Obesity

Certain ultraprocessed foods – especially candy, prepackaged pastries, and frozen desserts – could be “gateway foods” for adolescents, leading them to increase their intake of other unhealthy foods, a new study suggests.

“For teens, gateway ultraprocessed foods (candy, store pastries, frozen desserts) should be prioritized for preventive dietary interventions as they increase intake across all other UPFs,” lead researcher Maria Balhara said in an interview.

“The good news,” said Ms. Balhara, is that even small changes, such as reducing how often gateway foods are consumed, may reduce overall intake of unhealthy foods and have a “big impact” on overall health.

Ms. Balhara has a unique perspective on adolescent eating habits: She’s 16 years old, from Florida, and conducted the study while dual-enrolled at Broward College and Cooper City High School.

Her study was released Sept. 7 ahead of presentation at the American Heart Association Hypertension Scientific Sessions 2022 in San Diego.
 

Blame the pandemic?

Over the past 30 years, there’s been a steady increase in consumption of UPFs worldwide, coupled with mounting evidence that diets rich in UPFs raise the risk for several chronic diseases, including weight gain, hypertension, and increased risk for heart disease and premature death.

For her research, Ms. Balhara asked 315 teenagers (42% male) from 12 high schools in South Florida how often they consumed UPFs over two time periods – before COVID in 2019 and after COVID restrictions were eased in 2022 – using a survey that she developed called the Processed Intake Evaluation (PIE).

More than 2 in 5 teens (43%) increased their consumption of UPFs between 2019 and 2022.

During this time, increased consumption of frozen desserts was associated with an 11% increase in consumption of all other UPFs, whereas increased consumption of prepackaged pastries and candy was associated with a 12% and 31%, respectively, increase in consumption of all other UPFs, Ms. Balhara found.

Encouragingly, 57% of teens decreased their consumption of UPFs between 2019 and 2022.

During this time, decreased consumption of processed meats was associated with an 8% decrease in consumption of all other UPFs, whereas decreased consumption of white bread and biscuits was associated with a 9% and 10%, respectively, decrease in consumption of all other UPFs.

The results provide initial evidence for a new “gateway food model,” Ms. Balhara told this news organization, in which certain UPFs, when increased, drive overall consumption of all UPFs among teens.

Limitations of the study include the self-reported dietary data and the fact that the PIE survey has not been validated.
 

Not all UPFs are bad

“I commend Ms. Balhara for her project, which highlights the importance of establishing good dietary patterns early in life,” Donna K. Arnett, PhD, past president of the AHA, said in a news release.

“The relationship between poor dietary quality and cardiovascular risk factors is well-established. While this is a small, preliminary study, it’s an important topic to continue to investigate and help us understand ways we can influence dietary behaviors to promote optimal cardiovascular health for all ages,” said Dr. Arnett, executive vice president for academic affairs and provost at the University of South Carolina, Columbia.

Offering perspective on the study, Taylor C. Wallace, PhD, with the department of nutrition and food studies, George Mason University, Fairfax, Va., made the point that “food processing and ultraprocessed foods aren’t the problem. The problem is the types of ultraprocessed foods on the market that people consume.”

“Remember, non-fat, vitamin D fortified yogurt is also ‘ultra-processed,’ and it’s very healthy,” he told this news organization.

Dr. Wallace said that it’s no surprise that teens increased their intake of UPFs during the pandemic.

“Of course, people increased processed food intake during the pandemic. Processed foods are shelf stable at a time when grocery stores were running out of things and supply chains weren’t able to keep up. Also, many were depressed and use food to indulge,” he noted.

The study had no funding. Ms. Balhara has no relevant disclosures. Dr. Wallace is principal and CEO of Think Healthy Group; chief food and nutrition scientist with Produce for Better Health Foundation; editor, Journal of Dietary Supplements; deputy editor, Journal of the American College of Nutrition; nutrition section editor, Annals of Medicine; and an advisory board member with Forbes Health.

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

Certain ultraprocessed foods – especially candy, prepackaged pastries, and frozen desserts – could be “gateway foods” for adolescents, leading them to increase their intake of other unhealthy foods, a new study suggests.

“For teens, gateway ultraprocessed foods (candy, store pastries, frozen desserts) should be prioritized for preventive dietary interventions as they increase intake across all other UPFs,” lead researcher Maria Balhara said in an interview.

“The good news,” said Ms. Balhara, is that even small changes, such as reducing how often gateway foods are consumed, may reduce overall intake of unhealthy foods and have a “big impact” on overall health.

Ms. Balhara has a unique perspective on adolescent eating habits: She’s 16 years old, from Florida, and conducted the study while dual-enrolled at Broward College and Cooper City High School.

Her study was released Sept. 7 ahead of presentation at the American Heart Association Hypertension Scientific Sessions 2022 in San Diego.
 

Blame the pandemic?

Over the past 30 years, there’s been a steady increase in consumption of UPFs worldwide, coupled with mounting evidence that diets rich in UPFs raise the risk for several chronic diseases, including weight gain, hypertension, and increased risk for heart disease and premature death.

For her research, Ms. Balhara asked 315 teenagers (42% male) from 12 high schools in South Florida how often they consumed UPFs over two time periods – before COVID in 2019 and after COVID restrictions were eased in 2022 – using a survey that she developed called the Processed Intake Evaluation (PIE).

More than 2 in 5 teens (43%) increased their consumption of UPFs between 2019 and 2022.

During this time, increased consumption of frozen desserts was associated with an 11% increase in consumption of all other UPFs, whereas increased consumption of prepackaged pastries and candy was associated with a 12% and 31%, respectively, increase in consumption of all other UPFs, Ms. Balhara found.

Encouragingly, 57% of teens decreased their consumption of UPFs between 2019 and 2022.

During this time, decreased consumption of processed meats was associated with an 8% decrease in consumption of all other UPFs, whereas decreased consumption of white bread and biscuits was associated with a 9% and 10%, respectively, decrease in consumption of all other UPFs.

The results provide initial evidence for a new “gateway food model,” Ms. Balhara told this news organization, in which certain UPFs, when increased, drive overall consumption of all UPFs among teens.

Limitations of the study include the self-reported dietary data and the fact that the PIE survey has not been validated.
 

Not all UPFs are bad

“I commend Ms. Balhara for her project, which highlights the importance of establishing good dietary patterns early in life,” Donna K. Arnett, PhD, past president of the AHA, said in a news release.

“The relationship between poor dietary quality and cardiovascular risk factors is well-established. While this is a small, preliminary study, it’s an important topic to continue to investigate and help us understand ways we can influence dietary behaviors to promote optimal cardiovascular health for all ages,” said Dr. Arnett, executive vice president for academic affairs and provost at the University of South Carolina, Columbia.

Offering perspective on the study, Taylor C. Wallace, PhD, with the department of nutrition and food studies, George Mason University, Fairfax, Va., made the point that “food processing and ultraprocessed foods aren’t the problem. The problem is the types of ultraprocessed foods on the market that people consume.”

“Remember, non-fat, vitamin D fortified yogurt is also ‘ultra-processed,’ and it’s very healthy,” he told this news organization.

Dr. Wallace said that it’s no surprise that teens increased their intake of UPFs during the pandemic.

“Of course, people increased processed food intake during the pandemic. Processed foods are shelf stable at a time when grocery stores were running out of things and supply chains weren’t able to keep up. Also, many were depressed and use food to indulge,” he noted.

The study had no funding. Ms. Balhara has no relevant disclosures. Dr. Wallace is principal and CEO of Think Healthy Group; chief food and nutrition scientist with Produce for Better Health Foundation; editor, Journal of Dietary Supplements; deputy editor, Journal of the American College of Nutrition; nutrition section editor, Annals of Medicine; and an advisory board member with Forbes Health.

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

Certain ultraprocessed foods – especially candy, prepackaged pastries, and frozen desserts – could be “gateway foods” for adolescents, leading them to increase their intake of other unhealthy foods, a new study suggests.

“For teens, gateway ultraprocessed foods (candy, store pastries, frozen desserts) should be prioritized for preventive dietary interventions as they increase intake across all other UPFs,” lead researcher Maria Balhara said in an interview.

“The good news,” said Ms. Balhara, is that even small changes, such as reducing how often gateway foods are consumed, may reduce overall intake of unhealthy foods and have a “big impact” on overall health.

Ms. Balhara has a unique perspective on adolescent eating habits: She’s 16 years old, from Florida, and conducted the study while dual-enrolled at Broward College and Cooper City High School.

Her study was released Sept. 7 ahead of presentation at the American Heart Association Hypertension Scientific Sessions 2022 in San Diego.
 

Blame the pandemic?

Over the past 30 years, there’s been a steady increase in consumption of UPFs worldwide, coupled with mounting evidence that diets rich in UPFs raise the risk for several chronic diseases, including weight gain, hypertension, and increased risk for heart disease and premature death.

For her research, Ms. Balhara asked 315 teenagers (42% male) from 12 high schools in South Florida how often they consumed UPFs over two time periods – before COVID in 2019 and after COVID restrictions were eased in 2022 – using a survey that she developed called the Processed Intake Evaluation (PIE).

More than 2 in 5 teens (43%) increased their consumption of UPFs between 2019 and 2022.

During this time, increased consumption of frozen desserts was associated with an 11% increase in consumption of all other UPFs, whereas increased consumption of prepackaged pastries and candy was associated with a 12% and 31%, respectively, increase in consumption of all other UPFs, Ms. Balhara found.

Encouragingly, 57% of teens decreased their consumption of UPFs between 2019 and 2022.

During this time, decreased consumption of processed meats was associated with an 8% decrease in consumption of all other UPFs, whereas decreased consumption of white bread and biscuits was associated with a 9% and 10%, respectively, decrease in consumption of all other UPFs.

The results provide initial evidence for a new “gateway food model,” Ms. Balhara told this news organization, in which certain UPFs, when increased, drive overall consumption of all UPFs among teens.

Limitations of the study include the self-reported dietary data and the fact that the PIE survey has not been validated.
 

Not all UPFs are bad

“I commend Ms. Balhara for her project, which highlights the importance of establishing good dietary patterns early in life,” Donna K. Arnett, PhD, past president of the AHA, said in a news release.

“The relationship between poor dietary quality and cardiovascular risk factors is well-established. While this is a small, preliminary study, it’s an important topic to continue to investigate and help us understand ways we can influence dietary behaviors to promote optimal cardiovascular health for all ages,” said Dr. Arnett, executive vice president for academic affairs and provost at the University of South Carolina, Columbia.

Offering perspective on the study, Taylor C. Wallace, PhD, with the department of nutrition and food studies, George Mason University, Fairfax, Va., made the point that “food processing and ultraprocessed foods aren’t the problem. The problem is the types of ultraprocessed foods on the market that people consume.”

“Remember, non-fat, vitamin D fortified yogurt is also ‘ultra-processed,’ and it’s very healthy,” he told this news organization.

Dr. Wallace said that it’s no surprise that teens increased their intake of UPFs during the pandemic.

“Of course, people increased processed food intake during the pandemic. Processed foods are shelf stable at a time when grocery stores were running out of things and supply chains weren’t able to keep up. Also, many were depressed and use food to indulge,” he noted.

The study had no funding. Ms. Balhara has no relevant disclosures. Dr. Wallace is principal and CEO of Think Healthy Group; chief food and nutrition scientist with Produce for Better Health Foundation; editor, Journal of Dietary Supplements; deputy editor, Journal of the American College of Nutrition; nutrition section editor, Annals of Medicine; and an advisory board member with Forbes Health.

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

Doctors may want to advise parents against giving their infants lactose-reduced infant formula unless absolutely necessary, because doing so may be setting babies up for an increased risk of obesity in toddlerhood, new research shows.

Infants who drink infant formula instead of breast milk already carry an increased risk of obesity. But the new study, published in The American Journal of Clinical Nutrition, found a difference in types of formula and obesity outcomes for children.

Babies under 1 year who received lactose-reduced formula made partially of corn syrup solids were at a 10% greater risk (risk ratio, 1.10; 95% confidence interval, 1.02, 1.20; P = .02) of being obese by age 2 than infants who received regular cow’s milk formula.

“This is even another reason to not use a low-lactose formula,” said Mark R. Corkins, MD, division chief of pediatric gastroenterology, hepatology, and nutrition at the University of Tennessee Health Science Center, Memphis, who was not involved in the study. “Parents think if babies are fussy, or they spit up, they have lactose intolerance, but if you look at the actual numbers, lactose intolerance in infants is rare.”

Actual lactose intolerance in infancy is the result of a newborn receiving the same mutated gene from both parents, called congenital lactase deficiency, said Dr. Corkins.

“The reason the low-lactose formulas are even on the market is because parents want them, and they think their kid is lactose intolerant, but they are not,” Dr. Corkins said.

Researchers from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in southern California and the University of Southern California, Los Angeles, analyzed data from over 15,000 infants in southern California enrolled in WIC.

Records from infants born between Sept. 2012 and March 2016 were separated into two groups: infants that had stopped breastfeeding by month 3 and had started reduced-lactose formula and infants who received all other forms of formula. Over 80% of infants in both groups were Hispanic.

Infants who received the reduced-lactose formula with corn syrup solids were at an 8% increased risk of obesity by age 3 (RR = 1.08; 95% CI, 1.02, 1.15; P = .01), compared with children who received regular cow’s milk formula, and a 7% increased risk by age 4 (RR = 1.07; 95% CI; 1.01, 1.14; P = .01).

Tara Williams, MD, pediatrician and breastfeeding specialist associated with the Florida Chapter of American Academy of Pediatrics, said the findings should make pediatricians, parents, and others pause and consider what infant formulas contain.

pdnews@mdedge.com

Doctors may want to advise parents against giving their infants lactose-reduced infant formula unless absolutely necessary, because doing so may be setting babies up for an increased risk of obesity in toddlerhood, new research shows.

Infants who drink infant formula instead of breast milk already carry an increased risk of obesity. But the new study, published in The American Journal of Clinical Nutrition, found a difference in types of formula and obesity outcomes for children.

Babies under 1 year who received lactose-reduced formula made partially of corn syrup solids were at a 10% greater risk (risk ratio, 1.10; 95% confidence interval, 1.02, 1.20; P = .02) of being obese by age 2 than infants who received regular cow’s milk formula.

“This is even another reason to not use a low-lactose formula,” said Mark R. Corkins, MD, division chief of pediatric gastroenterology, hepatology, and nutrition at the University of Tennessee Health Science Center, Memphis, who was not involved in the study. “Parents think if babies are fussy, or they spit up, they have lactose intolerance, but if you look at the actual numbers, lactose intolerance in infants is rare.”

Actual lactose intolerance in infancy is the result of a newborn receiving the same mutated gene from both parents, called congenital lactase deficiency, said Dr. Corkins.

“The reason the low-lactose formulas are even on the market is because parents want them, and they think their kid is lactose intolerant, but they are not,” Dr. Corkins said.

Researchers from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in southern California and the University of Southern California, Los Angeles, analyzed data from over 15,000 infants in southern California enrolled in WIC.

Records from infants born between Sept. 2012 and March 2016 were separated into two groups: infants that had stopped breastfeeding by month 3 and had started reduced-lactose formula and infants who received all other forms of formula. Over 80% of infants in both groups were Hispanic.

Infants who received the reduced-lactose formula with corn syrup solids were at an 8% increased risk of obesity by age 3 (RR = 1.08; 95% CI, 1.02, 1.15; P = .01), compared with children who received regular cow’s milk formula, and a 7% increased risk by age 4 (RR = 1.07; 95% CI; 1.01, 1.14; P = .01).

Tara Williams, MD, pediatrician and breastfeeding specialist associated with the Florida Chapter of American Academy of Pediatrics, said the findings should make pediatricians, parents, and others pause and consider what infant formulas contain.

pdnews@mdedge.com

Doctors may want to advise parents against giving their infants lactose-reduced infant formula unless absolutely necessary, because doing so may be setting babies up for an increased risk of obesity in toddlerhood, new research shows.

Infants who drink infant formula instead of breast milk already carry an increased risk of obesity. But the new study, published in The American Journal of Clinical Nutrition, found a difference in types of formula and obesity outcomes for children.

Babies under 1 year who received lactose-reduced formula made partially of corn syrup solids were at a 10% greater risk (risk ratio, 1.10; 95% confidence interval, 1.02, 1.20; P = .02) of being obese by age 2 than infants who received regular cow’s milk formula.

“This is even another reason to not use a low-lactose formula,” said Mark R. Corkins, MD, division chief of pediatric gastroenterology, hepatology, and nutrition at the University of Tennessee Health Science Center, Memphis, who was not involved in the study. “Parents think if babies are fussy, or they spit up, they have lactose intolerance, but if you look at the actual numbers, lactose intolerance in infants is rare.”

Actual lactose intolerance in infancy is the result of a newborn receiving the same mutated gene from both parents, called congenital lactase deficiency, said Dr. Corkins.

“The reason the low-lactose formulas are even on the market is because parents want them, and they think their kid is lactose intolerant, but they are not,” Dr. Corkins said.

Researchers from the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) in southern California and the University of Southern California, Los Angeles, analyzed data from over 15,000 infants in southern California enrolled in WIC.

Records from infants born between Sept. 2012 and March 2016 were separated into two groups: infants that had stopped breastfeeding by month 3 and had started reduced-lactose formula and infants who received all other forms of formula. Over 80% of infants in both groups were Hispanic.

Infants who received the reduced-lactose formula with corn syrup solids were at an 8% increased risk of obesity by age 3 (RR = 1.08; 95% CI, 1.02, 1.15; P = .01), compared with children who received regular cow’s milk formula, and a 7% increased risk by age 4 (RR = 1.07; 95% CI; 1.01, 1.14; P = .01).

Tara Williams, MD, pediatrician and breastfeeding specialist associated with the Florida Chapter of American Academy of Pediatrics, said the findings should make pediatricians, parents, and others pause and consider what infant formulas contain.

pdnews@mdedge.com

Women giving birth for the first time have significantly higher odds of developing gestational diabetes if they have a high polygenic risk score (PRS) and low physical activity, new data suggest.

Researchers, led by Kymberleigh A. Pagel, PhD, with the department of computer science, Indiana University, Bloomington, concluded that physical activity early in pregnancy is associated with reduced risk of gestational diabetes and may help women who are at high risk because of genetic predisposition, age, family history of diabetes, and body mass index.

The researchers included 3,533 women in the analysis (average age, 28.6 years) which was a subcohort of a larger study. They found that physical activity’s association with lower gestational diabetes risk “was particularly significant in individuals who were genetically predisposed to diabetes through PRS or family history,” the authors wrote.

Women with high PRS and low level of physical activity had three times the odds of developing gestational diabetes (odds ratio, 3.4; 95% confidence interval, 2.3-5.3).

Those with high PRS and moderate to high activity levels in early pregnancy (metabolic equivalents of task [METs] of at least 450) had gestational diabetes risk similar to that of the general population, according to the researchers.

The findings were published in JAMA Network Open.

Maisa Feghali, MD, a maternal-fetal specialist at the University of Pittsburgh Medical Center, who was not part of the study, said in an interview she found the link of physical activity and compensation for high predisposition to gestational diabetes most interesting.

“That’s interesting because a lot of studies that have looked at prevention of gestational diabetes either through limited weight gain or through some form of counseling on physical activity have not really shown any benefit,” she noted. “It might just be it’s not just one size fits all and it may be that physical activity is mostly beneficial in those with a high predisposition.”

Research in this area is particularly important as 7% of pregnancies in the United States each year are affected by gestational diabetes and the risk for developing type 2 diabetes “has doubled in the past decade among patients with GD [gestational diabetes],” the authors wrote.

Researchers looked at risks for gestational diabetes in high-risk subgroups, including women who had a body mass index of more than 25 kg/m² or were at least 35 years old. In that group, women who were either in the in the top 25th percentile for PRS or had low physical activity (METs less than 450) had from 25% to 75% greater risk of developing gestational diabetes.

The findings are consistent with previous research and suggest exercise interventions may be important in improving pregnancy outcomes, the authors wrote.

Christina Han, MD, division director for maternal-fetal medicine at University of California, Los Angeles, who was not part of the study, pointed out several limitations of the study, however.

One of the biggest limitations, she said, was that “they excluded two-thirds of the original study. Essentially, they took only Caucasian [White] patients, which is about one-third of the study.” Additionally, the cohort was made up of people who had never had babies.

“Lots of our gestational diabetes patients are not first-time moms, so this makes the generalizability of the study very limited,” Dr. Han said.

She added that none of the sites where the study was conducted were in the South or Northwest, which also adds questions about generalizability.

Dr. Feghali and Dr. Han reported no relevant financial relationships.

Women giving birth for the first time have significantly higher odds of developing gestational diabetes if they have a high polygenic risk score (PRS) and low physical activity, new data suggest.

Researchers, led by Kymberleigh A. Pagel, PhD, with the department of computer science, Indiana University, Bloomington, concluded that physical activity early in pregnancy is associated with reduced risk of gestational diabetes and may help women who are at high risk because of genetic predisposition, age, family history of diabetes, and body mass index.

The researchers included 3,533 women in the analysis (average age, 28.6 years) which was a subcohort of a larger study. They found that physical activity’s association with lower gestational diabetes risk “was particularly significant in individuals who were genetically predisposed to diabetes through PRS or family history,” the authors wrote.

Women with high PRS and low level of physical activity had three times the odds of developing gestational diabetes (odds ratio, 3.4; 95% confidence interval, 2.3-5.3).

Those with high PRS and moderate to high activity levels in early pregnancy (metabolic equivalents of task [METs] of at least 450) had gestational diabetes risk similar to that of the general population, according to the researchers.

The findings were published in JAMA Network Open.

Maisa Feghali, MD, a maternal-fetal specialist at the University of Pittsburgh Medical Center, who was not part of the study, said in an interview she found the link of physical activity and compensation for high predisposition to gestational diabetes most interesting.

“That’s interesting because a lot of studies that have looked at prevention of gestational diabetes either through limited weight gain or through some form of counseling on physical activity have not really shown any benefit,” she noted. “It might just be it’s not just one size fits all and it may be that physical activity is mostly beneficial in those with a high predisposition.”

Research in this area is particularly important as 7% of pregnancies in the United States each year are affected by gestational diabetes and the risk for developing type 2 diabetes “has doubled in the past decade among patients with GD [gestational diabetes],” the authors wrote.

Researchers looked at risks for gestational diabetes in high-risk subgroups, including women who had a body mass index of more than 25 kg/m² or were at least 35 years old. In that group, women who were either in the in the top 25th percentile for PRS or had low physical activity (METs less than 450) had from 25% to 75% greater risk of developing gestational diabetes.

The findings are consistent with previous research and suggest exercise interventions may be important in improving pregnancy outcomes, the authors wrote.

Christina Han, MD, division director for maternal-fetal medicine at University of California, Los Angeles, who was not part of the study, pointed out several limitations of the study, however.

One of the biggest limitations, she said, was that “they excluded two-thirds of the original study. Essentially, they took only Caucasian [White] patients, which is about one-third of the study.” Additionally, the cohort was made up of people who had never had babies.

“Lots of our gestational diabetes patients are not first-time moms, so this makes the generalizability of the study very limited,” Dr. Han said.

She added that none of the sites where the study was conducted were in the South or Northwest, which also adds questions about generalizability.

Dr. Feghali and Dr. Han reported no relevant financial relationships.

Women giving birth for the first time have significantly higher odds of developing gestational diabetes if they have a high polygenic risk score (PRS) and low physical activity, new data suggest.

Researchers, led by Kymberleigh A. Pagel, PhD, with the department of computer science, Indiana University, Bloomington, concluded that physical activity early in pregnancy is associated with reduced risk of gestational diabetes and may help women who are at high risk because of genetic predisposition, age, family history of diabetes, and body mass index.

The researchers included 3,533 women in the analysis (average age, 28.6 years) which was a subcohort of a larger study. They found that physical activity’s association with lower gestational diabetes risk “was particularly significant in individuals who were genetically predisposed to diabetes through PRS or family history,” the authors wrote.

Women with high PRS and low level of physical activity had three times the odds of developing gestational diabetes (odds ratio, 3.4; 95% confidence interval, 2.3-5.3).

Those with high PRS and moderate to high activity levels in early pregnancy (metabolic equivalents of task [METs] of at least 450) had gestational diabetes risk similar to that of the general population, according to the researchers.

The findings were published in JAMA Network Open.

Maisa Feghali, MD, a maternal-fetal specialist at the University of Pittsburgh Medical Center, who was not part of the study, said in an interview she found the link of physical activity and compensation for high predisposition to gestational diabetes most interesting.

“That’s interesting because a lot of studies that have looked at prevention of gestational diabetes either through limited weight gain or through some form of counseling on physical activity have not really shown any benefit,” she noted. “It might just be it’s not just one size fits all and it may be that physical activity is mostly beneficial in those with a high predisposition.”

Research in this area is particularly important as 7% of pregnancies in the United States each year are affected by gestational diabetes and the risk for developing type 2 diabetes “has doubled in the past decade among patients with GD [gestational diabetes],” the authors wrote.

Researchers looked at risks for gestational diabetes in high-risk subgroups, including women who had a body mass index of more than 25 kg/m² or were at least 35 years old. In that group, women who were either in the in the top 25th percentile for PRS or had low physical activity (METs less than 450) had from 25% to 75% greater risk of developing gestational diabetes.

The findings are consistent with previous research and suggest exercise interventions may be important in improving pregnancy outcomes, the authors wrote.

Christina Han, MD, division director for maternal-fetal medicine at University of California, Los Angeles, who was not part of the study, pointed out several limitations of the study, however.

One of the biggest limitations, she said, was that “they excluded two-thirds of the original study. Essentially, they took only Caucasian [White] patients, which is about one-third of the study.” Additionally, the cohort was made up of people who had never had babies.

“Lots of our gestational diabetes patients are not first-time moms, so this makes the generalizability of the study very limited,” Dr. Han said.

She added that none of the sites where the study was conducted were in the South or Northwest, which also adds questions about generalizability.

Dr. Feghali and Dr. Han reported no relevant financial relationships.

A baby’s weight and neurodevelopment in the first 2 years of life could be influenced by maternal fat metabolism in the early stages of pregnancy, according to a study.

Patterns of fetal abdominal growth were associated with maternal lipid metabolites that tracked newborn growth, adiposity, and development into childhood and could be identified as early as the 5th month of pregnancy, according to researchers at the University of Oxford, working with colleagues at the University of California.

These fetal growth patterns were also associated with blood flow and nutrient transfer by the placenta, demonstrating a complex interaction between maternal and fetal nutrition early in pregnancy, with implications for postnatal weight and health in later life, they suggested.

Stephen Kennedy, MD, professor of reproductive medicine at the University of Oxford, who co-led the investigation, said it had “provided valuable new insights into the biological origins of childhood obesity, which is one of the most pressing public health issues facing governments around the world.”
 

International study

The prospective observational study, published in The Lancet Diabetes and Endocrinology, involved 3,598 pregnant women from six countries – Brazil, Kenya, Pakistan, South Africa, Thailand, and the United Kingdom – aged 18 and older and with a BMI of less than 35 kg/m². The women were monitored using regular fetal ultrasound scans and metabolomic analysis of early pregnancy maternal blood and umbilical cord venous blood at the time of birth.

Their infants, who were singletons, and conceived naturally, were then followed for 2 years to assess their growth and development.

Fetal abdominal circumference growth was found to accelerate or decelerate within “a crucial 20-25 week gestational age window” that followed 4 trajectories of faltering growth, early accelerating growth, late accelerating growth, or median growth. These traits were matched by fetus-placenta blood flow patterns throughout pregnancy and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood, researchers said.

Overall, 709 maternal metabolites had a positive effect for the faltering growth phenotype, and 54 for the early accelerating growth phenotype, whilst 31 had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype.

The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was “highly abundant” in the early accelerating growth phenotype group.
 

‘A unique insight’

Aris Papageorghiou, professor of Fetal Medicine at the University of Oxford, who co-led the research, said: “This study provides evidence of distinct patterns of fetal abdominal growth and placental transfer and how they relate to longer term health. The finding of an association with maternal lipid metabolism early in pregnancy also provides unique insights into how the mother’s health and diet influence her child’s adiposity.”

First author José Villar, MD, professor of perinatal medicine at Oxford, said: “The study complements our previous work that identified fetal head growth trajectories associated with different developmental, behavioral, visual, and growth outcomes at 2 years of age.” Taken together, “the growth of babies’ bodies and brain[s] track separately and early – while still within the womb,” he said.

According to Dr. Kennedy, the latest results “could contribute to earlier identification of infants at risk of obesity” and urged policymakers to “take notice of these findings in their efforts to prevent the oncoming epidemic of obesity, with all its likely adverse social and economic consequences.”

Funding for the study was provided by the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape UK.

A baby’s weight and neurodevelopment in the first 2 years of life could be influenced by maternal fat metabolism in the early stages of pregnancy, according to a study.

Patterns of fetal abdominal growth were associated with maternal lipid metabolites that tracked newborn growth, adiposity, and development into childhood and could be identified as early as the 5th month of pregnancy, according to researchers at the University of Oxford, working with colleagues at the University of California.

These fetal growth patterns were also associated with blood flow and nutrient transfer by the placenta, demonstrating a complex interaction between maternal and fetal nutrition early in pregnancy, with implications for postnatal weight and health in later life, they suggested.

Stephen Kennedy, MD, professor of reproductive medicine at the University of Oxford, who co-led the investigation, said it had “provided valuable new insights into the biological origins of childhood obesity, which is one of the most pressing public health issues facing governments around the world.”
 

International study

The prospective observational study, published in The Lancet Diabetes and Endocrinology, involved 3,598 pregnant women from six countries – Brazil, Kenya, Pakistan, South Africa, Thailand, and the United Kingdom – aged 18 and older and with a BMI of less than 35 kg/m². The women were monitored using regular fetal ultrasound scans and metabolomic analysis of early pregnancy maternal blood and umbilical cord venous blood at the time of birth.

Their infants, who were singletons, and conceived naturally, were then followed for 2 years to assess their growth and development.

Fetal abdominal circumference growth was found to accelerate or decelerate within “a crucial 20-25 week gestational age window” that followed 4 trajectories of faltering growth, early accelerating growth, late accelerating growth, or median growth. These traits were matched by fetus-placenta blood flow patterns throughout pregnancy and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood, researchers said.

Overall, 709 maternal metabolites had a positive effect for the faltering growth phenotype, and 54 for the early accelerating growth phenotype, whilst 31 had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype.

The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was “highly abundant” in the early accelerating growth phenotype group.
 

‘A unique insight’

Aris Papageorghiou, professor of Fetal Medicine at the University of Oxford, who co-led the research, said: “This study provides evidence of distinct patterns of fetal abdominal growth and placental transfer and how they relate to longer term health. The finding of an association with maternal lipid metabolism early in pregnancy also provides unique insights into how the mother’s health and diet influence her child’s adiposity.”

First author José Villar, MD, professor of perinatal medicine at Oxford, said: “The study complements our previous work that identified fetal head growth trajectories associated with different developmental, behavioral, visual, and growth outcomes at 2 years of age.” Taken together, “the growth of babies’ bodies and brain[s] track separately and early – while still within the womb,” he said.

According to Dr. Kennedy, the latest results “could contribute to earlier identification of infants at risk of obesity” and urged policymakers to “take notice of these findings in their efforts to prevent the oncoming epidemic of obesity, with all its likely adverse social and economic consequences.”

Funding for the study was provided by the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape UK.

A baby’s weight and neurodevelopment in the first 2 years of life could be influenced by maternal fat metabolism in the early stages of pregnancy, according to a study.

Patterns of fetal abdominal growth were associated with maternal lipid metabolites that tracked newborn growth, adiposity, and development into childhood and could be identified as early as the 5th month of pregnancy, according to researchers at the University of Oxford, working with colleagues at the University of California.

These fetal growth patterns were also associated with blood flow and nutrient transfer by the placenta, demonstrating a complex interaction between maternal and fetal nutrition early in pregnancy, with implications for postnatal weight and health in later life, they suggested.

Stephen Kennedy, MD, professor of reproductive medicine at the University of Oxford, who co-led the investigation, said it had “provided valuable new insights into the biological origins of childhood obesity, which is one of the most pressing public health issues facing governments around the world.”
 

International study

The prospective observational study, published in The Lancet Diabetes and Endocrinology, involved 3,598 pregnant women from six countries – Brazil, Kenya, Pakistan, South Africa, Thailand, and the United Kingdom – aged 18 and older and with a BMI of less than 35 kg/m². The women were monitored using regular fetal ultrasound scans and metabolomic analysis of early pregnancy maternal blood and umbilical cord venous blood at the time of birth.

Their infants, who were singletons, and conceived naturally, were then followed for 2 years to assess their growth and development.

Fetal abdominal circumference growth was found to accelerate or decelerate within “a crucial 20-25 week gestational age window” that followed 4 trajectories of faltering growth, early accelerating growth, late accelerating growth, or median growth. These traits were matched by fetus-placenta blood flow patterns throughout pregnancy and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood, researchers said.

Overall, 709 maternal metabolites had a positive effect for the faltering growth phenotype, and 54 for the early accelerating growth phenotype, whilst 31 had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype.

The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was “highly abundant” in the early accelerating growth phenotype group.
 

‘A unique insight’

Aris Papageorghiou, professor of Fetal Medicine at the University of Oxford, who co-led the research, said: “This study provides evidence of distinct patterns of fetal abdominal growth and placental transfer and how they relate to longer term health. The finding of an association with maternal lipid metabolism early in pregnancy also provides unique insights into how the mother’s health and diet influence her child’s adiposity.”

First author José Villar, MD, professor of perinatal medicine at Oxford, said: “The study complements our previous work that identified fetal head growth trajectories associated with different developmental, behavioral, visual, and growth outcomes at 2 years of age.” Taken together, “the growth of babies’ bodies and brain[s] track separately and early – while still within the womb,” he said.

According to Dr. Kennedy, the latest results “could contribute to earlier identification of infants at risk of obesity” and urged policymakers to “take notice of these findings in their efforts to prevent the oncoming epidemic of obesity, with all its likely adverse social and economic consequences.”

Funding for the study was provided by the Bill and Melinda Gates Foundation.

A version of this article first appeared on Medscape UK.

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.

Polycystic ovary syndrome (PCOS) affects an estimated 8%-13% of women, and yet “it has been quite a black box for many years,” as Margo Hudson, MD, an assistant professor of endocrinology, diabetes, and hypertension at Harvard Medical School, Boston, puts it. That black box encompasses not only uncertainty about the etiology and pathophysiology of the condition but even what constitutes a diagnosis.

Even the international guidelines on PCOS management endorsed by the American Society for Reproductive Medicine – a document developed over 15 months with the input of 37 medical organizations covering 71 countries – notes that PCOS diagnosis is “controversial and assessment and management are inconsistent.” The result, the guidelines note, is that “the needs of women with PCOS are not being adequately met.”

One of the earliest diagnostic criteria, defined in 1990 by the National Institutes of Health, required only hyperandrogenism and irregular menstruation. Then the 2003 Rotterdam Criteria added presence of polycystic ovaries on ultrasound as a third criterion. Then the Androgen Excess Society determined that PCOS required presence of hyperandrogenism with either polycystic ovaries or oligo/amenorrhea anovulation. Yet the Endocrine Society notes that excess androgen levels are seen in 60%-80% of those with PCOS, suggesting it’s not an essential requirement for diagnosis, leaving most to diagnose it in people who have two of the three key criteria. The only real agreement on diagnosis is the need to eliminate other potential diagnoses first, making PCOS always a diagnosis of exclusion.

Further, though PCOS is known as the leading cause of infertility in women, it is more than a reproductive condition, with metabolic and psychological features as well. Then there is the range of comorbidities, none of which occur in all patients with PCOS but all of which occur in a majority and which are themselves interrelated. Insulin resistance is a common feature, occurring in 50%-70% of people with PCOS. Accordingly, metabolic syndrome occurs in at least a third of people with PCOS and type 2 diabetes prevalence is higher in those with PCOS as well.

Obesity occurs in an estimated 80% of women with PCOS in the United States, though it affects only about 50% of women with PCOS outside the United States, and those with PCOS have an increased risk of hypertension. Mood disorders, particularly anxiety and depression but also, to a lesser extent, bipolar disorder and obsessive-compulsive disorder, are more likely in people with PCOS. And given that these comorbidities are all cardiovascular risk factors, it’s unsurprising that recent studies are finding those with PCOS to be at greater risk for cardiometabolic disease and major cardiovascular events.

“The reality is that PCOS is a heterogenous entity. It’s not one thing – it’s a syndrome,” Lubna Pal, MBBS, a professor of ob.gyn. and director of the PCOS Program at Yale University, New Haven, Conn., said in an interview. A whole host of factors are likely playing a role in the causes of PCOS, and those factors interact differently within different people. “We’re looking at things like lipid metabolism, fetal origins, the gut microbiome, genetics, epigenetics, and then dietary and environmental factors,” Nichole Tyson, MD, division chief of pediatric and adolescent gynecology and a clinical associate professor at Stanford (Calif.) Medicine Children’s Health, said in an interview. And most studies have identified associations that may or may not be causal. Take, for example, endocrine disruptors. BPA levels have been shown to be higher in women with PCOS than women without, but that correlation may or may not be related to the etiology of the condition.
 

The hypothalamic-pituitary-gonadal axis

In trying to understand the pathophysiology of the condition, much of the latest research has zeroed in on potential mechanisms in the hypothalamic-pituitary-gonadal axis. “A consistent feature of PCOS is disordered gonadotropin secretion with elevated mean LH [luteinizing hormone], low or low normal FSH [follicle-stimulating hormone], and a persistently rapid frequency of GnRH [gonadotropin-releasing hormone] pulse secretion,” wrote authors of a scientific statement on aspects of PCOS.

“I think the balance is heading more to central neurologic control of the reproductive system and that disturbances there impact the GnRH cells in the hypothalamus, which then go on to give us the findings that we can measure peripherally with the LH-FSH ratio,” Dr. Hudson said in an interview.

The increased LH levels are thought to be a major driver of increased androgen levels. Current thinking suggests that the primary driver of increased LH is GnRH pulsatility, supported not only by human studies but by animal models as well. This leads to the question of what drives GnRH dysregulation. One hypothesis posits that GABA neurons play a role here, given findings that GABA levels in cerebrospinal fluid were higher in women with PCOS than those with normal ovulation.

But the culprit garnering the most attention is kisspeptin, a protein encoded by the KISS1 gene that stimulates GnRH neurons and has been linked to regulation of LH and FSH secretion. Kisspeptin, along with neurokinin B and dynorphin, is part of the triumvirate that comprises KNDy neurons, also recently implicated in menopausal vasomotor symptoms. Multiple systematic reviewsand meta-analyses have found a correlation between higher kisspeptin levels in the blood and higher circulating LH levels, regardless of body mass index. While kisspeptin is expressed in several tissues, including liver, pancreas, gonad, and adipose, it’s neural kisspeptin signaling that appears most likely to play a role in activating GnRH hormones and disrupting normal function of the hypothalamic-pituitary-gonadal axis.

But as noted, in at least one systematic review of kisspeptin and PCOS, “findings from animal studies suggest that kisspeptin levels are not increased in all subtypes of PCOS.” And another review found “altered” levels of kisspeptin levels in non-PCOS patients who had obesity, potentially raising questions about any associations between kisspeptin and obesity or insulin resistance.
 

Remaining chicken-and-egg questions

A hallmark of PCOS has long been, and continues to be, the string of chicken-or-egg questions that plague understanding of it. One of these is how depression and anxiety fit into the etiology of PCOS. Exploring the role of specific neurons that may overstimulate GnRH pulsatility may hold clues to a common underlying mechanism for the involvement of depression and anxiety in patients with PCOS, Dr. Hudson speculated. While previous assumptions often attributed depression and anxiety in PCOS to the symptoms – such as thin scalp hair and increased facial hair, excess weight, acne, and irregular periods – Dr. Hudson pointed out that women can address many of these symptoms with laser hair removal, weight loss, acne treatment, and similar interventions, yet they still have a lot of underlying mental health issues.

It’s also unclear whether metabolic factors so common with PCOS, particularly insulin resistance and obesity, are a result of the condition or are contributors to it. Is insulin resistance contributing to dysregulation in the neurons that interferes with normal functioning of the hypothalamic-pituitary-adrenal axis? Is abnormal functioning along this axis contributing to insulin resistance? Or neither? Or both? Or does it depend? The authors of one paper wrote that “insulin may play both direct and indirect roles in the pathogenesis of androgen excess in PCOS,” since insulin can “stimulate ovarian androgen production” and “enhance ovarian growth and follicular cyst formation in rats.”

Dr. Pal noted that “obesity itself can evolve into a PCOS-like picture,” raising questions about whether obesity or insulin resistance might be part of the causal pathway to PCOS, or whether either can trigger its development in those genetically predisposed.

“Obesity does appear to exacerbate many aspects of the PCOS phenotype, particularly those risk factors related to metabolic syndrome,” wrote the authors of a scientific statement on aspects of PCOS, but they add that “it is currently debated whether obesity per se can cause PCOS.” While massive weight loss in those with PCOS and obesity has improved multiple reproductive and metabolic issues, it hasn’t resolved all of them, they write.

Dr. Hudson said she expects there’s “some degree of appetite dysregulation and metabolic dysregulation” that contributes, but then there are other women who don’t have much of an appetite or overeat and still struggle with their weight. Evidence has also found insulin resistance in women of normal weight with PCOS. “There may be some kind of metabolic dysregulation that they have at some level, and others are clearly bothered by overeating,” Dr. Hudson said.

Similarly, it’s not clear whether the recent discovery of increased cardiovascular risks in people with PCOS is a result of the comorbidities so common with PCOS, such as obesity, or whether an underlying mechanism links the cardiovascular risk and the dysregulation of hormones. Dr. Pal would argue that, again, it’s probably both, depending on the patient.

Then there is the key feature of hyperandrogenemia. “An outstanding debate is whether the elevated androgens in PCOS women are merely a downstream endocrine response to hyperactive GnRH and LH secretion driving the ovary, or do the elevated androgens themselves act in the brain (or pituitary) during development and/or adulthood to sculpt and maintain the hypersecretion of GnRH and LH?” wrote Eulalia A. Coutinho, PhD, and Alexander S. Kauffman, PhD, in a 2019 review of the brain’s role in PCOS.

These problems may be bidirectional or part of various feedback loops. Sleep apnea is more common in people with PCOS, Dr. Tyson noted, but sleep apnea is also linked to cardiovascular, metabolic, and depression risks, and depression can play a role in obesity, which increases the risk of obstructive sleep apnea. “So you’re in this vicious cycle,” Dr. Tyson said. That’s why she also believes it’s important to change the dialogue and perspective on PCOS, to reduce the stigma attached to it, and work with patients to empower them in treating its symptoms and reducing their risk of comorbidities.
 

Recent and upcoming changes in treatment

Current treatment of PCOS already changes according to the symptoms posing the greatest problems at each stage of a person’s life, Dr. Hudson said. Younger women tend to be more bothered about the cosmetic effects of PCOS, including hair growth patterns and acne, but as they grow out of adolescence and into their 20s and 30s, infertility becomes a bigger concern for many. Then, as they start approaching menopause, metabolic and cardiovascular issues take the lead, with more of a focus on lipids, diabetes risk, and heart health.

In some ways, management of PCOS hasn’t changed much in the past several decades, except in an increased awareness of the metabolic and cardiovascular risks, which has led to more frequent screening to catch potential conditions earlier in life. What has changed, however, is improvements in the treatments used for symptoms, such as expanded bariatric surgery options and GLP-1 agonists for treating obesity. Other examples include better options for menstrual management, such as new progesterone IUDs, and optimized fertility treatments, Dr. Tyson said.

“I think with more of these large-scale studies about the pathophysiology of PCOS and how it may look in different people and the different outcomes, we may be able to tailor our treatments even further,” Dr. Tyson said. She emphasized the importance of identifying the condition early, particularly in adolescents, even if it’s identifying young people at risk for the condition rather than actually having it yet.

Early identification “gives us this chance to do a lot of preventative care and motivate older teens to have a great lifestyle, work on their diet and exercise, and manage cardiovascular” risk factors, Dr. Tyson said.

“What we do know and recognize is that there’s so many spokes to this PCOS wheel that there really should be a multidisciplinary approach to care,” Dr. Tyson said. “When I think about who would be the real doctors for patients with PCOS, these would be gynecologists, endocrinologists, dermatologists, nutritionists, psychologists, sleep specialists, and primary care at a minimum.”

Dr. Pal worries that the label of PCOS leaves it in the laps of ob.gyns. whereas, “if it was called something else, everybody would be involved in being vigilant and managing those patients.” She frequently reiterated that the label of PCOS is less important than ensuring clinicians treat the symptoms that most bother the patient.

And even if kisspeptin does play a causal role in PCOS for some patients, it’s only a subset of individuals with PCOS who would benefit from therapies developed to target it. Given the complexity of the syndrome and its many manifestations, a “galaxy of pathways” are involved in different potential subtypes of the condition. “You can’t treat PCOS as one entity,” Dr. Pal said.

Still, Dr. Hudson is optimistic that the research into potential neuroendocrine contributions to PCOS will yield therapies that go beyond just managing symptoms.

“There aren’t a lot of treatments available yet, but there may be some on the horizon,” Dr. Hudson said. “We’re still in this very primitive stage in terms of therapeutics, where we’re only addressing specific symptoms, and we haven’t been able to really address the underlying cause because we haven’t understood it as well and because we don’t have therapies that can target it,” Dr. Hudson said. “But once there are therapies developed that will target some of these central mechanisms, I think it will change completely the approach to treating PCOS for patients.”

This story was updated on Sept. 6, 2022.

The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.

Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.

The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”

Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.

It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.

Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.

“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.

Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.

“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”

Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.

Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.

The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”

Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.

Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.

At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”

“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”

According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”

Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.

If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.

“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.

The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.

Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.

Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.

While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.

White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.

White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.

Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.

Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.

The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.

Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.

But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.

Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.

“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”

The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.

Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.

Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.

But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.

“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”

It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.

“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.

Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.

The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”

Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.

It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.

Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.

“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.

Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.

“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”

Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.

Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.

The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”

Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.

Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.

At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”

“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”

According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”

Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.

If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.

“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.

The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.

Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.

Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.

While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.

White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.

White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.

Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.

Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.

The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.

Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.

But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.

Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.

“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”

The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.

Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.

Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.

But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.

“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”

It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.

“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

The wife of a Northern California congressman died late in 2021 after ingesting a plant that is generally considered safe and is used as an herbal remedy for a variety of ailments, including diabetes, obesity, and high cholesterol.

Lori McClintock, the wife of U.S. Rep. Tom McClintock, died from dehydration due to gastroenteritis – an inflammation of the stomach and intestines – that was caused by “adverse effects of white mulberry leaf ingestion,” according to a report from the Sacramento County coroner that is dated March 10 but was not immediately released to the public. KHN obtained that report – in addition to the autopsy report and an amended death certificate containing an updated cause of death – in July.

The coroner’s office ruled her death an accident. The original death certificate, dated Dec. 20, 2021, listed the cause of death as “pending.”

Tom McClintock, a Republican who represents a district that spans multiple counties in northern and central California, found his 61-year-old wife unresponsive at their Elk Grove, Calif., home on Dec. 15, 2021, according to the coroner’s report. He had just returned from Washington after voting in Congress the night before.

It’s unclear from the autopsy report whether Lori McClintock took a dietary supplement containing white mulberry leaf, ate fresh or dried leaves, or drank them in a tea, but a “partially intact” white mulberry leaf was found in her stomach, according to the report.

Ms. McClintock’s death underscores the risks of the vast, booming market of dietary supplements and herbal remedies, which have grown into a $54 billion industry in the United States – one that both lawmakers and health care experts say needs more government scrutiny.

“Many people assume if that product is sold in the United States of America, somebody has inspected it, and it must be safe. Unfortunately, that’s not always true,” U.S. Sen. Richard Durbin (D-Ill.) said on the Senate floor this spring when he introduced legislation to strengthen oversight of dietary supplements.

Daniel Fabricant, CEO and president of the Natural Products Association, which represents the dietary supplements industry, questioned whether Ms. McClintock’s death was related to a supplement.

“It’s completely speculative. There’s a science to this. It’s not just what a coroner feels,” said Mr. Fabricant, who oversaw dietary supplements at the Food and Drug Administration during the Obama administration. “People unfortunately pass from dehydration every day, and there’s a lot of different reasons and a lot of different causes.”

Mr. Fabricant said it would have been ideal had the coroner or the family reported her death to the FDA so the agency could have launched an investigation.

Such reports are voluntary, and it’s not clear whether anyone reported her death to the agency. FDA spokesperson Courtney Rhodes said the agency does not discuss possible or ongoing investigations.

The FDA, Mr. Fabricant added, has a system in place to investigate deaths that might be linked to a supplement or drug. “It’s casework,” he said. “It’s good, old-fashioned police work that needs to be done.”

Tom McClintock has remained mostly silent about his wife’s death since he released a statement on Dec. 19, 2021, announcing it and gave a tribute to her at her Jan. 4 funeral. Until now, the cause of death had not been reported.

Mr. McClintock, contacted multiple times by phone and email Wednesday, was not immediately available for comment.

At his wife’s funeral, McClintock told mourners that she was fine when he spoke with her the day before he returned. She had told a friend that “she was on a roll” at a new job she loved in a Sacramento real estate office, he said, and “she was carefully dieting.”

“She just joined a gym,” he said. “At home, she was counting down the days to Christmas, wrapping all the gifts and making all the plans to make it the best family Christmas ever, and it would have been.”

According to the coroner’s report, however, the day before her death, “she had complaints of an upset stomach.”

Sacramento County spokesperson Kim Nava said via email Wednesday that the law prohibits the coroner’s office from discussing many details of specific cases. As part of any death investigation, the office “attempts to locate and review medical records and speak to family/witnesses to establish events leading up to and surrounding a death,” she said.

If any medications or supplements are found at the scene or if pertinent information is in the person’s medical records, those are passed along to the pathologist to help establish cause of death, Ms. Nava said.

“Any information the office obtains from medical records can’t be disseminated to a third party except by court order,” she said.

The leaves and fruit of the white mulberry tree, which is native to China, have been used for centuries in traditional medicine. Academic studies over the past decade have found that the extract from its leaves can lower blood sugar levels and help with weight loss. People take it in capsule or pill form, as an extract or powder. They can also brew the leaves as an herbal tea.

Lori McClintock’s reaction seems unusual. No deaths from the white mulberry plant have been reported to poison control officials in the past 10 years, according to the American Association of Poison Control Centers.

Since 2012, 148 cases of white mulberry plant ingestion were voluntarily reported to poison control officials nationally, most involving accidental ingestion by children 12 and under, said Kaitlyn Brown, clinical managing director for the association. Only one case required medical follow-up, she said.

While poison control centers track exposures to the white mulberry plant, the FDA oversees dietary supplements, such as products that contain white mulberry leaf extract. Since 2004, two cases of people sickened by mulberry supplements have been reported to the FDA, according to its database that tracks “adverse events.” It relies heavily on voluntary reports from health care professionals and consumers. At least one of those cases led to hospitalization.

White mulberry leaf can have side effects, including nausea and diarrhea, according to research. Independent lab tests ordered by the coroner’s office showed Ms. McClintock’s body had elevated levels of nitrogen, sodium, and creatinine – all signs of dehydration, according to three pathologists who reviewed the coroner’s documents, which KHN redacted to remove Ms. McClintock’s name.

White mulberry leaves “do tend to cause dehydration, and part of the uses for that can be to help someone lose weight, mostly through fluid loss, which in this case was just kind of excessive,” said D’Michelle DuPre, MD, a retired forensic pathologist and a former medical examiner in South Carolina who reviewed the documents.

Dietary supplements, which include a broad range of vitamins, herbs, and minerals, are regulated by the FDA. However, they are classified as food and don’t undergo the rigorous scientific and safety testing the government requires of prescription drugs and over-the-counter medicines.

Lawmakers aren’t proposing to put supplements into the same category as pharmaceuticals, but some say they are alarmed that neither the FDA nor the industry knows how many dietary supplements are out there – making it almost impossible for the government to oversee them and punish bad actors.

The FDA estimates 40,000 to 80,000 supplement products are on the market in the United States, and industry surveys estimate 80% of Americans use them.

Legislation by Sen. Durbin and U.S. Sen. Mike Braun (R-Ind.) would require manufacturers to register with the FDA and provide a public list of ingredients in their products, two provisions that are backed by the Council for Responsible Nutrition, another industry group that represents supplement makers.

But the council is lobbying against a provision that would require supplement makers to provide consumers with the ingredient amounts – or the blend – in their products, something they say is akin to giving a recipe to competitors. That’s proprietary information only government regulators should have access to, said Megan Olsen, the group’s senior vice president and general counsel.

Ms. Olsen explained that supplement manufacturers are regulated just like other food companies and are subject to strict labeling requirements and inspections by the FDA. They also must inform the agency about any adverse effects reported by consumers or doctors.

“Companies are testing products throughout the process, are reviewing how they’re being manufactured and what’s going into them,” Ms. Olsen said. “All of that is overseen and dictated by FDA regulation.”

The dietary supplement provisions were rolled into a larger Senate health committee bill that reauthorizes FDA programs, and senators are currently in negotiations with the House of Representatives. The Natural Products Association opposes all of the dietary supplement provisions.

Because dietary pills, teas, and other supplements are regulated as food products, manufacturers can’t advertise them as treatments or cures for health issues. But they can make claims about how the supplements affect the body. So someone who wants to lose weight or get their diabetes under control might reach for a bottle of white mulberry leaf extract because some supplement makers advertise it as a natural remedy that can lower blood sugar levels and promote weight loss.

Those kinds of claims are appealing to Americans and have been especially potent during the pandemic, as people sought to boost their immune systems and fend off COVID-19, said Debbie Petitpain, a registered dietitian nutritionist and a spokesperson for the Academy of Nutrition and Dietetics.

But dietary supplements can be dangerous and don’t affect everyone the same way. Mixing supplements and prescription medicines can compound the problem, according to the FDA.

“I think a lot of people are thinking, ‘Oh, it’s a plant.’ Or, ‘Oh, it’s just a vitamin. Certainly, that means that it’s not going to hurt me,’ ” Ms. Petitpain said. “But there’s always a risk for taking anything.”

It’s not clear why Lori McClintock was taking white mulberry leaf. Friends and family who gathered for her funeral described a vibrant, happy woman who loved her family and her work and already had wrapped Christmas presents under the tree in mid-December. She was planning to buy a recreational vehicle with her husband in retirement.

“We grieve the loss because of all the things she was looking forward to doing and all the years yet ahead,” Tom McClintock told mourners. “And we grieve for something else, because we’ve all lost a genuinely good person in our lives.”
 

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. Together with Policy Analysis and Polling, KHN is one of the three major operating programs at KFF (Kaiser Family Foundation). KFF is an endowed nonprofit organization providing information on health issues to the nation.

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

Neither metformin, ivermectin, or fluvoxamine had any impact on reducing disease severity, hospitalization, or death from COVID-19, according to results from more than 1,000 overweight or obese adult patients in the COVID-OUT randomized trial.

However, metformin showed some potential in a secondary analysis.

Early treatment to prevent severe disease remains a goal in managing the ongoing COVID-19 pandemic, and biophysical modeling suggested that metformin, ivermectin, and fluvoxamine may serve as antivirals to help reduce severe disease in COVID-19 patients, Carolyn T. Bramante, MD, of the University of Minnesota, Minneapolis, and colleagues wrote.

Thinglass/iStock Editorial/Getty Images

“We started enrolling patients at the end of December 2020,” Dr. Bramante said in an interview. “At that time, even though vaccine data were coming out, we thought it was important to test early outpatient treatment with widely available safe medications with no interactions, because the virus would evolve and vaccine availability may be limited.”

In a study published in the New England Journal of Medicine, the researchers used a two-by-three factorial design to test the ability of metformin, ivermectin, and fluvoxamine to prevent severe COVID-19 infection in nonhospitalized adults aged 30-85 years. A total of 1,431 patients at six U.S. sites were enrolled within 3 days of a confirmed infection and less than 7 days after the start of symptoms, then randomized to one of six groups: metformin plus fluvoxamine; metformin plus ivermectin; metformin plus placebo; placebo plus fluvoxamine; placebo plus ivermectin; and placebo plus placebo.

A total of 1,323 patients were included in the primary analysis. The median age of the patients was 46 years, 56% were female (of whom 6% were pregnant), and all individuals met criteria for overweight or obesity. About half (52%) of the patients had been vaccinated against COVID-19.

The primary endpoint was a composite of hypoxemia, ED visit, hospitalization, or death. The analyses were adjusted for COVID-19 vaccination and other trial medications. Overall, the adjusted odds ratios of any primary event, compared with placebo, was 0.84 for metformin (P = .19), 1.05 for ivermectin (P = .78), and 0.94 for fluvoxamine (P = .75).

The researchers also conducted a prespecified secondary analysis of components of the primary endpoint. In this analysis, the aORs for an ED visit, hospitalization, or death was 0.58 for metformin, 1.39 for ivermectin, and 1.17 for fluvoxamine. The aORs for hospitalization or death were 0.47, 0.73, and 1.11 for metformin, ivermectin, and fluvoxamine, respectively. No medication-related serious adverse events were reported with any of the drugs during the study period.

The possible benefit for prevention of severe COVID-19 with metformin was a prespecified secondary endpoint, and therefore not definitive until more research has been completed, the researchers said. Metformin has demonstrated anti-inflammatory actions in previous studies, and has shown protective effects against COVID-19 lung injury in animal studies.

Previous observational studies also have shown an association between metformin use and less severe COVID-19 in patients already taking metformin. “The proposed mechanisms of action against COVID-19 for metformin include anti-inflammatory and antiviral activity and the prevention of hyperglycemia during acute illness,” they added.

The study findings were limited by several factors including the population age range and focus on overweight and obese patients, which may limit generalizability, the researchers noted. Other limitations include the disproportionately small percentage of Black and Latino patients and the potential lack of accuracy in identifying hypoxemia via home oxygen monitors.

However, the results demonstrate that none of the three repurposed drugs – metformin, ivermectin, and fluvoxamine – prevented primary events or reduced symptom severity in COVID-19, compared with placebos, the researchers concluded.

“Metformin had several streams of evidence supporting its use: in vitro, in silico [computer modeled], observational, and in tissue. We were not surprised to see that it reduced emergency department visits, hospitalization, and death,” Dr. Bramante said in an interview.

The take-home message for clinicians is to continue to look to guideline committees for direction on COVID-19 treatments, but to continue to consider metformin along with other treatments, she said.

“All research should be replicated, whether the primary outcome is positive or negative,” Dr. Bramante emphasized. “In this case, when our positive outcome was negative and secondary outcome was positive, a confirmatory trial for metformin is particularly important.”

Ineffective drugs are inefficient use of resources

“The results of the COVID-OUT trial provide persuasive additional data that increase the confidence and degree of certainty that fluvoxamine and ivermectin are not effective in preventing progression to severe disease,” wrote Salim S. Abdool Karim, MB, and Nikita Devnarain, PhD, of the Centre for the AIDS Programme of Research in South Africa, Durban, in an accompanying editorial.

At the start of the study, in 2020, data on the use of the three drugs to prevent severe COVID-19 were “either unavailable or equivocal,” they said. Since then, accumulating data support the current study findings of the nonefficacy of ivermectin and fluvoxamine, and the World Health Organization has advised against their use for COVID-19, although the WHO has not provided guidance for the use of metformin.

The authors called on clinicians to stop using ivermectin and fluvoxamine to treat COVID-19 patients.

“With respect to clinical decisions about COVID-19 treatment, some drug choices, especially those that have negative [World Health Organization] recommendations, are clearly wrong,” they wrote. “In keeping with evidence-based medical practice, patients with COVID-19 must be treated with efficacious medications; they deserve nothing less.”

The study was supported by the Parsemus Foundation, Rainwater Charitable Foundation, Fast Grants, and UnitedHealth Group Foundation. The fluvoxamine placebo tablets were donated by Apotex Pharmaceuticals. The ivermectin placebo and active tablets were donated by Edenbridge Pharmaceuticals. Lead author Dr. Bramante was supported the National Center for Advancing Translational Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases. The researchers had no financial conflicts to disclose. Dr. Abdool Karim serves as a member of the World Health Organization Science Council. Dr. Devnarain had no financial conflicts to disclose.
 

What is the real goal of weight loss? In health care, reducing excess body fat is known to improve many complications faced by patients with obesity. Even modest to moderate weight loss contributes to improvements in health. Normalizing body weight is not required.

While our culture promotes an ideal body size, in the health care setting, our attention must focus on achieving health improvement. We need to be more tolerant of variations in body size if patients are healthy. Of note, varying amounts of weight loss produce improvement in the different complications of obesity, so the amount of weight loss required for improving one condition differs from that required to improve another condition.

When we prescribe weight loss for health improvement, we are trying to reduce both the mechanical burden of fat and the excess ectopic and visceral body fat that is driving disease. The good news about the physiology of weight loss is that we do not need to attain a body mass index (BMI) of 25 or even 30 to have health improvement. The excess abnormal body fat is the first to go!

Losing weight causes a disproportional reduction in ectopic and visceral fat depots. With a 5% weight loss, visceral fat is reduced by 9%. With 16% weight loss, visceral fat is reduced by 30%. Clearing of liver fat is even more dramatic. With 16% weight loss, 65% of liver fat is cleared.

Because ectopic abnormal fat is cleared preferentially with weight loss, it affects different tissues with varying amounts of weight loss.
 

Weight loss and diabetes

A close relationship exists between weight loss and insulin sensitivity. With just 5% weight loss, insulin sensitivity in the liver and adipose tissue is greatly improved, but while muscle insulin sensitivity is improved at just 5% weight loss, it continues to improve with further weight loss. Indeed, weight loss has enormous benefits in improving glycemia in prediabetes and diabetes.

In patients with impaired glucose tolerance, weight loss of 10% can eliminate progression to type 2 diabetes. In patients with type 2 diabetes who still have beta-cell reserve, 15% weight loss can produce diabetes remission – normoglycemia without diabetes medications.
 

Weight loss and cardiovascular risk factors

Even very small amounts of weight loss – 3% – can improve triglycerides and glycemia. It takes 5% weight loss to show benefits in systolic and diastolic blood pressure, as well as in HDL and LDL cholesterol levels. For all of these, additional weight loss brings more improvement. Inflammatory markers are more difficult. It takes 10%-15% weight loss to improve most of these – for example, C-reactive protein.

Weight loss and other complications

It takes 10% or more weight loss to demonstrate improvements in symptoms in obstructive sleep apnea and gastroesophageal reflux disease. For knee pain, the relationship to improvement is not based on achieving a percentage loss. Each pound of weight lost can result in a fourfold reduction in the load exerted on the knee per step during daily activities, but it is important to reduce weight before there is structural damage, because weight loss can’t repair damaged knee joints. Moderate weight loss (5%-10%) produces improvements in quality-of-life measures, in urinary stress incontinence symptoms, and in measures of sexual function. It probably takes 15% or more weight loss to demonstrate improvement in cardiovascular events.

Must heavier patients lose more weight?

To answer this question, it is important to think in terms of percent weight loss rather than pounds or kilograms. In large studies of lifestyle intervention, of course individuals with higher BMI lost more weight. But the percentage weight loss was the same across BMI categories: class 1 (BMI 30-35), class 2 (BMI 35-40), class 3 (BMI > 40). Furthermore, the improvement in risk factors was the same across BMI categories. Those with class 3 obesity had the same improvements as those with class 1. This provides further rationale for thinking about weight loss as a percentage from baseline weight rather than as simply a weight-loss goal in pounds.

Goal setting is an important part of any behavioral intervention

At the start of a weight-loss intervention, the health care provider should raise the issue of the goal and the time course for achieving it. Patients often have unrealistic expectations, wanting to achieve large amounts of weight loss rapidly. Unfortunately, popular culture has reinforced this idea with advertisements using “lose 10 pounds the first week” and promoting before-and-after pictures of weight-loss results. The job of the health care provider is to coach and guide the patient in terms of achievable weight loss that can bring health improvement safely. Managing patient expectations is critical to long-term success.

Think in terms of percentage weight loss, not pounds, and set goals at achievable time points

Help patients translate a percent weight-loss goal to a pounds goal at 3, 6, and 12 months. With the emergence of medications approved for chronic weight management with robust weight-loss efficacy, it now is possible to achieve a weight-loss goal of 10% or 15% with regularity, and some patients will be able to achieve 20% or 25% weight loss with newer medications.

We should help our patients set a goal by calculating a goal for certain time points. A good goal for 3 months would be 5% weight loss. For our 200-lb patient, we would translate that to 10 lb in 3 months. For 6 months, the goal should be 10% (20 lb for our 200-lb patient). The usual trajectory of weight loss with lifestyle intervention alone is for a “plateau” at 6 months, although with newer medications, weight loss will continue for more than a year. That 1-year goal might be 15% (30 lb for our 200-lb patient) or even more, based on the patient’s baseline weight and body composition.

Weight-loss calculators can be useful tools for patients and health care providers. They can be found online and include the National Institutes of Health Body Weight Planner and the Pennington Biomedical Weight Loss Predictor Calculator. These tools give patients a realistic expectation of how fast weight loss can occur and provide guidelines to measure success.
 

Can patients lose too much weight?

In this patient population, losing too much weight is not typically a concern. However, newer medications are achieving average weight losses of 17% and 22% at 62 weeks, as reported by this news organization. There is a wide variation in response to these newer agents which target appetite, and many patients are losing more than the average percentages.

Remembering that the goal of weight loss is the reduction of excess abnormal body fat, we want patients to preserve as much lean mass as possible. Weight-bearing exercise can help during the weight-loss phase, but large or rapid weight loss can be concerning, especially in older individuals. When the BMI drops below 25, we want to watch patients carefully. Measurement of body composition, including bone mineral density, with dual-energy x-ray absorptiometry (DEXA) can help. This is a scenario where dose reduction of antiobesity medication can be indicated, and good clinical judgment is required to keep weight loss at healthy levels.
 

The future of weight loss

In the past, our strategy has been to promote as much weight loss as possible. With more effective medications, our strategy will have to change to a treat-to-target approach, such as we already use in hypertension and diabetes.

With the ability to produce powerful effects on appetite will come the need to not only target weight loss but to target preservation of lean mass and even to target different approaches for weight-loss maintenance. At present, we have no evidence that stopping medications results in anything other than weight regain. The study of different approaches to weight-loss maintenance will require our full attention.

Dr. Ryan has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, consultant, or trustee for: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand. Received income in an amount equal to or greater than $250 from: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand.

Donna Ryan, MD, is Professor Emerita, Pennington Biomedical Research Center, Louisiana State University, New Orleans.

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

What is the real goal of weight loss? In health care, reducing excess body fat is known to improve many complications faced by patients with obesity. Even modest to moderate weight loss contributes to improvements in health. Normalizing body weight is not required.

While our culture promotes an ideal body size, in the health care setting, our attention must focus on achieving health improvement. We need to be more tolerant of variations in body size if patients are healthy. Of note, varying amounts of weight loss produce improvement in the different complications of obesity, so the amount of weight loss required for improving one condition differs from that required to improve another condition.

When we prescribe weight loss for health improvement, we are trying to reduce both the mechanical burden of fat and the excess ectopic and visceral body fat that is driving disease. The good news about the physiology of weight loss is that we do not need to attain a body mass index (BMI) of 25 or even 30 to have health improvement. The excess abnormal body fat is the first to go!

Losing weight causes a disproportional reduction in ectopic and visceral fat depots. With a 5% weight loss, visceral fat is reduced by 9%. With 16% weight loss, visceral fat is reduced by 30%. Clearing of liver fat is even more dramatic. With 16% weight loss, 65% of liver fat is cleared.

Because ectopic abnormal fat is cleared preferentially with weight loss, it affects different tissues with varying amounts of weight loss.
 

Weight loss and diabetes

A close relationship exists between weight loss and insulin sensitivity. With just 5% weight loss, insulin sensitivity in the liver and adipose tissue is greatly improved, but while muscle insulin sensitivity is improved at just 5% weight loss, it continues to improve with further weight loss. Indeed, weight loss has enormous benefits in improving glycemia in prediabetes and diabetes.

In patients with impaired glucose tolerance, weight loss of 10% can eliminate progression to type 2 diabetes. In patients with type 2 diabetes who still have beta-cell reserve, 15% weight loss can produce diabetes remission – normoglycemia without diabetes medications.
 

Weight loss and cardiovascular risk factors

Even very small amounts of weight loss – 3% – can improve triglycerides and glycemia. It takes 5% weight loss to show benefits in systolic and diastolic blood pressure, as well as in HDL and LDL cholesterol levels. For all of these, additional weight loss brings more improvement. Inflammatory markers are more difficult. It takes 10%-15% weight loss to improve most of these – for example, C-reactive protein.

Weight loss and other complications

It takes 10% or more weight loss to demonstrate improvements in symptoms in obstructive sleep apnea and gastroesophageal reflux disease. For knee pain, the relationship to improvement is not based on achieving a percentage loss. Each pound of weight lost can result in a fourfold reduction in the load exerted on the knee per step during daily activities, but it is important to reduce weight before there is structural damage, because weight loss can’t repair damaged knee joints. Moderate weight loss (5%-10%) produces improvements in quality-of-life measures, in urinary stress incontinence symptoms, and in measures of sexual function. It probably takes 15% or more weight loss to demonstrate improvement in cardiovascular events.

Must heavier patients lose more weight?

To answer this question, it is important to think in terms of percent weight loss rather than pounds or kilograms. In large studies of lifestyle intervention, of course individuals with higher BMI lost more weight. But the percentage weight loss was the same across BMI categories: class 1 (BMI 30-35), class 2 (BMI 35-40), class 3 (BMI > 40). Furthermore, the improvement in risk factors was the same across BMI categories. Those with class 3 obesity had the same improvements as those with class 1. This provides further rationale for thinking about weight loss as a percentage from baseline weight rather than as simply a weight-loss goal in pounds.

Goal setting is an important part of any behavioral intervention

At the start of a weight-loss intervention, the health care provider should raise the issue of the goal and the time course for achieving it. Patients often have unrealistic expectations, wanting to achieve large amounts of weight loss rapidly. Unfortunately, popular culture has reinforced this idea with advertisements using “lose 10 pounds the first week” and promoting before-and-after pictures of weight-loss results. The job of the health care provider is to coach and guide the patient in terms of achievable weight loss that can bring health improvement safely. Managing patient expectations is critical to long-term success.

Think in terms of percentage weight loss, not pounds, and set goals at achievable time points

Help patients translate a percent weight-loss goal to a pounds goal at 3, 6, and 12 months. With the emergence of medications approved for chronic weight management with robust weight-loss efficacy, it now is possible to achieve a weight-loss goal of 10% or 15% with regularity, and some patients will be able to achieve 20% or 25% weight loss with newer medications.

We should help our patients set a goal by calculating a goal for certain time points. A good goal for 3 months would be 5% weight loss. For our 200-lb patient, we would translate that to 10 lb in 3 months. For 6 months, the goal should be 10% (20 lb for our 200-lb patient). The usual trajectory of weight loss with lifestyle intervention alone is for a “plateau” at 6 months, although with newer medications, weight loss will continue for more than a year. That 1-year goal might be 15% (30 lb for our 200-lb patient) or even more, based on the patient’s baseline weight and body composition.

Weight-loss calculators can be useful tools for patients and health care providers. They can be found online and include the National Institutes of Health Body Weight Planner and the Pennington Biomedical Weight Loss Predictor Calculator. These tools give patients a realistic expectation of how fast weight loss can occur and provide guidelines to measure success.
 

Can patients lose too much weight?

In this patient population, losing too much weight is not typically a concern. However, newer medications are achieving average weight losses of 17% and 22% at 62 weeks, as reported by this news organization. There is a wide variation in response to these newer agents which target appetite, and many patients are losing more than the average percentages.

Remembering that the goal of weight loss is the reduction of excess abnormal body fat, we want patients to preserve as much lean mass as possible. Weight-bearing exercise can help during the weight-loss phase, but large or rapid weight loss can be concerning, especially in older individuals. When the BMI drops below 25, we want to watch patients carefully. Measurement of body composition, including bone mineral density, with dual-energy x-ray absorptiometry (DEXA) can help. This is a scenario where dose reduction of antiobesity medication can be indicated, and good clinical judgment is required to keep weight loss at healthy levels.
 

The future of weight loss

In the past, our strategy has been to promote as much weight loss as possible. With more effective medications, our strategy will have to change to a treat-to-target approach, such as we already use in hypertension and diabetes.

With the ability to produce powerful effects on appetite will come the need to not only target weight loss but to target preservation of lean mass and even to target different approaches for weight-loss maintenance. At present, we have no evidence that stopping medications results in anything other than weight regain. The study of different approaches to weight-loss maintenance will require our full attention.

Dr. Ryan has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, consultant, or trustee for: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand. Received income in an amount equal to or greater than $250 from: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand.

Donna Ryan, MD, is Professor Emerita, Pennington Biomedical Research Center, Louisiana State University, New Orleans.

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

What is the real goal of weight loss? In health care, reducing excess body fat is known to improve many complications faced by patients with obesity. Even modest to moderate weight loss contributes to improvements in health. Normalizing body weight is not required.

While our culture promotes an ideal body size, in the health care setting, our attention must focus on achieving health improvement. We need to be more tolerant of variations in body size if patients are healthy. Of note, varying amounts of weight loss produce improvement in the different complications of obesity, so the amount of weight loss required for improving one condition differs from that required to improve another condition.

When we prescribe weight loss for health improvement, we are trying to reduce both the mechanical burden of fat and the excess ectopic and visceral body fat that is driving disease. The good news about the physiology of weight loss is that we do not need to attain a body mass index (BMI) of 25 or even 30 to have health improvement. The excess abnormal body fat is the first to go!

Losing weight causes a disproportional reduction in ectopic and visceral fat depots. With a 5% weight loss, visceral fat is reduced by 9%. With 16% weight loss, visceral fat is reduced by 30%. Clearing of liver fat is even more dramatic. With 16% weight loss, 65% of liver fat is cleared.

Because ectopic abnormal fat is cleared preferentially with weight loss, it affects different tissues with varying amounts of weight loss.
 

Weight loss and diabetes

A close relationship exists between weight loss and insulin sensitivity. With just 5% weight loss, insulin sensitivity in the liver and adipose tissue is greatly improved, but while muscle insulin sensitivity is improved at just 5% weight loss, it continues to improve with further weight loss. Indeed, weight loss has enormous benefits in improving glycemia in prediabetes and diabetes.

In patients with impaired glucose tolerance, weight loss of 10% can eliminate progression to type 2 diabetes. In patients with type 2 diabetes who still have beta-cell reserve, 15% weight loss can produce diabetes remission – normoglycemia without diabetes medications.
 

Weight loss and cardiovascular risk factors

Even very small amounts of weight loss – 3% – can improve triglycerides and glycemia. It takes 5% weight loss to show benefits in systolic and diastolic blood pressure, as well as in HDL and LDL cholesterol levels. For all of these, additional weight loss brings more improvement. Inflammatory markers are more difficult. It takes 10%-15% weight loss to improve most of these – for example, C-reactive protein.

Weight loss and other complications

It takes 10% or more weight loss to demonstrate improvements in symptoms in obstructive sleep apnea and gastroesophageal reflux disease. For knee pain, the relationship to improvement is not based on achieving a percentage loss. Each pound of weight lost can result in a fourfold reduction in the load exerted on the knee per step during daily activities, but it is important to reduce weight before there is structural damage, because weight loss can’t repair damaged knee joints. Moderate weight loss (5%-10%) produces improvements in quality-of-life measures, in urinary stress incontinence symptoms, and in measures of sexual function. It probably takes 15% or more weight loss to demonstrate improvement in cardiovascular events.

Must heavier patients lose more weight?

To answer this question, it is important to think in terms of percent weight loss rather than pounds or kilograms. In large studies of lifestyle intervention, of course individuals with higher BMI lost more weight. But the percentage weight loss was the same across BMI categories: class 1 (BMI 30-35), class 2 (BMI 35-40), class 3 (BMI > 40). Furthermore, the improvement in risk factors was the same across BMI categories. Those with class 3 obesity had the same improvements as those with class 1. This provides further rationale for thinking about weight loss as a percentage from baseline weight rather than as simply a weight-loss goal in pounds.

Goal setting is an important part of any behavioral intervention

At the start of a weight-loss intervention, the health care provider should raise the issue of the goal and the time course for achieving it. Patients often have unrealistic expectations, wanting to achieve large amounts of weight loss rapidly. Unfortunately, popular culture has reinforced this idea with advertisements using “lose 10 pounds the first week” and promoting before-and-after pictures of weight-loss results. The job of the health care provider is to coach and guide the patient in terms of achievable weight loss that can bring health improvement safely. Managing patient expectations is critical to long-term success.

Think in terms of percentage weight loss, not pounds, and set goals at achievable time points

Help patients translate a percent weight-loss goal to a pounds goal at 3, 6, and 12 months. With the emergence of medications approved for chronic weight management with robust weight-loss efficacy, it now is possible to achieve a weight-loss goal of 10% or 15% with regularity, and some patients will be able to achieve 20% or 25% weight loss with newer medications.

We should help our patients set a goal by calculating a goal for certain time points. A good goal for 3 months would be 5% weight loss. For our 200-lb patient, we would translate that to 10 lb in 3 months. For 6 months, the goal should be 10% (20 lb for our 200-lb patient). The usual trajectory of weight loss with lifestyle intervention alone is for a “plateau” at 6 months, although with newer medications, weight loss will continue for more than a year. That 1-year goal might be 15% (30 lb for our 200-lb patient) or even more, based on the patient’s baseline weight and body composition.

Weight-loss calculators can be useful tools for patients and health care providers. They can be found online and include the National Institutes of Health Body Weight Planner and the Pennington Biomedical Weight Loss Predictor Calculator. These tools give patients a realistic expectation of how fast weight loss can occur and provide guidelines to measure success.
 

Can patients lose too much weight?

In this patient population, losing too much weight is not typically a concern. However, newer medications are achieving average weight losses of 17% and 22% at 62 weeks, as reported by this news organization. There is a wide variation in response to these newer agents which target appetite, and many patients are losing more than the average percentages.

Remembering that the goal of weight loss is the reduction of excess abnormal body fat, we want patients to preserve as much lean mass as possible. Weight-bearing exercise can help during the weight-loss phase, but large or rapid weight loss can be concerning, especially in older individuals. When the BMI drops below 25, we want to watch patients carefully. Measurement of body composition, including bone mineral density, with dual-energy x-ray absorptiometry (DEXA) can help. This is a scenario where dose reduction of antiobesity medication can be indicated, and good clinical judgment is required to keep weight loss at healthy levels.
 

The future of weight loss

In the past, our strategy has been to promote as much weight loss as possible. With more effective medications, our strategy will have to change to a treat-to-target approach, such as we already use in hypertension and diabetes.

With the ability to produce powerful effects on appetite will come the need to not only target weight loss but to target preservation of lean mass and even to target different approaches for weight-loss maintenance. At present, we have no evidence that stopping medications results in anything other than weight regain. The study of different approaches to weight-loss maintenance will require our full attention.

Dr. Ryan has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, consultant, or trustee for: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand. Received income in an amount equal to or greater than $250 from: Altimmune; Amgen; Calibrate; Epitomee; Gila; Lilly; Novo Nordisk; Scientific Intake; Wondr Health; Xeno Biosciences; YSOPIA; Zealand.

Donna Ryan, MD, is Professor Emerita, Pennington Biomedical Research Center, Louisiana State University, New Orleans.

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

New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.

Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.

The study was published online in the journal Cell.


 

Gut reaction?

Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.

They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.

BigRedCurlyGuy/Thinkstock

Weighing the evidence

Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).

“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”

The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.

“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.

Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.

“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.

“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.

The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”

They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”

Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”

The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.

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

This article was updated 8/29/22.

New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.

Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.

The study was published online in the journal Cell.


 

Gut reaction?

Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.

They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.

BigRedCurlyGuy/Thinkstock

Weighing the evidence

Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).

“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”

The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.

“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.

Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.

“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.

“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.

The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”

They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”

Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”

The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.

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

This article was updated 8/29/22.

New research discounts the long-held notion that aspartame and other nonnutritive sweeteners (NNS) have no effect on the human body.

Researchers found that these sugar substitutes are not metabolically inert and can alter the gut microbiome in a way that can influence blood glucose levels.

The study was published online in the journal Cell.


 

Gut reaction?

Several years ago, a team led by Eran Elinav, MD, PhD, an immunologist and microbiome researcher at the Weizmann Institute of Science, Rehovot, Israel, observed that these sweeteners affect the microbiome of mice in ways that could affect glycemic responses.

They have now confirmed this observation in a randomized controlled trial with 120 healthy adults.

BigRedCurlyGuy/Thinkstock

Weighing the evidence

Several experts weighed in on the results in a statement from the U.K. nonprofit organization, Science Media Centre.

Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow, Aston University, Birmingham, England, notes that the study does not show a link between all NNS and higher blood glucose levels in the long term (only after a glucose tolerance test).

“It did suggest, though, that some individuals who do not normally consume sweeteners may not tolerate glucose as well after consuming six sachets of either saccharin or sucralose mixed with glucose per day,” Dr. Mellor says.

Kim Barrett, PhD, distinguished professor of physiology and membrane biology, University of California, Davis, concurs, saying “this well-designed study indicates the potential for NNS to have adverse effects in at least some individuals.”

The study also does not provide any information about how people who normally consume sweeteners or people with either type 1 or type 2 diabetes respond to NNS.

“Therefore, for some people, it is likely to be a better option and more sustainable approach to use sweeteners as a ‘stepping stone’ allowing them to reduce the amount of added sugar in foods and drinks, to reduce their sugar intake and still enjoy what they eat and drink, on the way to reducing both added sugar and sweeteners in their diet,” Dr. Mellor suggests.

Kevin McConway, PhD, with the Open University, Milton Keynes, England, said it’s “important to understand that the research is not saying that these sweeteners are worse for us, in heath terms, than sugar.

“But exactly what the health consequences of all this, if any, might be is a subject for future research,” Dr. McConway added.

Kathy Redfern, PhD, lecturer in human nutrition, University of Plymouth (England) agrees.

“We still have a lot to learn about the human microbiome, and although this study suggests two of the sweeteners tested in this study (sucralose and saccharin) significantly affected glucose tolerance, these deviations were small,” she says.

The International Sweeteners Association also weighs in, saying, “No conclusions about the effects of low/no calorie sweeteners on glucose control or overall health can be extrapolated from this study for the general population or for people who typically consume sweeteners, including people living with diabetes.”

They add “a recent review of the literature concluded that there is clear evidence that changes in the diet unrelated to low/no calorie sweeteners consumption are likely the major determinants of change in gut microbiota.”

Nevertheless, Dr. Redfern says the results “warrant further investigation to assess how small changes in glucose tolerance in response to NNS consumption may influence longer-term glucose tolerance and risk for metabolic complications, such as type 2 diabetes.”

The study had no specific funding. Dr. Elinav is a scientific founder of DayTwo and BiomX, a paid consultant to Hello Inside and Aposense, and a member of the scientific advisory board of Cell. Dr. Mellor has provided consultancy to the International Sweetener Agency and has worked on projects funded by the Food Standards Agency that investigated the health effects of aspartame. Dr. Barrett, Dr. McConway, and Dr. Redfern report no relevant financial relationships.

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

This article was updated 8/29/22.

Is there a diet or weight-loss program out there that doesn’t work for those who stick with it during its first 12 weeks?

Truly, the world’s most backwards, upside-down, anti-science, nonsensical diets work over the short haul, fueled by the fact that short-term suffering for weight loss is a skill set that humanity has assiduously cultivated for at least the past 100 years. We’re really good at it!

It’s the keeping the weight off, though, that’s the hitch. Which leads me to the question, why are medical journals, even preeminent nonpredatory ones, publishing 12-week weight-loss program studies as if they have value? And does anyone truly imagine that after over 100 years of trying, there’ll be a short-term diet or program that’ll have the durable, reproducible results that no other short-term diet or program ever has? Why are we still pretending that there’s a magic bullet out there?

Take this study published by Obesity: “Pragmatic implementation of a fully automated online obesity treatment in primary care.” It details a 12-week online, automated, weight-loss program that led completers to lose the roughly 5% of weight that many diets and programs see lost over their first 12 weeks. By its description, aside from its automated provision, the program sounds like pretty much the same boilerplate weight management advice and recommendations that haven’t been shown to lead large numbers of people to sustain long-term weight loss.

Participants were provided with weekly lessons which no doubt in some manner told them that high-calorie foods had high numbers of calories and should be minimized, along with other weight-loss secrets. Users were to upload weekly self-monitored weight, energy intake, and exercise minutes and were told to use a food diary. Their goal was losing 10% of their body weight by consuming 1,200-1,500 calories per day if they weighed less than 250 pounds (113 kg) and 1,500-1,800 calories if they weighed more than 250 pounds, while also telling them to aim for 200 minutes per week of moderate- to vigorous-intensity physical activity.

What was found was wholly unsurprising. Perhaps speaking to the tremendous and wide-ranging degrees of privilege that are required to prioritize intentional behavior change in the name of health, 79% of those who were given a prescription for the program either didn’t start it or stopped it before the end of the first week.

Of those who actually started the program and completed more than 1 week, despite having been selected as appropriate and interested participants by their physicians, only 20% watched all of the automated programs’ video lessons while only 32% actually bothered to submit all 12 weeks of weight data. Of course, the authors found that those who watched the greatest number of videos and submitted the most self-reported weights lost more weight and ascribed that loss to the program. What the authors did not entertain was the possibility that those who weren’t losing weight, or who were gaining, might simply be less inclined to continue with a program that wasn’t leading them to their desired outcomes or to want to submit their lack of loss or gains.

Short-term weight-loss studies help no one and when, as in this case, the outcomes aren’t even mediocre, and the completion and engagement rates are terrible, the study is still presented as significant and important. This bolsters the harmful stereotype that weight management is achievable by way of simple messages and generic goals. It suggests that it’s individuals who fail programs by not trying hard enough and that those who do, or who want it the most, will succeed. It may also lead patients and clinicians to second-guess the use of antiobesity medications, the current generation of which lead to far greater weight loss and reproducibility than any behavioral program or diet ever has.

The good news here at least is that the small percentage of participants who made it through this program’s 12 weeks are being randomly assigned to differing 9-month maintenance programs which at least will then lead to a 1-year analysis on the completers.

Why this study was published now, rather than pushed until the 1-year data were available, speaks to the pervasiveness of the toxic weight-biased notion that simple education will overcome the physiology forged over millions of years of extreme dietary insecurity.

Our food environment is a veritable floodplain of hyperpalatable foods, and social determinants of health make intentional behavior change in the name of health an unattainable luxury for a huge swath of the population.
 

Dr. Freedhoff is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute. He reported serving as a director, officer, partner, employee, adviser, consultant, or trustee for Bariatric Medical Institute and Constant Health and receiving research grants from Novo Nordisk. A version of this article first appeared on Medscape.com.

Is there a diet or weight-loss program out there that doesn’t work for those who stick with it during its first 12 weeks?

Truly, the world’s most backwards, upside-down, anti-science, nonsensical diets work over the short haul, fueled by the fact that short-term suffering for weight loss is a skill set that humanity has assiduously cultivated for at least the past 100 years. We’re really good at it!

It’s the keeping the weight off, though, that’s the hitch. Which leads me to the question, why are medical journals, even preeminent nonpredatory ones, publishing 12-week weight-loss program studies as if they have value? And does anyone truly imagine that after over 100 years of trying, there’ll be a short-term diet or program that’ll have the durable, reproducible results that no other short-term diet or program ever has? Why are we still pretending that there’s a magic bullet out there?

Take this study published by Obesity: “Pragmatic implementation of a fully automated online obesity treatment in primary care.” It details a 12-week online, automated, weight-loss program that led completers to lose the roughly 5% of weight that many diets and programs see lost over their first 12 weeks. By its description, aside from its automated provision, the program sounds like pretty much the same boilerplate weight management advice and recommendations that haven’t been shown to lead large numbers of people to sustain long-term weight loss.

Participants were provided with weekly lessons which no doubt in some manner told them that high-calorie foods had high numbers of calories and should be minimized, along with other weight-loss secrets. Users were to upload weekly self-monitored weight, energy intake, and exercise minutes and were told to use a food diary. Their goal was losing 10% of their body weight by consuming 1,200-1,500 calories per day if they weighed less than 250 pounds (113 kg) and 1,500-1,800 calories if they weighed more than 250 pounds, while also telling them to aim for 200 minutes per week of moderate- to vigorous-intensity physical activity.

What was found was wholly unsurprising. Perhaps speaking to the tremendous and wide-ranging degrees of privilege that are required to prioritize intentional behavior change in the name of health, 79% of those who were given a prescription for the program either didn’t start it or stopped it before the end of the first week.

Of those who actually started the program and completed more than 1 week, despite having been selected as appropriate and interested participants by their physicians, only 20% watched all of the automated programs’ video lessons while only 32% actually bothered to submit all 12 weeks of weight data. Of course, the authors found that those who watched the greatest number of videos and submitted the most self-reported weights lost more weight and ascribed that loss to the program. What the authors did not entertain was the possibility that those who weren’t losing weight, or who were gaining, might simply be less inclined to continue with a program that wasn’t leading them to their desired outcomes or to want to submit their lack of loss or gains.

Short-term weight-loss studies help no one and when, as in this case, the outcomes aren’t even mediocre, and the completion and engagement rates are terrible, the study is still presented as significant and important. This bolsters the harmful stereotype that weight management is achievable by way of simple messages and generic goals. It suggests that it’s individuals who fail programs by not trying hard enough and that those who do, or who want it the most, will succeed. It may also lead patients and clinicians to second-guess the use of antiobesity medications, the current generation of which lead to far greater weight loss and reproducibility than any behavioral program or diet ever has.

The good news here at least is that the small percentage of participants who made it through this program’s 12 weeks are being randomly assigned to differing 9-month maintenance programs which at least will then lead to a 1-year analysis on the completers.

Why this study was published now, rather than pushed until the 1-year data were available, speaks to the pervasiveness of the toxic weight-biased notion that simple education will overcome the physiology forged over millions of years of extreme dietary insecurity.

Our food environment is a veritable floodplain of hyperpalatable foods, and social determinants of health make intentional behavior change in the name of health an unattainable luxury for a huge swath of the population.
 

Dr. Freedhoff is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute. He reported serving as a director, officer, partner, employee, adviser, consultant, or trustee for Bariatric Medical Institute and Constant Health and receiving research grants from Novo Nordisk. A version of this article first appeared on Medscape.com.

Is there a diet or weight-loss program out there that doesn’t work for those who stick with it during its first 12 weeks?

Truly, the world’s most backwards, upside-down, anti-science, nonsensical diets work over the short haul, fueled by the fact that short-term suffering for weight loss is a skill set that humanity has assiduously cultivated for at least the past 100 years. We’re really good at it!

It’s the keeping the weight off, though, that’s the hitch. Which leads me to the question, why are medical journals, even preeminent nonpredatory ones, publishing 12-week weight-loss program studies as if they have value? And does anyone truly imagine that after over 100 years of trying, there’ll be a short-term diet or program that’ll have the durable, reproducible results that no other short-term diet or program ever has? Why are we still pretending that there’s a magic bullet out there?

Take this study published by Obesity: “Pragmatic implementation of a fully automated online obesity treatment in primary care.” It details a 12-week online, automated, weight-loss program that led completers to lose the roughly 5% of weight that many diets and programs see lost over their first 12 weeks. By its description, aside from its automated provision, the program sounds like pretty much the same boilerplate weight management advice and recommendations that haven’t been shown to lead large numbers of people to sustain long-term weight loss.

Participants were provided with weekly lessons which no doubt in some manner told them that high-calorie foods had high numbers of calories and should be minimized, along with other weight-loss secrets. Users were to upload weekly self-monitored weight, energy intake, and exercise minutes and were told to use a food diary. Their goal was losing 10% of their body weight by consuming 1,200-1,500 calories per day if they weighed less than 250 pounds (113 kg) and 1,500-1,800 calories if they weighed more than 250 pounds, while also telling them to aim for 200 minutes per week of moderate- to vigorous-intensity physical activity.

What was found was wholly unsurprising. Perhaps speaking to the tremendous and wide-ranging degrees of privilege that are required to prioritize intentional behavior change in the name of health, 79% of those who were given a prescription for the program either didn’t start it or stopped it before the end of the first week.

Of those who actually started the program and completed more than 1 week, despite having been selected as appropriate and interested participants by their physicians, only 20% watched all of the automated programs’ video lessons while only 32% actually bothered to submit all 12 weeks of weight data. Of course, the authors found that those who watched the greatest number of videos and submitted the most self-reported weights lost more weight and ascribed that loss to the program. What the authors did not entertain was the possibility that those who weren’t losing weight, or who were gaining, might simply be less inclined to continue with a program that wasn’t leading them to their desired outcomes or to want to submit their lack of loss or gains.

Short-term weight-loss studies help no one and when, as in this case, the outcomes aren’t even mediocre, and the completion and engagement rates are terrible, the study is still presented as significant and important. This bolsters the harmful stereotype that weight management is achievable by way of simple messages and generic goals. It suggests that it’s individuals who fail programs by not trying hard enough and that those who do, or who want it the most, will succeed. It may also lead patients and clinicians to second-guess the use of antiobesity medications, the current generation of which lead to far greater weight loss and reproducibility than any behavioral program or diet ever has.

The good news here at least is that the small percentage of participants who made it through this program’s 12 weeks are being randomly assigned to differing 9-month maintenance programs which at least will then lead to a 1-year analysis on the completers.

Why this study was published now, rather than pushed until the 1-year data were available, speaks to the pervasiveness of the toxic weight-biased notion that simple education will overcome the physiology forged over millions of years of extreme dietary insecurity.

Our food environment is a veritable floodplain of hyperpalatable foods, and social determinants of health make intentional behavior change in the name of health an unattainable luxury for a huge swath of the population.
 

Dr. Freedhoff is an associate professor of family medicine at the University of Ottawa and medical director of the Bariatric Medical Institute. He reported serving as a director, officer, partner, employee, adviser, consultant, or trustee for Bariatric Medical Institute and Constant Health and receiving research grants from Novo Nordisk. A version of this article first appeared on Medscape.com.