, noting that this “may be explained by the poorer weight loss and resolution of comorbidities observed in patients who underwent surgery at an older age.”

SOURCE:

The study, with first author Peter Gerber, MD, PhD, Department of Surgery, Capio St Göran’s Hospital, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

Data on smoking status and body mass index were not available. The observational design limited the ability to draw causal inferences. The null association between bariatric surgery and outcomes may be due to limited power.

DISCLOSURES:

The study was funded by the Swedish Society of Medicine. The authors reported no conflicts of interest.

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

 

TOPLINE:

For older adults with obesity, bariatric surgery does not appear to significantly reduce the risk for obesity-related cancer and cardiovascular disease (CVD), as it does in younger adults.

METHODOLOGY:

  • Bariatric surgery has been shown to decrease the risk for obesity-related cancer and CVD but is typically reserved for patients aged < 60 years. Whether the same holds for patients who undergo surgery at older ages is unclear.
  • Researchers analyzed nationwide data from three countries (Denmark, Finland, and Sweden) to compare patients with no history of cancer or CVD and age ≥ 60 years who underwent bariatric surgery against matched controls who received nonoperative treatment for obesity.
  • The main outcome was obesity-related cancer, defined as a composite outcome of breast, endometrial, esophageal, colorectal, and kidney cancer. The secondary outcome was CVD, defined as a composite of myocardial infarction, ischemic stroke, and cerebral hemorrhage.
  • Analyses were adjusted for diabetes, hypertension, peripheral vascular disease, chronic obstructive pulmonary disease, kidney disease, and frailty.

TAKEAWAY:

  • Of the 15,300 patients (66.4% women) included, 2550 underwent bariatric surgery (including gastric bypass in 1930) and 12,750 matched controls received nonoperative treatment for obesity.
  • During a median 5.8 years of follow-up, 658 (4.3%) people developed obesity-related cancer and 1436 (9.4%) developed CVD.
  • Bariatric surgery in adults aged ≥ 60 years was not associated with a reduced risk for obesity-related cancer (hazard ratio [HR], 0.81) or CVD (HR, 0.86) compared with matched nonoperative controls.
  • Bariatric surgery appeared to be associated with a decreased risk for obesity-related cancer in women (HR, 0.76).
  • There was a decreased risk for both obesity-related cancer (HR, 0.74) and CVD (HR, 0.82) in patients who underwent gastric bypass.

IN PRACTICE:

“The findings from this study suggest a limited role of bariatric surgery in older patients for the prevention of obesity-related cancer or cardiovascular disease,” the authors wrote, noting that this “may be explained by the poorer weight loss and resolution of comorbidities observed in patients who underwent surgery at an older age.”

SOURCE:

The study, with first author Peter Gerber, MD, PhD, Department of Surgery, Capio St Göran’s Hospital, Stockholm, Sweden, was published online in JAMA Network Open.

LIMITATIONS:

Data on smoking status and body mass index were not available. The observational design limited the ability to draw causal inferences. The null association between bariatric surgery and outcomes may be due to limited power.

DISCLOSURES:

The study was funded by the Swedish Society of Medicine. The authors reported no conflicts of interest.

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

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Eating the Right Fats May Help Patients Live Longer

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Changed
Wed, 09/11/2024 - 13:58

 

A diet in which the primary source of fat is plant sources is associated with decreased mortality. Animal fat, on the other hand, is associated with an increased risk for death. These are the results of a study published in JAMA Internal Medicine that followed more than 600,000 participants over 2 decades.

Bin Zhao, PhD, of the National Clinical Research Center for Metabolic Diseases at the Key Laboratory of Diabetes Immunology in Changsha, China, and colleagues concluded from these data that consuming plant-based fats instead of animal fats could be beneficial for health and improve survival.

It may not be so simple, however. “We are one step ahead of the publication: We no longer just distinguish between animal and plant fats but mainly consider the composition,” said Stefan Lorkowski, PhD, chair of biochemistry and physiology of nutrition at the Institute of Nutritional Sciences at the University of Jena in Germany, in response to inquiries from this news organization.
 

What’s in a Fat?

Although Dr. Zhao and colleagues studied the effect of different plant and animal fat sources (eg, grains, nuts, legumes, plant oils, red and white meat, dairy, eggs, and fish), they did not consider the composition of the fatty acids that they contained. “It matters which dairy products, which plant oils, and which fish are consumed,” said Dr. Lorkowski.

The data analyzed in the Chinese study come from a prospective cohort study (NIH-AARP Diet and Health Study) conducted in the United States from 1995 to 2019. At the beginning, the 407,531 study participants (average age, 61 years) filled out dietary questionnaires once. They were then followed for up to 24 years for total and cardiovascular mortality.

During this period, 185,111 study participants died, including 58,526 from cardiovascular diseases. Participants who consumed the most plant-based fats, according to the dietary questionnaires filled out in 1995, had a lower risk for death than those who consumed the least plant-based fats. Their overall mortality risk was 9% lower, and their cardiovascular mortality risk was 14% lower. This finding was especially noticeable when it came to plant fats from grains or plant oils.
 

Animal Fat and Mortality

In contrast, a higher intake of animal fat was associated with both a higher overall mortality risk (16%) and a higher cardiovascular mortality risk (14%). This was especially true for fat from dairy products and eggs.

A trend towards a reduced overall and cardiovascular mortality risk was observed for fat from fish. “The fact that only a trend towards fish consumption was observed may be due to the study having many more meat eaters than fish eaters,” said Dr. Lorkowski.

Another imbalance limits the significance of the study, he added. The two groups, those who primarily consumed plant fats and those who primarily consumed animal fats, were already distinct at the beginning of the study. Those who consumed more plant fats were more likely to have diabetes, a higher body mass index (BMI), higher energy intake, and higher alcohol consumption but consumed more fiber, fruits, and vegetables and were more physically active. “They may have been trying to live healthier because they were sicker,” said Dr. Lorkowski.
 

Potential Confounding

Dr. Zhao and his team adjusted the results for various potential confounding factors, including age, gender, BMI, ethnicity, smoking, physical activity, education, marital status, diabetes, health status, vitamin intake, protein, carbohydrates, fiber, trans fats, cholesterol intake, and alcohol consumption. However, according to Dr. Lorkowski, “statistical adjustment is always incomplete, and confounding cannot be completely ruled out.”

Nevertheless, these results provide relevant insights for dietary recommendations that could help improve health and related outcomes, according to the authors. “Replacement of 5% energy from animal fat with 5% energy from plant fat, particularly fat from grains or vegetable oils, was associated with a lower risk for mortality: 4%-24% reduction in overall mortality and 5%-30% reduction in cardiovascular disease mortality.”
 

Fat Composition Matters

Animal fat, however, should not simply be replaced with plant fat, said Dr. Lorkowski. “Cold-water fish, which provides important long-chain omega-3 fatty acids, is also considered animal fat. And palm and coconut fat, while plant-based, contain unhealthy long-chain saturated fats. And the type of plant oils also makes a difference, whether one uses corn germ or sunflower oil rich in omega-6 fatty acids or flaxseed or rapeseed oil rich in omega-3 fatty acids.

“A diet rich in unsaturated fats, with sufficient and balanced intake of omega-3 and omega-6 fatty acids, that is also abundant in fiber-rich carbohydrate sources and plant-based protein, is always better than too much fat from animal sources.”

This story was translated from the Medscape German edition 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.

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A diet in which the primary source of fat is plant sources is associated with decreased mortality. Animal fat, on the other hand, is associated with an increased risk for death. These are the results of a study published in JAMA Internal Medicine that followed more than 600,000 participants over 2 decades.

Bin Zhao, PhD, of the National Clinical Research Center for Metabolic Diseases at the Key Laboratory of Diabetes Immunology in Changsha, China, and colleagues concluded from these data that consuming plant-based fats instead of animal fats could be beneficial for health and improve survival.

It may not be so simple, however. “We are one step ahead of the publication: We no longer just distinguish between animal and plant fats but mainly consider the composition,” said Stefan Lorkowski, PhD, chair of biochemistry and physiology of nutrition at the Institute of Nutritional Sciences at the University of Jena in Germany, in response to inquiries from this news organization.
 

What’s in a Fat?

Although Dr. Zhao and colleagues studied the effect of different plant and animal fat sources (eg, grains, nuts, legumes, plant oils, red and white meat, dairy, eggs, and fish), they did not consider the composition of the fatty acids that they contained. “It matters which dairy products, which plant oils, and which fish are consumed,” said Dr. Lorkowski.

The data analyzed in the Chinese study come from a prospective cohort study (NIH-AARP Diet and Health Study) conducted in the United States from 1995 to 2019. At the beginning, the 407,531 study participants (average age, 61 years) filled out dietary questionnaires once. They were then followed for up to 24 years for total and cardiovascular mortality.

During this period, 185,111 study participants died, including 58,526 from cardiovascular diseases. Participants who consumed the most plant-based fats, according to the dietary questionnaires filled out in 1995, had a lower risk for death than those who consumed the least plant-based fats. Their overall mortality risk was 9% lower, and their cardiovascular mortality risk was 14% lower. This finding was especially noticeable when it came to plant fats from grains or plant oils.
 

Animal Fat and Mortality

In contrast, a higher intake of animal fat was associated with both a higher overall mortality risk (16%) and a higher cardiovascular mortality risk (14%). This was especially true for fat from dairy products and eggs.

A trend towards a reduced overall and cardiovascular mortality risk was observed for fat from fish. “The fact that only a trend towards fish consumption was observed may be due to the study having many more meat eaters than fish eaters,” said Dr. Lorkowski.

Another imbalance limits the significance of the study, he added. The two groups, those who primarily consumed plant fats and those who primarily consumed animal fats, were already distinct at the beginning of the study. Those who consumed more plant fats were more likely to have diabetes, a higher body mass index (BMI), higher energy intake, and higher alcohol consumption but consumed more fiber, fruits, and vegetables and were more physically active. “They may have been trying to live healthier because they were sicker,” said Dr. Lorkowski.
 

Potential Confounding

Dr. Zhao and his team adjusted the results for various potential confounding factors, including age, gender, BMI, ethnicity, smoking, physical activity, education, marital status, diabetes, health status, vitamin intake, protein, carbohydrates, fiber, trans fats, cholesterol intake, and alcohol consumption. However, according to Dr. Lorkowski, “statistical adjustment is always incomplete, and confounding cannot be completely ruled out.”

Nevertheless, these results provide relevant insights for dietary recommendations that could help improve health and related outcomes, according to the authors. “Replacement of 5% energy from animal fat with 5% energy from plant fat, particularly fat from grains or vegetable oils, was associated with a lower risk for mortality: 4%-24% reduction in overall mortality and 5%-30% reduction in cardiovascular disease mortality.”
 

Fat Composition Matters

Animal fat, however, should not simply be replaced with plant fat, said Dr. Lorkowski. “Cold-water fish, which provides important long-chain omega-3 fatty acids, is also considered animal fat. And palm and coconut fat, while plant-based, contain unhealthy long-chain saturated fats. And the type of plant oils also makes a difference, whether one uses corn germ or sunflower oil rich in omega-6 fatty acids or flaxseed or rapeseed oil rich in omega-3 fatty acids.

“A diet rich in unsaturated fats, with sufficient and balanced intake of omega-3 and omega-6 fatty acids, that is also abundant in fiber-rich carbohydrate sources and plant-based protein, is always better than too much fat from animal sources.”

This story was translated from the Medscape German edition 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.

 

A diet in which the primary source of fat is plant sources is associated with decreased mortality. Animal fat, on the other hand, is associated with an increased risk for death. These are the results of a study published in JAMA Internal Medicine that followed more than 600,000 participants over 2 decades.

Bin Zhao, PhD, of the National Clinical Research Center for Metabolic Diseases at the Key Laboratory of Diabetes Immunology in Changsha, China, and colleagues concluded from these data that consuming plant-based fats instead of animal fats could be beneficial for health and improve survival.

It may not be so simple, however. “We are one step ahead of the publication: We no longer just distinguish between animal and plant fats but mainly consider the composition,” said Stefan Lorkowski, PhD, chair of biochemistry and physiology of nutrition at the Institute of Nutritional Sciences at the University of Jena in Germany, in response to inquiries from this news organization.
 

What’s in a Fat?

Although Dr. Zhao and colleagues studied the effect of different plant and animal fat sources (eg, grains, nuts, legumes, plant oils, red and white meat, dairy, eggs, and fish), they did not consider the composition of the fatty acids that they contained. “It matters which dairy products, which plant oils, and which fish are consumed,” said Dr. Lorkowski.

The data analyzed in the Chinese study come from a prospective cohort study (NIH-AARP Diet and Health Study) conducted in the United States from 1995 to 2019. At the beginning, the 407,531 study participants (average age, 61 years) filled out dietary questionnaires once. They were then followed for up to 24 years for total and cardiovascular mortality.

During this period, 185,111 study participants died, including 58,526 from cardiovascular diseases. Participants who consumed the most plant-based fats, according to the dietary questionnaires filled out in 1995, had a lower risk for death than those who consumed the least plant-based fats. Their overall mortality risk was 9% lower, and their cardiovascular mortality risk was 14% lower. This finding was especially noticeable when it came to plant fats from grains or plant oils.
 

Animal Fat and Mortality

In contrast, a higher intake of animal fat was associated with both a higher overall mortality risk (16%) and a higher cardiovascular mortality risk (14%). This was especially true for fat from dairy products and eggs.

A trend towards a reduced overall and cardiovascular mortality risk was observed for fat from fish. “The fact that only a trend towards fish consumption was observed may be due to the study having many more meat eaters than fish eaters,” said Dr. Lorkowski.

Another imbalance limits the significance of the study, he added. The two groups, those who primarily consumed plant fats and those who primarily consumed animal fats, were already distinct at the beginning of the study. Those who consumed more plant fats were more likely to have diabetes, a higher body mass index (BMI), higher energy intake, and higher alcohol consumption but consumed more fiber, fruits, and vegetables and were more physically active. “They may have been trying to live healthier because they were sicker,” said Dr. Lorkowski.
 

Potential Confounding

Dr. Zhao and his team adjusted the results for various potential confounding factors, including age, gender, BMI, ethnicity, smoking, physical activity, education, marital status, diabetes, health status, vitamin intake, protein, carbohydrates, fiber, trans fats, cholesterol intake, and alcohol consumption. However, according to Dr. Lorkowski, “statistical adjustment is always incomplete, and confounding cannot be completely ruled out.”

Nevertheless, these results provide relevant insights for dietary recommendations that could help improve health and related outcomes, according to the authors. “Replacement of 5% energy from animal fat with 5% energy from plant fat, particularly fat from grains or vegetable oils, was associated with a lower risk for mortality: 4%-24% reduction in overall mortality and 5%-30% reduction in cardiovascular disease mortality.”
 

Fat Composition Matters

Animal fat, however, should not simply be replaced with plant fat, said Dr. Lorkowski. “Cold-water fish, which provides important long-chain omega-3 fatty acids, is also considered animal fat. And palm and coconut fat, while plant-based, contain unhealthy long-chain saturated fats. And the type of plant oils also makes a difference, whether one uses corn germ or sunflower oil rich in omega-6 fatty acids or flaxseed or rapeseed oil rich in omega-3 fatty acids.

“A diet rich in unsaturated fats, with sufficient and balanced intake of omega-3 and omega-6 fatty acids, that is also abundant in fiber-rich carbohydrate sources and plant-based protein, is always better than too much fat from animal sources.”

This story was translated from the Medscape German edition 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.

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A Simple Blood Test May Predict Cancer Risk in T2D

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Changed
Wed, 09/11/2024 - 13:30

 

TOPLINE:

— Elevated interleukin (IL) 6 levels are associated with an increased risk for obesity-related cancers in patients newly diagnosed with type 2 diabetes (T2D), potentially enabling the identification of higher-risk individuals through a simple blood test.

METHODOLOGY:

  • T2D is associated with an increased risk for obesity-related cancers, including breast, renal, uterine, thyroid, ovarian, and gastrointestinal cancers, as well as multiple myeloma, possibly because of chronic low-grade inflammation.
  • Researchers explored whether the markers of inflammation IL-6, tumor necrosis factor alpha (TNF-alpha), and high-sensitivity C-reactive protein (hsCRP) can serve as predictive biomarkers for obesity-related cancers in patients recently diagnosed with T2D.
  • They identified patients with recent-onset T2D and no prior history of cancer participating in the ongoing Danish Centre for Strategic Research in Type 2 Diabetes cohort study.
  • At study initiation, plasma levels of IL-6 and TNF-alpha were measured using Meso Scale Discovery assays, and serum levels of hsCRP were measured using immunofluorometric assays.

TAKEAWAY:

  • Among 6,466 eligible patients (40.5% women; median age, 60.9 years), 327 developed obesity-related cancers over a median follow-up of 8.8 years.
  • Each SD increase in log-transformed IL-6 levels increased the risk for obesity-related cancers by 19%.
  • The researchers did not find a strong association between TNF-alpha or hsCRP and obesity-related cancers.
  • The addition of baseline IL-6 levels to other well-known risk factors for obesity-related cancers improved the performance of a cancer prediction model from 0.685 to 0.693, translating to a small but important increase in the ability to predict whether an individual would develop one of these cancers.

IN PRACTICE:

“In future, a simple blood test could identify those at higher risk of the cancers,” said the study’s lead author in an accompanying press release.

SOURCE:

The study was led by Mathilde D. Bennetsen, Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark, and published online on August 27 as an early release from the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

LIMITATIONS:

No limitations were discussed in this abstract. However, the reliance on registry data may have introduced potential biases related to data accuracy and completeness.

DISCLOSURES:

The Danish Centre for Strategic Research in Type 2 Diabetes was supported by grants from the Danish Agency for Science and the Novo Nordisk Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

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TOPLINE:

— Elevated interleukin (IL) 6 levels are associated with an increased risk for obesity-related cancers in patients newly diagnosed with type 2 diabetes (T2D), potentially enabling the identification of higher-risk individuals through a simple blood test.

METHODOLOGY:

  • T2D is associated with an increased risk for obesity-related cancers, including breast, renal, uterine, thyroid, ovarian, and gastrointestinal cancers, as well as multiple myeloma, possibly because of chronic low-grade inflammation.
  • Researchers explored whether the markers of inflammation IL-6, tumor necrosis factor alpha (TNF-alpha), and high-sensitivity C-reactive protein (hsCRP) can serve as predictive biomarkers for obesity-related cancers in patients recently diagnosed with T2D.
  • They identified patients with recent-onset T2D and no prior history of cancer participating in the ongoing Danish Centre for Strategic Research in Type 2 Diabetes cohort study.
  • At study initiation, plasma levels of IL-6 and TNF-alpha were measured using Meso Scale Discovery assays, and serum levels of hsCRP were measured using immunofluorometric assays.

TAKEAWAY:

  • Among 6,466 eligible patients (40.5% women; median age, 60.9 years), 327 developed obesity-related cancers over a median follow-up of 8.8 years.
  • Each SD increase in log-transformed IL-6 levels increased the risk for obesity-related cancers by 19%.
  • The researchers did not find a strong association between TNF-alpha or hsCRP and obesity-related cancers.
  • The addition of baseline IL-6 levels to other well-known risk factors for obesity-related cancers improved the performance of a cancer prediction model from 0.685 to 0.693, translating to a small but important increase in the ability to predict whether an individual would develop one of these cancers.

IN PRACTICE:

“In future, a simple blood test could identify those at higher risk of the cancers,” said the study’s lead author in an accompanying press release.

SOURCE:

The study was led by Mathilde D. Bennetsen, Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark, and published online on August 27 as an early release from the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

LIMITATIONS:

No limitations were discussed in this abstract. However, the reliance on registry data may have introduced potential biases related to data accuracy and completeness.

DISCLOSURES:

The Danish Centre for Strategic Research in Type 2 Diabetes was supported by grants from the Danish Agency for Science and the Novo Nordisk Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

 

TOPLINE:

— Elevated interleukin (IL) 6 levels are associated with an increased risk for obesity-related cancers in patients newly diagnosed with type 2 diabetes (T2D), potentially enabling the identification of higher-risk individuals through a simple blood test.

METHODOLOGY:

  • T2D is associated with an increased risk for obesity-related cancers, including breast, renal, uterine, thyroid, ovarian, and gastrointestinal cancers, as well as multiple myeloma, possibly because of chronic low-grade inflammation.
  • Researchers explored whether the markers of inflammation IL-6, tumor necrosis factor alpha (TNF-alpha), and high-sensitivity C-reactive protein (hsCRP) can serve as predictive biomarkers for obesity-related cancers in patients recently diagnosed with T2D.
  • They identified patients with recent-onset T2D and no prior history of cancer participating in the ongoing Danish Centre for Strategic Research in Type 2 Diabetes cohort study.
  • At study initiation, plasma levels of IL-6 and TNF-alpha were measured using Meso Scale Discovery assays, and serum levels of hsCRP were measured using immunofluorometric assays.

TAKEAWAY:

  • Among 6,466 eligible patients (40.5% women; median age, 60.9 years), 327 developed obesity-related cancers over a median follow-up of 8.8 years.
  • Each SD increase in log-transformed IL-6 levels increased the risk for obesity-related cancers by 19%.
  • The researchers did not find a strong association between TNF-alpha or hsCRP and obesity-related cancers.
  • The addition of baseline IL-6 levels to other well-known risk factors for obesity-related cancers improved the performance of a cancer prediction model from 0.685 to 0.693, translating to a small but important increase in the ability to predict whether an individual would develop one of these cancers.

IN PRACTICE:

“In future, a simple blood test could identify those at higher risk of the cancers,” said the study’s lead author in an accompanying press release.

SOURCE:

The study was led by Mathilde D. Bennetsen, Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark, and published online on August 27 as an early release from the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

LIMITATIONS:

No limitations were discussed in this abstract. However, the reliance on registry data may have introduced potential biases related to data accuracy and completeness.

DISCLOSURES:

The Danish Centre for Strategic Research in Type 2 Diabetes was supported by grants from the Danish Agency for Science and the Novo Nordisk Foundation. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

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GLP-1 RA Therapy for Alcohol Use Disorder?

Article Type
Changed
Tue, 09/17/2024 - 19:46

 

This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

 

 

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

 

 

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

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

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This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

 

 

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

 

 

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

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

 

This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

 

 

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

 

 

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

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

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MRI-Derived Abdominal Adipose Tissue Linked to Chronic Musculoskeletal Pain

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Changed
Wed, 09/11/2024 - 12:28

 

TOPLINE:

MRI-derived abdominal adipose tissue is linked to chronic musculoskeletal pain in multiple sites. The association is stronger in women, suggesting sex differences in fat distribution and hormones.

METHODOLOGY:

  • Researchers used data from the UK Biobank, a large population-based cohort study, to investigate the associations between MRI-measured abdominal adipose tissue and chronic musculoskeletal pain.
  • A total of 32,409 participants (50.8% women; mean age, 55.0 ± 7.4 years) were included in the analysis, with abdominal MRI scans performed at two imaging visits.
  • Pain in the neck/shoulder, back, hip, knee, or “all over the body” was assessed, and participants were categorized based on the number of chronic pain sites.
  • Mixed-effects ordinal, multinomial, and logistic regression models were used to analyze the associations between visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and their ratio with chronic pain.

TAKEAWAY:

  • According to the authors, there was a dose-response association between VAT, SAT, and their ratio with the number of chronic pain sites in both women and men.
  • Higher levels of abdominal adipose tissue were associated with greater odds of reporting chronic pain in both sexes, with effect estimates being relatively larger in women.
  • The researchers found that the VAT/SAT ratio was associated with the number of chronic pain sites and chronic pain in both sexes, reflecting differences in fat distribution and hormones.
  • The study suggested that excessive abdominal adipose tissue may be involved in the pathogenesis of multisite and widespread chronic musculoskeletal pain.

IN PRACTICE:

“Abdominal adipose tissue was associated with chronic musculoskeletal pain, suggesting that excessive and ectopic fat depositions may be involved in the pathogenesis of multisite and widespread chronic musculoskeletal pain,” wrote the authors of the study.

SOURCE:

This study was led by Zemene Demelash Kifle, University of Tasmania Menzies Institute for Medical Research in Hobart, Australia. It was published online in Regional Anesthesia & Pain Medicine.

LIMITATIONS: 

The study’s limitations included the use of a pain questionnaire that did not assess pain severity, which limited the ability to examine the relationship between fat measures and pain severity. Additionally, MRI was conducted on only two occasions, which may have not captured patterns and fluctuations in chronic pain sites. The relatively small size of the imaging sample, compared with the original baseline sample limited the generalizability of the findings. The predominant White ethnicity of participants also limited the generalizability to diverse populations.

DISCLOSURES:

The study was supported by grants from the Australian National Health and Medical Research Council (NHMRC). Mr. Kifle disclosed receiving grants from the Australian NHMRC. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Publications
Topics
Sections

 

TOPLINE:

MRI-derived abdominal adipose tissue is linked to chronic musculoskeletal pain in multiple sites. The association is stronger in women, suggesting sex differences in fat distribution and hormones.

METHODOLOGY:

  • Researchers used data from the UK Biobank, a large population-based cohort study, to investigate the associations between MRI-measured abdominal adipose tissue and chronic musculoskeletal pain.
  • A total of 32,409 participants (50.8% women; mean age, 55.0 ± 7.4 years) were included in the analysis, with abdominal MRI scans performed at two imaging visits.
  • Pain in the neck/shoulder, back, hip, knee, or “all over the body” was assessed, and participants were categorized based on the number of chronic pain sites.
  • Mixed-effects ordinal, multinomial, and logistic regression models were used to analyze the associations between visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and their ratio with chronic pain.

TAKEAWAY:

  • According to the authors, there was a dose-response association between VAT, SAT, and their ratio with the number of chronic pain sites in both women and men.
  • Higher levels of abdominal adipose tissue were associated with greater odds of reporting chronic pain in both sexes, with effect estimates being relatively larger in women.
  • The researchers found that the VAT/SAT ratio was associated with the number of chronic pain sites and chronic pain in both sexes, reflecting differences in fat distribution and hormones.
  • The study suggested that excessive abdominal adipose tissue may be involved in the pathogenesis of multisite and widespread chronic musculoskeletal pain.

IN PRACTICE:

“Abdominal adipose tissue was associated with chronic musculoskeletal pain, suggesting that excessive and ectopic fat depositions may be involved in the pathogenesis of multisite and widespread chronic musculoskeletal pain,” wrote the authors of the study.

SOURCE:

This study was led by Zemene Demelash Kifle, University of Tasmania Menzies Institute for Medical Research in Hobart, Australia. It was published online in Regional Anesthesia & Pain Medicine.

LIMITATIONS: 

The study’s limitations included the use of a pain questionnaire that did not assess pain severity, which limited the ability to examine the relationship between fat measures and pain severity. Additionally, MRI was conducted on only two occasions, which may have not captured patterns and fluctuations in chronic pain sites. The relatively small size of the imaging sample, compared with the original baseline sample limited the generalizability of the findings. The predominant White ethnicity of participants also limited the generalizability to diverse populations.

DISCLOSURES:

The study was supported by grants from the Australian National Health and Medical Research Council (NHMRC). Mr. Kifle disclosed receiving grants from the Australian NHMRC. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

 

TOPLINE:

MRI-derived abdominal adipose tissue is linked to chronic musculoskeletal pain in multiple sites. The association is stronger in women, suggesting sex differences in fat distribution and hormones.

METHODOLOGY:

  • Researchers used data from the UK Biobank, a large population-based cohort study, to investigate the associations between MRI-measured abdominal adipose tissue and chronic musculoskeletal pain.
  • A total of 32,409 participants (50.8% women; mean age, 55.0 ± 7.4 years) were included in the analysis, with abdominal MRI scans performed at two imaging visits.
  • Pain in the neck/shoulder, back, hip, knee, or “all over the body” was assessed, and participants were categorized based on the number of chronic pain sites.
  • Mixed-effects ordinal, multinomial, and logistic regression models were used to analyze the associations between visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and their ratio with chronic pain.

TAKEAWAY:

  • According to the authors, there was a dose-response association between VAT, SAT, and their ratio with the number of chronic pain sites in both women and men.
  • Higher levels of abdominal adipose tissue were associated with greater odds of reporting chronic pain in both sexes, with effect estimates being relatively larger in women.
  • The researchers found that the VAT/SAT ratio was associated with the number of chronic pain sites and chronic pain in both sexes, reflecting differences in fat distribution and hormones.
  • The study suggested that excessive abdominal adipose tissue may be involved in the pathogenesis of multisite and widespread chronic musculoskeletal pain.

IN PRACTICE:

“Abdominal adipose tissue was associated with chronic musculoskeletal pain, suggesting that excessive and ectopic fat depositions may be involved in the pathogenesis of multisite and widespread chronic musculoskeletal pain,” wrote the authors of the study.

SOURCE:

This study was led by Zemene Demelash Kifle, University of Tasmania Menzies Institute for Medical Research in Hobart, Australia. It was published online in Regional Anesthesia & Pain Medicine.

LIMITATIONS: 

The study’s limitations included the use of a pain questionnaire that did not assess pain severity, which limited the ability to examine the relationship between fat measures and pain severity. Additionally, MRI was conducted on only two occasions, which may have not captured patterns and fluctuations in chronic pain sites. The relatively small size of the imaging sample, compared with the original baseline sample limited the generalizability of the findings. The predominant White ethnicity of participants also limited the generalizability to diverse populations.

DISCLOSURES:

The study was supported by grants from the Australian National Health and Medical Research Council (NHMRC). Mr. Kifle disclosed receiving grants from the Australian NHMRC. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

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Night Owls May Be at Greater Risk for T2D, Beyond Lifestyle

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Changed
Wed, 09/11/2024 - 10:20

 

Night owls — individuals with late chronotypes — may be at an increased risk for type 2 diabetes (T2D), beyond the risks conferred by an unhealthy lifestyle, research presented at the annual meeting of the European Association for the Study of Diabetes suggested.

In the study, night owls were almost 50% more likely to develop T2D than those who went to sleep earlier.

“The magnitude of this risk was more than I expected, [although] residual confounding may have occurred,” said Jeroen van der Velde, PhD, Leiden University Medical Center in the Netherlands, who presented the study.

“Late chronotype has previously been associated with unhealthy lifestyle and overweight or obesity and, subsequently, cardiometabolic diseases,” he said in an interview. However, although the current study found that individuals with late chronotypes did indeed have larger waists and more visceral fat, “we (and others) believe that lifestyle cannot fully explain the relation between late chronotype and metabolic disorders.”

“In addition,” he noted, “previous studies that observed that late chronotype is associated with overweight or obesity mainly focused on body mass index [BMI]. However, BMI alone does not provide accurate information regarding fat distribution in the body. People with similar BMI may have different underlying fat distribution, and this may be more relevant than BMI for metabolic risk.”

The researchers examined associations between chronotype and BMI, waist circumference, visceral fat, liver fat, and the risk for T2D in a middle-aged population from the Netherlands Epidemiology of Obesity study. Among the 5026 participants, the mean age was 56 years, 54% were women, and mean BMI was 30.

Using data from the study, the study investigators calculated the midpoint of sleep (MPS) and divided participants into three chronotypes: Early MPS < 2:30 PM (20% of participants); intermediate MPS 2:30–4:00 PM (reference category; 60% of participants); and late MPS ≥ 4:00 PM (20% of participants). BMI and waist circumference were measured in all participants, and visceral fat and liver fat were measured in 1576 participants using MRI scans and MR spectroscopy, respectively.

During a median follow-up of 6.6 years, 225 participants were diagnosed with T2D. After adjustment for age, sex, education, physical activity, smoking, alcohol intake, diet quality, sleep quality and duration, and total body fat, participants with a late chronotype had a 46% increased risk for T2D.

Further, those with a late chronotype had 0.7 higher BMI, 1.9-cm larger waist circumference, 7 cm2 more visceral fat, and 14% more liver fat.
 

Body Clock Out of Sync?

“Late chronotype was associated with increased ectopic body fat and with an increased risk of T2D independent of lifestyle factors and is an emerging risk factor for metabolic diseases,” the researchers concluded.

“A likely explanation is that the circadian rhythm or body clock in late chronotypes is out of sync with the work and social schedules followed by society,” Dr. van der Velde suggested. “This can lead to circadian misalignment, which we know can lead to metabolic disturbances and ultimately type 2 diabetes.”

Might trying to adjust chronotype earlier in life have an effect on risk?

“Chronotype, as measured via midpoint of sleep, does change a lot in the first 30 years or so in life,” he said. “After that it seems to stabilize. I suppose that if you adapt an intermediate or early chronotype around the age of 30 years, this will help to maintain an earlier chronotype later in life, although we cannot answer this from our study.”

Nevertheless, with respect to T2D risk, “chronotype is likely only part of the puzzle,” he noted.

“People with late chronotypes typically eat late in the evening, and this has also been associated with adverse metabolic effects. At this stage, we do not know if a person changes his/her chronotype that this will also lead to metabolic improvements. More research is needed before we can make recommendations regarding chronotype and timing of other lifestyle behaviors.”

Commenting on the study, Gianluca Iacobellis, MD, PhD, director of the University of Miami Hospital Diabetes Service, Coral Gables, Florida, said: “Interesting data. Altering the physiological circadian rhythm can affect the complex hormonal system — including cortisol, ghrelin, leptin, and serotonin — that regulates insulin sensitivity, glucose, and blood pressure control. The night owl may become more insulin resistant and therefore at higher risk of developing diabetes.”

Like Dr. van der Velde, he noted that “late sleep may be associated with night binging that can cause weight gain and ultimately obesity, further increasing the risk of diabetes.”

Dr. Iacobellis’s group recently showed that vital exhaustion, which is characterized by fatigue and loss of vigor, is associated with a higher cardiovascular risk for and markers of visceral adiposity.

“Abnormal circadian rhythms can be easily associated with vital exhaustion,” he said. Therefore, night owls with more visceral than peripheral fat accumulation might also be at higher cardiometabolic risk through that mechanism.

“However environmental factors and family history can play an important role too,” he added.

Regardless of the mechanisms involved, “preventive actions should be taken to educate teenagers and individuals at higher risk to have healthy sleep habits,” Dr. Iacobellis concluded.

No information regarding funding was provided; Dr. van der Velde and Dr. Iacobellis reported no conflicts of interest.

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

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Night owls — individuals with late chronotypes — may be at an increased risk for type 2 diabetes (T2D), beyond the risks conferred by an unhealthy lifestyle, research presented at the annual meeting of the European Association for the Study of Diabetes suggested.

In the study, night owls were almost 50% more likely to develop T2D than those who went to sleep earlier.

“The magnitude of this risk was more than I expected, [although] residual confounding may have occurred,” said Jeroen van der Velde, PhD, Leiden University Medical Center in the Netherlands, who presented the study.

“Late chronotype has previously been associated with unhealthy lifestyle and overweight or obesity and, subsequently, cardiometabolic diseases,” he said in an interview. However, although the current study found that individuals with late chronotypes did indeed have larger waists and more visceral fat, “we (and others) believe that lifestyle cannot fully explain the relation between late chronotype and metabolic disorders.”

“In addition,” he noted, “previous studies that observed that late chronotype is associated with overweight or obesity mainly focused on body mass index [BMI]. However, BMI alone does not provide accurate information regarding fat distribution in the body. People with similar BMI may have different underlying fat distribution, and this may be more relevant than BMI for metabolic risk.”

The researchers examined associations between chronotype and BMI, waist circumference, visceral fat, liver fat, and the risk for T2D in a middle-aged population from the Netherlands Epidemiology of Obesity study. Among the 5026 participants, the mean age was 56 years, 54% were women, and mean BMI was 30.

Using data from the study, the study investigators calculated the midpoint of sleep (MPS) and divided participants into three chronotypes: Early MPS < 2:30 PM (20% of participants); intermediate MPS 2:30–4:00 PM (reference category; 60% of participants); and late MPS ≥ 4:00 PM (20% of participants). BMI and waist circumference were measured in all participants, and visceral fat and liver fat were measured in 1576 participants using MRI scans and MR spectroscopy, respectively.

During a median follow-up of 6.6 years, 225 participants were diagnosed with T2D. After adjustment for age, sex, education, physical activity, smoking, alcohol intake, diet quality, sleep quality and duration, and total body fat, participants with a late chronotype had a 46% increased risk for T2D.

Further, those with a late chronotype had 0.7 higher BMI, 1.9-cm larger waist circumference, 7 cm2 more visceral fat, and 14% more liver fat.
 

Body Clock Out of Sync?

“Late chronotype was associated with increased ectopic body fat and with an increased risk of T2D independent of lifestyle factors and is an emerging risk factor for metabolic diseases,” the researchers concluded.

“A likely explanation is that the circadian rhythm or body clock in late chronotypes is out of sync with the work and social schedules followed by society,” Dr. van der Velde suggested. “This can lead to circadian misalignment, which we know can lead to metabolic disturbances and ultimately type 2 diabetes.”

Might trying to adjust chronotype earlier in life have an effect on risk?

“Chronotype, as measured via midpoint of sleep, does change a lot in the first 30 years or so in life,” he said. “After that it seems to stabilize. I suppose that if you adapt an intermediate or early chronotype around the age of 30 years, this will help to maintain an earlier chronotype later in life, although we cannot answer this from our study.”

Nevertheless, with respect to T2D risk, “chronotype is likely only part of the puzzle,” he noted.

“People with late chronotypes typically eat late in the evening, and this has also been associated with adverse metabolic effects. At this stage, we do not know if a person changes his/her chronotype that this will also lead to metabolic improvements. More research is needed before we can make recommendations regarding chronotype and timing of other lifestyle behaviors.”

Commenting on the study, Gianluca Iacobellis, MD, PhD, director of the University of Miami Hospital Diabetes Service, Coral Gables, Florida, said: “Interesting data. Altering the physiological circadian rhythm can affect the complex hormonal system — including cortisol, ghrelin, leptin, and serotonin — that regulates insulin sensitivity, glucose, and blood pressure control. The night owl may become more insulin resistant and therefore at higher risk of developing diabetes.”

Like Dr. van der Velde, he noted that “late sleep may be associated with night binging that can cause weight gain and ultimately obesity, further increasing the risk of diabetes.”

Dr. Iacobellis’s group recently showed that vital exhaustion, which is characterized by fatigue and loss of vigor, is associated with a higher cardiovascular risk for and markers of visceral adiposity.

“Abnormal circadian rhythms can be easily associated with vital exhaustion,” he said. Therefore, night owls with more visceral than peripheral fat accumulation might also be at higher cardiometabolic risk through that mechanism.

“However environmental factors and family history can play an important role too,” he added.

Regardless of the mechanisms involved, “preventive actions should be taken to educate teenagers and individuals at higher risk to have healthy sleep habits,” Dr. Iacobellis concluded.

No information regarding funding was provided; Dr. van der Velde and Dr. Iacobellis reported no conflicts of interest.

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

 

Night owls — individuals with late chronotypes — may be at an increased risk for type 2 diabetes (T2D), beyond the risks conferred by an unhealthy lifestyle, research presented at the annual meeting of the European Association for the Study of Diabetes suggested.

In the study, night owls were almost 50% more likely to develop T2D than those who went to sleep earlier.

“The magnitude of this risk was more than I expected, [although] residual confounding may have occurred,” said Jeroen van der Velde, PhD, Leiden University Medical Center in the Netherlands, who presented the study.

“Late chronotype has previously been associated with unhealthy lifestyle and overweight or obesity and, subsequently, cardiometabolic diseases,” he said in an interview. However, although the current study found that individuals with late chronotypes did indeed have larger waists and more visceral fat, “we (and others) believe that lifestyle cannot fully explain the relation between late chronotype and metabolic disorders.”

“In addition,” he noted, “previous studies that observed that late chronotype is associated with overweight or obesity mainly focused on body mass index [BMI]. However, BMI alone does not provide accurate information regarding fat distribution in the body. People with similar BMI may have different underlying fat distribution, and this may be more relevant than BMI for metabolic risk.”

The researchers examined associations between chronotype and BMI, waist circumference, visceral fat, liver fat, and the risk for T2D in a middle-aged population from the Netherlands Epidemiology of Obesity study. Among the 5026 participants, the mean age was 56 years, 54% were women, and mean BMI was 30.

Using data from the study, the study investigators calculated the midpoint of sleep (MPS) and divided participants into three chronotypes: Early MPS < 2:30 PM (20% of participants); intermediate MPS 2:30–4:00 PM (reference category; 60% of participants); and late MPS ≥ 4:00 PM (20% of participants). BMI and waist circumference were measured in all participants, and visceral fat and liver fat were measured in 1576 participants using MRI scans and MR spectroscopy, respectively.

During a median follow-up of 6.6 years, 225 participants were diagnosed with T2D. After adjustment for age, sex, education, physical activity, smoking, alcohol intake, diet quality, sleep quality and duration, and total body fat, participants with a late chronotype had a 46% increased risk for T2D.

Further, those with a late chronotype had 0.7 higher BMI, 1.9-cm larger waist circumference, 7 cm2 more visceral fat, and 14% more liver fat.
 

Body Clock Out of Sync?

“Late chronotype was associated with increased ectopic body fat and with an increased risk of T2D independent of lifestyle factors and is an emerging risk factor for metabolic diseases,” the researchers concluded.

“A likely explanation is that the circadian rhythm or body clock in late chronotypes is out of sync with the work and social schedules followed by society,” Dr. van der Velde suggested. “This can lead to circadian misalignment, which we know can lead to metabolic disturbances and ultimately type 2 diabetes.”

Might trying to adjust chronotype earlier in life have an effect on risk?

“Chronotype, as measured via midpoint of sleep, does change a lot in the first 30 years or so in life,” he said. “After that it seems to stabilize. I suppose that if you adapt an intermediate or early chronotype around the age of 30 years, this will help to maintain an earlier chronotype later in life, although we cannot answer this from our study.”

Nevertheless, with respect to T2D risk, “chronotype is likely only part of the puzzle,” he noted.

“People with late chronotypes typically eat late in the evening, and this has also been associated with adverse metabolic effects. At this stage, we do not know if a person changes his/her chronotype that this will also lead to metabolic improvements. More research is needed before we can make recommendations regarding chronotype and timing of other lifestyle behaviors.”

Commenting on the study, Gianluca Iacobellis, MD, PhD, director of the University of Miami Hospital Diabetes Service, Coral Gables, Florida, said: “Interesting data. Altering the physiological circadian rhythm can affect the complex hormonal system — including cortisol, ghrelin, leptin, and serotonin — that regulates insulin sensitivity, glucose, and blood pressure control. The night owl may become more insulin resistant and therefore at higher risk of developing diabetes.”

Like Dr. van der Velde, he noted that “late sleep may be associated with night binging that can cause weight gain and ultimately obesity, further increasing the risk of diabetes.”

Dr. Iacobellis’s group recently showed that vital exhaustion, which is characterized by fatigue and loss of vigor, is associated with a higher cardiovascular risk for and markers of visceral adiposity.

“Abnormal circadian rhythms can be easily associated with vital exhaustion,” he said. Therefore, night owls with more visceral than peripheral fat accumulation might also be at higher cardiometabolic risk through that mechanism.

“However environmental factors and family history can play an important role too,” he added.

Regardless of the mechanisms involved, “preventive actions should be taken to educate teenagers and individuals at higher risk to have healthy sleep habits,” Dr. Iacobellis concluded.

No information regarding funding was provided; Dr. van der Velde and Dr. Iacobellis reported no conflicts of interest.

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

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Will Tirzepatide Vials Help Patients? Endos Weigh in

Article Type
Changed
Tue, 09/10/2024 - 09:28

 

Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.

As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”

For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)

“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.

The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.

And there’s the rub.
 

‘Only Two Different Doses’

Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.

“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.

“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”

If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”

Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”

And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”

A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”

But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”

In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”

The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
 

Protection From Compounders?

According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”

Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.

Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”

But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.

Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”

“For 20 months now,” he continued, “compounders have been a lifeline for many patients, filling prescriptions for compounded tirzepatide injection at a time when the FDA-approved drug has been in shortage. We’ll be eager to see whether Lilly’s direct-to-patient approach actually works.”

Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”

Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.

A version of this article appeared on Medscape.com.

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Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.

As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”

For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)

“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.

The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.

And there’s the rub.
 

‘Only Two Different Doses’

Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.

“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.

“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”

If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”

Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”

And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”

A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”

But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”

In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”

The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
 

Protection From Compounders?

According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”

Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.

Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”

But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.

Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”

“For 20 months now,” he continued, “compounders have been a lifeline for many patients, filling prescriptions for compounded tirzepatide injection at a time when the FDA-approved drug has been in shortage. We’ll be eager to see whether Lilly’s direct-to-patient approach actually works.”

Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”

Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.

A version of this article appeared on Medscape.com.

 

Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.

As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”

For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)

“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.

The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.

And there’s the rub.
 

‘Only Two Different Doses’

Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.

“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.

“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”

If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”

Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”

And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”

A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”

But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”

In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”

The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
 

Protection From Compounders?

According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”

Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.

Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”

But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.

Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”

“For 20 months now,” he continued, “compounders have been a lifeline for many patients, filling prescriptions for compounded tirzepatide injection at a time when the FDA-approved drug has been in shortage. We’ll be eager to see whether Lilly’s direct-to-patient approach actually works.”

Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”

Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.

A version of this article appeared on Medscape.com.

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Time-Restricted Eating Fails for Weight Loss and Glucose Homeostasis

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Changed
Mon, 09/09/2024 - 16:23

 

In the setting of isocaloric eating, time-restricted eating (TRE) did not reduce weight or improve glucose homeostasis relative to a usual eating pattern (UEP), a small randomized controlled trial found.

The results suggested that any effects of TRE on weight observed in prior studies may be due to reductions in caloric intake and not timing, according to Nisa M. Maruthur, MD, MHS, of the Division of General Internal Medicine at the Johns Hopkins School of Medicine in Baltimore, and colleagues.

Published in Annals of Internal Medicine, the 12-week trial randomly assigned 41 adults aged 18-69 years with obesity and prediabetes or diet-controlled diabetes 1:1 as follows: To TRE, involving a 10-hour eating window with 80% of calories consumed before 1 PM, or to UEP, involving a ≤ 16-hour window, with at least 50% of calories consumed after 5 PM. The regimen in each group was based on the OmniHeart unsaturated fat diet and the SPICE study.

“The diet was similar to the DASH [Dietary Approaches to Stop Hypertension] diet for hypertension and maybe a bit higher in unsaturated fat and micronutrients,” said study co-author Scott J. Pilla, MD, MHS, an assistant professor of medicine at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. For each participant, macro- and micronutrient content remained constant throughout the study period, with total calories individually determined at baseline and ranging from 1600 to 3500 kcal/d. “That differs from some TRE studies in which calories were adjusted according to whether participants lost or gained weight,” he said. “This was a purely mechanistic study to determine the impact of time of eating alone with no change in calories.”

Scott J. Pilla, MD, MHS, Johns Hopkins Bloomberg School of Public Health, Baltimore
Dr. Scott J. Pilla
 

Although the current findings revealed no weight loss advantage, some evidence suggests that limiting the food consumption window to 4-10 hours naturally reduces energy intake by approximately 200-550 calories per day and can result in a loss of 3%-5% of baseline body weight for 2-12 months. In addition, TRE has been shown to improve metabolic risk factors, such as insulin resistance, blood pressure, and triglyceride concentrations — but not in this study.
 

The Cohort

The mean age was 59 years, 93% of patients were women, and 93% were Black. The mean body mass index was 36, and the mean baseline weight was 96.2 kg — 95.6 kg in the TRE group and 103.7 kg in the UEP group.

At 12 weeks, weight decreased comparably by 2.3 kg (95% CI, 1.0-3.5) in the TRE group and by 2.6 kg (95% CI, 1.5-3.7) in the UEP group. Change in glycemic measures did not differ between the two groups.

Interestingly, self-reporting questionnaires revealed a slight reduction in physical activity in the TRE group, an effect that requires further study. “We don’t know why but anecdotally, some TRE participants said they tended to go to bed earlier,” Dr. Pilla said. Earlier bedtimes may put an end sooner to the daily eating pattern.

Subanalyses of the data are ongoing and will be published later.

“In the context of several clinical trials that suggest a benefit of TRE, our findings suggest that if or when TRE interventions induce weight loss, it is likely in part due to a reduction in energy intake, and therefore, clinicians can counsel patients that TRE may help them lose weight by decreasing their caloric intake,” the authors wrote.

In an accompanying editorial, Krista A. Varady, PhD, and Vanessa M. Oddo, PhD, of the Department of Kinesiology and Nutrition at the University of Illinois–Chicago, said the study results have important clinical implications. “Many patients stop following standard-care diets (such as daily calorie restriction) because they become frustrated with having to monitor food intake vigilantly each day,” they wrote.

Dr. Krista A. Varady, Department of Kinesiology and Nutrition at the University of Illinois--Chicago
Dr. Krista A. Varady


Although TRE is no more effective than other diet interventions for weight reduction, it offers a simplified approach to treat obesity by omitting the need for calorie counting. “TRE bypasses this requirement simply by allowing participants to ‘watch the clock’ instead of monitoring calories, while still producing weight loss,” they wrote.

The straightforward nature of this diet makes it well suited for remote delivery, which can reduce the scheduling and financial barriers associated with inpatient visits, they added. “Moreover, TRE does not require the purchase of expensive food products and allows a person to continue consuming familiar foods, making it a high accessible diet for lower-resource populations.”
 

 

 

Gastroenterologists and Obesity

Of late, support has grown for gastroenterologists to become actively involved in obesity treatment — even to “take ownership” of this field.

In a 2023 article in Gut, Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, made the case for the natural fit between gastrointestinal (GI) specialists and obesity management. He noted that obesity is a significant risk factor for GI, pancreatic, and liver diseases. It can even affect inflammatory bowel disease.

Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota
Dr. Michael Camilleri


“Treating obesity starting when patients present in gastroenterology and hepatology clinics has potential to impact serious consequences of obesity such as cardiovascular risks,” he wrote.

Gastroenterologists already treat GI conditions with pharmacologic and surgical interventions that can also be used to treat obesity and improve glycemic control. These include pancreatic lipase inhibitors and incretin, bariatric endoscopy and surgery, and combination therapies targeting metabolic problems.

This study was supported by the American Heart Association. 

Dr. Maruthur reported receiving royalties from a virtual diabetes prevention program. Dr. Pilla reported receiving travel, advisory, and speaker fees from the American Diabetes Association. Numerous authors reported receiving grants from government and nonprofit research funding organizations. Dr. Varady disclosed having no competing interests. Dr. Odda reported receiving research support and honoraria from government nonprofit funding organizations.

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

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In the setting of isocaloric eating, time-restricted eating (TRE) did not reduce weight or improve glucose homeostasis relative to a usual eating pattern (UEP), a small randomized controlled trial found.

The results suggested that any effects of TRE on weight observed in prior studies may be due to reductions in caloric intake and not timing, according to Nisa M. Maruthur, MD, MHS, of the Division of General Internal Medicine at the Johns Hopkins School of Medicine in Baltimore, and colleagues.

Published in Annals of Internal Medicine, the 12-week trial randomly assigned 41 adults aged 18-69 years with obesity and prediabetes or diet-controlled diabetes 1:1 as follows: To TRE, involving a 10-hour eating window with 80% of calories consumed before 1 PM, or to UEP, involving a ≤ 16-hour window, with at least 50% of calories consumed after 5 PM. The regimen in each group was based on the OmniHeart unsaturated fat diet and the SPICE study.

“The diet was similar to the DASH [Dietary Approaches to Stop Hypertension] diet for hypertension and maybe a bit higher in unsaturated fat and micronutrients,” said study co-author Scott J. Pilla, MD, MHS, an assistant professor of medicine at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. For each participant, macro- and micronutrient content remained constant throughout the study period, with total calories individually determined at baseline and ranging from 1600 to 3500 kcal/d. “That differs from some TRE studies in which calories were adjusted according to whether participants lost or gained weight,” he said. “This was a purely mechanistic study to determine the impact of time of eating alone with no change in calories.”

Scott J. Pilla, MD, MHS, Johns Hopkins Bloomberg School of Public Health, Baltimore
Dr. Scott J. Pilla
 

Although the current findings revealed no weight loss advantage, some evidence suggests that limiting the food consumption window to 4-10 hours naturally reduces energy intake by approximately 200-550 calories per day and can result in a loss of 3%-5% of baseline body weight for 2-12 months. In addition, TRE has been shown to improve metabolic risk factors, such as insulin resistance, blood pressure, and triglyceride concentrations — but not in this study.
 

The Cohort

The mean age was 59 years, 93% of patients were women, and 93% were Black. The mean body mass index was 36, and the mean baseline weight was 96.2 kg — 95.6 kg in the TRE group and 103.7 kg in the UEP group.

At 12 weeks, weight decreased comparably by 2.3 kg (95% CI, 1.0-3.5) in the TRE group and by 2.6 kg (95% CI, 1.5-3.7) in the UEP group. Change in glycemic measures did not differ between the two groups.

Interestingly, self-reporting questionnaires revealed a slight reduction in physical activity in the TRE group, an effect that requires further study. “We don’t know why but anecdotally, some TRE participants said they tended to go to bed earlier,” Dr. Pilla said. Earlier bedtimes may put an end sooner to the daily eating pattern.

Subanalyses of the data are ongoing and will be published later.

“In the context of several clinical trials that suggest a benefit of TRE, our findings suggest that if or when TRE interventions induce weight loss, it is likely in part due to a reduction in energy intake, and therefore, clinicians can counsel patients that TRE may help them lose weight by decreasing their caloric intake,” the authors wrote.

In an accompanying editorial, Krista A. Varady, PhD, and Vanessa M. Oddo, PhD, of the Department of Kinesiology and Nutrition at the University of Illinois–Chicago, said the study results have important clinical implications. “Many patients stop following standard-care diets (such as daily calorie restriction) because they become frustrated with having to monitor food intake vigilantly each day,” they wrote.

Dr. Krista A. Varady, Department of Kinesiology and Nutrition at the University of Illinois--Chicago
Dr. Krista A. Varady


Although TRE is no more effective than other diet interventions for weight reduction, it offers a simplified approach to treat obesity by omitting the need for calorie counting. “TRE bypasses this requirement simply by allowing participants to ‘watch the clock’ instead of monitoring calories, while still producing weight loss,” they wrote.

The straightforward nature of this diet makes it well suited for remote delivery, which can reduce the scheduling and financial barriers associated with inpatient visits, they added. “Moreover, TRE does not require the purchase of expensive food products and allows a person to continue consuming familiar foods, making it a high accessible diet for lower-resource populations.”
 

 

 

Gastroenterologists and Obesity

Of late, support has grown for gastroenterologists to become actively involved in obesity treatment — even to “take ownership” of this field.

In a 2023 article in Gut, Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, made the case for the natural fit between gastrointestinal (GI) specialists and obesity management. He noted that obesity is a significant risk factor for GI, pancreatic, and liver diseases. It can even affect inflammatory bowel disease.

Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota
Dr. Michael Camilleri


“Treating obesity starting when patients present in gastroenterology and hepatology clinics has potential to impact serious consequences of obesity such as cardiovascular risks,” he wrote.

Gastroenterologists already treat GI conditions with pharmacologic and surgical interventions that can also be used to treat obesity and improve glycemic control. These include pancreatic lipase inhibitors and incretin, bariatric endoscopy and surgery, and combination therapies targeting metabolic problems.

This study was supported by the American Heart Association. 

Dr. Maruthur reported receiving royalties from a virtual diabetes prevention program. Dr. Pilla reported receiving travel, advisory, and speaker fees from the American Diabetes Association. Numerous authors reported receiving grants from government and nonprofit research funding organizations. Dr. Varady disclosed having no competing interests. Dr. Odda reported receiving research support and honoraria from government nonprofit funding organizations.

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

 

In the setting of isocaloric eating, time-restricted eating (TRE) did not reduce weight or improve glucose homeostasis relative to a usual eating pattern (UEP), a small randomized controlled trial found.

The results suggested that any effects of TRE on weight observed in prior studies may be due to reductions in caloric intake and not timing, according to Nisa M. Maruthur, MD, MHS, of the Division of General Internal Medicine at the Johns Hopkins School of Medicine in Baltimore, and colleagues.

Published in Annals of Internal Medicine, the 12-week trial randomly assigned 41 adults aged 18-69 years with obesity and prediabetes or diet-controlled diabetes 1:1 as follows: To TRE, involving a 10-hour eating window with 80% of calories consumed before 1 PM, or to UEP, involving a ≤ 16-hour window, with at least 50% of calories consumed after 5 PM. The regimen in each group was based on the OmniHeart unsaturated fat diet and the SPICE study.

“The diet was similar to the DASH [Dietary Approaches to Stop Hypertension] diet for hypertension and maybe a bit higher in unsaturated fat and micronutrients,” said study co-author Scott J. Pilla, MD, MHS, an assistant professor of medicine at the Johns Hopkins Bloomberg School of Public Health, Baltimore, in an interview. For each participant, macro- and micronutrient content remained constant throughout the study period, with total calories individually determined at baseline and ranging from 1600 to 3500 kcal/d. “That differs from some TRE studies in which calories were adjusted according to whether participants lost or gained weight,” he said. “This was a purely mechanistic study to determine the impact of time of eating alone with no change in calories.”

Scott J. Pilla, MD, MHS, Johns Hopkins Bloomberg School of Public Health, Baltimore
Dr. Scott J. Pilla
 

Although the current findings revealed no weight loss advantage, some evidence suggests that limiting the food consumption window to 4-10 hours naturally reduces energy intake by approximately 200-550 calories per day and can result in a loss of 3%-5% of baseline body weight for 2-12 months. In addition, TRE has been shown to improve metabolic risk factors, such as insulin resistance, blood pressure, and triglyceride concentrations — but not in this study.
 

The Cohort

The mean age was 59 years, 93% of patients were women, and 93% were Black. The mean body mass index was 36, and the mean baseline weight was 96.2 kg — 95.6 kg in the TRE group and 103.7 kg in the UEP group.

At 12 weeks, weight decreased comparably by 2.3 kg (95% CI, 1.0-3.5) in the TRE group and by 2.6 kg (95% CI, 1.5-3.7) in the UEP group. Change in glycemic measures did not differ between the two groups.

Interestingly, self-reporting questionnaires revealed a slight reduction in physical activity in the TRE group, an effect that requires further study. “We don’t know why but anecdotally, some TRE participants said they tended to go to bed earlier,” Dr. Pilla said. Earlier bedtimes may put an end sooner to the daily eating pattern.

Subanalyses of the data are ongoing and will be published later.

“In the context of several clinical trials that suggest a benefit of TRE, our findings suggest that if or when TRE interventions induce weight loss, it is likely in part due to a reduction in energy intake, and therefore, clinicians can counsel patients that TRE may help them lose weight by decreasing their caloric intake,” the authors wrote.

In an accompanying editorial, Krista A. Varady, PhD, and Vanessa M. Oddo, PhD, of the Department of Kinesiology and Nutrition at the University of Illinois–Chicago, said the study results have important clinical implications. “Many patients stop following standard-care diets (such as daily calorie restriction) because they become frustrated with having to monitor food intake vigilantly each day,” they wrote.

Dr. Krista A. Varady, Department of Kinesiology and Nutrition at the University of Illinois--Chicago
Dr. Krista A. Varady


Although TRE is no more effective than other diet interventions for weight reduction, it offers a simplified approach to treat obesity by omitting the need for calorie counting. “TRE bypasses this requirement simply by allowing participants to ‘watch the clock’ instead of monitoring calories, while still producing weight loss,” they wrote.

The straightforward nature of this diet makes it well suited for remote delivery, which can reduce the scheduling and financial barriers associated with inpatient visits, they added. “Moreover, TRE does not require the purchase of expensive food products and allows a person to continue consuming familiar foods, making it a high accessible diet for lower-resource populations.”
 

 

 

Gastroenterologists and Obesity

Of late, support has grown for gastroenterologists to become actively involved in obesity treatment — even to “take ownership” of this field.

In a 2023 article in Gut, Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, made the case for the natural fit between gastrointestinal (GI) specialists and obesity management. He noted that obesity is a significant risk factor for GI, pancreatic, and liver diseases. It can even affect inflammatory bowel disease.

Michael Camilleri, MD, AGAF, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota
Dr. Michael Camilleri


“Treating obesity starting when patients present in gastroenterology and hepatology clinics has potential to impact serious consequences of obesity such as cardiovascular risks,” he wrote.

Gastroenterologists already treat GI conditions with pharmacologic and surgical interventions that can also be used to treat obesity and improve glycemic control. These include pancreatic lipase inhibitors and incretin, bariatric endoscopy and surgery, and combination therapies targeting metabolic problems.

This study was supported by the American Heart Association. 

Dr. Maruthur reported receiving royalties from a virtual diabetes prevention program. Dr. Pilla reported receiving travel, advisory, and speaker fees from the American Diabetes Association. Numerous authors reported receiving grants from government and nonprofit research funding organizations. Dr. Varady disclosed having no competing interests. Dr. Odda reported receiving research support and honoraria from government nonprofit funding organizations.

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

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Being An Outsider

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Changed
Fri, 09/06/2024 - 16:44

Our son works for a Maine-based company that produces and sells clothing and outdoor recreation equipment. One of its tag lines is “Be an Outsider.” In his role as chief marketing officer, he was recently given an app for his phone that can calculate how many minutes he spends outside each day. He assured me: “Dad, you don’t need one of these on your phone. Your weather-beaten skin says you are already logging in way more than enough minutes outdoors.”

But, it got me thinking about several avenues of research where an app like that would be useful. As luck would have it, the following week I stumbled across a paper describing just such a study.

Dr. William G. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years.
Dr. William G. Wilkoff

Researchers in Shanghai, China, placed smartwatches with technology similar to my son’s phone on nearly 3000 children and found “that outdoor exposure patterns characterized by a continuous period of at least 15 minutes, accompanied by a sunlight intensity of more than 2000 lux, were associated with less myopic shift.” In other words, children getting more time outside were less likely to become nearsighted.” Whether this was an effect of being outside instead of staring at a screen indoors is an interesting question.

I have alway suspected that being outdoors was important for wellness and this paper meshed nicely with an article I had recently read in The Washington Post titled, “How time in nature builds happier, healthier and more social children” (Jamie Friedlander Serrano, 2024 Aug 4). The reporter quotes numerous experts in child health and includes links to several articles that tout the benefits of outdoor experiences, particularly ones in a natural environment. There are the vitamin D effects on growth and bone health. There are studies suggesting that being out in nature can reduce stress, anxiety, and aggression, and improve working memory and attention.

In this country there is a small but growing group of schools modeling themselves after the “Forest kindergartens” that have become popular in Europe in which a large portion of the students’ days are spent outside surrounded by nature. It will be interesting to see how robustly this trend grows here in the United States. However, in a nation like ours in which the Environmental Protection Agency estimates that the average American spends 90% of his day indoors, it’s going to require a seismic shift in our societal norms.

I think my mother always knew that being outdoors was healthy for children. I also suspect that she and most my friends’ mothers were primarily motivated by a desire to have the house to themselves. This was primarily to allow them to get the housework done unimpeded by pestering children. But, there may have been times when a busy housewife simply needed to sit down with a book in the peace and quiet of a childless environment. We kids were told to get out of the house and return for lunch and dinner, hopefully not in the tow of a police officer. There were few rules and for the most part we were left to invent our own amusement.

Yes, you’ve heard this old-fogey legend before. But it was true. Those were the halcyon days of the 1950s in a small suburban town of 5000 of a little more than 1 square mile with its own swimming pool. My particular idyll was aptly named Pleasantville but I know we were not alone as the only community where children were allowed – or let’s say “encouraged” – to be outdoors if they weren’t in school. It was a different time.

I am not so naive to believe that we will ever return to those good old days when children roamed free, but it is worth considering what has changed to drive children inside and away from all the health benefits of being outdoors. Is there anything we can do to reverse this unfortunate trend?

First, we must first face up to the reality that our society has become so focused on the potential downsides of everything that we seem to be driven primarily by risk avoidance. We hear how things can go terribly wrong in the world outside, a world we can’t control. Although the data from the pandemic don’t support it, more of us believe children are safer indoors. Parents in particular seem to worry more now than they did 75 years ago. I don’t think we can point to a single event such as the tragedies of September 11 to explain the shift.

While bad news has always traveled fast, today (with communication being almost instantaneous) a story about a child abduction at 6 in the morning in Nevada can be on my local TV channel by lunchtime here in Maine. Parents worry that if bad stuff can happen to a child in Mount Elsewhere, it could happen to my child playing in the backyard across the street.

I think we pediatricians should consider how large a role we may be playing in driving parental anxiety with our frequent warnings about the dangers a child can encounter outdoors whether they come in the form of accidents or exposure to the elements.

While parents have grown more hesitant to send their children outside to play, as a society we have failed to adequately acknowledge and respond to the role that unhealthy attraction of indoor alternatives to outdoor play may be contributing to indoorism. Here we’re talking about television, smartphones, and the internet.

So, what can we do as pediatricians to get our patients outside? First, we can set an example and cover our office walls with pictures of ourselves and our families enjoying the outdoors. We can be vocal advocates for creating and maintaining accessible outdoor spaces in our community. We can advocate for more outside time during recess in school and encourage the school officials to consider having more courses taught outside.

We can be more diligent in asking families about their screen use and not be afraid to express our concern when we hear how little outdoor time their child is getting. Finally, we can strive for more balance in our messaging. For example for every warning we give about playing outside on poor air quality days there should be a reminder of the health benefits of being outdoors on the other days. Every message about the importance of sunscreen should be preceded by a few sentences promoting outdoor activities in wooded environments where sun exposure is less of a concern.

We should all be looking for ways in which our communities can remove the barriers that prevent our patients for reaping the health benefits of being outdoors. Being an outsider is just as important as getting enough sleep, eating the right food and staying physically active.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

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Our son works for a Maine-based company that produces and sells clothing and outdoor recreation equipment. One of its tag lines is “Be an Outsider.” In his role as chief marketing officer, he was recently given an app for his phone that can calculate how many minutes he spends outside each day. He assured me: “Dad, you don’t need one of these on your phone. Your weather-beaten skin says you are already logging in way more than enough minutes outdoors.”

But, it got me thinking about several avenues of research where an app like that would be useful. As luck would have it, the following week I stumbled across a paper describing just such a study.

Dr. William G. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years.
Dr. William G. Wilkoff

Researchers in Shanghai, China, placed smartwatches with technology similar to my son’s phone on nearly 3000 children and found “that outdoor exposure patterns characterized by a continuous period of at least 15 minutes, accompanied by a sunlight intensity of more than 2000 lux, were associated with less myopic shift.” In other words, children getting more time outside were less likely to become nearsighted.” Whether this was an effect of being outside instead of staring at a screen indoors is an interesting question.

I have alway suspected that being outdoors was important for wellness and this paper meshed nicely with an article I had recently read in The Washington Post titled, “How time in nature builds happier, healthier and more social children” (Jamie Friedlander Serrano, 2024 Aug 4). The reporter quotes numerous experts in child health and includes links to several articles that tout the benefits of outdoor experiences, particularly ones in a natural environment. There are the vitamin D effects on growth and bone health. There are studies suggesting that being out in nature can reduce stress, anxiety, and aggression, and improve working memory and attention.

In this country there is a small but growing group of schools modeling themselves after the “Forest kindergartens” that have become popular in Europe in which a large portion of the students’ days are spent outside surrounded by nature. It will be interesting to see how robustly this trend grows here in the United States. However, in a nation like ours in which the Environmental Protection Agency estimates that the average American spends 90% of his day indoors, it’s going to require a seismic shift in our societal norms.

I think my mother always knew that being outdoors was healthy for children. I also suspect that she and most my friends’ mothers were primarily motivated by a desire to have the house to themselves. This was primarily to allow them to get the housework done unimpeded by pestering children. But, there may have been times when a busy housewife simply needed to sit down with a book in the peace and quiet of a childless environment. We kids were told to get out of the house and return for lunch and dinner, hopefully not in the tow of a police officer. There were few rules and for the most part we were left to invent our own amusement.

Yes, you’ve heard this old-fogey legend before. But it was true. Those were the halcyon days of the 1950s in a small suburban town of 5000 of a little more than 1 square mile with its own swimming pool. My particular idyll was aptly named Pleasantville but I know we were not alone as the only community where children were allowed – or let’s say “encouraged” – to be outdoors if they weren’t in school. It was a different time.

I am not so naive to believe that we will ever return to those good old days when children roamed free, but it is worth considering what has changed to drive children inside and away from all the health benefits of being outdoors. Is there anything we can do to reverse this unfortunate trend?

First, we must first face up to the reality that our society has become so focused on the potential downsides of everything that we seem to be driven primarily by risk avoidance. We hear how things can go terribly wrong in the world outside, a world we can’t control. Although the data from the pandemic don’t support it, more of us believe children are safer indoors. Parents in particular seem to worry more now than they did 75 years ago. I don’t think we can point to a single event such as the tragedies of September 11 to explain the shift.

While bad news has always traveled fast, today (with communication being almost instantaneous) a story about a child abduction at 6 in the morning in Nevada can be on my local TV channel by lunchtime here in Maine. Parents worry that if bad stuff can happen to a child in Mount Elsewhere, it could happen to my child playing in the backyard across the street.

I think we pediatricians should consider how large a role we may be playing in driving parental anxiety with our frequent warnings about the dangers a child can encounter outdoors whether they come in the form of accidents or exposure to the elements.

While parents have grown more hesitant to send their children outside to play, as a society we have failed to adequately acknowledge and respond to the role that unhealthy attraction of indoor alternatives to outdoor play may be contributing to indoorism. Here we’re talking about television, smartphones, and the internet.

So, what can we do as pediatricians to get our patients outside? First, we can set an example and cover our office walls with pictures of ourselves and our families enjoying the outdoors. We can be vocal advocates for creating and maintaining accessible outdoor spaces in our community. We can advocate for more outside time during recess in school and encourage the school officials to consider having more courses taught outside.

We can be more diligent in asking families about their screen use and not be afraid to express our concern when we hear how little outdoor time their child is getting. Finally, we can strive for more balance in our messaging. For example for every warning we give about playing outside on poor air quality days there should be a reminder of the health benefits of being outdoors on the other days. Every message about the importance of sunscreen should be preceded by a few sentences promoting outdoor activities in wooded environments where sun exposure is less of a concern.

We should all be looking for ways in which our communities can remove the barriers that prevent our patients for reaping the health benefits of being outdoors. Being an outsider is just as important as getting enough sleep, eating the right food and staying physically active.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

Our son works for a Maine-based company that produces and sells clothing and outdoor recreation equipment. One of its tag lines is “Be an Outsider.” In his role as chief marketing officer, he was recently given an app for his phone that can calculate how many minutes he spends outside each day. He assured me: “Dad, you don’t need one of these on your phone. Your weather-beaten skin says you are already logging in way more than enough minutes outdoors.”

But, it got me thinking about several avenues of research where an app like that would be useful. As luck would have it, the following week I stumbled across a paper describing just such a study.

Dr. William G. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years.
Dr. William G. Wilkoff

Researchers in Shanghai, China, placed smartwatches with technology similar to my son’s phone on nearly 3000 children and found “that outdoor exposure patterns characterized by a continuous period of at least 15 minutes, accompanied by a sunlight intensity of more than 2000 lux, were associated with less myopic shift.” In other words, children getting more time outside were less likely to become nearsighted.” Whether this was an effect of being outside instead of staring at a screen indoors is an interesting question.

I have alway suspected that being outdoors was important for wellness and this paper meshed nicely with an article I had recently read in The Washington Post titled, “How time in nature builds happier, healthier and more social children” (Jamie Friedlander Serrano, 2024 Aug 4). The reporter quotes numerous experts in child health and includes links to several articles that tout the benefits of outdoor experiences, particularly ones in a natural environment. There are the vitamin D effects on growth and bone health. There are studies suggesting that being out in nature can reduce stress, anxiety, and aggression, and improve working memory and attention.

In this country there is a small but growing group of schools modeling themselves after the “Forest kindergartens” that have become popular in Europe in which a large portion of the students’ days are spent outside surrounded by nature. It will be interesting to see how robustly this trend grows here in the United States. However, in a nation like ours in which the Environmental Protection Agency estimates that the average American spends 90% of his day indoors, it’s going to require a seismic shift in our societal norms.

I think my mother always knew that being outdoors was healthy for children. I also suspect that she and most my friends’ mothers were primarily motivated by a desire to have the house to themselves. This was primarily to allow them to get the housework done unimpeded by pestering children. But, there may have been times when a busy housewife simply needed to sit down with a book in the peace and quiet of a childless environment. We kids were told to get out of the house and return for lunch and dinner, hopefully not in the tow of a police officer. There were few rules and for the most part we were left to invent our own amusement.

Yes, you’ve heard this old-fogey legend before. But it was true. Those were the halcyon days of the 1950s in a small suburban town of 5000 of a little more than 1 square mile with its own swimming pool. My particular idyll was aptly named Pleasantville but I know we were not alone as the only community where children were allowed – or let’s say “encouraged” – to be outdoors if they weren’t in school. It was a different time.

I am not so naive to believe that we will ever return to those good old days when children roamed free, but it is worth considering what has changed to drive children inside and away from all the health benefits of being outdoors. Is there anything we can do to reverse this unfortunate trend?

First, we must first face up to the reality that our society has become so focused on the potential downsides of everything that we seem to be driven primarily by risk avoidance. We hear how things can go terribly wrong in the world outside, a world we can’t control. Although the data from the pandemic don’t support it, more of us believe children are safer indoors. Parents in particular seem to worry more now than they did 75 years ago. I don’t think we can point to a single event such as the tragedies of September 11 to explain the shift.

While bad news has always traveled fast, today (with communication being almost instantaneous) a story about a child abduction at 6 in the morning in Nevada can be on my local TV channel by lunchtime here in Maine. Parents worry that if bad stuff can happen to a child in Mount Elsewhere, it could happen to my child playing in the backyard across the street.

I think we pediatricians should consider how large a role we may be playing in driving parental anxiety with our frequent warnings about the dangers a child can encounter outdoors whether they come in the form of accidents or exposure to the elements.

While parents have grown more hesitant to send their children outside to play, as a society we have failed to adequately acknowledge and respond to the role that unhealthy attraction of indoor alternatives to outdoor play may be contributing to indoorism. Here we’re talking about television, smartphones, and the internet.

So, what can we do as pediatricians to get our patients outside? First, we can set an example and cover our office walls with pictures of ourselves and our families enjoying the outdoors. We can be vocal advocates for creating and maintaining accessible outdoor spaces in our community. We can advocate for more outside time during recess in school and encourage the school officials to consider having more courses taught outside.

We can be more diligent in asking families about their screen use and not be afraid to express our concern when we hear how little outdoor time their child is getting. Finally, we can strive for more balance in our messaging. For example for every warning we give about playing outside on poor air quality days there should be a reminder of the health benefits of being outdoors on the other days. Every message about the importance of sunscreen should be preceded by a few sentences promoting outdoor activities in wooded environments where sun exposure is less of a concern.

We should all be looking for ways in which our communities can remove the barriers that prevent our patients for reaping the health benefits of being outdoors. Being an outsider is just as important as getting enough sleep, eating the right food and staying physically active.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com.

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