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The Food and Drug Administration has authorized Pfizer’s COVID-19 vaccine for children ages 5 to 11, which means vaccines could be available to school-aged children starting next week.

The move brings families with young children a step closer to resuming their normal activities, and it should help further slow transmission of the coronavirus virus in the United States.

States have already placed their orders for initial doses of the vaccines. The Oct. 29 FDA authorization triggers the shipment of millions of doses to pediatricians, family practice doctors, children’s hospitals, community health centers, and pharmacies.

Next, a panel of experts known as the Advisory Committee on Immunization Practices, or ACIP, will meet Nov. 2 to vote on recommendations for use of the vaccine.

As soon as the Centers for Disease Control and Prevention’s director signs off on those recommendations, children can get the shots, perhaps as early as Nov. 3.

Pfizer’s vaccine for children is 10 micrograms, or one-third of the dose given to teens and adults. Kids get two doses of the vaccine 3 weeks apart. In clinical trials, the most common side effects were pain at the injection site, fatigue, and headache. These side effects were mild and disappeared quickly. There were no serious adverse events detected in the studies, which included about 3,100 children. In one study, the vaccine was 90% effective at preventing COVID-19 infections with symptoms in younger children.

There are about 28 million children in the United States between the ages of 5 and 12.

“As a mother and a physician, I know that parents, caregivers, school staff, and children have been waiting for today’s authorization. Vaccinating younger children against COVID-19 will bring us closer to returning to a sense of normalcy,” Acting FDA Commissioner Janet Woodcock, MD, said in an FDA news release.

“Our comprehensive and rigorous evaluation of the data pertaining to the vaccine’s safety and effectiveness should help assure parents and guardians that this vaccine meets our high standards,” she said.

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

The Food and Drug Administration has authorized Pfizer’s COVID-19 vaccine for children ages 5 to 11, which means vaccines could be available to school-aged children starting next week.

The move brings families with young children a step closer to resuming their normal activities, and it should help further slow transmission of the coronavirus virus in the United States.

States have already placed their orders for initial doses of the vaccines. The Oct. 29 FDA authorization triggers the shipment of millions of doses to pediatricians, family practice doctors, children’s hospitals, community health centers, and pharmacies.

Next, a panel of experts known as the Advisory Committee on Immunization Practices, or ACIP, will meet Nov. 2 to vote on recommendations for use of the vaccine.

As soon as the Centers for Disease Control and Prevention’s director signs off on those recommendations, children can get the shots, perhaps as early as Nov. 3.

Pfizer’s vaccine for children is 10 micrograms, or one-third of the dose given to teens and adults. Kids get two doses of the vaccine 3 weeks apart. In clinical trials, the most common side effects were pain at the injection site, fatigue, and headache. These side effects were mild and disappeared quickly. There were no serious adverse events detected in the studies, which included about 3,100 children. In one study, the vaccine was 90% effective at preventing COVID-19 infections with symptoms in younger children.

There are about 28 million children in the United States between the ages of 5 and 12.

“As a mother and a physician, I know that parents, caregivers, school staff, and children have been waiting for today’s authorization. Vaccinating younger children against COVID-19 will bring us closer to returning to a sense of normalcy,” Acting FDA Commissioner Janet Woodcock, MD, said in an FDA news release.

“Our comprehensive and rigorous evaluation of the data pertaining to the vaccine’s safety and effectiveness should help assure parents and guardians that this vaccine meets our high standards,” she said.

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

The Food and Drug Administration has authorized Pfizer’s COVID-19 vaccine for children ages 5 to 11, which means vaccines could be available to school-aged children starting next week.

The move brings families with young children a step closer to resuming their normal activities, and it should help further slow transmission of the coronavirus virus in the United States.

States have already placed their orders for initial doses of the vaccines. The Oct. 29 FDA authorization triggers the shipment of millions of doses to pediatricians, family practice doctors, children’s hospitals, community health centers, and pharmacies.

Next, a panel of experts known as the Advisory Committee on Immunization Practices, or ACIP, will meet Nov. 2 to vote on recommendations for use of the vaccine.

As soon as the Centers for Disease Control and Prevention’s director signs off on those recommendations, children can get the shots, perhaps as early as Nov. 3.

Pfizer’s vaccine for children is 10 micrograms, or one-third of the dose given to teens and adults. Kids get two doses of the vaccine 3 weeks apart. In clinical trials, the most common side effects were pain at the injection site, fatigue, and headache. These side effects were mild and disappeared quickly. There were no serious adverse events detected in the studies, which included about 3,100 children. In one study, the vaccine was 90% effective at preventing COVID-19 infections with symptoms in younger children.

There are about 28 million children in the United States between the ages of 5 and 12.

“As a mother and a physician, I know that parents, caregivers, school staff, and children have been waiting for today’s authorization. Vaccinating younger children against COVID-19 will bring us closer to returning to a sense of normalcy,” Acting FDA Commissioner Janet Woodcock, MD, said in an FDA news release.

“Our comprehensive and rigorous evaluation of the data pertaining to the vaccine’s safety and effectiveness should help assure parents and guardians that this vaccine meets our high standards,” she said.

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

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

A “green” adaptation to the traditional Mediterranean diet could help improve insulin sensitivity and reduce visceral fat by increasing levels of ghrelin, the “hunger hormone,” new research suggests.

The current study is a new analysis of data from the randomized DIRECT-PLUS trial, which showed that the addition of green tea and substitution of red meat for a plant-based (Mankai) protein shake at dinner – dubbed the “green Mediterranean diet” – resulted in further improved cardiometabolic benefits compared with the traditional Mediterranean diet among people with baseline abdominal obesity and/or dyslipidemia, according to the researchers.

They specifically looked at ghrelin, nicknamed the “hunger hormone,” a neuropeptide mainly secreted by the gastric epithelium. It acts on the pituitary gland to release growth hormone. Ghrelin concentrations increase during fasting and decrease after eating. Lower levels are associated with insulin resistance and obesity.

Fasting ghrelin levels were elevated with weight loss, but those increases were associated with improved insulin sensitivity and regression of visceral adipose tissue even beyond weight loss.

Although the caloric restriction and weight loss were comparable with the two Mediterranean diets, the green Mediterranean diet group had double the increase in fasting ghrelin as the traditional Mediterranean diet group, the researchers point out in their report .
 

‘Hypothesis-generating’ study pushes many hot topic buttons

“This specific study is the first to show that ghrelin levels play an important role in metabolic adaptation to a dietary or lifestyle intervention and that ghrelin is an important player in the axis of adiposity, insulin resistance, and metabolic health,” lead researcher Gal Tsaban, MD, told this news organization.

The data partially explain some of the prior beneficial effects seen with the Green Mediterranean diet, even after adjustment for weight loss, he explained, noting that the revised version of the diet “could be considered as an alternative lifestyle intervention with possible metabolic benefits even beyond the Mediterranean diet, which is what we currently recommend for patients.”

Asked for comment, Christopher Gardner, PhD, was not as enthusiastic.

He took issue with the fact that ghrelin wasn’t a primary or even a prespecified secondary outcome of the DIRECT-PLUS trial and because the specific plant-based ingredients of the green Mediterranean diet used in the study may not be widely available or desirable and therefore limit the study’s generalizability.

Dr. Gardner, who is director of nutrition studies at the Stanford Prevention Research Center, California, also said: “They’re tying lots of interesting things together. The Mediterranean diet is a cool thing, ghrelin is a cool thing, and insulin resistance is hugely important in this day and age, even though we don’t all agree on how to measure it.”

“But it gets tough as you try to link them all together for an exploratory outcome. ... To me it’s an interesting hypothesis-generating study that pushes a lot of interesting buttons that are hot topics in the field.”
 

Green Mediterranean diet led to higher ghrelin, metabolic benefits

In DIRECT-PLUS, a total of 294 adults (88% men) older than 30 years of age with abdominal obesity (waist circumference >102 cm for men or >88 cm for women), or dyslipidemia (triglycerides >150 mg/dL and HDL-cholesterol ≤40 mg/dL for men or ≤50 mg/dL for women) were included. Half had prediabetes or type 2 diabetes.

They were randomized to one of three diets: a diet based on standard healthy dietary guidelines; a traditional Mediterranean diet low in simple carbohydrates, rich in vegetables, with poultry and fish replacing beef and lamb and 28 g/day of walnuts; or the Green-Mediterranean diet, including 3-4 cups/day of green tea and 100 g/day of a green shake made from the Mankai strain of Wolffia globosa (also known as duckweed) replacing dinner, and 28 g/day of walnuts.

The Green Mediterranean diet included 800 mg more polyphenols than the traditional Mediterranean diet. Both were equally calorie-restricted, at about 1,500-1,800 kcal/day for men and 1,200-1,400 kcal/day for women. All three groups were instructed to engage in regular physical activity and were given free gym memberships.

The retention rate was 98.3% after 6 months and 89.8% after 18 months.

Weight loss was similar between the two Mediterranean diet groups (2.9% and 3.9% for the traditional and green versions, respectively) compared with the standard healthy diet (0.6%) (P < .05 for both Mediterranean diet groups vs. control).

After 6 months, fasting ghrelin increased in the traditional (8.0%; P = .015) and green (10.5%; P = 0.031) Mediterranean groups versus baseline, with no significant change in the control group.

By 18 months, fasting ghrelin was significantly greater compared with baseline only in the green Mediterranean group (P = .012).

Because the differences in fasting ghrelin trajectories were only significant in men – likely due to the small sample size of women – a subsequent 18-month analysis was limited to the men. In a multivariate model adjusted for age, intervention group, baseline biomarker values, and 18-month weight changes, the 18-month change in fasting ghrelin remained a significant predictor for changes in A1c and homeostatic model of insulin resistance (HOMA-IR; P = .022).

Because weight loss remained the most significant predictor of improved insulin resistance, a further analysis examined the association between changes in fasting ghrelin levels with changes in the fraction of insulin resistance marker that were not attributed to weight loss, per se. With the other adjustments, fasting ghrelin was associated with residual reductions in A1c (P = .003), HOMA-IR (P = .021), increased HDL-cholesterol (P = .024), and relative visceral adipose tissue loss (P = .003).  
 

No specific product needed to push Mediterranean diet towards vegan

Dr. Tsaban, a nutritional researcher and cardiologist at Ben-Gurion University and Soroka University Medical Center, Be’er-Sheva, Israel, said the Mankai shake is commonly consumed in Israel but is also available worldwide. The study participants, all employees at an isolated nuclear research facility in the Negev, were particularly motivated. “They didn’t have a satiety problem with the drink. It made them very full,” he said. The manufacturer supplied the shakes but didn’t fund the study, he added.

However, Dr. Tsaban said that the “green Mediterranean diet” doesn’t depend on specific products.

Rather, “the concept is to push the Mediterranean diet a bit further and to replace the animal-based protein with vegetable-based protein, to shift your dietary habits towards a more vegan lifestyle. It’s not completely vegan, but it’s trending there. ... Our main goal was to increase the polyphenol intake, the antioxidant intake from vegetables. ... I think it can be replicated.”

Dr. Gardner said, “At the end of the day, it’s an exploratory study. ... It raises some interesting points that give the rest of us room to follow-up on.”

The study was funded by grants from the German Research Foundation, the Israel Ministry of Health, the Israel Ministry of Science and Technology, and the California Walnut Commission. Dr. Tsaban has reported no further relevant financial relationships. Dr. Gardner has reported receiving study funding from Beyond Meat.

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

Researchers writing in the British Journal of Dermatology confirm the long-term use of hydrochlorothiazide is associated with a dose-dependent, twofold increased risk of squamous cell carcinoma, compared with calcium channel blocker use.

The findings were originally reported in two Danish case-control studies in which physicians reported a fourfold increased risk of squamous cell carcinoma, and a moderate increased risk of basal cell carcinoma and cutaneous malignant melanoma in patients who used hydrochlorothiazide long-term.

And, while the new study did not find an increased risk of basal cell carcinoma and cutaneous malignant melanoma among long-term users of hydrochlorothiazide, they suggest that bendroflumethiazide “may be a safer alternative for patients at increased risk of skin cancer.” The long-term use of indapamide was associated with a moderately increased risk of cutaneous malignant melanoma but did not alter the risk of either squamous cell or basal cell carcinoma

“Our results suggest that bendroflumethiazide may be a safer alternative to hydrochlorothiazide and indapamide, especially for patients at increased risk of skin cancer, but future studies are needed to rule out a causal association between bendroflumethiazide and cutaneous malignant melanoma,” wrote authors who were led by Christoph R. Meier, PhD, a professor in pharmacy with University Hospital Basel (Switzerland) and a contributor to the Boston Collaborative Drug Surveillance Program.

This study adds to existing evidence that there is a dose-dependent increased risk of squamous cell carcinoma in users of high cumulative doses of hydrochlorothiazide, compared with non–hydrochlorothiazide users.

The study, an observational cohort study, was published earlier this year. It is based on data from the U.K.-based Clinical Practice Research Datalink. It included 271,154 new users of thiazides and thiazidelike diuretics, the majority at 87.6% having been prescribed bendroflumethiazide, 5.8% indapamide, and 3.6% hydrochlorothiazide. Outcomes were compared to those observed in 275,263 users of calcium channel blockers.

“The three primary outcomes of interest were a first-time diagnosis of cutaneous malignant melanoma, basal cell carcinoma, or squamous cell carcinoma,” the authors wrote.

Incidence rates and incidence rate ratios were estimated for both short-term and long-term users of thiazidelike diuretics and calcium channel blockers, while a propensity score (PS) analysis was done in order to control for 23 baseline covariates. The mean follow-up after PS weighting was 3.9 years for indapamide users and 5.5 years for hydrochlorothiazide users. Overall, the incidence rate ratios of squamous cell carcinoma were not markedly increased for either short-term or long-term users of thiazidelike diuretics, the authors reported.

In contrast, the incidence rate ratios of squamous cell carcinoma for hydrochlorothiazide users were increased by 29% for short-term users at an IRR of 1.29 while they were increased by almost twofold for long-term hydrochlorothiazide users at an IRR of 1.95.

Long-term use of hydrochlorothiazide was again associated with a 64% increased risk of basal cell carcinoma, compared with users of a renin-angiotensin inhibitor at a weighted IRR of 1.64.

In contrast, weighted incident rate ratios for basal cell carcinoma for both short-term and long-term thiazide users were not significantly different and results were similar for patients who took hydrochlorothiazide, indapamide, or bendroflumethiazide.

Weighted overall incident rate ratios for cutaneous malignant melanoma were not significantly different for either short-term or long-term users of thiazidelike diuretics, compared with calcium channel blocker users.

However, there was a 43% increased risk of cutaneous malignant melanoma among long-term indapamide users at a weighted IRR of 1.43, compared with calcium channel blocker users, the authors reported.

“Given the biological plausibility and the severe clinical implications of cutaneous malignant melanoma, this finding should be considered carefully,” they cautioned.

Limitations to the study include the fact that the database analyzed does not have information on sun exposure, skin characteristics, or socioeconomic status which may affect the amount of sun exposure participants received.

The authors had no conflicts of interest to declare.

Researchers writing in the British Journal of Dermatology confirm the long-term use of hydrochlorothiazide is associated with a dose-dependent, twofold increased risk of squamous cell carcinoma, compared with calcium channel blocker use.

The findings were originally reported in two Danish case-control studies in which physicians reported a fourfold increased risk of squamous cell carcinoma, and a moderate increased risk of basal cell carcinoma and cutaneous malignant melanoma in patients who used hydrochlorothiazide long-term.

And, while the new study did not find an increased risk of basal cell carcinoma and cutaneous malignant melanoma among long-term users of hydrochlorothiazide, they suggest that bendroflumethiazide “may be a safer alternative for patients at increased risk of skin cancer.” The long-term use of indapamide was associated with a moderately increased risk of cutaneous malignant melanoma but did not alter the risk of either squamous cell or basal cell carcinoma

“Our results suggest that bendroflumethiazide may be a safer alternative to hydrochlorothiazide and indapamide, especially for patients at increased risk of skin cancer, but future studies are needed to rule out a causal association between bendroflumethiazide and cutaneous malignant melanoma,” wrote authors who were led by Christoph R. Meier, PhD, a professor in pharmacy with University Hospital Basel (Switzerland) and a contributor to the Boston Collaborative Drug Surveillance Program.

This study adds to existing evidence that there is a dose-dependent increased risk of squamous cell carcinoma in users of high cumulative doses of hydrochlorothiazide, compared with non–hydrochlorothiazide users.

The study, an observational cohort study, was published earlier this year. It is based on data from the U.K.-based Clinical Practice Research Datalink. It included 271,154 new users of thiazides and thiazidelike diuretics, the majority at 87.6% having been prescribed bendroflumethiazide, 5.8% indapamide, and 3.6% hydrochlorothiazide. Outcomes were compared to those observed in 275,263 users of calcium channel blockers.

“The three primary outcomes of interest were a first-time diagnosis of cutaneous malignant melanoma, basal cell carcinoma, or squamous cell carcinoma,” the authors wrote.

Incidence rates and incidence rate ratios were estimated for both short-term and long-term users of thiazidelike diuretics and calcium channel blockers, while a propensity score (PS) analysis was done in order to control for 23 baseline covariates. The mean follow-up after PS weighting was 3.9 years for indapamide users and 5.5 years for hydrochlorothiazide users. Overall, the incidence rate ratios of squamous cell carcinoma were not markedly increased for either short-term or long-term users of thiazidelike diuretics, the authors reported.

In contrast, the incidence rate ratios of squamous cell carcinoma for hydrochlorothiazide users were increased by 29% for short-term users at an IRR of 1.29 while they were increased by almost twofold for long-term hydrochlorothiazide users at an IRR of 1.95.

Long-term use of hydrochlorothiazide was again associated with a 64% increased risk of basal cell carcinoma, compared with users of a renin-angiotensin inhibitor at a weighted IRR of 1.64.

In contrast, weighted incident rate ratios for basal cell carcinoma for both short-term and long-term thiazide users were not significantly different and results were similar for patients who took hydrochlorothiazide, indapamide, or bendroflumethiazide.

Weighted overall incident rate ratios for cutaneous malignant melanoma were not significantly different for either short-term or long-term users of thiazidelike diuretics, compared with calcium channel blocker users.

However, there was a 43% increased risk of cutaneous malignant melanoma among long-term indapamide users at a weighted IRR of 1.43, compared with calcium channel blocker users, the authors reported.

“Given the biological plausibility and the severe clinical implications of cutaneous malignant melanoma, this finding should be considered carefully,” they cautioned.

Limitations to the study include the fact that the database analyzed does not have information on sun exposure, skin characteristics, or socioeconomic status which may affect the amount of sun exposure participants received.

The authors had no conflicts of interest to declare.

Researchers writing in the British Journal of Dermatology confirm the long-term use of hydrochlorothiazide is associated with a dose-dependent, twofold increased risk of squamous cell carcinoma, compared with calcium channel blocker use.

The findings were originally reported in two Danish case-control studies in which physicians reported a fourfold increased risk of squamous cell carcinoma, and a moderate increased risk of basal cell carcinoma and cutaneous malignant melanoma in patients who used hydrochlorothiazide long-term.

And, while the new study did not find an increased risk of basal cell carcinoma and cutaneous malignant melanoma among long-term users of hydrochlorothiazide, they suggest that bendroflumethiazide “may be a safer alternative for patients at increased risk of skin cancer.” The long-term use of indapamide was associated with a moderately increased risk of cutaneous malignant melanoma but did not alter the risk of either squamous cell or basal cell carcinoma

“Our results suggest that bendroflumethiazide may be a safer alternative to hydrochlorothiazide and indapamide, especially for patients at increased risk of skin cancer, but future studies are needed to rule out a causal association between bendroflumethiazide and cutaneous malignant melanoma,” wrote authors who were led by Christoph R. Meier, PhD, a professor in pharmacy with University Hospital Basel (Switzerland) and a contributor to the Boston Collaborative Drug Surveillance Program.

This study adds to existing evidence that there is a dose-dependent increased risk of squamous cell carcinoma in users of high cumulative doses of hydrochlorothiazide, compared with non–hydrochlorothiazide users.

The study, an observational cohort study, was published earlier this year. It is based on data from the U.K.-based Clinical Practice Research Datalink. It included 271,154 new users of thiazides and thiazidelike diuretics, the majority at 87.6% having been prescribed bendroflumethiazide, 5.8% indapamide, and 3.6% hydrochlorothiazide. Outcomes were compared to those observed in 275,263 users of calcium channel blockers.

“The three primary outcomes of interest were a first-time diagnosis of cutaneous malignant melanoma, basal cell carcinoma, or squamous cell carcinoma,” the authors wrote.

Incidence rates and incidence rate ratios were estimated for both short-term and long-term users of thiazidelike diuretics and calcium channel blockers, while a propensity score (PS) analysis was done in order to control for 23 baseline covariates. The mean follow-up after PS weighting was 3.9 years for indapamide users and 5.5 years for hydrochlorothiazide users. Overall, the incidence rate ratios of squamous cell carcinoma were not markedly increased for either short-term or long-term users of thiazidelike diuretics, the authors reported.

In contrast, the incidence rate ratios of squamous cell carcinoma for hydrochlorothiazide users were increased by 29% for short-term users at an IRR of 1.29 while they were increased by almost twofold for long-term hydrochlorothiazide users at an IRR of 1.95.

Long-term use of hydrochlorothiazide was again associated with a 64% increased risk of basal cell carcinoma, compared with users of a renin-angiotensin inhibitor at a weighted IRR of 1.64.

In contrast, weighted incident rate ratios for basal cell carcinoma for both short-term and long-term thiazide users were not significantly different and results were similar for patients who took hydrochlorothiazide, indapamide, or bendroflumethiazide.

Weighted overall incident rate ratios for cutaneous malignant melanoma were not significantly different for either short-term or long-term users of thiazidelike diuretics, compared with calcium channel blocker users.

However, there was a 43% increased risk of cutaneous malignant melanoma among long-term indapamide users at a weighted IRR of 1.43, compared with calcium channel blocker users, the authors reported.

“Given the biological plausibility and the severe clinical implications of cutaneous malignant melanoma, this finding should be considered carefully,” they cautioned.

Limitations to the study include the fact that the database analyzed does not have information on sun exposure, skin characteristics, or socioeconomic status which may affect the amount of sun exposure participants received.

The authors had no conflicts of interest to declare.

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at [email protected].
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at [email protected].
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.

A human chorionic gonadotropin (hCG) test is commonly ordered by gynecologists prior to surgical procedures, in the workup of bleeding abnormalities, and in the follow-up of ectopic and molar pregnancies, to name a few indications. In doing so, occasionally clinicians will find themselves in the diagnostic dilemma of discovering an inexplicable low-level elevation in hCG, such as in a postmenopausal patient. This clinical picture can be confusing and can be concerning for conditions such as postmolar gestational trophoblastic neoplasia (GTN). However, there can be benign causes of this phenomenon.¹ To prevent unnecessary worry, investigation of treatments is important. In fact, misdiagnosis and inappropriate treatment of benign, low-level hCG levels with unnecessary chemotherapy is problematic mismanagement of gestational trophoblastic disease (GTD), and a major cause of litigation.

Human chorionic gonadotropin is a glycoprotein hormone with two subunits (alpha and beta). It can come from multiple sources, including trophoblastic cells, malignant trophoblastic cells, the pituitary gland, and exogenous sources.¹ Its alpha-subunit is identical to that of follicle stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH). Its beta-subunit is unique, though very similar to that of LH. The free hCG beta subunit can be produced by nontrophoblastic neoplasms. The gene for the beta subunit of hCG is in close proximity to the beta subunit of LH and increases in gonadotropin-releasing hormone (GnRH) in menopause can result in the stimulation of both genes. Understanding the sources of hCG-like glycoproteins and mechanisms for testing is important when considering possible causes for falsely elevated hCG.

Most commercially available serum hCG assays detect normal intact hCG and free beta subunits. They are typically sandwich assays utilizing antibody binding sites in which a solid-phase anti-hCG antibody to a specific hCG target is then mixed with the patient’s serum, trapping or binding the hCG, which is then treated with an indicator antibody. After being washed with the indicator or “capture” antibody, its relative (quantitative) levels can be measured.¹

Urine hCG testing (such as urine pregnancy tests) work through capillary action, drawing the patient’s urine across absorbent pads before reaching a pad which contains anti-hCG antibodies (the detection zone) in the test line. These tests are less sensitive than serum tests, but many can detect hCG levels <15-20 mIU/mL.¹

When ob.gyns. are asked to consult on or evaluate persistently low-level elevations of hCG in nonpregnant patients they should consider both malignant and nonmalignant etiologies. Malignant causes include GTN or quiescent GTD (e.g., after treatment of a molar pregnancy or GTN), choriocarcinoma (e.g., ovarian germ cell tumors), and nonchoriocarcinoma malignancies (such as cervical, pancreatic, breast, renal). Nonmalignant causes of hCG elevations in nonpregnant patients include pituitary hCG (in postmenopausal patients), exogenous hCG, and phantom hCG.

The first step in diagnostic workup is to perform a urine pregnancy test. Provided that the serum hCG level is > 20 mIU/mL, the urine HCG should be positive unless the cause of elevated levels is “phantom hCG” from heterophilic antibodies. When patients are exposed to animal antigens (such as in vaccines) they can develop antibodies such as human anti-mouse antibody. These antibodies have affinity to the binding antibodies used in many hCG sandwich assays and form a linkage between the solid phase antibody and the detection antibody creating a false-positive result. This false-positive test is only present in serum testing but not urine tests because the patient’s heterophilic antibodies are not excreted by the kidney and thus not available to create a false-positive result. An alternative method to make the diagnosis of phantom hCG is to request that the hCG testing be run at a different lab with a different assay (which may not react with the same affinity to the patient’s anti-animal heterophile antibodies), or to request that the lab perform serial dilutions. If phantom hCG from heterophile antibodies is at play, serial dilutions will result in a nonlinear dilution response.

If the patient’s urine hCG test is positive, then pregnancy should be ruled out with a transvaginal ultrasound. If negative, an ectopic pregnancy should still be considered (unless not medically plausible, such as in postmenopausal women or women who have undergone hysterectomy). In the absence of an intrauterine or ectopic pregnancy, a positive serum and urine pregnancy test could be from exogenous hCG, from malignancy or pituitary hCG. Use of exogenous hCG can be ruled out by taking a thorough history, with particular focus on asking about weight loss medications and muscle building therapies.

If pregnancy and exogenous hCG are ruled out, clinicians should assess for an occult hCG-secreting malignancy. The lab should be asked to measure the proportion of the free beta subunit of hCG, as this is typically what is secreted by malignancies. CT imaging of the chest, abdomen, and pelvis to search for an occult primary tumor should take place. If the patient has been recently treated for molar pregnancy or GTN, and serum hCG levels reside between 100 and 300 mIU/mL, quiescent GTD should be considered the diagnosis. Determination of the proportion of hyperglycosylated hCG to total hCG can help differentiate active choriocarcinoma from quiescent GTD. After restaging imaging has been done to confirm no measurable metastatic foci, observation can follow with monthly hCG measurements. The majority of these cases will eventually resolve without intervention within a year. Quiescent GTD and persistent low-level HCG in the absence of measurable GTN on imaging or symptoms does not require treatment with chemotherapy or hysterectomy, particularly in women who desire future fertility.²

Once occult malignancy has been ruled out, the remaining potential source of hCG is the pituitary gland. As mentioned earlier, hCG shares its morphology with TSH, LH, and FSH. This can result in cross reactivity and false positives. In the menopausal state, GnRH levels increase and thus so do pituitary LH and hCG levels. To confirm that the pituitary is the source of the low-level hCG levels, the provider should prescribe a course of hormonal treatment such as an oral contraceptive pill for a 2- to 3-month period. This should result in suppression of pituitary hCG, and serum hCG levels, as part of a negative feedback loop. Pituitary source of hCG is a benign condition, and, like quiescent GTD, phantom hCG or exogenous hCG does not require intervention.

Getting to the bottom of persistent low-level hCG elevations can be challenging. By following the step-wise algorithm listed here, clinicians can sequentially test for urine hCG, heterophilic antibodies, elevated free beta-subunit, occult malignancy, and pituitary hCG.
 

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She has no conflicts of interest. Email her at [email protected].
 

References

1. Oyatogun O et al. Ther Adv Reprod Health 2021 Jun 13. doi: 10.1177/2F26334941211016412.

2. Soper JT. Obstet Gynecol. 2021 Feb 1;137(2):355-70.

Social media isn’t everyone’s cup of tea, but for those who want to become a significant influencer on Instagram, YouTube, TikTok, or other platforms, “you have to enjoy it,” Sandra Lee, MD, said during a virtual course on laser and aesthetic skin therapy.

“I admit that I’m somewhat obsessed with it. I kind of blame it on my work as a dermatologist, that I’m trying to grow my social media as well. It’s interesting to me, fascinating, and I want to understand it more. I think that’s the mindset you need to approach it with.”

Perhaps no other public figure in dermatology has enjoyed success in social media more than Dr. Lee, a board-certified dermatologist who practices in Upland, Calif. In the fall of 2014, she started using Instagram to provide followers a glimpse into her life as a dermatologist, everything from Mohs surgery and Botox to keloid removals and ear lobe repair surgeries. From this she formed her alter ego, “Dr. Pimple Popper,” and became a YouTube sensation, building 7.1 million subscribers over the course of a few years, amounting to 4.5 billion lifetime views. She also grew 12 million followers on TikTok, 4.4 million followers on Instagram, 3 million on Facebook, and more than 139,000 on Twitter. About 80% of her followers are women who range between 18 and 40 years of age.

During the meeting she offered five social media marketing tips for busy clinicians:

You have to ‘play’ to ‘win.’ Active participation in social media is required to develop followers. “You cannot delegate this content,” Dr. Lee said. “You can hire people to help you or leave the task to a social media-savvy medical assistant in your office, but the content should be your responsibility ultimately, because you are the physician,” she added. Not everyone chooses to participate in social media, but it’s also something not to shy away from out of intimidation. “There is some talent associated with it, but it takes a lot of persistence as well,” she said.

Patients come first. Protect them at all costs. Dr. Lee rarely posts the faces of patients she cares for unless they grant consent in advance. “I try to show the work that I do and the beauty of dermatology,” she said during the meeting, which was named “Laser & Aesthetic Skin Therapy: What’s the Truth?” and was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. She added that taking part in social media can help you improve communication skills by engaging with followers who like, share, or respond to the material posted. “When you look back at your posts objectively, you learn about yourself and how you relate to your patients,” she said. “It helps to hone my bedside manner and my skills as a dermatologist.”

Show that you are human. Many dermatologists and other “skin influencers” have established their presence on the Internet and may be direct competitors for patients, but that doesn’t mean you can’t establish your own identity. One way to stand out is by posting content related to your authentic self, such as a photo or video that shows you engaged in a hobby, dining at a favorite restaurant, or visiting a beloved vacation spot. “Your followers don’t want a robot, someone who thinks they’re amazing and can do everything,” said Dr. Lee, who stars in her own TV reality show on TLC. “Show that you have a funny side. You want them to fall in love with you and see a little bit of your world, whatever it might be. Charm the socks off of them.”

Entertain first, educate a close second. The main way you’re going to get people to follow and watch you is to provide some entertainment, “not at the expense of a patient or your practice, though,” she said. “Then you’re going to educate people. We dermatologists have something to teach the world because we are experts on skin, hair, and nails. You want to impart this knowledge in a way that captivates people.” It’s like the sense of accomplishment that comes from learning something new after reading a book or watching a movie, she explained. “You feel good about it, and you can take that knowledge with you somewhere else. I love it when kids come up to me and tell me they know what a lipoma is, what a cyst is, and what psoriasis is because they’ve seen my show, or because they follow me on social media. It’s wonderful because I can see that I’ve educated them.”

Be kind and don’t activate the trolls. Dr. Lee allows positivity and kindness to rule the day on her social media content. “This is what I try to relay to followers, but I also do not engage with the negativity,” she said. “Every now and then, there will be someone who tries to insult what you do or who insults you personally. If you engage with them, it almost invites them to do it more. It almost gives them the ability to fight with you. Try to stay above that; just put out goodness and kindness.”

Several years ago, YouTube and Instagram temporarily shut down Dr. Lee’s accounts because she posted graphic images of skin lesions and procedures – a practice that wasn’t so commonplace at the time. “Don’t just post a graphic image just to be graphic,” she advised. “Make sure it has an educational message associated with it. That will help to validate your content. Posting a warning sign that some images may be graphic could help, too.”

Dr. Lee reported having no relevant financial disclosures.

[email protected]

Social media isn’t everyone’s cup of tea, but for those who want to become a significant influencer on Instagram, YouTube, TikTok, or other platforms, “you have to enjoy it,” Sandra Lee, MD, said during a virtual course on laser and aesthetic skin therapy.

“I admit that I’m somewhat obsessed with it. I kind of blame it on my work as a dermatologist, that I’m trying to grow my social media as well. It’s interesting to me, fascinating, and I want to understand it more. I think that’s the mindset you need to approach it with.”

Perhaps no other public figure in dermatology has enjoyed success in social media more than Dr. Lee, a board-certified dermatologist who practices in Upland, Calif. In the fall of 2014, she started using Instagram to provide followers a glimpse into her life as a dermatologist, everything from Mohs surgery and Botox to keloid removals and ear lobe repair surgeries. From this she formed her alter ego, “Dr. Pimple Popper,” and became a YouTube sensation, building 7.1 million subscribers over the course of a few years, amounting to 4.5 billion lifetime views. She also grew 12 million followers on TikTok, 4.4 million followers on Instagram, 3 million on Facebook, and more than 139,000 on Twitter. About 80% of her followers are women who range between 18 and 40 years of age.

During the meeting she offered five social media marketing tips for busy clinicians:

You have to ‘play’ to ‘win.’ Active participation in social media is required to develop followers. “You cannot delegate this content,” Dr. Lee said. “You can hire people to help you or leave the task to a social media-savvy medical assistant in your office, but the content should be your responsibility ultimately, because you are the physician,” she added. Not everyone chooses to participate in social media, but it’s also something not to shy away from out of intimidation. “There is some talent associated with it, but it takes a lot of persistence as well,” she said.

Patients come first. Protect them at all costs. Dr. Lee rarely posts the faces of patients she cares for unless they grant consent in advance. “I try to show the work that I do and the beauty of dermatology,” she said during the meeting, which was named “Laser & Aesthetic Skin Therapy: What’s the Truth?” and was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. She added that taking part in social media can help you improve communication skills by engaging with followers who like, share, or respond to the material posted. “When you look back at your posts objectively, you learn about yourself and how you relate to your patients,” she said. “It helps to hone my bedside manner and my skills as a dermatologist.”

Show that you are human. Many dermatologists and other “skin influencers” have established their presence on the Internet and may be direct competitors for patients, but that doesn’t mean you can’t establish your own identity. One way to stand out is by posting content related to your authentic self, such as a photo or video that shows you engaged in a hobby, dining at a favorite restaurant, or visiting a beloved vacation spot. “Your followers don’t want a robot, someone who thinks they’re amazing and can do everything,” said Dr. Lee, who stars in her own TV reality show on TLC. “Show that you have a funny side. You want them to fall in love with you and see a little bit of your world, whatever it might be. Charm the socks off of them.”

Entertain first, educate a close second. The main way you’re going to get people to follow and watch you is to provide some entertainment, “not at the expense of a patient or your practice, though,” she said. “Then you’re going to educate people. We dermatologists have something to teach the world because we are experts on skin, hair, and nails. You want to impart this knowledge in a way that captivates people.” It’s like the sense of accomplishment that comes from learning something new after reading a book or watching a movie, she explained. “You feel good about it, and you can take that knowledge with you somewhere else. I love it when kids come up to me and tell me they know what a lipoma is, what a cyst is, and what psoriasis is because they’ve seen my show, or because they follow me on social media. It’s wonderful because I can see that I’ve educated them.”

Be kind and don’t activate the trolls. Dr. Lee allows positivity and kindness to rule the day on her social media content. “This is what I try to relay to followers, but I also do not engage with the negativity,” she said. “Every now and then, there will be someone who tries to insult what you do or who insults you personally. If you engage with them, it almost invites them to do it more. It almost gives them the ability to fight with you. Try to stay above that; just put out goodness and kindness.”

Several years ago, YouTube and Instagram temporarily shut down Dr. Lee’s accounts because she posted graphic images of skin lesions and procedures – a practice that wasn’t so commonplace at the time. “Don’t just post a graphic image just to be graphic,” she advised. “Make sure it has an educational message associated with it. That will help to validate your content. Posting a warning sign that some images may be graphic could help, too.”

Dr. Lee reported having no relevant financial disclosures.

[email protected]

Social media isn’t everyone’s cup of tea, but for those who want to become a significant influencer on Instagram, YouTube, TikTok, or other platforms, “you have to enjoy it,” Sandra Lee, MD, said during a virtual course on laser and aesthetic skin therapy.

“I admit that I’m somewhat obsessed with it. I kind of blame it on my work as a dermatologist, that I’m trying to grow my social media as well. It’s interesting to me, fascinating, and I want to understand it more. I think that’s the mindset you need to approach it with.”

Perhaps no other public figure in dermatology has enjoyed success in social media more than Dr. Lee, a board-certified dermatologist who practices in Upland, Calif. In the fall of 2014, she started using Instagram to provide followers a glimpse into her life as a dermatologist, everything from Mohs surgery and Botox to keloid removals and ear lobe repair surgeries. From this she formed her alter ego, “Dr. Pimple Popper,” and became a YouTube sensation, building 7.1 million subscribers over the course of a few years, amounting to 4.5 billion lifetime views. She also grew 12 million followers on TikTok, 4.4 million followers on Instagram, 3 million on Facebook, and more than 139,000 on Twitter. About 80% of her followers are women who range between 18 and 40 years of age.

During the meeting she offered five social media marketing tips for busy clinicians:

You have to ‘play’ to ‘win.’ Active participation in social media is required to develop followers. “You cannot delegate this content,” Dr. Lee said. “You can hire people to help you or leave the task to a social media-savvy medical assistant in your office, but the content should be your responsibility ultimately, because you are the physician,” she added. Not everyone chooses to participate in social media, but it’s also something not to shy away from out of intimidation. “There is some talent associated with it, but it takes a lot of persistence as well,” she said.

Patients come first. Protect them at all costs. Dr. Lee rarely posts the faces of patients she cares for unless they grant consent in advance. “I try to show the work that I do and the beauty of dermatology,” she said during the meeting, which was named “Laser & Aesthetic Skin Therapy: What’s the Truth?” and was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. She added that taking part in social media can help you improve communication skills by engaging with followers who like, share, or respond to the material posted. “When you look back at your posts objectively, you learn about yourself and how you relate to your patients,” she said. “It helps to hone my bedside manner and my skills as a dermatologist.”

Show that you are human. Many dermatologists and other “skin influencers” have established their presence on the Internet and may be direct competitors for patients, but that doesn’t mean you can’t establish your own identity. One way to stand out is by posting content related to your authentic self, such as a photo or video that shows you engaged in a hobby, dining at a favorite restaurant, or visiting a beloved vacation spot. “Your followers don’t want a robot, someone who thinks they’re amazing and can do everything,” said Dr. Lee, who stars in her own TV reality show on TLC. “Show that you have a funny side. You want them to fall in love with you and see a little bit of your world, whatever it might be. Charm the socks off of them.”

Entertain first, educate a close second. The main way you’re going to get people to follow and watch you is to provide some entertainment, “not at the expense of a patient or your practice, though,” she said. “Then you’re going to educate people. We dermatologists have something to teach the world because we are experts on skin, hair, and nails. You want to impart this knowledge in a way that captivates people.” It’s like the sense of accomplishment that comes from learning something new after reading a book or watching a movie, she explained. “You feel good about it, and you can take that knowledge with you somewhere else. I love it when kids come up to me and tell me they know what a lipoma is, what a cyst is, and what psoriasis is because they’ve seen my show, or because they follow me on social media. It’s wonderful because I can see that I’ve educated them.”

Be kind and don’t activate the trolls. Dr. Lee allows positivity and kindness to rule the day on her social media content. “This is what I try to relay to followers, but I also do not engage with the negativity,” she said. “Every now and then, there will be someone who tries to insult what you do or who insults you personally. If you engage with them, it almost invites them to do it more. It almost gives them the ability to fight with you. Try to stay above that; just put out goodness and kindness.”

Several years ago, YouTube and Instagram temporarily shut down Dr. Lee’s accounts because she posted graphic images of skin lesions and procedures – a practice that wasn’t so commonplace at the time. “Don’t just post a graphic image just to be graphic,” she advised. “Make sure it has an educational message associated with it. That will help to validate your content. Posting a warning sign that some images may be graphic could help, too.”

Dr. Lee reported having no relevant financial disclosures.

[email protected]

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

Trick-or-treaters may not be so easily tricked into loving sugar-free treats, thanks to taste buds hard-wired to seek calorie-containing sweets, a new study suggests.

Taste isn’t all about choosing peanut butter cups over jelly beans. Since earliest humanity, our sense of taste has helped us detect salty, sweet, sour, savory, and bitter so that we can choose foods high in energy and low in poisons.

But these new findings suggest that our taste buds have another hidden talent: identifying foods that don’t give us any energy at all.

Scientists suspected this ability after research in mice showed that their taste buds could distinguish between sugar and calorie-free artificial sweeteners.

To test this possibility in humans, scientists asked people to drink a series of clear beverages and identify whether they were plain water or sweetened. The goal was to compare how people responded to glucose – a natural caloric sweetener in fruits, honey, and table sugar – and sucralose, a calorie-free artificial sweetener.

All participants wore nose plugs, ensuring that they would use only their taste buds and not their sense of smell for detection.

As expected, people could easily tell plain water from sweetened drinks, whether with glucose or sucralose, confirming that taste buds detect sweetness.

In a twist, researchers then mixed in flavorless chemicals that block taste buds from picking up sweetness. With these drinks, people could no longer distinguish sucralose-sweetened beverages from plain water. But they could still tell when they had a beverage sweetened with glucose.

This finding indicates that two separate pathways underlie the mouth’s response to sugar, researchers report in PLOS One. The first pathway identifies sweet flavors, and the second one detects foods that contain energy that can be used for fuel.

Scientists might one day come up with calorie-free sweets that trick taste buds into detecting the presence of calories, enhancing their appeal. But in the lab studies, the participants had no visual cues or smell to guide their reactions, meaning how these other sensory inputs would affect treat perception isn’t known.

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

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.

They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.

However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.

“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.

Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”

The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”

Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.

The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
 

‘Important study,’ but lacked newer meds

This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.

“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.

The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”

However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.

The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.

For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”

One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.

Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.

The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.

Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.

Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
 

Study rationale and findings

Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.

To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.

They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).

The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.

Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.

The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.

They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).

Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).

In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).

The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).

The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).

In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.

Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).

However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).

There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).

There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).

The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).

The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.

“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.

They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.

However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.

“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.

Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”

The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”

Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.

The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
 

‘Important study,’ but lacked newer meds

This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.

“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.

The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”

However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.

The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.

For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”

One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.

Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.

The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.

Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.

Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
 

Study rationale and findings

Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.

To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.

They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).

The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.

Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.

The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.

They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).

Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).

In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).

The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).

The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).

In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.

Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).

However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).

There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).

There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).

The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).

The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.

“Short-term hospitalization [for reasons other than diabetes] may not be the time to intervene in long-term diabetes management,” researchers conclude.

They found that, in a national cohort of older almost entirely male veterans with non–insulin-treated type 2 diabetes who were hospitalized for non–diabetes-related common medical conditions, intensified diabetes treatment on hospital discharge was linked to an increased risk of severe hypoglycemia in the immediate postdischarge period.

However, diabetes treatment intensification – that is, receiving a prescription for a new or higher dose of diabetes medicine – was not associated with decreased risks of severe hyperglycemia or with improved glycemic (hemoglobin A1c) control at 30 days or 1 year, according to study results, published in JAMA Network Open.

“We didn’t see a reduction in diabetes emergencies in more intensively treated patients,” lead investigator Timothy S. Anderson, MD, said in an interview.

Also, importantly, there was a low rate of persistence with the new treatment. “Half of the patients were no longer taking these [intensified diabetes medicines] at 1 year, which tells me that context is key,” he pointed out. “If a patient is in the hospital for diabetes [unlike the patients in this study], I think it makes a lot of sense to modify and adjust their regimen to try to help them right then and there.”

The overall risk of severe hyperglycemia or severe hypoglycemia was pretty small in the overall cohort, Dr. Anderson noted, “but we do put people at risk of leaving the hospital and ending up back in the hospital with low blood sugar when we intensify medications, and there’s not necessarily a good signal to suggest that it’s all that urgent to change these medicines.”

Instead, the “safer path” may be to make recommendations to the patient’s outpatient physician and also inform the patient – for example, “We saw some concerns about your diabetes while you were in the hospital, and this is really something that should be looked at when you’re recovered and feeling better from the rest of your health standpoint” – rather than making a diabetes medication change while the person is acutely ill or recovering from illness, said Dr. Anderson, from Beth Israel Deaconess Medical Center and Harvard Medical School, Boston.

The researchers also found an “unexpected” significant decrease in 30-day mortality in the patients with intensified diabetes treatment, which was probably because of confounding that was not accounted for, Dr. Anderson speculated, since clinical trials have consistently shown that benefits from diabetes medications take a longer time to show an effect.
 

‘Important study,’ but lacked newer meds

This is an “important” study for primary care and in-hospital physicians that shows that “hospitalization is really not the time and the place” to intensify diabetes medication, Rozalina G. McCoy, MD, coauthor of an invited commentary, told this news organization in an interview.

“While overcoming treatment inertia is important, [it should be] done appropriately, so that we don’t overtreat patients,” Dr. McCoy, of the Mayo Clinic in Rochester, Minn., stressed.

The very low rate of persistence of taking intensified medications is a major finding, she agreed. Hospitalized patients “are not in their usual state of health, so if we make long-term treatment decisions based on their acute abnormal situation, that may not be appropriate.”

However, patients with high A1c may benefit from a change at hospital discharge rather than when they see their primary care provider, with the caveat that they need close follow-up as an outpatient.

The study emphasizes the “need for longitudinal patient care rather than episodic patches,” according to Dr. McCoy.

For example, a patient who is hospitalized for a chronic obstructive pulmonary disease or asthma exacerbation may be receiving steroids that cause high blood glucose levels but as soon as they’re done with their steroid course, blood glucose will decrease, so the “need for close outpatient follow-up is very important.”

One limitation of the current work is that an earlier study in the same population by the research group showed that 49% of patients whose treatment regimens were intensified had limited life expectancy or were at or below their A1c goal, so they would not have benefited from the stepped-up treatment, she noted.

Another limitation is that the findings cannot be generalized to women or younger patients, or to patients treated with glucagonlike peptide 1 (GLP-1)–receptor agonists or sodium-glucose cotransporter 2 (SGLT2) inhibitors.

The study patients were seen in the U.S. Veterans Health Administration health system when these newer agents were not used. Three-quarters of patients received intensified treatment with sulfonylurea or insulin, and only one patient received a new GLP-1–receptor agonist.

Ideally, Dr. McCoy said, patients should have been prescribed a GLP-1–receptor agonist if they had atherosclerotic cardiovascular disease or kidney disease, or an SGLT2 inhibitor if they had kidney disease or heart failure, which may have led to different results, and would need to be determined in further study.

Dr. Anderson agreed that “SGLT2 inhibitors and GLP1 agonists are broadly much safer than the older diabetes medicines, at least when it comes to risk of hypoglycemia, and may have more clear benefits in heart disease and mortality. So I would not want to extrapolate our findings to those new classes,” he said. “A similar set of studies would need to be done.”
 

Study rationale and findings

Hospitalized older adults with diabetes commonly have transiently elevated blood glucose levels that might lead clinicians to discharge them from hospital with a prescription for more intensive diabetes medications than they were on before they were hospitalized, but it is not clear if these diabetes medication changes would improve outcomes.

To investigate this, the researchers analyzed data from patients with diabetes who were 65 and older and hospitalized for common medical conditions in VHA hospitals during January 2011–September 2016, and then discharged to the community.

They excluded patients who were hospitalized for things that require immediate change in diabetes treatment and patients who were using insulin before their hospitalization (because instructions to modify insulin dosing frequently don’t have a new prescription).

The researchers identified 28,198 adults with diabetes who were not on insulin and were hospitalized in the VHA health system for heart failure (18%), coronary artery disease (13%), chronic obstructive pulmonary disease (10%), pneumonia (9.6%), and urinary tract infection (7.5%), and less often and not in decreasing order, for acute coronary syndrome, arrhythmia, asthma, chest pain, conduction disorders, heart valve disorders, sepsis, skin infection, stroke, and transient ischemic attack.

Of these patients, 2,768 patients (9.8%) received diabetes medication intensification, and the researchers matched 2,648 of these patients with an equal number of patients who did not receive this treatment intensification.

The patients in each group had a mean age of 73 and 98.5% were male; 78% were White.

They had a mean A1c of 7.9%. Most were receiving sulfonylurea (43%) or metformin (39%), and few were receiving thiazolidinediones (4.1%), alpha-glucosidase inhibitors (2.7%), dipeptidyl peptidase 4 inhibitors (2.0%), or other types of diabetes drugs (0.1%).

Of the 2,768 patients who received intensified diabetes medication, most received a prescription for insulin (51%) or sulfonylurea (23%).

In the propensity-matched cohort, patients with intensified diabetes medication had a higher rate of severe hypoglycemia at 30 days (1% vs. 0.5%), which translated into a significant twofold higher risk (hazard ratio, 2.17).

The rates of severe hypoglycemia at 1 year were similar in both groups (3.1% and 2.9%).

The incidence of severe hyperglycemia was the same in both groups at 30 days (0.3%) and 1 year (1.3%).

In secondary outcomes, at 1 year, 48% of new oral diabetes medications and 39% of new insulin prescriptions were no longer being filled.

Overall, patients who were discharged with intensified diabetes medication were significantly less likely to die within 30 days than the other patients (1.3% vs. 2.4%; HR, 0.55).

However, this mortality benefit was found only in the subgroup of 2,524 patients who had uncontrolled diabetes when they were admitted to hospital (A1c >7.5%; mean A1c, 9.1%), and not in the propensity-matched subgroup of 2,672 patients who had controlled diabetes then (A1c up to 7.5%; mean A1c, 6.8%).

There was no significant difference in 1-year mortality in patients with versus without intensified treatment (15.8% vs. 17.8%).

There were also no significant between-group difference in rates of hospital readmission at 30 days (roughly 17%) or 1 year (roughly 51%).

The decreases in mean A1c from hospital discharge to 1 year later were also the same in both groups (going from 7.9% to 7.7%).

The study was funded by grants from the National Institute on Aging and the American College of Cardiology. Dr. Anderson has no relevant financial disclosures. Dr. McCoy reported receiving grants from the National Institute of Diabetes and Digestive and Kidney Diseases, AARP, and the Patient-Centered Outcomes Research Institute outside the submitted work. The disclosures of the other authors and the editorial coauthor are available with the article and commentary.

In the clinical assessment of vitamin D concentrations, free 25-hydroxyvitamin D shows little added benefit to the current standard of total 25(OH)D, with deficiencies in each associated with at least a twofold risk of all-cause mortality, new research shows.

“In this prospective, population-based study of middle-aged and older European men, total 25(OH)D levels below 20 mcg/L were independently associated with a twofold increased all-cause mortality,” the researchers reported.

“Lower concentrations of free 25(OH)D were also predictive of mortality, but did not provide any additional information,” they noted. “The data do not support routine measurement of free 25(OH)D or 1,25(OH)2D [1,25-dihydroxyvitamin D] over total 25(OH)D levels.”

Despite vitamin D deficiency being well established as playing a role in a wide range of adverse health effects, including cardiovascular disease and mortality, there has been a lack of consensus on the optimal concentration of total 25(OH)D, with studies showing inconsistent levels to define insufficiency and deficiency.

One aspect of the debate has focused on precisely how to measure the concentrations, with some evidence supporting the “free hormone hypothesis,” which suggests that free 25(OH)D could represent a better indicator than the standard total 25(OH)D of functional availability of vitamin D, and have stronger clinical utility.

To investigate both issues, Marian Dejaeger, MD, PhD, and colleagues evaluated prospective data on 1,915 men recruited from eight centers around Europe in the European Male Aging Study in a report published in the Journal of Clinical Endocrinology & Metabolism

The men, who were aged between 40 and 79 years, had a mean follow-up of 12.3 years; during that time, about a quarter (23.5%) of them died.

In addition to other factors, including being older, having a higher body mass index, and having at least two comorbidities, men who died had significantly lower levels of total 25(OH)D, total 1,25(OH)2D, free 25(OH)D, and free 1,25(OH)2D, as well as higher parathyroid hormone and creatinine values.

After adjustment for key confounders, including body mass index, smoking, alcohol consumption, kidney function, number of comorbidities at baseline and other factors, men with a total 25(OH)D below 20 mcg/L had a significantly increased risk of mortality, compared with those who had normal levels of vitamin D, defined as above 30 mcg/L (hazard ratio, 2.03; P < .001).

In terms of free 25(OH)D, the lowest three free 25(OH)D quintiles (under 4.43 ng/L) similarly had a significantly higher mortality risk, compared with the highest quintile (HR, 2.09; P < .01) after adjustment for the confounders.

Further observations of all quintiles of other measures of 1,25(OH)2D and vitamin D binding protein (DBP) showed no associations with mortality after adjusting for confounders.
 

Methods of measurement

An important caveat of the study is the type of method used to measure free 25(OH)D. The authors calculated free 25(OH)D using a formula, as opposed to the alternative of direct measurement with an enzyme-linked immunosorbent assay kit, and there can be important differences between the two approaches, said Daniel Bikle, MD, PhD, a professor of medicine and dermatology at the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, in a comment on the research.

“The biggest problem is that calculating free 25(OH)D does not give an accurate estimate of the real free level, so making conclusions regarding its role in clinical situations is subject to error,” said Dr. Bikle, who recently authored a review of the free hormone hypothesis.

A calculation approach “depends heavily on the total 25(OH)D level, so in a population with reasonably normal DBP and albumin levels, the correlation with total 25(OH)D is very high, so I am not surprised by the results showing no additional value,” he said in an interview.

The authors addressed their use of the calculation over the direct measurement in the study, noting that there is a “high correlation between both methods.”

But they added that, “as no equilibrium analysis method is available for free 25(OH)D, nor for free 1,25(OH)2D, no method can be considered superior.”

Dr. Dejaeger, of the department of public health and primary care, Katholieke Universiteit Leuven (Belgium), added that she agreed that high or low DBP could potentially shift some correlations, but noted that other research has shown calculated and direct measures to match relatively well.

“So we partly agree [with Dr. Bikle] not being surprised that we did not find an added value because we also found little variation in DBP, but we are not convinced that a different measurement method could make the difference here.”

Another caveat of the study is that, despite half of the measurements being taken in the summer, more than 90% of subjects in the study’s cohort had vitamin D insufficiency, defined in the study as total 25(OH)D levels below 30 mcg/L, and as many as 70% had deficiency, with levels below 20 mcg/L.

Therefore, “as the number of participants with high levels of total 25(OH)D in our study is small, a true threshold concentration for optimal vitamin D status cannot be defined on basis of our data,” the authors noted.

Under current recommendations, the Endocrine Society indicates that concentrations below 30 mcg/L are insufficient, while other groups, including the Institute of Medicine, suggest concentrations of 20 mcg/L or above are adequate.
 

Free hormone hypothesis

Under the free hormone hypothesis, which is observed with thyroid hormones and sex steroids, the very small fraction of free hormones that are not bound to protein carriers can enter cells and help facilitate biologic activity.

The hypothesis of a role of free 25(OH)D in mortality was supported by a recent study, in which free 25(OH)D levels – but not total 25(OH)D levels, were found to be independently associated with an increased risk of all-cause and cardiovascular mortality among patients with coronary artery disease.

However, two other studies are more consistent with the new findings, including one study showing no added value of free 25(OH)D as a marker for bone mineral density in older women, and another study showing no value as a marker of metabolic variables in healthy children.

“Currently, there are no hard data to support routine measurements of free 25(OH)D or 1,25(OH)2D over total 25(OH)D, the current standard of assessing vitamin D status, as stated in guidelines from different scientific bodies,” Dr. Dejaeger said in an interview.

The study received support from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre. Dr. Dejaeger and Dr. Bikle had no disclosures to report.

In the clinical assessment of vitamin D concentrations, free 25-hydroxyvitamin D shows little added benefit to the current standard of total 25(OH)D, with deficiencies in each associated with at least a twofold risk of all-cause mortality, new research shows.

“In this prospective, population-based study of middle-aged and older European men, total 25(OH)D levels below 20 mcg/L were independently associated with a twofold increased all-cause mortality,” the researchers reported.

“Lower concentrations of free 25(OH)D were also predictive of mortality, but did not provide any additional information,” they noted. “The data do not support routine measurement of free 25(OH)D or 1,25(OH)2D [1,25-dihydroxyvitamin D] over total 25(OH)D levels.”

Despite vitamin D deficiency being well established as playing a role in a wide range of adverse health effects, including cardiovascular disease and mortality, there has been a lack of consensus on the optimal concentration of total 25(OH)D, with studies showing inconsistent levels to define insufficiency and deficiency.

One aspect of the debate has focused on precisely how to measure the concentrations, with some evidence supporting the “free hormone hypothesis,” which suggests that free 25(OH)D could represent a better indicator than the standard total 25(OH)D of functional availability of vitamin D, and have stronger clinical utility.

To investigate both issues, Marian Dejaeger, MD, PhD, and colleagues evaluated prospective data on 1,915 men recruited from eight centers around Europe in the European Male Aging Study in a report published in the Journal of Clinical Endocrinology & Metabolism

The men, who were aged between 40 and 79 years, had a mean follow-up of 12.3 years; during that time, about a quarter (23.5%) of them died.

In addition to other factors, including being older, having a higher body mass index, and having at least two comorbidities, men who died had significantly lower levels of total 25(OH)D, total 1,25(OH)2D, free 25(OH)D, and free 1,25(OH)2D, as well as higher parathyroid hormone and creatinine values.

After adjustment for key confounders, including body mass index, smoking, alcohol consumption, kidney function, number of comorbidities at baseline and other factors, men with a total 25(OH)D below 20 mcg/L had a significantly increased risk of mortality, compared with those who had normal levels of vitamin D, defined as above 30 mcg/L (hazard ratio, 2.03; P < .001).

In terms of free 25(OH)D, the lowest three free 25(OH)D quintiles (under 4.43 ng/L) similarly had a significantly higher mortality risk, compared with the highest quintile (HR, 2.09; P < .01) after adjustment for the confounders.

Further observations of all quintiles of other measures of 1,25(OH)2D and vitamin D binding protein (DBP) showed no associations with mortality after adjusting for confounders.
 

Methods of measurement

An important caveat of the study is the type of method used to measure free 25(OH)D. The authors calculated free 25(OH)D using a formula, as opposed to the alternative of direct measurement with an enzyme-linked immunosorbent assay kit, and there can be important differences between the two approaches, said Daniel Bikle, MD, PhD, a professor of medicine and dermatology at the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, in a comment on the research.

“The biggest problem is that calculating free 25(OH)D does not give an accurate estimate of the real free level, so making conclusions regarding its role in clinical situations is subject to error,” said Dr. Bikle, who recently authored a review of the free hormone hypothesis.

A calculation approach “depends heavily on the total 25(OH)D level, so in a population with reasonably normal DBP and albumin levels, the correlation with total 25(OH)D is very high, so I am not surprised by the results showing no additional value,” he said in an interview.

The authors addressed their use of the calculation over the direct measurement in the study, noting that there is a “high correlation between both methods.”

But they added that, “as no equilibrium analysis method is available for free 25(OH)D, nor for free 1,25(OH)2D, no method can be considered superior.”

Dr. Dejaeger, of the department of public health and primary care, Katholieke Universiteit Leuven (Belgium), added that she agreed that high or low DBP could potentially shift some correlations, but noted that other research has shown calculated and direct measures to match relatively well.

“So we partly agree [with Dr. Bikle] not being surprised that we did not find an added value because we also found little variation in DBP, but we are not convinced that a different measurement method could make the difference here.”

Another caveat of the study is that, despite half of the measurements being taken in the summer, more than 90% of subjects in the study’s cohort had vitamin D insufficiency, defined in the study as total 25(OH)D levels below 30 mcg/L, and as many as 70% had deficiency, with levels below 20 mcg/L.

Therefore, “as the number of participants with high levels of total 25(OH)D in our study is small, a true threshold concentration for optimal vitamin D status cannot be defined on basis of our data,” the authors noted.

Under current recommendations, the Endocrine Society indicates that concentrations below 30 mcg/L are insufficient, while other groups, including the Institute of Medicine, suggest concentrations of 20 mcg/L or above are adequate.
 

Free hormone hypothesis

Under the free hormone hypothesis, which is observed with thyroid hormones and sex steroids, the very small fraction of free hormones that are not bound to protein carriers can enter cells and help facilitate biologic activity.

The hypothesis of a role of free 25(OH)D in mortality was supported by a recent study, in which free 25(OH)D levels – but not total 25(OH)D levels, were found to be independently associated with an increased risk of all-cause and cardiovascular mortality among patients with coronary artery disease.

However, two other studies are more consistent with the new findings, including one study showing no added value of free 25(OH)D as a marker for bone mineral density in older women, and another study showing no value as a marker of metabolic variables in healthy children.

“Currently, there are no hard data to support routine measurements of free 25(OH)D or 1,25(OH)2D over total 25(OH)D, the current standard of assessing vitamin D status, as stated in guidelines from different scientific bodies,” Dr. Dejaeger said in an interview.

The study received support from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre. Dr. Dejaeger and Dr. Bikle had no disclosures to report.

In the clinical assessment of vitamin D concentrations, free 25-hydroxyvitamin D shows little added benefit to the current standard of total 25(OH)D, with deficiencies in each associated with at least a twofold risk of all-cause mortality, new research shows.

“In this prospective, population-based study of middle-aged and older European men, total 25(OH)D levels below 20 mcg/L were independently associated with a twofold increased all-cause mortality,” the researchers reported.

“Lower concentrations of free 25(OH)D were also predictive of mortality, but did not provide any additional information,” they noted. “The data do not support routine measurement of free 25(OH)D or 1,25(OH)2D [1,25-dihydroxyvitamin D] over total 25(OH)D levels.”

Despite vitamin D deficiency being well established as playing a role in a wide range of adverse health effects, including cardiovascular disease and mortality, there has been a lack of consensus on the optimal concentration of total 25(OH)D, with studies showing inconsistent levels to define insufficiency and deficiency.

One aspect of the debate has focused on precisely how to measure the concentrations, with some evidence supporting the “free hormone hypothesis,” which suggests that free 25(OH)D could represent a better indicator than the standard total 25(OH)D of functional availability of vitamin D, and have stronger clinical utility.

To investigate both issues, Marian Dejaeger, MD, PhD, and colleagues evaluated prospective data on 1,915 men recruited from eight centers around Europe in the European Male Aging Study in a report published in the Journal of Clinical Endocrinology & Metabolism

The men, who were aged between 40 and 79 years, had a mean follow-up of 12.3 years; during that time, about a quarter (23.5%) of them died.

In addition to other factors, including being older, having a higher body mass index, and having at least two comorbidities, men who died had significantly lower levels of total 25(OH)D, total 1,25(OH)2D, free 25(OH)D, and free 1,25(OH)2D, as well as higher parathyroid hormone and creatinine values.

After adjustment for key confounders, including body mass index, smoking, alcohol consumption, kidney function, number of comorbidities at baseline and other factors, men with a total 25(OH)D below 20 mcg/L had a significantly increased risk of mortality, compared with those who had normal levels of vitamin D, defined as above 30 mcg/L (hazard ratio, 2.03; P < .001).

In terms of free 25(OH)D, the lowest three free 25(OH)D quintiles (under 4.43 ng/L) similarly had a significantly higher mortality risk, compared with the highest quintile (HR, 2.09; P < .01) after adjustment for the confounders.

Further observations of all quintiles of other measures of 1,25(OH)2D and vitamin D binding protein (DBP) showed no associations with mortality after adjusting for confounders.
 

Methods of measurement

An important caveat of the study is the type of method used to measure free 25(OH)D. The authors calculated free 25(OH)D using a formula, as opposed to the alternative of direct measurement with an enzyme-linked immunosorbent assay kit, and there can be important differences between the two approaches, said Daniel Bikle, MD, PhD, a professor of medicine and dermatology at the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, in a comment on the research.

“The biggest problem is that calculating free 25(OH)D does not give an accurate estimate of the real free level, so making conclusions regarding its role in clinical situations is subject to error,” said Dr. Bikle, who recently authored a review of the free hormone hypothesis.

A calculation approach “depends heavily on the total 25(OH)D level, so in a population with reasonably normal DBP and albumin levels, the correlation with total 25(OH)D is very high, so I am not surprised by the results showing no additional value,” he said in an interview.

The authors addressed their use of the calculation over the direct measurement in the study, noting that there is a “high correlation between both methods.”

But they added that, “as no equilibrium analysis method is available for free 25(OH)D, nor for free 1,25(OH)2D, no method can be considered superior.”

Dr. Dejaeger, of the department of public health and primary care, Katholieke Universiteit Leuven (Belgium), added that she agreed that high or low DBP could potentially shift some correlations, but noted that other research has shown calculated and direct measures to match relatively well.

“So we partly agree [with Dr. Bikle] not being surprised that we did not find an added value because we also found little variation in DBP, but we are not convinced that a different measurement method could make the difference here.”

Another caveat of the study is that, despite half of the measurements being taken in the summer, more than 90% of subjects in the study’s cohort had vitamin D insufficiency, defined in the study as total 25(OH)D levels below 30 mcg/L, and as many as 70% had deficiency, with levels below 20 mcg/L.

Therefore, “as the number of participants with high levels of total 25(OH)D in our study is small, a true threshold concentration for optimal vitamin D status cannot be defined on basis of our data,” the authors noted.

Under current recommendations, the Endocrine Society indicates that concentrations below 30 mcg/L are insufficient, while other groups, including the Institute of Medicine, suggest concentrations of 20 mcg/L or above are adequate.
 

Free hormone hypothesis

Under the free hormone hypothesis, which is observed with thyroid hormones and sex steroids, the very small fraction of free hormones that are not bound to protein carriers can enter cells and help facilitate biologic activity.

The hypothesis of a role of free 25(OH)D in mortality was supported by a recent study, in which free 25(OH)D levels – but not total 25(OH)D levels, were found to be independently associated with an increased risk of all-cause and cardiovascular mortality among patients with coronary artery disease.

However, two other studies are more consistent with the new findings, including one study showing no added value of free 25(OH)D as a marker for bone mineral density in older women, and another study showing no value as a marker of metabolic variables in healthy children.

“Currently, there are no hard data to support routine measurements of free 25(OH)D or 1,25(OH)2D over total 25(OH)D, the current standard of assessing vitamin D status, as stated in guidelines from different scientific bodies,” Dr. Dejaeger said in an interview.

The study received support from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre. Dr. Dejaeger and Dr. Bikle had no disclosures to report.