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Osteoporosis risk rises with air pollution levels
COPENHAGEN – Chronic exposure to high levels of particulate matter (PM) air pollution 2.5 mcm (PM2.5) or larger, and 10 mcm (PM10) or larger, in size is associated with a significantly higher likelihood of having osteoporosis, according to research presented at the annual European Congress of Rheumatology.
The results of the 7-year longitudinal study carried out across Italy from 2013 to 2019 dovetail with other recent published accounts from the same team of Italian researchers, led by Giovanni Adami, MD, of the rheumatology unit at the University of Verona (Italy). In addition to the current report presented at EULAR 2022, Dr. Adami and associates have reported an increased risk of flares of both rheumatoid arthritis and psoriasis following periods of elevated pollution, as well as an overall elevated risk for autoimmune diseases with higher concentrations of PM2.5 and PM10.
The pathogenesis of osteoporosis is thought to involve both genetic and environmental input, such as smoking, which is itself environmental air pollution, Dr. Adami said. The biological rationale for why air pollution might contribute to risk for osteoporosis comes from studies showing that exposure to indoor air pollution from biomass combustion raises serum levels of RANKL (receptor activator of nuclear factor-kappa ligand 1) but lowers serum osteoprotegerin – suggesting an increased risk of bone resorption – and that toxic metals such as lead, cadmium, mercury, and aluminum accumulate in the skeleton and negatively affect bone health.
In their study, Dr. Adami and colleagues found that, overall, the average exposure during the period 2013-2019 across Italy was 16.0 mcg/m3 for PM2.5 and 25.0 mcg/m3 for PM10.
“I can tell you that [25.0 mcg/m3 for PM10] is a very high exposure. It’s not very good for your health,” Dr. Adami said.
Data on more than 59,000 Italian women
Dr. Adami and colleagues used clinical characteristics and densitometric data from Italy’s osteoporosis fracture risk and osteoporosis screening reimbursement tool known as DeFRAcalc79, which has amassed variables from more than 59,000 women across the country. They used long-term average PM concentrations across Italy during 2013-2019 that were obtained from the Italian Institute for Environmental Protection and Research’s 617 air quality stations in 110 Italian provinces. The researchers linked individuals to a PM exposure value determined from the average concentration of urban, rural, and near-traffic stations in each person’s province of residence.
For 59,950 women across Italy who were at high risk for fracture, the researchers found 64.5% with bone mineral density that was defined as osteoporotic. At PM10 concentrations of 30 mcg/m3 or greater, there was a significantly higher likelihood of osteoporosis at both the femoral neck (odds ratio, 1.15) and lumbar spine (OR, 1.17).
The likelihood of osteoporosis was slightly greater with PM2.5 at concentrations of 25 mcg/m3 or more at the femoral neck (OR, 1.22) and lumbar spine (OR, 1.18). These comparisons were adjusted for age, body mass index (BMI), presence of prevalent fragility fractures, family history of osteoporosis, menopause, glucocorticoid use, comorbidities, and for residency in northern, central, or southern Italy.
Both thresholds of PM10 > 30 mcg/m3 and PM2.5 > 25 mcg/m3 “are considered safe … by the World Health Organization,” Dr. Adami pointed out.
“If you live in a place where the chronic exposure is less than 30 mcg/m3, you probably have slightly lower risk of osteoporosis as compared to those who live in a highly industrialized, polluted zone,” he explained.
“The cortical bone – femoral neck – seemed to be more susceptible, compared to trabecular bone, which is the lumbar spine. We have no idea why this is true, but we might speculate that somehow chronic inflammation like the [kind] seen in rheumatoid arthritis might be responsible for cortical bone impairment and not trabecular bone impairment,” Dr. Adami said.
One audience member, Kenneth Poole, BM, PhD, senior lecturer and honorary consultant in Metabolic Bone Disease and Rheumatology at the University of Cambridge (England), asked whether it was possible to account for the possibility of confounding caused by areas with dense housing in places where the particulate matter would be highest, and where residents may be less active and use stairs less often.
Dr. Adami noted that confounding is indeed a possibility, but he said Italy is unique in that its most polluted area – the Po River valley – is also its most wealthy area and in general has less crowded living situations with a healthier population, which could have attenuated, rather than reinforced, the results.
Does air pollution have an immunologic effect?
In interviews with this news organization, session comoderators Filipe Araújo, MD, and Irene Bultink, MD, PhD, said that the growth in evidence for the impact of air pollution on risk for, and severity of, various diseases suggests air pollution might have an immunologic effect.
“I think it’s very important to point this out. I also think it’s very hard to rule out confounding, because when you’re living in a city with crowded housing you may not walk or ride your bike but instead go by car or metro, and [the lifestyle is different],” said Dr. Bultink of Amsterdam University Medical Centers.
“It stresses that these diseases [that are associated with air pollution] although they are different in their pathophysiology, it points toward the systemic nature of rheumatic diseases, including osteoporosis,” said Dr. Araújo of Hospital Cuf Cascais (Portugal) and Hospital Ortopédico de Sant’Ana, Parede, Portugal.
The study was independently supported.Dr. Adami disclosed being a shareholder of Galapagos and Theramex.
A version of this article first appeared on Medscape.com.
COPENHAGEN – Chronic exposure to high levels of particulate matter (PM) air pollution 2.5 mcm (PM2.5) or larger, and 10 mcm (PM10) or larger, in size is associated with a significantly higher likelihood of having osteoporosis, according to research presented at the annual European Congress of Rheumatology.
The results of the 7-year longitudinal study carried out across Italy from 2013 to 2019 dovetail with other recent published accounts from the same team of Italian researchers, led by Giovanni Adami, MD, of the rheumatology unit at the University of Verona (Italy). In addition to the current report presented at EULAR 2022, Dr. Adami and associates have reported an increased risk of flares of both rheumatoid arthritis and psoriasis following periods of elevated pollution, as well as an overall elevated risk for autoimmune diseases with higher concentrations of PM2.5 and PM10.
The pathogenesis of osteoporosis is thought to involve both genetic and environmental input, such as smoking, which is itself environmental air pollution, Dr. Adami said. The biological rationale for why air pollution might contribute to risk for osteoporosis comes from studies showing that exposure to indoor air pollution from biomass combustion raises serum levels of RANKL (receptor activator of nuclear factor-kappa ligand 1) but lowers serum osteoprotegerin – suggesting an increased risk of bone resorption – and that toxic metals such as lead, cadmium, mercury, and aluminum accumulate in the skeleton and negatively affect bone health.
In their study, Dr. Adami and colleagues found that, overall, the average exposure during the period 2013-2019 across Italy was 16.0 mcg/m3 for PM2.5 and 25.0 mcg/m3 for PM10.
“I can tell you that [25.0 mcg/m3 for PM10] is a very high exposure. It’s not very good for your health,” Dr. Adami said.
Data on more than 59,000 Italian women
Dr. Adami and colleagues used clinical characteristics and densitometric data from Italy’s osteoporosis fracture risk and osteoporosis screening reimbursement tool known as DeFRAcalc79, which has amassed variables from more than 59,000 women across the country. They used long-term average PM concentrations across Italy during 2013-2019 that were obtained from the Italian Institute for Environmental Protection and Research’s 617 air quality stations in 110 Italian provinces. The researchers linked individuals to a PM exposure value determined from the average concentration of urban, rural, and near-traffic stations in each person’s province of residence.
For 59,950 women across Italy who were at high risk for fracture, the researchers found 64.5% with bone mineral density that was defined as osteoporotic. At PM10 concentrations of 30 mcg/m3 or greater, there was a significantly higher likelihood of osteoporosis at both the femoral neck (odds ratio, 1.15) and lumbar spine (OR, 1.17).
The likelihood of osteoporosis was slightly greater with PM2.5 at concentrations of 25 mcg/m3 or more at the femoral neck (OR, 1.22) and lumbar spine (OR, 1.18). These comparisons were adjusted for age, body mass index (BMI), presence of prevalent fragility fractures, family history of osteoporosis, menopause, glucocorticoid use, comorbidities, and for residency in northern, central, or southern Italy.
Both thresholds of PM10 > 30 mcg/m3 and PM2.5 > 25 mcg/m3 “are considered safe … by the World Health Organization,” Dr. Adami pointed out.
“If you live in a place where the chronic exposure is less than 30 mcg/m3, you probably have slightly lower risk of osteoporosis as compared to those who live in a highly industrialized, polluted zone,” he explained.
“The cortical bone – femoral neck – seemed to be more susceptible, compared to trabecular bone, which is the lumbar spine. We have no idea why this is true, but we might speculate that somehow chronic inflammation like the [kind] seen in rheumatoid arthritis might be responsible for cortical bone impairment and not trabecular bone impairment,” Dr. Adami said.
One audience member, Kenneth Poole, BM, PhD, senior lecturer and honorary consultant in Metabolic Bone Disease and Rheumatology at the University of Cambridge (England), asked whether it was possible to account for the possibility of confounding caused by areas with dense housing in places where the particulate matter would be highest, and where residents may be less active and use stairs less often.
Dr. Adami noted that confounding is indeed a possibility, but he said Italy is unique in that its most polluted area – the Po River valley – is also its most wealthy area and in general has less crowded living situations with a healthier population, which could have attenuated, rather than reinforced, the results.
Does air pollution have an immunologic effect?
In interviews with this news organization, session comoderators Filipe Araújo, MD, and Irene Bultink, MD, PhD, said that the growth in evidence for the impact of air pollution on risk for, and severity of, various diseases suggests air pollution might have an immunologic effect.
“I think it’s very important to point this out. I also think it’s very hard to rule out confounding, because when you’re living in a city with crowded housing you may not walk or ride your bike but instead go by car or metro, and [the lifestyle is different],” said Dr. Bultink of Amsterdam University Medical Centers.
“It stresses that these diseases [that are associated with air pollution] although they are different in their pathophysiology, it points toward the systemic nature of rheumatic diseases, including osteoporosis,” said Dr. Araújo of Hospital Cuf Cascais (Portugal) and Hospital Ortopédico de Sant’Ana, Parede, Portugal.
The study was independently supported.Dr. Adami disclosed being a shareholder of Galapagos and Theramex.
A version of this article first appeared on Medscape.com.
COPENHAGEN – Chronic exposure to high levels of particulate matter (PM) air pollution 2.5 mcm (PM2.5) or larger, and 10 mcm (PM10) or larger, in size is associated with a significantly higher likelihood of having osteoporosis, according to research presented at the annual European Congress of Rheumatology.
The results of the 7-year longitudinal study carried out across Italy from 2013 to 2019 dovetail with other recent published accounts from the same team of Italian researchers, led by Giovanni Adami, MD, of the rheumatology unit at the University of Verona (Italy). In addition to the current report presented at EULAR 2022, Dr. Adami and associates have reported an increased risk of flares of both rheumatoid arthritis and psoriasis following periods of elevated pollution, as well as an overall elevated risk for autoimmune diseases with higher concentrations of PM2.5 and PM10.
The pathogenesis of osteoporosis is thought to involve both genetic and environmental input, such as smoking, which is itself environmental air pollution, Dr. Adami said. The biological rationale for why air pollution might contribute to risk for osteoporosis comes from studies showing that exposure to indoor air pollution from biomass combustion raises serum levels of RANKL (receptor activator of nuclear factor-kappa ligand 1) but lowers serum osteoprotegerin – suggesting an increased risk of bone resorption – and that toxic metals such as lead, cadmium, mercury, and aluminum accumulate in the skeleton and negatively affect bone health.
In their study, Dr. Adami and colleagues found that, overall, the average exposure during the period 2013-2019 across Italy was 16.0 mcg/m3 for PM2.5 and 25.0 mcg/m3 for PM10.
“I can tell you that [25.0 mcg/m3 for PM10] is a very high exposure. It’s not very good for your health,” Dr. Adami said.
Data on more than 59,000 Italian women
Dr. Adami and colleagues used clinical characteristics and densitometric data from Italy’s osteoporosis fracture risk and osteoporosis screening reimbursement tool known as DeFRAcalc79, which has amassed variables from more than 59,000 women across the country. They used long-term average PM concentrations across Italy during 2013-2019 that were obtained from the Italian Institute for Environmental Protection and Research’s 617 air quality stations in 110 Italian provinces. The researchers linked individuals to a PM exposure value determined from the average concentration of urban, rural, and near-traffic stations in each person’s province of residence.
For 59,950 women across Italy who were at high risk for fracture, the researchers found 64.5% with bone mineral density that was defined as osteoporotic. At PM10 concentrations of 30 mcg/m3 or greater, there was a significantly higher likelihood of osteoporosis at both the femoral neck (odds ratio, 1.15) and lumbar spine (OR, 1.17).
The likelihood of osteoporosis was slightly greater with PM2.5 at concentrations of 25 mcg/m3 or more at the femoral neck (OR, 1.22) and lumbar spine (OR, 1.18). These comparisons were adjusted for age, body mass index (BMI), presence of prevalent fragility fractures, family history of osteoporosis, menopause, glucocorticoid use, comorbidities, and for residency in northern, central, or southern Italy.
Both thresholds of PM10 > 30 mcg/m3 and PM2.5 > 25 mcg/m3 “are considered safe … by the World Health Organization,” Dr. Adami pointed out.
“If you live in a place where the chronic exposure is less than 30 mcg/m3, you probably have slightly lower risk of osteoporosis as compared to those who live in a highly industrialized, polluted zone,” he explained.
“The cortical bone – femoral neck – seemed to be more susceptible, compared to trabecular bone, which is the lumbar spine. We have no idea why this is true, but we might speculate that somehow chronic inflammation like the [kind] seen in rheumatoid arthritis might be responsible for cortical bone impairment and not trabecular bone impairment,” Dr. Adami said.
One audience member, Kenneth Poole, BM, PhD, senior lecturer and honorary consultant in Metabolic Bone Disease and Rheumatology at the University of Cambridge (England), asked whether it was possible to account for the possibility of confounding caused by areas with dense housing in places where the particulate matter would be highest, and where residents may be less active and use stairs less often.
Dr. Adami noted that confounding is indeed a possibility, but he said Italy is unique in that its most polluted area – the Po River valley – is also its most wealthy area and in general has less crowded living situations with a healthier population, which could have attenuated, rather than reinforced, the results.
Does air pollution have an immunologic effect?
In interviews with this news organization, session comoderators Filipe Araújo, MD, and Irene Bultink, MD, PhD, said that the growth in evidence for the impact of air pollution on risk for, and severity of, various diseases suggests air pollution might have an immunologic effect.
“I think it’s very important to point this out. I also think it’s very hard to rule out confounding, because when you’re living in a city with crowded housing you may not walk or ride your bike but instead go by car or metro, and [the lifestyle is different],” said Dr. Bultink of Amsterdam University Medical Centers.
“It stresses that these diseases [that are associated with air pollution] although they are different in their pathophysiology, it points toward the systemic nature of rheumatic diseases, including osteoporosis,” said Dr. Araújo of Hospital Cuf Cascais (Portugal) and Hospital Ortopédico de Sant’Ana, Parede, Portugal.
The study was independently supported.Dr. Adami disclosed being a shareholder of Galapagos and Theramex.
A version of this article first appeared on Medscape.com.
AT THE EULAR 2022 CONGRESS
What’s the best time of day to exercise? It depends on your goals
For most of us, the “best” time of day to work out is simple: When we can.
Maybe that’s before or after work. Or when the gym offers free daycare. Or when our favorite instructor teaches our favorite class.
That’s why we call it a “routine.” And if the results are the same, it’s hard to imagine changing it up.
But what if the results aren’t the same?
They may not be, according to a new study from a research team at Skidmore College in Saratoga Springs, N.Y.
Women who worked out in the morning lost more fat, while those who trained in the evening gained more upper-body strength and power. As for men, the performance improvements were similar no matter when they exercised. But those who did so in the evening had a significant drop in blood pressure, among other benefits.
The study is part of a growing body of research showing different results for different times of day among different populations. As it turns out, when you exercise can ultimately have a big effect, not just on strength and fat loss, but also heart health, mood, and quality of sleep.
An accidental discovery
The original goal of the Skidmore study was to test a unique fitness program with a group of healthy, fit, and extremely active adults in early middle age.
The program includes four workouts a week, each with a different focus: strength, steady-pace endurance, high-intensity intervals, and flexibility (traditional stretching combined with yoga and Pilates exercises).
But because the group was so large – 27 women and 20 men completed the 3-month program – they had to split them into morning and evening workout groups.
It wasn’t until researchers looked at the results that they saw the differences between morning and evening exercise, says lead author Paul Arciero, PhD.
Dr. Arciero stressed that participants in every group got leaner and stronger. But the women who worked out in the morning got much bigger reductions in body fat and body-fat percentage than the evening group. Meanwhile, women in the evening group got much bigger gains in upper-body strength, power, and muscular endurance than their morning counterparts.
Among the men, the evening group had significantly larger improvements in blood pressure, cholesterol levels, and the percentage of fat they burned for energy, along with a bigger drop in feelings of fatigue.
Strategic timing for powerful results
Some of these findings are consistent with previous research. For example, a study published in 2021 showed that the ability to exert high effort and express strength and power peaks in the late afternoon, about the same time that your core body temperature is at its highest point.
On the other hand, you’ll probably perform better in the morning when the activity requires a lot of skill and coordination or depends on strategic decision-making.
The findings apply to both men and women.
Performance aside, exercise timing might offer strong health benefits for men with type 2 diabetes, or at high risk for it.
A study showed that men who exercised between 3 p.m. and 6 p.m. saw dramatic improvements in blood sugar management and insulin sensitivity, compared to a group that worked out between 8 a.m. and 10 a.m.
They also lost more fat during the 12-week program, even though they were doing the exact same workouts.
Train consistently, sleep well
When you exercise can affect your sleep quality in many ways, said neuroscientist Jennifer Heisz, PhD, of McMaster University, Hamilton, Ont.
First, she said, “exercise helps you fall asleep faster and sleep deeper at night.” (The only exception is if you exercise so intensely or so close to bedtime that your heart rate is still elevated.)
Second, “exercising at a consistent time every day helps regulate the body’s circadian rhythms.” It doesn’t matter if the exercise is in the morning, evening, or anywhere in between. As long as it’s predictable, it will help you fall asleep and wake up at the same times.
Outdoor exercise is even better, she said. The sun is the most powerful regulator of the circadian clock and works in tandem with physical activity.
Third, exercising at specific times can help you overcome jet lag or adjust to an earlier or later shift at work.
“Exercising at 7 a.m. or between 1 and 4 p.m. helps your circadian clock to ‘fall back’ in time, making it easier to wake up earlier,” Dr. Heisz said. If you need to train your body to wake up later in the morning, try working out between 7 p.m. and 10 p.m.
All exercise is good, but the right timing can make it even better
“The best time to exercise is when you can fit it in,” Dr. Arciero said. “You’ve got to choose the time that fits your lifestyle best.”
But context matters, he noted.
“For someone needing to achieve an improvement in their risk for cardiometabolic disease,” his study shows an advantage to working out later in the day, especially for men. If you’re more focused on building upper-body strength and power, you’ll probably get better results from training in the afternoon or evening.
And for fat loss, the Skidmore study shows better results for women who did morning workouts.
And if you’re still not sure? Try sleeping on it – preferably after your workout.
A version of this article first appeared on WebMD.com.
For most of us, the “best” time of day to work out is simple: When we can.
Maybe that’s before or after work. Or when the gym offers free daycare. Or when our favorite instructor teaches our favorite class.
That’s why we call it a “routine.” And if the results are the same, it’s hard to imagine changing it up.
But what if the results aren’t the same?
They may not be, according to a new study from a research team at Skidmore College in Saratoga Springs, N.Y.
Women who worked out in the morning lost more fat, while those who trained in the evening gained more upper-body strength and power. As for men, the performance improvements were similar no matter when they exercised. But those who did so in the evening had a significant drop in blood pressure, among other benefits.
The study is part of a growing body of research showing different results for different times of day among different populations. As it turns out, when you exercise can ultimately have a big effect, not just on strength and fat loss, but also heart health, mood, and quality of sleep.
An accidental discovery
The original goal of the Skidmore study was to test a unique fitness program with a group of healthy, fit, and extremely active adults in early middle age.
The program includes four workouts a week, each with a different focus: strength, steady-pace endurance, high-intensity intervals, and flexibility (traditional stretching combined with yoga and Pilates exercises).
But because the group was so large – 27 women and 20 men completed the 3-month program – they had to split them into morning and evening workout groups.
It wasn’t until researchers looked at the results that they saw the differences between morning and evening exercise, says lead author Paul Arciero, PhD.
Dr. Arciero stressed that participants in every group got leaner and stronger. But the women who worked out in the morning got much bigger reductions in body fat and body-fat percentage than the evening group. Meanwhile, women in the evening group got much bigger gains in upper-body strength, power, and muscular endurance than their morning counterparts.
Among the men, the evening group had significantly larger improvements in blood pressure, cholesterol levels, and the percentage of fat they burned for energy, along with a bigger drop in feelings of fatigue.
Strategic timing for powerful results
Some of these findings are consistent with previous research. For example, a study published in 2021 showed that the ability to exert high effort and express strength and power peaks in the late afternoon, about the same time that your core body temperature is at its highest point.
On the other hand, you’ll probably perform better in the morning when the activity requires a lot of skill and coordination or depends on strategic decision-making.
The findings apply to both men and women.
Performance aside, exercise timing might offer strong health benefits for men with type 2 diabetes, or at high risk for it.
A study showed that men who exercised between 3 p.m. and 6 p.m. saw dramatic improvements in blood sugar management and insulin sensitivity, compared to a group that worked out between 8 a.m. and 10 a.m.
They also lost more fat during the 12-week program, even though they were doing the exact same workouts.
Train consistently, sleep well
When you exercise can affect your sleep quality in many ways, said neuroscientist Jennifer Heisz, PhD, of McMaster University, Hamilton, Ont.
First, she said, “exercise helps you fall asleep faster and sleep deeper at night.” (The only exception is if you exercise so intensely or so close to bedtime that your heart rate is still elevated.)
Second, “exercising at a consistent time every day helps regulate the body’s circadian rhythms.” It doesn’t matter if the exercise is in the morning, evening, or anywhere in between. As long as it’s predictable, it will help you fall asleep and wake up at the same times.
Outdoor exercise is even better, she said. The sun is the most powerful regulator of the circadian clock and works in tandem with physical activity.
Third, exercising at specific times can help you overcome jet lag or adjust to an earlier or later shift at work.
“Exercising at 7 a.m. or between 1 and 4 p.m. helps your circadian clock to ‘fall back’ in time, making it easier to wake up earlier,” Dr. Heisz said. If you need to train your body to wake up later in the morning, try working out between 7 p.m. and 10 p.m.
All exercise is good, but the right timing can make it even better
“The best time to exercise is when you can fit it in,” Dr. Arciero said. “You’ve got to choose the time that fits your lifestyle best.”
But context matters, he noted.
“For someone needing to achieve an improvement in their risk for cardiometabolic disease,” his study shows an advantage to working out later in the day, especially for men. If you’re more focused on building upper-body strength and power, you’ll probably get better results from training in the afternoon or evening.
And for fat loss, the Skidmore study shows better results for women who did morning workouts.
And if you’re still not sure? Try sleeping on it – preferably after your workout.
A version of this article first appeared on WebMD.com.
For most of us, the “best” time of day to work out is simple: When we can.
Maybe that’s before or after work. Or when the gym offers free daycare. Or when our favorite instructor teaches our favorite class.
That’s why we call it a “routine.” And if the results are the same, it’s hard to imagine changing it up.
But what if the results aren’t the same?
They may not be, according to a new study from a research team at Skidmore College in Saratoga Springs, N.Y.
Women who worked out in the morning lost more fat, while those who trained in the evening gained more upper-body strength and power. As for men, the performance improvements were similar no matter when they exercised. But those who did so in the evening had a significant drop in blood pressure, among other benefits.
The study is part of a growing body of research showing different results for different times of day among different populations. As it turns out, when you exercise can ultimately have a big effect, not just on strength and fat loss, but also heart health, mood, and quality of sleep.
An accidental discovery
The original goal of the Skidmore study was to test a unique fitness program with a group of healthy, fit, and extremely active adults in early middle age.
The program includes four workouts a week, each with a different focus: strength, steady-pace endurance, high-intensity intervals, and flexibility (traditional stretching combined with yoga and Pilates exercises).
But because the group was so large – 27 women and 20 men completed the 3-month program – they had to split them into morning and evening workout groups.
It wasn’t until researchers looked at the results that they saw the differences between morning and evening exercise, says lead author Paul Arciero, PhD.
Dr. Arciero stressed that participants in every group got leaner and stronger. But the women who worked out in the morning got much bigger reductions in body fat and body-fat percentage than the evening group. Meanwhile, women in the evening group got much bigger gains in upper-body strength, power, and muscular endurance than their morning counterparts.
Among the men, the evening group had significantly larger improvements in blood pressure, cholesterol levels, and the percentage of fat they burned for energy, along with a bigger drop in feelings of fatigue.
Strategic timing for powerful results
Some of these findings are consistent with previous research. For example, a study published in 2021 showed that the ability to exert high effort and express strength and power peaks in the late afternoon, about the same time that your core body temperature is at its highest point.
On the other hand, you’ll probably perform better in the morning when the activity requires a lot of skill and coordination or depends on strategic decision-making.
The findings apply to both men and women.
Performance aside, exercise timing might offer strong health benefits for men with type 2 diabetes, or at high risk for it.
A study showed that men who exercised between 3 p.m. and 6 p.m. saw dramatic improvements in blood sugar management and insulin sensitivity, compared to a group that worked out between 8 a.m. and 10 a.m.
They also lost more fat during the 12-week program, even though they were doing the exact same workouts.
Train consistently, sleep well
When you exercise can affect your sleep quality in many ways, said neuroscientist Jennifer Heisz, PhD, of McMaster University, Hamilton, Ont.
First, she said, “exercise helps you fall asleep faster and sleep deeper at night.” (The only exception is if you exercise so intensely or so close to bedtime that your heart rate is still elevated.)
Second, “exercising at a consistent time every day helps regulate the body’s circadian rhythms.” It doesn’t matter if the exercise is in the morning, evening, or anywhere in between. As long as it’s predictable, it will help you fall asleep and wake up at the same times.
Outdoor exercise is even better, she said. The sun is the most powerful regulator of the circadian clock and works in tandem with physical activity.
Third, exercising at specific times can help you overcome jet lag or adjust to an earlier or later shift at work.
“Exercising at 7 a.m. or between 1 and 4 p.m. helps your circadian clock to ‘fall back’ in time, making it easier to wake up earlier,” Dr. Heisz said. If you need to train your body to wake up later in the morning, try working out between 7 p.m. and 10 p.m.
All exercise is good, but the right timing can make it even better
“The best time to exercise is when you can fit it in,” Dr. Arciero said. “You’ve got to choose the time that fits your lifestyle best.”
But context matters, he noted.
“For someone needing to achieve an improvement in their risk for cardiometabolic disease,” his study shows an advantage to working out later in the day, especially for men. If you’re more focused on building upper-body strength and power, you’ll probably get better results from training in the afternoon or evening.
And for fat loss, the Skidmore study shows better results for women who did morning workouts.
And if you’re still not sure? Try sleeping on it – preferably after your workout.
A version of this article first appeared on WebMD.com.
FROM FRONTIERS IN PHYSIOLOGY
Can the ketogenic diet treat polycystic ovary syndrome?
MADRID – During the International Scientific Symposium “New Frontiers in Scientific Research” that recently took place in Barcelona, specialists analyzed the role of the very-low-calorie ketogenic diet. This analysis was in relation to three comorbidities that have a higher incidence among overweight and obese patients: polycystic ovary syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. The experts’ aim? To analyze and update the latest evidence on the benefits of this dietary choice.
Polycystic ovary syndrome
Alessandra Gambineri, MD, PhD, associate professor at the department of medicine and surgery (DIMEC) at the University of Bologna, Italy, addressed the link between obesity and polycystic ovary syndrome, which she described as a chronic disease that affects about 10% of women of childbearing age and that presents diverse phenotypes with different characteristics.
“The pathophysiology of this syndrome is characterized by the interaction of three factors: androgen excess, adipose tissue dysfunction, and insulin resistance. These factors interact with each other and are expressed differently in each phenotype,” said Dr. Gambineri.
She indicated that adipose tissue dysfunction is central to this pathology. This centrality results from its association with secretions, such as free fatty acids, proinflammatory cytokines, certain adipokines that promote insulin resistance, glucocorticosteroids, androgens, and oxidative stress.
“Similarly, the oxidative stress that characterizes this syndrome is increasingly present in obese individuals,” said Dr. Gambineri. “This oxidative stress also produces ovary hypotoxicity that aggravates ovulatory function. In this context, the very-low-calorie ketogenic diet can be useful in several ways: weight reduction; promoting the loss of mainly visceral/abdominal fat; decreasing lipotoxicity; and improving inflammation, hyperinsulinemia, and insulin resistance.”
This was the path followed to carry out a study that aimed to analyze the effects of the very-low-calorie ketogenic diet on manifestations of polycystic ovary syndrome in the obesity phenotype. Dr. Gambineri presented its results.
“The objective was to compare the effects of a very-low-calorie ketogenic diet and the standard low-calorie (hypocaloric) diet as a control group,” she said. “The effects studied include body weight, insulin resistance, menstrual cycle, ovulation, ovarian morphology, and hyperandrogenism in a population of 30 obese women with polycystic ovary syndrome and insulin resistance.”
Study participants had a diagnosis of polycystic ovary syndrome as defined by the National Institutes of Health criteria and were aged 18-45 years. These women were randomly assigned to two groups of equal size: experimental (very-low-calorie ketogenic diet) and control (hypocaloric diet). “The women assigned to the experimental group followed the ketogenic stage for eight weeks and then moved to the second, low-calorie diet phase for an additional eight weeks, while those in the control group (hypocaloric diet) followed the low-calorie diet for all 16 weeks.”
The primary outcomes were changes in weight and body composition, specifically fat mass and lean mass, measured by bioimpedance. “The changes observed in the following aspects were considered secondary outcomes: abdominal fat distribution, metabolic parameters, ovulation, ovarian morphology, hirsutism, hyperandrogenism, psychological well-being, and psychological distress,” said Dr. Gambineri. “Any reduction in the ovarian stroma, the area where androgens are synthesized, was also analyzed.”
The study authors found that although BMI decreased in both groups, this reduction was greater in the group that followed the very-low-calorie ketogenic diet. Significant weight loss was observed in both groups, 12.4 kg versus 4.7 kg. Significant differences were also observed in waist circumference (−8.1% in the experimental group vs. −2.2% in the control group), fat mass (−15.1% vs. −8.5%), and free testosterone (−30.3% vs. +10.6%). Only the experimental group saw a reduction in insulin.
“A key point regarding hyperandrogenism, especially regarding what’s referred to as free testosterone, there was only a significant reduction in the very-low-calorie ketogenic diet group,” said Dr. Gambineri. “This reduction was especially evident in the first part of the study, coinciding with the ketogenic period. The reason for this effect lies in the significant increase in the concentration of sex hormone-binding globulins, SHB6. Said globulins bind to the testosterone present in female blood, producing a reduction in free testosterone, a very important effect considering that this syndrome is an androgenic disorder. Furthermore, current treatments for polycystic ovary syndrome do not reduce free testosterone as much as this dietary approach does.”
For the specialist, among all these positive effects in these patients, perhaps most important is the notable improvement that occurs in ovulation. “At the beginning of the study, only 38.5% of the participants in the experimental group and 14.3% of those in the control group had ovulatory cycles. After the intervention, 84.6% managed to ovulate, compared to 35.7% who achieved this goal in the other group.”
Dr. Gambineri suggested that this method is “valid for reducing fat mass and rapidly improving hyperandrogenism and ovulatory dysfunction in women with obesity and polycystic ovary syndrome.”
Reversing type 2 diabetes?
Daniela Sofrà, MD, an endocrinologist specializing in diabetology at La Source Clinic, Lausanne, Switzerland, reviewed the current evidence on the role of the very-low-calorie ketogenic diet in the management of type 2 diabetes.
“It’s time to rethink diabetes treatment and focus efforts on managing obesity as an associated factor,” she said. “One of the hypotheses being examined in this regard is the twin cycle, which postulates that type 2 diabetes is the result of excess fat in the liver. This in turn is associated with insulin resistance with pancreas dysfunction.”
Dr. Sofrà added that there is a study documenting for the first time the reversibility of the morphology of the diabetic pancreas after caloric restriction with the very-low-calorie ketogenic diet. “The reason for this effect is the use of visceral and intrahepatic fat, which can lead to the remission of the clinical manifestation of type 2 diabetes, understanding as such the definition made by the American Diabetes Association: glycosylated hemoglobin < 6.5% without pharmacological therapy.”
Specifically, the results of this research showed that after following the very-low-calorie ketogenic diet and achieving a 15% weight loss (mean weight loss of the participants), liver glucose levels returned to normal levels within 7 days. Beta cell function returned to near normal within 8 weeks.
“Subsequent studies have shown the durability of remission of type 2 diabetes, thanks to the reactivation of the insulin-secreting function of beta cells that had become dedifferentiated in the face of chronic nutrient excess. Specifically, 6 out of 10 patients maintained glycosylated hemoglobin < 6% after 6 months without the need for pharmacological therapy,” Dr. Sofrà added.
Likewise, she highlighted that the probability of achieving remission is mainly determined by the duration of the disease. “The years with diabetes are one of the main predictors of the response that the patient will have with this dietary intervention. Studies have shown that remission is possible in patients with diabetes for less than 6 years, although there are other projects that indicate that it can be achieved with up to 10 years’ duration.”
Based on these data, Dr. Sofrà emphasized the pleiotropic effects of the very-low-calorie ketogenic diet on glycemic control, favoring the possible remission of diabetes or the reduction of drugs, as well as the reduction of the HOMA-IR index (insulin resistance) and waist circumference in people with type 2 diabetes.
Nonalcoholic fatty liver disease
The third comorbidity of obesity that may benefit from the very-low-calorie ketogenic diet is hepatic steatosis, or nonalcoholic fatty liver disease, said Hardy Walle, MD, an internal medicine specialist and director/founder of the Bodymed center, Kirkel, Germany, and one of the authors of this research.
“Recent research shows that ectopic fat and nonalcoholic fatty liver disease could be considered a cause, or at least one of the causes, of most of the diseases that affect the population as a consequence of overweight and obesity,” said Dr. Walle. “Some authors have stated that without fatty liver, there is no type 2 diabetes.”
Dr. Walle pointed out that between 30% and 40% of the adult population has nonalcoholic fatty liver disease, a percentage that increases considerably in people with obesity, reaching 70% prevalence and increasing, in the case of type 2 diabetes, to almost 90%. “Even normal weight does not rule out fatty liver; in fact, about 15% of people with nonalcoholic fatty liver disease are not overweight.”
In a setting where there are no approved drugs for the treatment of fatty liver (the current standard approach focuses on lifestyle interventions), a short-term hypocaloric diet (or liver fasting) is considered an effective method for management of this pathology. This principle was demonstrated by a study by the Saarland University, Saarbrücken, Germany, that Dr. Walle used to illustrate this statement.
“The participants (60 patients with hepatic steatosis) followed a hypocaloric diet (less than 1,000 kcal/day) for 14 days with a formula rich in protein and fiber specially developed for the treatment of nonalcoholic fatty liver disease. A fibroscan was then performed with controlled attenuation parameter measurement to quantify fatty liver disease. The results showed not only a significant improvement in nonalcoholic fatty liver disease parameters but also a marked improvement in all relevant metabolic parameters (serum lipids, liver enzymes),” explained Dr. Walle.
“This evidence leads us to affirm that the concept of hepatic fasting (by means of a hypocaloric diet) marks a point of reference for a future treatment approach for nonalcoholic fatty liver disease,” he concluded.
The study that Dr. Gambineri presented was carried out with the collaboration of the Pronokal Group (Nestlé Health Science). Dr. Gambineri, Dr. Sofrà, and Dr. Walle disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MADRID – During the International Scientific Symposium “New Frontiers in Scientific Research” that recently took place in Barcelona, specialists analyzed the role of the very-low-calorie ketogenic diet. This analysis was in relation to three comorbidities that have a higher incidence among overweight and obese patients: polycystic ovary syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. The experts’ aim? To analyze and update the latest evidence on the benefits of this dietary choice.
Polycystic ovary syndrome
Alessandra Gambineri, MD, PhD, associate professor at the department of medicine and surgery (DIMEC) at the University of Bologna, Italy, addressed the link between obesity and polycystic ovary syndrome, which she described as a chronic disease that affects about 10% of women of childbearing age and that presents diverse phenotypes with different characteristics.
“The pathophysiology of this syndrome is characterized by the interaction of three factors: androgen excess, adipose tissue dysfunction, and insulin resistance. These factors interact with each other and are expressed differently in each phenotype,” said Dr. Gambineri.
She indicated that adipose tissue dysfunction is central to this pathology. This centrality results from its association with secretions, such as free fatty acids, proinflammatory cytokines, certain adipokines that promote insulin resistance, glucocorticosteroids, androgens, and oxidative stress.
“Similarly, the oxidative stress that characterizes this syndrome is increasingly present in obese individuals,” said Dr. Gambineri. “This oxidative stress also produces ovary hypotoxicity that aggravates ovulatory function. In this context, the very-low-calorie ketogenic diet can be useful in several ways: weight reduction; promoting the loss of mainly visceral/abdominal fat; decreasing lipotoxicity; and improving inflammation, hyperinsulinemia, and insulin resistance.”
This was the path followed to carry out a study that aimed to analyze the effects of the very-low-calorie ketogenic diet on manifestations of polycystic ovary syndrome in the obesity phenotype. Dr. Gambineri presented its results.
“The objective was to compare the effects of a very-low-calorie ketogenic diet and the standard low-calorie (hypocaloric) diet as a control group,” she said. “The effects studied include body weight, insulin resistance, menstrual cycle, ovulation, ovarian morphology, and hyperandrogenism in a population of 30 obese women with polycystic ovary syndrome and insulin resistance.”
Study participants had a diagnosis of polycystic ovary syndrome as defined by the National Institutes of Health criteria and were aged 18-45 years. These women were randomly assigned to two groups of equal size: experimental (very-low-calorie ketogenic diet) and control (hypocaloric diet). “The women assigned to the experimental group followed the ketogenic stage for eight weeks and then moved to the second, low-calorie diet phase for an additional eight weeks, while those in the control group (hypocaloric diet) followed the low-calorie diet for all 16 weeks.”
The primary outcomes were changes in weight and body composition, specifically fat mass and lean mass, measured by bioimpedance. “The changes observed in the following aspects were considered secondary outcomes: abdominal fat distribution, metabolic parameters, ovulation, ovarian morphology, hirsutism, hyperandrogenism, psychological well-being, and psychological distress,” said Dr. Gambineri. “Any reduction in the ovarian stroma, the area where androgens are synthesized, was also analyzed.”
The study authors found that although BMI decreased in both groups, this reduction was greater in the group that followed the very-low-calorie ketogenic diet. Significant weight loss was observed in both groups, 12.4 kg versus 4.7 kg. Significant differences were also observed in waist circumference (−8.1% in the experimental group vs. −2.2% in the control group), fat mass (−15.1% vs. −8.5%), and free testosterone (−30.3% vs. +10.6%). Only the experimental group saw a reduction in insulin.
“A key point regarding hyperandrogenism, especially regarding what’s referred to as free testosterone, there was only a significant reduction in the very-low-calorie ketogenic diet group,” said Dr. Gambineri. “This reduction was especially evident in the first part of the study, coinciding with the ketogenic period. The reason for this effect lies in the significant increase in the concentration of sex hormone-binding globulins, SHB6. Said globulins bind to the testosterone present in female blood, producing a reduction in free testosterone, a very important effect considering that this syndrome is an androgenic disorder. Furthermore, current treatments for polycystic ovary syndrome do not reduce free testosterone as much as this dietary approach does.”
For the specialist, among all these positive effects in these patients, perhaps most important is the notable improvement that occurs in ovulation. “At the beginning of the study, only 38.5% of the participants in the experimental group and 14.3% of those in the control group had ovulatory cycles. After the intervention, 84.6% managed to ovulate, compared to 35.7% who achieved this goal in the other group.”
Dr. Gambineri suggested that this method is “valid for reducing fat mass and rapidly improving hyperandrogenism and ovulatory dysfunction in women with obesity and polycystic ovary syndrome.”
Reversing type 2 diabetes?
Daniela Sofrà, MD, an endocrinologist specializing in diabetology at La Source Clinic, Lausanne, Switzerland, reviewed the current evidence on the role of the very-low-calorie ketogenic diet in the management of type 2 diabetes.
“It’s time to rethink diabetes treatment and focus efforts on managing obesity as an associated factor,” she said. “One of the hypotheses being examined in this regard is the twin cycle, which postulates that type 2 diabetes is the result of excess fat in the liver. This in turn is associated with insulin resistance with pancreas dysfunction.”
Dr. Sofrà added that there is a study documenting for the first time the reversibility of the morphology of the diabetic pancreas after caloric restriction with the very-low-calorie ketogenic diet. “The reason for this effect is the use of visceral and intrahepatic fat, which can lead to the remission of the clinical manifestation of type 2 diabetes, understanding as such the definition made by the American Diabetes Association: glycosylated hemoglobin < 6.5% without pharmacological therapy.”
Specifically, the results of this research showed that after following the very-low-calorie ketogenic diet and achieving a 15% weight loss (mean weight loss of the participants), liver glucose levels returned to normal levels within 7 days. Beta cell function returned to near normal within 8 weeks.
“Subsequent studies have shown the durability of remission of type 2 diabetes, thanks to the reactivation of the insulin-secreting function of beta cells that had become dedifferentiated in the face of chronic nutrient excess. Specifically, 6 out of 10 patients maintained glycosylated hemoglobin < 6% after 6 months without the need for pharmacological therapy,” Dr. Sofrà added.
Likewise, she highlighted that the probability of achieving remission is mainly determined by the duration of the disease. “The years with diabetes are one of the main predictors of the response that the patient will have with this dietary intervention. Studies have shown that remission is possible in patients with diabetes for less than 6 years, although there are other projects that indicate that it can be achieved with up to 10 years’ duration.”
Based on these data, Dr. Sofrà emphasized the pleiotropic effects of the very-low-calorie ketogenic diet on glycemic control, favoring the possible remission of diabetes or the reduction of drugs, as well as the reduction of the HOMA-IR index (insulin resistance) and waist circumference in people with type 2 diabetes.
Nonalcoholic fatty liver disease
The third comorbidity of obesity that may benefit from the very-low-calorie ketogenic diet is hepatic steatosis, or nonalcoholic fatty liver disease, said Hardy Walle, MD, an internal medicine specialist and director/founder of the Bodymed center, Kirkel, Germany, and one of the authors of this research.
“Recent research shows that ectopic fat and nonalcoholic fatty liver disease could be considered a cause, or at least one of the causes, of most of the diseases that affect the population as a consequence of overweight and obesity,” said Dr. Walle. “Some authors have stated that without fatty liver, there is no type 2 diabetes.”
Dr. Walle pointed out that between 30% and 40% of the adult population has nonalcoholic fatty liver disease, a percentage that increases considerably in people with obesity, reaching 70% prevalence and increasing, in the case of type 2 diabetes, to almost 90%. “Even normal weight does not rule out fatty liver; in fact, about 15% of people with nonalcoholic fatty liver disease are not overweight.”
In a setting where there are no approved drugs for the treatment of fatty liver (the current standard approach focuses on lifestyle interventions), a short-term hypocaloric diet (or liver fasting) is considered an effective method for management of this pathology. This principle was demonstrated by a study by the Saarland University, Saarbrücken, Germany, that Dr. Walle used to illustrate this statement.
“The participants (60 patients with hepatic steatosis) followed a hypocaloric diet (less than 1,000 kcal/day) for 14 days with a formula rich in protein and fiber specially developed for the treatment of nonalcoholic fatty liver disease. A fibroscan was then performed with controlled attenuation parameter measurement to quantify fatty liver disease. The results showed not only a significant improvement in nonalcoholic fatty liver disease parameters but also a marked improvement in all relevant metabolic parameters (serum lipids, liver enzymes),” explained Dr. Walle.
“This evidence leads us to affirm that the concept of hepatic fasting (by means of a hypocaloric diet) marks a point of reference for a future treatment approach for nonalcoholic fatty liver disease,” he concluded.
The study that Dr. Gambineri presented was carried out with the collaboration of the Pronokal Group (Nestlé Health Science). Dr. Gambineri, Dr. Sofrà, and Dr. Walle disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
MADRID – During the International Scientific Symposium “New Frontiers in Scientific Research” that recently took place in Barcelona, specialists analyzed the role of the very-low-calorie ketogenic diet. This analysis was in relation to three comorbidities that have a higher incidence among overweight and obese patients: polycystic ovary syndrome, nonalcoholic fatty liver disease, and type 2 diabetes. The experts’ aim? To analyze and update the latest evidence on the benefits of this dietary choice.
Polycystic ovary syndrome
Alessandra Gambineri, MD, PhD, associate professor at the department of medicine and surgery (DIMEC) at the University of Bologna, Italy, addressed the link between obesity and polycystic ovary syndrome, which she described as a chronic disease that affects about 10% of women of childbearing age and that presents diverse phenotypes with different characteristics.
“The pathophysiology of this syndrome is characterized by the interaction of three factors: androgen excess, adipose tissue dysfunction, and insulin resistance. These factors interact with each other and are expressed differently in each phenotype,” said Dr. Gambineri.
She indicated that adipose tissue dysfunction is central to this pathology. This centrality results from its association with secretions, such as free fatty acids, proinflammatory cytokines, certain adipokines that promote insulin resistance, glucocorticosteroids, androgens, and oxidative stress.
“Similarly, the oxidative stress that characterizes this syndrome is increasingly present in obese individuals,” said Dr. Gambineri. “This oxidative stress also produces ovary hypotoxicity that aggravates ovulatory function. In this context, the very-low-calorie ketogenic diet can be useful in several ways: weight reduction; promoting the loss of mainly visceral/abdominal fat; decreasing lipotoxicity; and improving inflammation, hyperinsulinemia, and insulin resistance.”
This was the path followed to carry out a study that aimed to analyze the effects of the very-low-calorie ketogenic diet on manifestations of polycystic ovary syndrome in the obesity phenotype. Dr. Gambineri presented its results.
“The objective was to compare the effects of a very-low-calorie ketogenic diet and the standard low-calorie (hypocaloric) diet as a control group,” she said. “The effects studied include body weight, insulin resistance, menstrual cycle, ovulation, ovarian morphology, and hyperandrogenism in a population of 30 obese women with polycystic ovary syndrome and insulin resistance.”
Study participants had a diagnosis of polycystic ovary syndrome as defined by the National Institutes of Health criteria and were aged 18-45 years. These women were randomly assigned to two groups of equal size: experimental (very-low-calorie ketogenic diet) and control (hypocaloric diet). “The women assigned to the experimental group followed the ketogenic stage for eight weeks and then moved to the second, low-calorie diet phase for an additional eight weeks, while those in the control group (hypocaloric diet) followed the low-calorie diet for all 16 weeks.”
The primary outcomes were changes in weight and body composition, specifically fat mass and lean mass, measured by bioimpedance. “The changes observed in the following aspects were considered secondary outcomes: abdominal fat distribution, metabolic parameters, ovulation, ovarian morphology, hirsutism, hyperandrogenism, psychological well-being, and psychological distress,” said Dr. Gambineri. “Any reduction in the ovarian stroma, the area where androgens are synthesized, was also analyzed.”
The study authors found that although BMI decreased in both groups, this reduction was greater in the group that followed the very-low-calorie ketogenic diet. Significant weight loss was observed in both groups, 12.4 kg versus 4.7 kg. Significant differences were also observed in waist circumference (−8.1% in the experimental group vs. −2.2% in the control group), fat mass (−15.1% vs. −8.5%), and free testosterone (−30.3% vs. +10.6%). Only the experimental group saw a reduction in insulin.
“A key point regarding hyperandrogenism, especially regarding what’s referred to as free testosterone, there was only a significant reduction in the very-low-calorie ketogenic diet group,” said Dr. Gambineri. “This reduction was especially evident in the first part of the study, coinciding with the ketogenic period. The reason for this effect lies in the significant increase in the concentration of sex hormone-binding globulins, SHB6. Said globulins bind to the testosterone present in female blood, producing a reduction in free testosterone, a very important effect considering that this syndrome is an androgenic disorder. Furthermore, current treatments for polycystic ovary syndrome do not reduce free testosterone as much as this dietary approach does.”
For the specialist, among all these positive effects in these patients, perhaps most important is the notable improvement that occurs in ovulation. “At the beginning of the study, only 38.5% of the participants in the experimental group and 14.3% of those in the control group had ovulatory cycles. After the intervention, 84.6% managed to ovulate, compared to 35.7% who achieved this goal in the other group.”
Dr. Gambineri suggested that this method is “valid for reducing fat mass and rapidly improving hyperandrogenism and ovulatory dysfunction in women with obesity and polycystic ovary syndrome.”
Reversing type 2 diabetes?
Daniela Sofrà, MD, an endocrinologist specializing in diabetology at La Source Clinic, Lausanne, Switzerland, reviewed the current evidence on the role of the very-low-calorie ketogenic diet in the management of type 2 diabetes.
“It’s time to rethink diabetes treatment and focus efforts on managing obesity as an associated factor,” she said. “One of the hypotheses being examined in this regard is the twin cycle, which postulates that type 2 diabetes is the result of excess fat in the liver. This in turn is associated with insulin resistance with pancreas dysfunction.”
Dr. Sofrà added that there is a study documenting for the first time the reversibility of the morphology of the diabetic pancreas after caloric restriction with the very-low-calorie ketogenic diet. “The reason for this effect is the use of visceral and intrahepatic fat, which can lead to the remission of the clinical manifestation of type 2 diabetes, understanding as such the definition made by the American Diabetes Association: glycosylated hemoglobin < 6.5% without pharmacological therapy.”
Specifically, the results of this research showed that after following the very-low-calorie ketogenic diet and achieving a 15% weight loss (mean weight loss of the participants), liver glucose levels returned to normal levels within 7 days. Beta cell function returned to near normal within 8 weeks.
“Subsequent studies have shown the durability of remission of type 2 diabetes, thanks to the reactivation of the insulin-secreting function of beta cells that had become dedifferentiated in the face of chronic nutrient excess. Specifically, 6 out of 10 patients maintained glycosylated hemoglobin < 6% after 6 months without the need for pharmacological therapy,” Dr. Sofrà added.
Likewise, she highlighted that the probability of achieving remission is mainly determined by the duration of the disease. “The years with diabetes are one of the main predictors of the response that the patient will have with this dietary intervention. Studies have shown that remission is possible in patients with diabetes for less than 6 years, although there are other projects that indicate that it can be achieved with up to 10 years’ duration.”
Based on these data, Dr. Sofrà emphasized the pleiotropic effects of the very-low-calorie ketogenic diet on glycemic control, favoring the possible remission of diabetes or the reduction of drugs, as well as the reduction of the HOMA-IR index (insulin resistance) and waist circumference in people with type 2 diabetes.
Nonalcoholic fatty liver disease
The third comorbidity of obesity that may benefit from the very-low-calorie ketogenic diet is hepatic steatosis, or nonalcoholic fatty liver disease, said Hardy Walle, MD, an internal medicine specialist and director/founder of the Bodymed center, Kirkel, Germany, and one of the authors of this research.
“Recent research shows that ectopic fat and nonalcoholic fatty liver disease could be considered a cause, or at least one of the causes, of most of the diseases that affect the population as a consequence of overweight and obesity,” said Dr. Walle. “Some authors have stated that without fatty liver, there is no type 2 diabetes.”
Dr. Walle pointed out that between 30% and 40% of the adult population has nonalcoholic fatty liver disease, a percentage that increases considerably in people with obesity, reaching 70% prevalence and increasing, in the case of type 2 diabetes, to almost 90%. “Even normal weight does not rule out fatty liver; in fact, about 15% of people with nonalcoholic fatty liver disease are not overweight.”
In a setting where there are no approved drugs for the treatment of fatty liver (the current standard approach focuses on lifestyle interventions), a short-term hypocaloric diet (or liver fasting) is considered an effective method for management of this pathology. This principle was demonstrated by a study by the Saarland University, Saarbrücken, Germany, that Dr. Walle used to illustrate this statement.
“The participants (60 patients with hepatic steatosis) followed a hypocaloric diet (less than 1,000 kcal/day) for 14 days with a formula rich in protein and fiber specially developed for the treatment of nonalcoholic fatty liver disease. A fibroscan was then performed with controlled attenuation parameter measurement to quantify fatty liver disease. The results showed not only a significant improvement in nonalcoholic fatty liver disease parameters but also a marked improvement in all relevant metabolic parameters (serum lipids, liver enzymes),” explained Dr. Walle.
“This evidence leads us to affirm that the concept of hepatic fasting (by means of a hypocaloric diet) marks a point of reference for a future treatment approach for nonalcoholic fatty liver disease,” he concluded.
The study that Dr. Gambineri presented was carried out with the collaboration of the Pronokal Group (Nestlé Health Science). Dr. Gambineri, Dr. Sofrà, and Dr. Walle disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Ultra-processed: Doctors debate whether putting this label on foods is useful
The NOVA system divides foods into “fresh or minimally processed,” such as strawberries or steel-cut oats; “processed culinary ingredients,” such as olive oil; “processed foods,” such as cheeses; and “ultra-processed foods.” UPFs are defined as “industrial formulations made by deconstructing natural food into its chemical constituents, modifying them and recombining them with additives into products liable to displace all other NOVA food groups.”
According to doctors who presented during the meeting, ultra-processed foods are drawing increased attention, because researchers have been examining them in National Institutes of Health–funded studies and journalists have been writing about them.
During the debate session at the meeting, some experts said that, with obesity and poor health skyrocketing, increased awareness and labeling of UPFs can only be a good thing. In contrast others noted at the meeting that the classification system that has come to be used for identifying UPFs – the NOVA Food Classification system – is too mushy, confusing, and, ultimately unhelpful.
Carlos Monteiro, MD, PhD, professor of nutrition and public health at the University of Sao Paolo, was part of the group favoring the NOVA system’s classifying certain foods as UPFs, during the debate. He drew attention to the extent to which the world’s population is getting its calories from UPFs.
Mexico and France get about 30% of calories from these foods. In Canada, it’s 48%. And in the United States, it’s 57%, Dr. Monteiro said.
Studies have found that UPFs, many of which are designed to be exceedingly flavorful and intended to replace consumption of unprocessed whole foods, lead to more overall energy intake, more added sugar in the diet, and less fiber and protein intake, he said.
To further support his arguments, Dr. Monteiro pointed to studies suggesting that it is not just the resulting change in the nutritional intake that is unhealthy, but the UPF manufacturing process itself. When adjusting for fat, sugar, and sodium intake, for example, health outcomes associated with UPFs remain poor, he explained.
“I’m sorry,” he said in the debate. “If you don’t reduce this, you don’t reduce your obesity, your diabetes prevalence.”
A study presented by Jacqueline Vernarelli, PhD, during a different session at the meeting suggested there may be other downsides to consuming UPFs. This research, which was based on the U.S. National Youth Fitness Survey, found that poorer locomotor skills among children aged 3-5 and poorer cardiovascular fitness among those aged 12-15 were associated with getting more calories from UPFs.
Those with lower cardiovascular fitness consumed 1,234 calories a day from UPFs, and those with higher cardiovascular fitness consumed 1,007 calories a day from UPFs (P = .002), according to the new research.
“It’s notable here that, although these differences are significant, both groups are consuming a pretty high proportion of their diet from ultra-processed foods,” said Dr. Vernarelli, associate professor of public health at Sacred Heart University, Fairfield, Conn., during her presentation.
In the debate session, Arne Astrup, MD, PhD, senior project director at the Healthy Weight Center at the Novo Nordisk Foundation, Hellerup, Denmark, presented an opposing view.
He said the definition of UPFs makes it too difficult to categorize many foods, pointing to a study from this year in which about 150 nutrition experts, doctors, and dietitians classified 120 foods. Only three marketed foods and one generic food were classified the same by all the evaluators.
Referring to the study Dr. Astrup cited, Dr. Monteiro said it was a mere “exercise,” and the experts involved in it had conflicts of interest.
Dr. Astrup touted this study’s size and its appearance in the peer-reviewed journal the European Journal of Clinical Nutrition.
Defending his point of view, Dr. Astrup said, “The definition and classification is so ambiguous, and the risk of misclassification is so extremely high, I think we really miss the basic requirement of science, namely that we know what we are talking about,” he said.
If you take an unprocessed food, and insert a “little additive … suddenly it’s an ultra-processed food,” he added.
UPF definition doesn’t flag some unhealthy foods
Susan Roberts, PhD, professor of nutrition at Tufts University, Boston, was a discussant at the debate and touched on the merits of both sides. She noted that the UPF definition doesn’t flag some “clearly unhealthy foods,” such as table sugar, but does flag some healthy ones, such as plant-based burgers – to which Dr. Monteiro said that the system was not a system meant to divide foods into healthy and unhealthy groups, during the debate session.
The inclusion of both healthy and unhealthy foods in NOVA’s definition of a UPF is a serious problem, Dr. Roberts said.
“It’s almost like it’s an emotional classification designed to get at the food industry rather than focusing on health – and I think that’s asking for trouble because it’s just going to be such a mess to tell consumers, ‘Well, this ultra-processed food is healthy and this one isn’t,’ ” she said. What’s happening is the term ultra-processed is being used interchangeably with unhealthy.
The discussion that the UPF classification has generated is useful, Dr. Roberts continued. “This definition grew out of that recognition that we’re engaged in an unprecedented experiment of how unhealthy can you make the world without having a major catastrophe.”
She added that the UPF concept deserves a more formalized and rigorous evaluation.
“This is an important topic for the future of public health, and I think it needs big committees to address it seriously,” she said. “I think we should not be dealing with this individually in different labs.”
Doctor’s take on usefulness of discussing UPF concept with patients
Mark Corkins, MD, who did not participate in the debate at the meeting, said he talks to parents and children about nutrition at every office visit in which he sees a child with an unhealthy weight.
“Persistence wears down resistance,” said the chair of the American Academy of Pediatrics nutrition committee, in an interview.“A consistent message – you say the same thing and you say it multiple times.”
The idea of “ultra-processed foods” plays a role in those conversations, but largely in the background. It’s a topic that’s important for pediatric health, Dr. Corkins said – but he doesn’t make it the focal point.
“It’s not a direct attack on ultra-processed foods that usually I take as my direction,” said Dr. Corkins, who is also chief of pediatric gastroenterology at Le Bonheur Children’s Hospital in Memphis, Tenn.. “What I try to focus on, and what I think the American Academy of Pediatrics would focus on, is that we need to focus on making the diet better.”
He added, “Parents are aware – they don’t call it ultra-processed food, they call it junk food.”
Dr. Corkins continued that he is reluctant to directly challenge parents on feeding their children unhealthy foods – ultra-processed or not – lest he shame them and harm the relationship.
“Guilt as a motivator isn’t really highly successful,” he said, in an interview.
Dr. Astrup reported advisory committee or board member involvement with Green Leaf Medical and RNPC, France. Dr. Roberts reported advisory committee or board member involvement with Danone, and an ownership interest in Instinct Health Science. Dr. Monteiro and Dr. Corkins reported no relevant disclosures.
The NOVA system divides foods into “fresh or minimally processed,” such as strawberries or steel-cut oats; “processed culinary ingredients,” such as olive oil; “processed foods,” such as cheeses; and “ultra-processed foods.” UPFs are defined as “industrial formulations made by deconstructing natural food into its chemical constituents, modifying them and recombining them with additives into products liable to displace all other NOVA food groups.”
According to doctors who presented during the meeting, ultra-processed foods are drawing increased attention, because researchers have been examining them in National Institutes of Health–funded studies and journalists have been writing about them.
During the debate session at the meeting, some experts said that, with obesity and poor health skyrocketing, increased awareness and labeling of UPFs can only be a good thing. In contrast others noted at the meeting that the classification system that has come to be used for identifying UPFs – the NOVA Food Classification system – is too mushy, confusing, and, ultimately unhelpful.
Carlos Monteiro, MD, PhD, professor of nutrition and public health at the University of Sao Paolo, was part of the group favoring the NOVA system’s classifying certain foods as UPFs, during the debate. He drew attention to the extent to which the world’s population is getting its calories from UPFs.
Mexico and France get about 30% of calories from these foods. In Canada, it’s 48%. And in the United States, it’s 57%, Dr. Monteiro said.
Studies have found that UPFs, many of which are designed to be exceedingly flavorful and intended to replace consumption of unprocessed whole foods, lead to more overall energy intake, more added sugar in the diet, and less fiber and protein intake, he said.
To further support his arguments, Dr. Monteiro pointed to studies suggesting that it is not just the resulting change in the nutritional intake that is unhealthy, but the UPF manufacturing process itself. When adjusting for fat, sugar, and sodium intake, for example, health outcomes associated with UPFs remain poor, he explained.
“I’m sorry,” he said in the debate. “If you don’t reduce this, you don’t reduce your obesity, your diabetes prevalence.”
A study presented by Jacqueline Vernarelli, PhD, during a different session at the meeting suggested there may be other downsides to consuming UPFs. This research, which was based on the U.S. National Youth Fitness Survey, found that poorer locomotor skills among children aged 3-5 and poorer cardiovascular fitness among those aged 12-15 were associated with getting more calories from UPFs.
Those with lower cardiovascular fitness consumed 1,234 calories a day from UPFs, and those with higher cardiovascular fitness consumed 1,007 calories a day from UPFs (P = .002), according to the new research.
“It’s notable here that, although these differences are significant, both groups are consuming a pretty high proportion of their diet from ultra-processed foods,” said Dr. Vernarelli, associate professor of public health at Sacred Heart University, Fairfield, Conn., during her presentation.
In the debate session, Arne Astrup, MD, PhD, senior project director at the Healthy Weight Center at the Novo Nordisk Foundation, Hellerup, Denmark, presented an opposing view.
He said the definition of UPFs makes it too difficult to categorize many foods, pointing to a study from this year in which about 150 nutrition experts, doctors, and dietitians classified 120 foods. Only three marketed foods and one generic food were classified the same by all the evaluators.
Referring to the study Dr. Astrup cited, Dr. Monteiro said it was a mere “exercise,” and the experts involved in it had conflicts of interest.
Dr. Astrup touted this study’s size and its appearance in the peer-reviewed journal the European Journal of Clinical Nutrition.
Defending his point of view, Dr. Astrup said, “The definition and classification is so ambiguous, and the risk of misclassification is so extremely high, I think we really miss the basic requirement of science, namely that we know what we are talking about,” he said.
If you take an unprocessed food, and insert a “little additive … suddenly it’s an ultra-processed food,” he added.
UPF definition doesn’t flag some unhealthy foods
Susan Roberts, PhD, professor of nutrition at Tufts University, Boston, was a discussant at the debate and touched on the merits of both sides. She noted that the UPF definition doesn’t flag some “clearly unhealthy foods,” such as table sugar, but does flag some healthy ones, such as plant-based burgers – to which Dr. Monteiro said that the system was not a system meant to divide foods into healthy and unhealthy groups, during the debate session.
The inclusion of both healthy and unhealthy foods in NOVA’s definition of a UPF is a serious problem, Dr. Roberts said.
“It’s almost like it’s an emotional classification designed to get at the food industry rather than focusing on health – and I think that’s asking for trouble because it’s just going to be such a mess to tell consumers, ‘Well, this ultra-processed food is healthy and this one isn’t,’ ” she said. What’s happening is the term ultra-processed is being used interchangeably with unhealthy.
The discussion that the UPF classification has generated is useful, Dr. Roberts continued. “This definition grew out of that recognition that we’re engaged in an unprecedented experiment of how unhealthy can you make the world without having a major catastrophe.”
She added that the UPF concept deserves a more formalized and rigorous evaluation.
“This is an important topic for the future of public health, and I think it needs big committees to address it seriously,” she said. “I think we should not be dealing with this individually in different labs.”
Doctor’s take on usefulness of discussing UPF concept with patients
Mark Corkins, MD, who did not participate in the debate at the meeting, said he talks to parents and children about nutrition at every office visit in which he sees a child with an unhealthy weight.
“Persistence wears down resistance,” said the chair of the American Academy of Pediatrics nutrition committee, in an interview.“A consistent message – you say the same thing and you say it multiple times.”
The idea of “ultra-processed foods” plays a role in those conversations, but largely in the background. It’s a topic that’s important for pediatric health, Dr. Corkins said – but he doesn’t make it the focal point.
“It’s not a direct attack on ultra-processed foods that usually I take as my direction,” said Dr. Corkins, who is also chief of pediatric gastroenterology at Le Bonheur Children’s Hospital in Memphis, Tenn.. “What I try to focus on, and what I think the American Academy of Pediatrics would focus on, is that we need to focus on making the diet better.”
He added, “Parents are aware – they don’t call it ultra-processed food, they call it junk food.”
Dr. Corkins continued that he is reluctant to directly challenge parents on feeding their children unhealthy foods – ultra-processed or not – lest he shame them and harm the relationship.
“Guilt as a motivator isn’t really highly successful,” he said, in an interview.
Dr. Astrup reported advisory committee or board member involvement with Green Leaf Medical and RNPC, France. Dr. Roberts reported advisory committee or board member involvement with Danone, and an ownership interest in Instinct Health Science. Dr. Monteiro and Dr. Corkins reported no relevant disclosures.
The NOVA system divides foods into “fresh or minimally processed,” such as strawberries or steel-cut oats; “processed culinary ingredients,” such as olive oil; “processed foods,” such as cheeses; and “ultra-processed foods.” UPFs are defined as “industrial formulations made by deconstructing natural food into its chemical constituents, modifying them and recombining them with additives into products liable to displace all other NOVA food groups.”
According to doctors who presented during the meeting, ultra-processed foods are drawing increased attention, because researchers have been examining them in National Institutes of Health–funded studies and journalists have been writing about them.
During the debate session at the meeting, some experts said that, with obesity and poor health skyrocketing, increased awareness and labeling of UPFs can only be a good thing. In contrast others noted at the meeting that the classification system that has come to be used for identifying UPFs – the NOVA Food Classification system – is too mushy, confusing, and, ultimately unhelpful.
Carlos Monteiro, MD, PhD, professor of nutrition and public health at the University of Sao Paolo, was part of the group favoring the NOVA system’s classifying certain foods as UPFs, during the debate. He drew attention to the extent to which the world’s population is getting its calories from UPFs.
Mexico and France get about 30% of calories from these foods. In Canada, it’s 48%. And in the United States, it’s 57%, Dr. Monteiro said.
Studies have found that UPFs, many of which are designed to be exceedingly flavorful and intended to replace consumption of unprocessed whole foods, lead to more overall energy intake, more added sugar in the diet, and less fiber and protein intake, he said.
To further support his arguments, Dr. Monteiro pointed to studies suggesting that it is not just the resulting change in the nutritional intake that is unhealthy, but the UPF manufacturing process itself. When adjusting for fat, sugar, and sodium intake, for example, health outcomes associated with UPFs remain poor, he explained.
“I’m sorry,” he said in the debate. “If you don’t reduce this, you don’t reduce your obesity, your diabetes prevalence.”
A study presented by Jacqueline Vernarelli, PhD, during a different session at the meeting suggested there may be other downsides to consuming UPFs. This research, which was based on the U.S. National Youth Fitness Survey, found that poorer locomotor skills among children aged 3-5 and poorer cardiovascular fitness among those aged 12-15 were associated with getting more calories from UPFs.
Those with lower cardiovascular fitness consumed 1,234 calories a day from UPFs, and those with higher cardiovascular fitness consumed 1,007 calories a day from UPFs (P = .002), according to the new research.
“It’s notable here that, although these differences are significant, both groups are consuming a pretty high proportion of their diet from ultra-processed foods,” said Dr. Vernarelli, associate professor of public health at Sacred Heart University, Fairfield, Conn., during her presentation.
In the debate session, Arne Astrup, MD, PhD, senior project director at the Healthy Weight Center at the Novo Nordisk Foundation, Hellerup, Denmark, presented an opposing view.
He said the definition of UPFs makes it too difficult to categorize many foods, pointing to a study from this year in which about 150 nutrition experts, doctors, and dietitians classified 120 foods. Only three marketed foods and one generic food were classified the same by all the evaluators.
Referring to the study Dr. Astrup cited, Dr. Monteiro said it was a mere “exercise,” and the experts involved in it had conflicts of interest.
Dr. Astrup touted this study’s size and its appearance in the peer-reviewed journal the European Journal of Clinical Nutrition.
Defending his point of view, Dr. Astrup said, “The definition and classification is so ambiguous, and the risk of misclassification is so extremely high, I think we really miss the basic requirement of science, namely that we know what we are talking about,” he said.
If you take an unprocessed food, and insert a “little additive … suddenly it’s an ultra-processed food,” he added.
UPF definition doesn’t flag some unhealthy foods
Susan Roberts, PhD, professor of nutrition at Tufts University, Boston, was a discussant at the debate and touched on the merits of both sides. She noted that the UPF definition doesn’t flag some “clearly unhealthy foods,” such as table sugar, but does flag some healthy ones, such as plant-based burgers – to which Dr. Monteiro said that the system was not a system meant to divide foods into healthy and unhealthy groups, during the debate session.
The inclusion of both healthy and unhealthy foods in NOVA’s definition of a UPF is a serious problem, Dr. Roberts said.
“It’s almost like it’s an emotional classification designed to get at the food industry rather than focusing on health – and I think that’s asking for trouble because it’s just going to be such a mess to tell consumers, ‘Well, this ultra-processed food is healthy and this one isn’t,’ ” she said. What’s happening is the term ultra-processed is being used interchangeably with unhealthy.
The discussion that the UPF classification has generated is useful, Dr. Roberts continued. “This definition grew out of that recognition that we’re engaged in an unprecedented experiment of how unhealthy can you make the world without having a major catastrophe.”
She added that the UPF concept deserves a more formalized and rigorous evaluation.
“This is an important topic for the future of public health, and I think it needs big committees to address it seriously,” she said. “I think we should not be dealing with this individually in different labs.”
Doctor’s take on usefulness of discussing UPF concept with patients
Mark Corkins, MD, who did not participate in the debate at the meeting, said he talks to parents and children about nutrition at every office visit in which he sees a child with an unhealthy weight.
“Persistence wears down resistance,” said the chair of the American Academy of Pediatrics nutrition committee, in an interview.“A consistent message – you say the same thing and you say it multiple times.”
The idea of “ultra-processed foods” plays a role in those conversations, but largely in the background. It’s a topic that’s important for pediatric health, Dr. Corkins said – but he doesn’t make it the focal point.
“It’s not a direct attack on ultra-processed foods that usually I take as my direction,” said Dr. Corkins, who is also chief of pediatric gastroenterology at Le Bonheur Children’s Hospital in Memphis, Tenn.. “What I try to focus on, and what I think the American Academy of Pediatrics would focus on, is that we need to focus on making the diet better.”
He added, “Parents are aware – they don’t call it ultra-processed food, they call it junk food.”
Dr. Corkins continued that he is reluctant to directly challenge parents on feeding their children unhealthy foods – ultra-processed or not – lest he shame them and harm the relationship.
“Guilt as a motivator isn’t really highly successful,” he said, in an interview.
Dr. Astrup reported advisory committee or board member involvement with Green Leaf Medical and RNPC, France. Dr. Roberts reported advisory committee or board member involvement with Danone, and an ownership interest in Instinct Health Science. Dr. Monteiro and Dr. Corkins reported no relevant disclosures.
FROM NUTRITION 2022
Diabetes tied to risk of long COVID, too
Individuals with diabetes who experience COVID-19 are at increased risk for long COVID compared to individuals without diabetes, according to data from a literature review of seven studies.
Diabetes remains a risk factor for severe COVID-19, but whether it is a risk factor for postacute sequelae of COVID-19 (PASC), also known as long COVID, remains unclear, Jessica L. Harding, PhD, of Emory University, said in a late-breaking poster session at the annual scientific sessions of the American Diabetes Association.
Long COVID is generally defined as “sequelae that extend beyond the 4 weeks after initial infection” and may include a range of symptoms that affect multiple organs, Dr. Harding said. A study conducted in January of 2022 suggested that type 2 diabetes was one of several strong risk factors for long COVID, she noted.
Dr. Harding and colleagues reviewed data from seven studies published from Jan. 1, 2020, to Jan. 27, 2022, on the risk of PASC in people with and without diabetes. The studies included patients with a minimum of 4 weeks’ follow-up after COVID-19 diagnosis. All seven studies had a longitudinal cohort design, and included adults from high-income countries, with study populations ranging from 104 to 4,182.
Across the studies, long COVID definitions varied, but included ongoing symptoms of fatigue, cough, and dyspnea, with follow-up periods of 4 weeks to 7 months.
Overall, three of the seven studies indicated that diabetes was a risk factor for long COVID (odds ratio [OR] greater than 4 for all) and four studies indicated that diabetes was not a risk factor for long COVID (OR, 0.5-2.2).
One of the three studies showing increased risk included 2,334 individuals hospitalized with COVID-19; of these about 5% had diabetes. The odds ratio for PASC for individuals with diabetes was 4.18. In another study of 209 persons with COVID-19, of whom 22% had diabetes, diabetes was significantly correlated with respiratory viral disease (meaning at least two respiratory symptoms). The third study showing an increased risk of long COVID in diabetes patients included 104 kidney transplant patients, of whom 20% had diabetes; the odds ratio for PASC was 4.42.
The findings were limited by several factors, including the relatively small number of studies and the heterogeneity of studies regarding definitions of long COVID, specific populations at risk, follow-up times, and risk adjustment, Dr. Harding noted.
More high-quality studies across multiple populations and settings are needed to determine if diabetes is indeed a risk factor for long COVID, she said.
In the meantime, “careful monitoring of people with diabetes for development of PASC may be advised,” Dr. Harding concluded.
Findings support need for screening
“Given the devastating impact of COVID on people with diabetes, it’s important to know what data has been accumulated on long COVID for future research and discoveries in this area,” Robert A. Gabbay, MD, chief science and medical officer for the American Diabetes Association, said in an interview. “The more information we have, the better we can understand the implications.”
Dr. Gabbay said he was surprised by the current study findings. “We know very little on this subject, so yes, I am surprised to see just how significant the risk of long COVID for people with diabetes seems to be, but clearly, more research needs to be done to understand long COVID,” he emphasized.
The take-home message for clinicians is the importance of screening patients for PASC; also “ask your patients if they had COVID, to better understand any symptoms they might have that could be related to PACS,” he noted.
“It is crucial that we confirm these results and then look at risk factors in people with diabetes that might explain who is at highest risk and ultimately understand the causes and potential cure,” Dr. Gabbay added.
The study was supported by the National Heart, Lung, and Blood Institute. Dr. Harding and Dr. Gabbay had no financial conflicts to disclose.
Individuals with diabetes who experience COVID-19 are at increased risk for long COVID compared to individuals without diabetes, according to data from a literature review of seven studies.
Diabetes remains a risk factor for severe COVID-19, but whether it is a risk factor for postacute sequelae of COVID-19 (PASC), also known as long COVID, remains unclear, Jessica L. Harding, PhD, of Emory University, said in a late-breaking poster session at the annual scientific sessions of the American Diabetes Association.
Long COVID is generally defined as “sequelae that extend beyond the 4 weeks after initial infection” and may include a range of symptoms that affect multiple organs, Dr. Harding said. A study conducted in January of 2022 suggested that type 2 diabetes was one of several strong risk factors for long COVID, she noted.
Dr. Harding and colleagues reviewed data from seven studies published from Jan. 1, 2020, to Jan. 27, 2022, on the risk of PASC in people with and without diabetes. The studies included patients with a minimum of 4 weeks’ follow-up after COVID-19 diagnosis. All seven studies had a longitudinal cohort design, and included adults from high-income countries, with study populations ranging from 104 to 4,182.
Across the studies, long COVID definitions varied, but included ongoing symptoms of fatigue, cough, and dyspnea, with follow-up periods of 4 weeks to 7 months.
Overall, three of the seven studies indicated that diabetes was a risk factor for long COVID (odds ratio [OR] greater than 4 for all) and four studies indicated that diabetes was not a risk factor for long COVID (OR, 0.5-2.2).
One of the three studies showing increased risk included 2,334 individuals hospitalized with COVID-19; of these about 5% had diabetes. The odds ratio for PASC for individuals with diabetes was 4.18. In another study of 209 persons with COVID-19, of whom 22% had diabetes, diabetes was significantly correlated with respiratory viral disease (meaning at least two respiratory symptoms). The third study showing an increased risk of long COVID in diabetes patients included 104 kidney transplant patients, of whom 20% had diabetes; the odds ratio for PASC was 4.42.
The findings were limited by several factors, including the relatively small number of studies and the heterogeneity of studies regarding definitions of long COVID, specific populations at risk, follow-up times, and risk adjustment, Dr. Harding noted.
More high-quality studies across multiple populations and settings are needed to determine if diabetes is indeed a risk factor for long COVID, she said.
In the meantime, “careful monitoring of people with diabetes for development of PASC may be advised,” Dr. Harding concluded.
Findings support need for screening
“Given the devastating impact of COVID on people with diabetes, it’s important to know what data has been accumulated on long COVID for future research and discoveries in this area,” Robert A. Gabbay, MD, chief science and medical officer for the American Diabetes Association, said in an interview. “The more information we have, the better we can understand the implications.”
Dr. Gabbay said he was surprised by the current study findings. “We know very little on this subject, so yes, I am surprised to see just how significant the risk of long COVID for people with diabetes seems to be, but clearly, more research needs to be done to understand long COVID,” he emphasized.
The take-home message for clinicians is the importance of screening patients for PASC; also “ask your patients if they had COVID, to better understand any symptoms they might have that could be related to PACS,” he noted.
“It is crucial that we confirm these results and then look at risk factors in people with diabetes that might explain who is at highest risk and ultimately understand the causes and potential cure,” Dr. Gabbay added.
The study was supported by the National Heart, Lung, and Blood Institute. Dr. Harding and Dr. Gabbay had no financial conflicts to disclose.
Individuals with diabetes who experience COVID-19 are at increased risk for long COVID compared to individuals without diabetes, according to data from a literature review of seven studies.
Diabetes remains a risk factor for severe COVID-19, but whether it is a risk factor for postacute sequelae of COVID-19 (PASC), also known as long COVID, remains unclear, Jessica L. Harding, PhD, of Emory University, said in a late-breaking poster session at the annual scientific sessions of the American Diabetes Association.
Long COVID is generally defined as “sequelae that extend beyond the 4 weeks after initial infection” and may include a range of symptoms that affect multiple organs, Dr. Harding said. A study conducted in January of 2022 suggested that type 2 diabetes was one of several strong risk factors for long COVID, she noted.
Dr. Harding and colleagues reviewed data from seven studies published from Jan. 1, 2020, to Jan. 27, 2022, on the risk of PASC in people with and without diabetes. The studies included patients with a minimum of 4 weeks’ follow-up after COVID-19 diagnosis. All seven studies had a longitudinal cohort design, and included adults from high-income countries, with study populations ranging from 104 to 4,182.
Across the studies, long COVID definitions varied, but included ongoing symptoms of fatigue, cough, and dyspnea, with follow-up periods of 4 weeks to 7 months.
Overall, three of the seven studies indicated that diabetes was a risk factor for long COVID (odds ratio [OR] greater than 4 for all) and four studies indicated that diabetes was not a risk factor for long COVID (OR, 0.5-2.2).
One of the three studies showing increased risk included 2,334 individuals hospitalized with COVID-19; of these about 5% had diabetes. The odds ratio for PASC for individuals with diabetes was 4.18. In another study of 209 persons with COVID-19, of whom 22% had diabetes, diabetes was significantly correlated with respiratory viral disease (meaning at least two respiratory symptoms). The third study showing an increased risk of long COVID in diabetes patients included 104 kidney transplant patients, of whom 20% had diabetes; the odds ratio for PASC was 4.42.
The findings were limited by several factors, including the relatively small number of studies and the heterogeneity of studies regarding definitions of long COVID, specific populations at risk, follow-up times, and risk adjustment, Dr. Harding noted.
More high-quality studies across multiple populations and settings are needed to determine if diabetes is indeed a risk factor for long COVID, she said.
In the meantime, “careful monitoring of people with diabetes for development of PASC may be advised,” Dr. Harding concluded.
Findings support need for screening
“Given the devastating impact of COVID on people with diabetes, it’s important to know what data has been accumulated on long COVID for future research and discoveries in this area,” Robert A. Gabbay, MD, chief science and medical officer for the American Diabetes Association, said in an interview. “The more information we have, the better we can understand the implications.”
Dr. Gabbay said he was surprised by the current study findings. “We know very little on this subject, so yes, I am surprised to see just how significant the risk of long COVID for people with diabetes seems to be, but clearly, more research needs to be done to understand long COVID,” he emphasized.
The take-home message for clinicians is the importance of screening patients for PASC; also “ask your patients if they had COVID, to better understand any symptoms they might have that could be related to PACS,” he noted.
“It is crucial that we confirm these results and then look at risk factors in people with diabetes that might explain who is at highest risk and ultimately understand the causes and potential cure,” Dr. Gabbay added.
The study was supported by the National Heart, Lung, and Blood Institute. Dr. Harding and Dr. Gabbay had no financial conflicts to disclose.
FROM ADA 2022
Why do we treat menopause as a disease?
Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.
Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.
It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.
“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.
Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.
“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
The ‘untold misery of oestrogen-starved women’
These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken
homes caused by these unstable, oestrogen-starved women.’ ”
Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.
“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”
The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
Promoting exercise, stopping smoking among positive messages
An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.
The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).
The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.
While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
Menopause blamed in a difficult time of life
Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.
It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.
People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.
The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”
Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.
Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.
Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”
She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.
The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.
Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.
Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.
It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.
“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.
Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.
“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
The ‘untold misery of oestrogen-starved women’
These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken
homes caused by these unstable, oestrogen-starved women.’ ”
Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.
“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”
The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
Promoting exercise, stopping smoking among positive messages
An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.
The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).
The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.
While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
Menopause blamed in a difficult time of life
Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.
It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.
People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.
The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”
Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.
Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.
Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”
She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.
The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.
Menopause gets a bad rap in medical literature and throughout society, say authors of a new analysis. And they argue that the negativity undermines women’s health outlook in the years that should be a natural life transition.
Menopause has been medicalized over centuries and talked about as if it were a disease, they say, and that may increase women’s anxiety and apprehension about the midlife stage.
It’s time to change the narrative, says Martha Hickey, MD, with the department of obstetrics and gynaecology at the Royal Women’s Hospital in Victoria, Australia, and her coauthors. Their analysis was published online in the BMJ.
“The message that menopause signals decay and decline, which can potentially be delayed or reversed by hormonal treatments, persists and is reinforced by the media, medical literature, and information for women, often driven by marketing interests,” they write.
Such messages may chip away at women’s confidence. Dr. Hickey and colleagues cite surveys in the United States and Ireland that found that most women (65%-77%) feel unprepared for menopause.
“Together with limited public discussion and education and shame attached to ageing in women, this may contribute to embarrassment and negative expectations about menopause,” the authors write.
The ‘untold misery of oestrogen-starved women’
These messages have deep roots. Take for instance, gynecologist Robert Wilson’s words in his 1966 book “Feminine Forever.” The authors note he recommended estrogen for all menopausal women “to treat their ‘serious, painful and often crippling disease’ and avoid the ‘untold misery of alcoholism, drug addiction, divorce, and broken
homes caused by these unstable, oestrogen-starved women.’ ”
Women experience menopause in very different ways. Experience with menopause also differs by country, the authors explain. “Women’s experience of menopause is also strongly influenced by social values around reproduction and ageing, with positive or negative ramifications,” they write.
“For example, women tend to have worse experiences of menopause in countries where their value is predicated on youth and reproductive capacity and ageing is associated with decline.”
The authors argue that the medicalization of menopause has condensed the wide range of women’s experiences at a typical age into “a narrowly defined disease requiring treatment.”
Promoting exercise, stopping smoking among positive messages
An editorial by Haitham Hamoda, MD, and Sara Moger, with the British Menopause Society, notes that more than 75% of women experiencing menopause report symptoms, and more than 25% describe severe symptoms.
The editorialists point out that the National Institute of Health and Care Excellence and others recommend an individualized approach to addressing menopause that includes a comprehensive approach – advice on exercise, weight management, stopping smoking, and reducing alcohol as well as options such as hormone therapy (HT).
The literature says the main indication for HT is for severe symptoms and not as a preventive measure. “Evidence does not support use of HT to reduce the risk of dementia,” they point out.
While some women may benefit from HT, that should not be explored to the exclusion of other avenues of help, Dr. Hickey and colleagues write. Risks must also be considered.
Menopause blamed in a difficult time of life
Jennifer Howell, MD, an obstetrician/gynecologist and certified menopause provider at Duke University in Durham, N.C., told this news organization that menopause is often blamed in a time of life when women naturally are experiencing an array of stressful and emotional changes.
It often coincides with children heading to college, navigating midlife challenges in marriage, helping aging parents, managing demanding careers, and health issues.
People want a reason for changes women experience, and too often the finger gets pointed at menopause, Dr. Howell said.
The message women hear has always been, “It’s got to be your hormones. And people want to hear that there’s a hormonal solution.”
Making menopause the target also has led to nonevidence-based “snake-oil” type remedies sold in unregulated powders, creams, and pellets, Dr. Howell noted.
Dr. Howell has treated thousands of menopausal women in her clinic and she says she spends a good deal of time with them explaining a holistic view of the process, much like what the authors describe, with lifestyle changes and treatment options.
Sometimes HT is the solution, Dr. Howell says, but “it’s become a crutch. Hormones are not a panacea.”
She is frustrated with the amount of disinformation circulating online. Groups like the North American Menopause Society put out reliable evidence-based information, but they compete “with a lot of nonsense,” she says.
The message that women should hear, she says is that “[menopause] is a natural part of aging and there may or may not be symptoms that come along with it. If there are, there are things we can do,” she says.
FROM BMJ
Hypothyroidism: No more waiting to eat or drink with liquid thyroxine?
ATLANTA -- Liquid formulations of levothyroxine offer the possibility of allowing patients with hypothyroidism to take their medication with meals or coffee and skip the currently recommended 30- to 60-minute waiting period before doing either, new data suggest.
Because food, coffee, and certain medications can interfere with intestinal absorption of levothyroxine (also known as LT4), current guidelines recommend that the drug be taken in a fasting state, typically 30-60 minutes before breakfast. However, compliance may be difficult for some patients.
Now, a potential solution may come from new evidence that liquid levothyroxine formulations that bypass the gastric dissolution phase of absorption may mitigate the interference with food and coffee.
Findings from two bioavailability studies showing no difference in comparisons of Thyquidity (levothyroxine sodium oral solution, Vertice Pharma) with or without waiting periods before consuming coffee or a high-fat meal were presented at the annual meeting of the Endocrine Society (ENDO 2022), by Vertice Pharma Medical Director Kris Washington, PharmD.
And just last month, similar data were published in Thyroid for another levothyroxine oral solution, Tirosint-SOL (IBSA). No difference in pharmacokinetic properties were found with this product with a shorter versus a longer waiting period before consuming a high-fat meal.
Liquid thyroxine may be less affected by food/drink but is expensive
Both products have been approved by the U.S. Food and Drug Administration, but current labeling for both still calls for a 30- to 60-minute waiting period between taking the medication and eating or drinking. Thyquidity is an oral solution of 100 µg/mL levothyroxine sodium that has been shown to be bioequivalent to one of the most popular branded levothyroxine tablets, Synthroid (AbbVie), under fasting conditions. Tirosint-SOL is also an oral solution that comes in 15 different dosage ampules.
“It is important to note that while these findings are exciting and encouraging, we do want you to continue to follow the current FDA-approved label for Thyquidity, recommending that it be taken on an empty stomach 30-60 minutes prior to breakfast and that patients continue to follow all other label instructions,” Dr. Washington said during a press briefing at ENDO 2022.
When asked whether the new data would be submitted to the FDA for a possible amendment to this message, she replied: “We’re still discussing that. We’re exploring all options. ... This is fairly new data. ... It makes sense and certainly solves a lot of the challenges for people who can’t swallow or don’t choose to swallow, or the challenges of splitting or crushing with tablets.”
Asked to comment, Benjamin J. Gigliotti, MD, a clinical thyroidologist at the University of Rochester, New York, told this news organization: “Liquid levothyroxine has the potential to be a clinically useful formulation,” noting that these recent data corroborate prior findings from Europe and elsewhere that liquid levothyroxine is absorbed more rapidly and thus may be less impacted by food or beverages.
However, Dr. Gigliotti also pointed out, “I don’t think malabsorption is a major contributor to suboptimal treatment because if [patients] malabsorb the hormone, we typically just increase their dose a little bit or ask them to take it separately, and that works just fine for most people.”
And the higher cost of the liquid products is a major issue, he noted.
A quick search on GoodRx shows that the lowest price of Tirosint-SOL is $115.52 for a 1 month supply and Thyquidity is $181.04/month. “In the few patients where I tried to obtain Tirosint-SOL, it was not covered by insurance, even with a prior authorization,” Dr. Gigliotti commented.
In contrast, generic levothyroxine tablets are about $4/month, while a common brand name of levothyroxine tablets are $47.81/month.
“Until these liquid formulations are more widely covered by insurance for a reasonable copay, or come down in price compared to generic levothyroxine tablets, most of my patients have voiced that they’d rather deal with the inconveniences of a tablet compared to higher medication cost, especially with rising economic insecurity imposed by the COVID-19 pandemic and recent world events,” Dr. Gigliotti said.
Bioequivalence with shorter versus longer waits before coffee/breakfast
The Thyquidity coffee study was a single-center open-label, randomized, crossover study of 40 healthy adults randomized after a 10-hour overnight fast to 600 µg Thyquidity with water under fasting conditions or to the same dose given 5 minutes prior to drinking an 8-ounce cup of American coffee without milk or sweeteners. After a 40-day washout period, the same participants received the other treatment.
Mean serum thyroxine (T4) concentrations over 48 hours were nearly identical, demonstrating comparable bioavailability. Pharmacokinetics parameters, including area under the curve (AUC) and Cmax, were also comparable for both groups. The geometric least square mean ratios for baseline-adjusted LT4 were 96.0% for Cmax and 94% for AUC. And the corresponding 90% confidence intervals fell within the 80%-125% FDA acceptance range for absence of a food effect on bioavailability, said Dr. Washington when presenting the findings.
There was one adverse event, a decrease in blood glucose level, which was deemed to be mild and unrelated to study treatment. No deaths, serious adverse events, or discontinuations due to adverse events were reported. There were no significant changes in vital signs or on ECG.
In the second Thyquidity study of 38 healthy adults, after a 10-hour fast, the same doses were given 10 or 30 minutes prior to the consumption of a 950-calorie standardized high-fat breakfast.
Again, over 48 hours, mean serum T4 levels were comparable between the two groups. The geometric least squares mean ratios for both AUC and Cmax for baseline-adjusted LT4 were 88.7% and 85.1%, respectively. Again, the corresponding 90% confidence intervals fell within the FDA’s noninterference definition, again demonstrating lack of a food effect on bioavailability, Dr. Washington noted.
Four adverse events were reported in three participants, with three deemed to be possibly related to the medication. All were isolated lab abnormalities without clinical symptoms and deemed to be mild. Three were normal on repeat testing.
There were no deaths or serious adverse events or study discontinuations for adverse events and no significant findings for vital signs or on ECG.
Similar findings for Tirosint-SOL but longer-term studies needed
The recently published Tirosint-SOL study included 36 healthy volunteers randomized to single 600-µg doses of the LT4 oral solution after a 10-hour fast, either 15 or 30 minutes before eating a standardized high-fat, high-calorie meal. Mean serum total thyroxine concentration profiles were similar for both the 15- and 30-minute waits, with similar AUCs.
Geometric mean ratios for AUCs at 48 and 72 hours were 90% and 92%, respectively, and the 90% confidence intervals fell within the 80%-125% FDA boundaries, suggesting similar exposures whether taken 15 or 30 minutes before a meal.
Senior author Francesco S. Celi, MD, chair of the division of endocrinology, diabetes, and metabolism at Virginia Commonwealth University, Richmond, told this news organization: “There is an interest in providing more opportunities for patients and improving adherence to the medication. ... Whatever makes life a bit easier for patients and results in a more predictable response to treatment means down the road there will be fewer visits to the doctor to make adjustments.”
However, he said that in addition to the cost and reimbursement issue, all of these studies have been short term and not conducted in real-life settings.
“Another question is: What happens if the patient goes on low-dose LT4? The studies were conducted on much higher pharmacologic doses. But at least from a safety standpoint, there’s no specific concern.”
Dr. Washington is an employee of Vertice Pharma. Dr. Celi has received unrestricted research grants and worked as a consultant for IBSA. Dr. Gigliotti has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ATLANTA -- Liquid formulations of levothyroxine offer the possibility of allowing patients with hypothyroidism to take their medication with meals or coffee and skip the currently recommended 30- to 60-minute waiting period before doing either, new data suggest.
Because food, coffee, and certain medications can interfere with intestinal absorption of levothyroxine (also known as LT4), current guidelines recommend that the drug be taken in a fasting state, typically 30-60 minutes before breakfast. However, compliance may be difficult for some patients.
Now, a potential solution may come from new evidence that liquid levothyroxine formulations that bypass the gastric dissolution phase of absorption may mitigate the interference with food and coffee.
Findings from two bioavailability studies showing no difference in comparisons of Thyquidity (levothyroxine sodium oral solution, Vertice Pharma) with or without waiting periods before consuming coffee or a high-fat meal were presented at the annual meeting of the Endocrine Society (ENDO 2022), by Vertice Pharma Medical Director Kris Washington, PharmD.
And just last month, similar data were published in Thyroid for another levothyroxine oral solution, Tirosint-SOL (IBSA). No difference in pharmacokinetic properties were found with this product with a shorter versus a longer waiting period before consuming a high-fat meal.
Liquid thyroxine may be less affected by food/drink but is expensive
Both products have been approved by the U.S. Food and Drug Administration, but current labeling for both still calls for a 30- to 60-minute waiting period between taking the medication and eating or drinking. Thyquidity is an oral solution of 100 µg/mL levothyroxine sodium that has been shown to be bioequivalent to one of the most popular branded levothyroxine tablets, Synthroid (AbbVie), under fasting conditions. Tirosint-SOL is also an oral solution that comes in 15 different dosage ampules.
“It is important to note that while these findings are exciting and encouraging, we do want you to continue to follow the current FDA-approved label for Thyquidity, recommending that it be taken on an empty stomach 30-60 minutes prior to breakfast and that patients continue to follow all other label instructions,” Dr. Washington said during a press briefing at ENDO 2022.
When asked whether the new data would be submitted to the FDA for a possible amendment to this message, she replied: “We’re still discussing that. We’re exploring all options. ... This is fairly new data. ... It makes sense and certainly solves a lot of the challenges for people who can’t swallow or don’t choose to swallow, or the challenges of splitting or crushing with tablets.”
Asked to comment, Benjamin J. Gigliotti, MD, a clinical thyroidologist at the University of Rochester, New York, told this news organization: “Liquid levothyroxine has the potential to be a clinically useful formulation,” noting that these recent data corroborate prior findings from Europe and elsewhere that liquid levothyroxine is absorbed more rapidly and thus may be less impacted by food or beverages.
However, Dr. Gigliotti also pointed out, “I don’t think malabsorption is a major contributor to suboptimal treatment because if [patients] malabsorb the hormone, we typically just increase their dose a little bit or ask them to take it separately, and that works just fine for most people.”
And the higher cost of the liquid products is a major issue, he noted.
A quick search on GoodRx shows that the lowest price of Tirosint-SOL is $115.52 for a 1 month supply and Thyquidity is $181.04/month. “In the few patients where I tried to obtain Tirosint-SOL, it was not covered by insurance, even with a prior authorization,” Dr. Gigliotti commented.
In contrast, generic levothyroxine tablets are about $4/month, while a common brand name of levothyroxine tablets are $47.81/month.
“Until these liquid formulations are more widely covered by insurance for a reasonable copay, or come down in price compared to generic levothyroxine tablets, most of my patients have voiced that they’d rather deal with the inconveniences of a tablet compared to higher medication cost, especially with rising economic insecurity imposed by the COVID-19 pandemic and recent world events,” Dr. Gigliotti said.
Bioequivalence with shorter versus longer waits before coffee/breakfast
The Thyquidity coffee study was a single-center open-label, randomized, crossover study of 40 healthy adults randomized after a 10-hour overnight fast to 600 µg Thyquidity with water under fasting conditions or to the same dose given 5 minutes prior to drinking an 8-ounce cup of American coffee without milk or sweeteners. After a 40-day washout period, the same participants received the other treatment.
Mean serum thyroxine (T4) concentrations over 48 hours were nearly identical, demonstrating comparable bioavailability. Pharmacokinetics parameters, including area under the curve (AUC) and Cmax, were also comparable for both groups. The geometric least square mean ratios for baseline-adjusted LT4 were 96.0% for Cmax and 94% for AUC. And the corresponding 90% confidence intervals fell within the 80%-125% FDA acceptance range for absence of a food effect on bioavailability, said Dr. Washington when presenting the findings.
There was one adverse event, a decrease in blood glucose level, which was deemed to be mild and unrelated to study treatment. No deaths, serious adverse events, or discontinuations due to adverse events were reported. There were no significant changes in vital signs or on ECG.
In the second Thyquidity study of 38 healthy adults, after a 10-hour fast, the same doses were given 10 or 30 minutes prior to the consumption of a 950-calorie standardized high-fat breakfast.
Again, over 48 hours, mean serum T4 levels were comparable between the two groups. The geometric least squares mean ratios for both AUC and Cmax for baseline-adjusted LT4 were 88.7% and 85.1%, respectively. Again, the corresponding 90% confidence intervals fell within the FDA’s noninterference definition, again demonstrating lack of a food effect on bioavailability, Dr. Washington noted.
Four adverse events were reported in three participants, with three deemed to be possibly related to the medication. All were isolated lab abnormalities without clinical symptoms and deemed to be mild. Three were normal on repeat testing.
There were no deaths or serious adverse events or study discontinuations for adverse events and no significant findings for vital signs or on ECG.
Similar findings for Tirosint-SOL but longer-term studies needed
The recently published Tirosint-SOL study included 36 healthy volunteers randomized to single 600-µg doses of the LT4 oral solution after a 10-hour fast, either 15 or 30 minutes before eating a standardized high-fat, high-calorie meal. Mean serum total thyroxine concentration profiles were similar for both the 15- and 30-minute waits, with similar AUCs.
Geometric mean ratios for AUCs at 48 and 72 hours were 90% and 92%, respectively, and the 90% confidence intervals fell within the 80%-125% FDA boundaries, suggesting similar exposures whether taken 15 or 30 minutes before a meal.
Senior author Francesco S. Celi, MD, chair of the division of endocrinology, diabetes, and metabolism at Virginia Commonwealth University, Richmond, told this news organization: “There is an interest in providing more opportunities for patients and improving adherence to the medication. ... Whatever makes life a bit easier for patients and results in a more predictable response to treatment means down the road there will be fewer visits to the doctor to make adjustments.”
However, he said that in addition to the cost and reimbursement issue, all of these studies have been short term and not conducted in real-life settings.
“Another question is: What happens if the patient goes on low-dose LT4? The studies were conducted on much higher pharmacologic doses. But at least from a safety standpoint, there’s no specific concern.”
Dr. Washington is an employee of Vertice Pharma. Dr. Celi has received unrestricted research grants and worked as a consultant for IBSA. Dr. Gigliotti has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ATLANTA -- Liquid formulations of levothyroxine offer the possibility of allowing patients with hypothyroidism to take their medication with meals or coffee and skip the currently recommended 30- to 60-minute waiting period before doing either, new data suggest.
Because food, coffee, and certain medications can interfere with intestinal absorption of levothyroxine (also known as LT4), current guidelines recommend that the drug be taken in a fasting state, typically 30-60 minutes before breakfast. However, compliance may be difficult for some patients.
Now, a potential solution may come from new evidence that liquid levothyroxine formulations that bypass the gastric dissolution phase of absorption may mitigate the interference with food and coffee.
Findings from two bioavailability studies showing no difference in comparisons of Thyquidity (levothyroxine sodium oral solution, Vertice Pharma) with or without waiting periods before consuming coffee or a high-fat meal were presented at the annual meeting of the Endocrine Society (ENDO 2022), by Vertice Pharma Medical Director Kris Washington, PharmD.
And just last month, similar data were published in Thyroid for another levothyroxine oral solution, Tirosint-SOL (IBSA). No difference in pharmacokinetic properties were found with this product with a shorter versus a longer waiting period before consuming a high-fat meal.
Liquid thyroxine may be less affected by food/drink but is expensive
Both products have been approved by the U.S. Food and Drug Administration, but current labeling for both still calls for a 30- to 60-minute waiting period between taking the medication and eating or drinking. Thyquidity is an oral solution of 100 µg/mL levothyroxine sodium that has been shown to be bioequivalent to one of the most popular branded levothyroxine tablets, Synthroid (AbbVie), under fasting conditions. Tirosint-SOL is also an oral solution that comes in 15 different dosage ampules.
“It is important to note that while these findings are exciting and encouraging, we do want you to continue to follow the current FDA-approved label for Thyquidity, recommending that it be taken on an empty stomach 30-60 minutes prior to breakfast and that patients continue to follow all other label instructions,” Dr. Washington said during a press briefing at ENDO 2022.
When asked whether the new data would be submitted to the FDA for a possible amendment to this message, she replied: “We’re still discussing that. We’re exploring all options. ... This is fairly new data. ... It makes sense and certainly solves a lot of the challenges for people who can’t swallow or don’t choose to swallow, or the challenges of splitting or crushing with tablets.”
Asked to comment, Benjamin J. Gigliotti, MD, a clinical thyroidologist at the University of Rochester, New York, told this news organization: “Liquid levothyroxine has the potential to be a clinically useful formulation,” noting that these recent data corroborate prior findings from Europe and elsewhere that liquid levothyroxine is absorbed more rapidly and thus may be less impacted by food or beverages.
However, Dr. Gigliotti also pointed out, “I don’t think malabsorption is a major contributor to suboptimal treatment because if [patients] malabsorb the hormone, we typically just increase their dose a little bit or ask them to take it separately, and that works just fine for most people.”
And the higher cost of the liquid products is a major issue, he noted.
A quick search on GoodRx shows that the lowest price of Tirosint-SOL is $115.52 for a 1 month supply and Thyquidity is $181.04/month. “In the few patients where I tried to obtain Tirosint-SOL, it was not covered by insurance, even with a prior authorization,” Dr. Gigliotti commented.
In contrast, generic levothyroxine tablets are about $4/month, while a common brand name of levothyroxine tablets are $47.81/month.
“Until these liquid formulations are more widely covered by insurance for a reasonable copay, or come down in price compared to generic levothyroxine tablets, most of my patients have voiced that they’d rather deal with the inconveniences of a tablet compared to higher medication cost, especially with rising economic insecurity imposed by the COVID-19 pandemic and recent world events,” Dr. Gigliotti said.
Bioequivalence with shorter versus longer waits before coffee/breakfast
The Thyquidity coffee study was a single-center open-label, randomized, crossover study of 40 healthy adults randomized after a 10-hour overnight fast to 600 µg Thyquidity with water under fasting conditions or to the same dose given 5 minutes prior to drinking an 8-ounce cup of American coffee without milk or sweeteners. After a 40-day washout period, the same participants received the other treatment.
Mean serum thyroxine (T4) concentrations over 48 hours were nearly identical, demonstrating comparable bioavailability. Pharmacokinetics parameters, including area under the curve (AUC) and Cmax, were also comparable for both groups. The geometric least square mean ratios for baseline-adjusted LT4 were 96.0% for Cmax and 94% for AUC. And the corresponding 90% confidence intervals fell within the 80%-125% FDA acceptance range for absence of a food effect on bioavailability, said Dr. Washington when presenting the findings.
There was one adverse event, a decrease in blood glucose level, which was deemed to be mild and unrelated to study treatment. No deaths, serious adverse events, or discontinuations due to adverse events were reported. There were no significant changes in vital signs or on ECG.
In the second Thyquidity study of 38 healthy adults, after a 10-hour fast, the same doses were given 10 or 30 minutes prior to the consumption of a 950-calorie standardized high-fat breakfast.
Again, over 48 hours, mean serum T4 levels were comparable between the two groups. The geometric least squares mean ratios for both AUC and Cmax for baseline-adjusted LT4 were 88.7% and 85.1%, respectively. Again, the corresponding 90% confidence intervals fell within the FDA’s noninterference definition, again demonstrating lack of a food effect on bioavailability, Dr. Washington noted.
Four adverse events were reported in three participants, with three deemed to be possibly related to the medication. All were isolated lab abnormalities without clinical symptoms and deemed to be mild. Three were normal on repeat testing.
There were no deaths or serious adverse events or study discontinuations for adverse events and no significant findings for vital signs or on ECG.
Similar findings for Tirosint-SOL but longer-term studies needed
The recently published Tirosint-SOL study included 36 healthy volunteers randomized to single 600-µg doses of the LT4 oral solution after a 10-hour fast, either 15 or 30 minutes before eating a standardized high-fat, high-calorie meal. Mean serum total thyroxine concentration profiles were similar for both the 15- and 30-minute waits, with similar AUCs.
Geometric mean ratios for AUCs at 48 and 72 hours were 90% and 92%, respectively, and the 90% confidence intervals fell within the 80%-125% FDA boundaries, suggesting similar exposures whether taken 15 or 30 minutes before a meal.
Senior author Francesco S. Celi, MD, chair of the division of endocrinology, diabetes, and metabolism at Virginia Commonwealth University, Richmond, told this news organization: “There is an interest in providing more opportunities for patients and improving adherence to the medication. ... Whatever makes life a bit easier for patients and results in a more predictable response to treatment means down the road there will be fewer visits to the doctor to make adjustments.”
However, he said that in addition to the cost and reimbursement issue, all of these studies have been short term and not conducted in real-life settings.
“Another question is: What happens if the patient goes on low-dose LT4? The studies were conducted on much higher pharmacologic doses. But at least from a safety standpoint, there’s no specific concern.”
Dr. Washington is an employee of Vertice Pharma. Dr. Celi has received unrestricted research grants and worked as a consultant for IBSA. Dr. Gigliotti has reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ENDO 2022
New National Lipid Association statement on statin intolerance
The U.S. National Lipid Association has issued a new scientific statement on the management of patients with statin intolerance, which recommends different strategies to help patients stay on statin medications, and also suggests alternatives that can be used in patients who really cannot tolerate statin drugs.
The statement was published online in the Journal of Clinical Lipidology.
It notes that, although statins are generally well tolerated, statin intolerance is reported in 5%-30% of patients and contributes to reduced statin adherence and persistence, as well as higher risk for adverse cardiovascular outcomes.
The statement acknowledges the importance of identifying modifiable risk factors for statin intolerance and recognizes the possibility of a “nocebo” effect, basically the patient expectation of harm resulting in perceived side effects.
To identify a tolerable statin regimen, it recommends that clinicians consider using several different strategies (different statin, dose, and/or dosing frequency), and to classify a patient as having statin intolerance, a minimum of two statins should have been attempted, including at least one at the lowest-approved daily dosage.
The statement says that nonstatin therapy may be required for patients who cannot reach therapeutic objectives with lifestyle and maximal tolerated statin therapy, and in these cases, therapies with outcomes data from randomized trials showing reduced cardiovascular events are favored.
In high and very high-risk patients who are statin intolerant, clinicians should consider initiating nonstatin therapy while additional attempts are made to identify a tolerable statin in order to limit the time of exposure to elevated levels of atherogenic lipoproteins, it suggests.
“There is strong evidence that statins reduce risk of cardiovascular events particularly in patients with atherosclerotic cardiovascular disease, but recent research shows that only about half of patients with ASCVD are on a statin,” Kevin C. Maki, PhD, coauthor of the statement and current president of the National Lipid Association, said in an interview.
“There is an urgent problem with underutilization of statins and undertreatment of ASCVD. And we know that perceived side effects associated with statins are a common reason for discontinuation of these drugs and the consequent failure to manage ASCVD adequately,” he said.
Dr. Maki noted that the NLA’s first message is that, when experiencing symptoms taking statins, a large majority of patients can still tolerate a statin. “They can try a different agent or a different dose. But for those who still can’t tolerate a statin, we then recommend nonstatin therapies and we favor those therapies with evidence from randomized trials.”
He pointed out that many patients who believe they are experiencing side effects from taking statins still experience the same effects on a placebo, a condition known as the nocebo effect.
“Several studies have shown that the nocebo effect is very common and accounts for more than half of perceived statin side effects. It is therefore estimated that many of the complaints of statin intolerance are probably not directly related to the pharmacodynamic actions of the drugs,” Dr. Maki said.
One recent study on the nocebo effect, the SAMSON study, suggested that 90% of symptoms attributed to statins were elicited by placebo tablets too.
But Dr. Maki added that it can be a losing battle for the clinician if patients think their symptoms are related to taking a statin.
“We suggest that clinicians inform patients that most people can tolerate a statin – maybe with a different agent or an alternative dose – and it is really important to lower LDL cholesterol as that will lower the risk of MI and stroke, so we need to find a regimen that works for each individual,” he said. “Most people can find a regimen that works. If this means taking a lower dose of a statin, they can take some additional therapy as well. This is a better situation than stopping taking statins altogether and allowing ASCVD to progress.”
Dr. Maki stressed that statins should still be the first choice as they are effective, taken orally, and inexpensive.
“Other medications do not have all these advantages. For example, PCSK9 inhibitors are very effective but they are expensive and injectable,” he noted. “And while ezetimibe [Zetia] is now generic so inexpensive, it has a more modest effect on LDL-lowering compared to statins, so by itself it is not normally enough for most patients to get to their target LDL, but it is an option for use in combination with a statin.”
He added that the NLA message is to do everything possible to keep patients on a statin, especially patients with preexisting ASCVD.
“We would like these patients to be on high-intensity statins. If they really can’t tolerate this, then they could be on a low-intensity statin plus an additional agent.”
Commenting on the NLA statement, SAMSON study coauthor James Howard, MB BChir, PhD, Imperial College London, said he had reservations about some of the recommendations.
“Whilst I think it is great news that the existence and importance of the nocebo effect is increasingly recognized in international guidelines and statements, I think we need to be very careful about recommending reduced doses and frequencies of statins,” Dr. Howard said.
“Studies such as SAMSON and StatinWISE indicate the vast majority of side effects reported by patients taking statins are not caused by the statin molecule, but instead are caused by either the nocebo effect, or ever-present background symptoms that are wrongly attributed to the statins,” he commented. “Therefore, to recommend that the correct approach in a patient with a history of MI suffering symptoms on 80 mg of atorvastatin is to reduce the dose or try alternate daily dosing. This reinforces the view that these drugs are side-effect prone and need to be carefully titrated.”
Dr. Howard suggested that patients should be educated on the possibility of the nocebo effect or background symptoms and encouraged to retrial statins at the same dose. “If that doesn’t work, then formal recording with a symptom diary might help patients recognize background symptoms,” he added.
Dr. Howard noted that, if symptoms still persist, an “n-of-1” trial could be conducted, in which the patient rotates between multiple periods of taking a statin and a placebo, but he acknowledged that this is expensive and time consuming.
Also commenting, Steve Nissen, MD, Cleveland Clinic, said he thought the NLA statement was “reasonable and thoughtful.”
“Regardless of whether the symptoms are due to the nocebo effect or not, some patients will just not take a statin no matter how hard you try to convince them to persevere, so we do need alternatives,” Dr. Nissen said.
He noted that current alternatives would include the PCSK9 inhibitors and ezetimibe, but a future candidate could be the oral bempedoic acid (Nexletol), which is currently being evaluated in a large outcomes trial (CLEAR Outcomes).
A version of this article first appeared on Medscape.com.
The U.S. National Lipid Association has issued a new scientific statement on the management of patients with statin intolerance, which recommends different strategies to help patients stay on statin medications, and also suggests alternatives that can be used in patients who really cannot tolerate statin drugs.
The statement was published online in the Journal of Clinical Lipidology.
It notes that, although statins are generally well tolerated, statin intolerance is reported in 5%-30% of patients and contributes to reduced statin adherence and persistence, as well as higher risk for adverse cardiovascular outcomes.
The statement acknowledges the importance of identifying modifiable risk factors for statin intolerance and recognizes the possibility of a “nocebo” effect, basically the patient expectation of harm resulting in perceived side effects.
To identify a tolerable statin regimen, it recommends that clinicians consider using several different strategies (different statin, dose, and/or dosing frequency), and to classify a patient as having statin intolerance, a minimum of two statins should have been attempted, including at least one at the lowest-approved daily dosage.
The statement says that nonstatin therapy may be required for patients who cannot reach therapeutic objectives with lifestyle and maximal tolerated statin therapy, and in these cases, therapies with outcomes data from randomized trials showing reduced cardiovascular events are favored.
In high and very high-risk patients who are statin intolerant, clinicians should consider initiating nonstatin therapy while additional attempts are made to identify a tolerable statin in order to limit the time of exposure to elevated levels of atherogenic lipoproteins, it suggests.
“There is strong evidence that statins reduce risk of cardiovascular events particularly in patients with atherosclerotic cardiovascular disease, but recent research shows that only about half of patients with ASCVD are on a statin,” Kevin C. Maki, PhD, coauthor of the statement and current president of the National Lipid Association, said in an interview.
“There is an urgent problem with underutilization of statins and undertreatment of ASCVD. And we know that perceived side effects associated with statins are a common reason for discontinuation of these drugs and the consequent failure to manage ASCVD adequately,” he said.
Dr. Maki noted that the NLA’s first message is that, when experiencing symptoms taking statins, a large majority of patients can still tolerate a statin. “They can try a different agent or a different dose. But for those who still can’t tolerate a statin, we then recommend nonstatin therapies and we favor those therapies with evidence from randomized trials.”
He pointed out that many patients who believe they are experiencing side effects from taking statins still experience the same effects on a placebo, a condition known as the nocebo effect.
“Several studies have shown that the nocebo effect is very common and accounts for more than half of perceived statin side effects. It is therefore estimated that many of the complaints of statin intolerance are probably not directly related to the pharmacodynamic actions of the drugs,” Dr. Maki said.
One recent study on the nocebo effect, the SAMSON study, suggested that 90% of symptoms attributed to statins were elicited by placebo tablets too.
But Dr. Maki added that it can be a losing battle for the clinician if patients think their symptoms are related to taking a statin.
“We suggest that clinicians inform patients that most people can tolerate a statin – maybe with a different agent or an alternative dose – and it is really important to lower LDL cholesterol as that will lower the risk of MI and stroke, so we need to find a regimen that works for each individual,” he said. “Most people can find a regimen that works. If this means taking a lower dose of a statin, they can take some additional therapy as well. This is a better situation than stopping taking statins altogether and allowing ASCVD to progress.”
Dr. Maki stressed that statins should still be the first choice as they are effective, taken orally, and inexpensive.
“Other medications do not have all these advantages. For example, PCSK9 inhibitors are very effective but they are expensive and injectable,” he noted. “And while ezetimibe [Zetia] is now generic so inexpensive, it has a more modest effect on LDL-lowering compared to statins, so by itself it is not normally enough for most patients to get to their target LDL, but it is an option for use in combination with a statin.”
He added that the NLA message is to do everything possible to keep patients on a statin, especially patients with preexisting ASCVD.
“We would like these patients to be on high-intensity statins. If they really can’t tolerate this, then they could be on a low-intensity statin plus an additional agent.”
Commenting on the NLA statement, SAMSON study coauthor James Howard, MB BChir, PhD, Imperial College London, said he had reservations about some of the recommendations.
“Whilst I think it is great news that the existence and importance of the nocebo effect is increasingly recognized in international guidelines and statements, I think we need to be very careful about recommending reduced doses and frequencies of statins,” Dr. Howard said.
“Studies such as SAMSON and StatinWISE indicate the vast majority of side effects reported by patients taking statins are not caused by the statin molecule, but instead are caused by either the nocebo effect, or ever-present background symptoms that are wrongly attributed to the statins,” he commented. “Therefore, to recommend that the correct approach in a patient with a history of MI suffering symptoms on 80 mg of atorvastatin is to reduce the dose or try alternate daily dosing. This reinforces the view that these drugs are side-effect prone and need to be carefully titrated.”
Dr. Howard suggested that patients should be educated on the possibility of the nocebo effect or background symptoms and encouraged to retrial statins at the same dose. “If that doesn’t work, then formal recording with a symptom diary might help patients recognize background symptoms,” he added.
Dr. Howard noted that, if symptoms still persist, an “n-of-1” trial could be conducted, in which the patient rotates between multiple periods of taking a statin and a placebo, but he acknowledged that this is expensive and time consuming.
Also commenting, Steve Nissen, MD, Cleveland Clinic, said he thought the NLA statement was “reasonable and thoughtful.”
“Regardless of whether the symptoms are due to the nocebo effect or not, some patients will just not take a statin no matter how hard you try to convince them to persevere, so we do need alternatives,” Dr. Nissen said.
He noted that current alternatives would include the PCSK9 inhibitors and ezetimibe, but a future candidate could be the oral bempedoic acid (Nexletol), which is currently being evaluated in a large outcomes trial (CLEAR Outcomes).
A version of this article first appeared on Medscape.com.
The U.S. National Lipid Association has issued a new scientific statement on the management of patients with statin intolerance, which recommends different strategies to help patients stay on statin medications, and also suggests alternatives that can be used in patients who really cannot tolerate statin drugs.
The statement was published online in the Journal of Clinical Lipidology.
It notes that, although statins are generally well tolerated, statin intolerance is reported in 5%-30% of patients and contributes to reduced statin adherence and persistence, as well as higher risk for adverse cardiovascular outcomes.
The statement acknowledges the importance of identifying modifiable risk factors for statin intolerance and recognizes the possibility of a “nocebo” effect, basically the patient expectation of harm resulting in perceived side effects.
To identify a tolerable statin regimen, it recommends that clinicians consider using several different strategies (different statin, dose, and/or dosing frequency), and to classify a patient as having statin intolerance, a minimum of two statins should have been attempted, including at least one at the lowest-approved daily dosage.
The statement says that nonstatin therapy may be required for patients who cannot reach therapeutic objectives with lifestyle and maximal tolerated statin therapy, and in these cases, therapies with outcomes data from randomized trials showing reduced cardiovascular events are favored.
In high and very high-risk patients who are statin intolerant, clinicians should consider initiating nonstatin therapy while additional attempts are made to identify a tolerable statin in order to limit the time of exposure to elevated levels of atherogenic lipoproteins, it suggests.
“There is strong evidence that statins reduce risk of cardiovascular events particularly in patients with atherosclerotic cardiovascular disease, but recent research shows that only about half of patients with ASCVD are on a statin,” Kevin C. Maki, PhD, coauthor of the statement and current president of the National Lipid Association, said in an interview.
“There is an urgent problem with underutilization of statins and undertreatment of ASCVD. And we know that perceived side effects associated with statins are a common reason for discontinuation of these drugs and the consequent failure to manage ASCVD adequately,” he said.
Dr. Maki noted that the NLA’s first message is that, when experiencing symptoms taking statins, a large majority of patients can still tolerate a statin. “They can try a different agent or a different dose. But for those who still can’t tolerate a statin, we then recommend nonstatin therapies and we favor those therapies with evidence from randomized trials.”
He pointed out that many patients who believe they are experiencing side effects from taking statins still experience the same effects on a placebo, a condition known as the nocebo effect.
“Several studies have shown that the nocebo effect is very common and accounts for more than half of perceived statin side effects. It is therefore estimated that many of the complaints of statin intolerance are probably not directly related to the pharmacodynamic actions of the drugs,” Dr. Maki said.
One recent study on the nocebo effect, the SAMSON study, suggested that 90% of symptoms attributed to statins were elicited by placebo tablets too.
But Dr. Maki added that it can be a losing battle for the clinician if patients think their symptoms are related to taking a statin.
“We suggest that clinicians inform patients that most people can tolerate a statin – maybe with a different agent or an alternative dose – and it is really important to lower LDL cholesterol as that will lower the risk of MI and stroke, so we need to find a regimen that works for each individual,” he said. “Most people can find a regimen that works. If this means taking a lower dose of a statin, they can take some additional therapy as well. This is a better situation than stopping taking statins altogether and allowing ASCVD to progress.”
Dr. Maki stressed that statins should still be the first choice as they are effective, taken orally, and inexpensive.
“Other medications do not have all these advantages. For example, PCSK9 inhibitors are very effective but they are expensive and injectable,” he noted. “And while ezetimibe [Zetia] is now generic so inexpensive, it has a more modest effect on LDL-lowering compared to statins, so by itself it is not normally enough for most patients to get to their target LDL, but it is an option for use in combination with a statin.”
He added that the NLA message is to do everything possible to keep patients on a statin, especially patients with preexisting ASCVD.
“We would like these patients to be on high-intensity statins. If they really can’t tolerate this, then they could be on a low-intensity statin plus an additional agent.”
Commenting on the NLA statement, SAMSON study coauthor James Howard, MB BChir, PhD, Imperial College London, said he had reservations about some of the recommendations.
“Whilst I think it is great news that the existence and importance of the nocebo effect is increasingly recognized in international guidelines and statements, I think we need to be very careful about recommending reduced doses and frequencies of statins,” Dr. Howard said.
“Studies such as SAMSON and StatinWISE indicate the vast majority of side effects reported by patients taking statins are not caused by the statin molecule, but instead are caused by either the nocebo effect, or ever-present background symptoms that are wrongly attributed to the statins,” he commented. “Therefore, to recommend that the correct approach in a patient with a history of MI suffering symptoms on 80 mg of atorvastatin is to reduce the dose or try alternate daily dosing. This reinforces the view that these drugs are side-effect prone and need to be carefully titrated.”
Dr. Howard suggested that patients should be educated on the possibility of the nocebo effect or background symptoms and encouraged to retrial statins at the same dose. “If that doesn’t work, then formal recording with a symptom diary might help patients recognize background symptoms,” he added.
Dr. Howard noted that, if symptoms still persist, an “n-of-1” trial could be conducted, in which the patient rotates between multiple periods of taking a statin and a placebo, but he acknowledged that this is expensive and time consuming.
Also commenting, Steve Nissen, MD, Cleveland Clinic, said he thought the NLA statement was “reasonable and thoughtful.”
“Regardless of whether the symptoms are due to the nocebo effect or not, some patients will just not take a statin no matter how hard you try to convince them to persevere, so we do need alternatives,” Dr. Nissen said.
He noted that current alternatives would include the PCSK9 inhibitors and ezetimibe, but a future candidate could be the oral bempedoic acid (Nexletol), which is currently being evaluated in a large outcomes trial (CLEAR Outcomes).
A version of this article first appeared on Medscape.com.
FROM THE JOURNAL OF CLINICAL LIPIDOLOGY
New studies show growing number of trans, nonbinary youth in U.S.
Two new studies point to an ever-increasing number of young people in the United States who identify as transgender and nonbinary, with the figures doubling among 18- to 24-year-olds in one institute’s research – from 0.66% of the population in 2016 to 1.3% (398,900) in 2022.
In addition, 1.4% (300,100) of 13- to 17-year-olds identify as trans or nonbinary, according to the report from that group, the Williams Institute at the University of California, Los Angeles, School of Law.
Williams, which conducts independent research on sexual orientation and gender identity law and public policy, did not contain data on 13- to 17-year-olds in its 2016 study, so the growth in that group over the past 5+ years is not as well documented.
Overall, some 1.6 million Americans older than age 13 now identify as transgender, reported the Williams researchers.
And in a new Pew Research Center survey, 2% of adults aged 18-29 identify as transgender and 3% identify as nonbinary, a far greater number than in other age cohorts.
These reports are likely underestimates. The Human Rights Campaign estimates that some 2 million Americans of all ages identify as transgender.
The Pew survey is weighted to be representative but still has limitations, said the organization. The Williams analysis, based on responses to two CDC surveys – the Behavioral Risk Factor Surveillance System (BRFSS) and Youth Risk Behavior Survey (YRBS) – is incomplete, say researchers, because not every state collects data on gender identity.
Transgender identities more predominant among youth
The Williams researchers report that 18.3% of those who identified as trans were 13- to 17-year-olds; that age group makes up 7.6% of the United States population 13 and older.
And despite not having firm figures from earlier reports, they comment: “Youth ages 13-17 comprise a larger share of the transgender-identified population than we previously estimated, currently comprising about 18% of the transgender-identified population in the United State, up from 10% previously.”
About one-quarter of those who identified as trans in the new 2022 report were aged 18-24; that age cohort accounts for 11% of Americans.
The number of older Americans who identify as trans are more proportionate to their representation in the population, according to Williams. Overall, about half of those who said they were trans were aged 25-64; that group accounts for 62% of the overall American population. Some 10% of trans-identified individuals were over age 65. About 20% of Americans are 65 or older, said the researchers.
The Pew research – based on the responses of 10,188 individuals surveyed in May – also found growing numbers of young people who identify as trans. “The share of U.S. adults who are transgender is particularly high among adults younger than 25,” reported Pew in a blog post.
In the 18- to 25-year-old group, 3.1% identified as a trans man or a trans woman, compared with just 0.5% of those ages 25-29.
That compares to 0.3% of those aged 30-49 and 0.2% of those older than 50.
Racial and state-by-state variation
Similar percentages of youth aged 13-17 of all races and ethnicities in the Williams study report they are transgender, ranging from 1% of those who are Asian, to 1.3% of White youth, 1.4% of Black youth, 1.8% of American Indian or Alaska Native, and 1.8% of Latinx youth. The institute reported that 1.5% of biracial and multiracial youth identified as transgender.
The researchers said, however, that “transgender-identified youth and adults appear more likely to report being Latinx and less likely to report being White, as compared to the United States population.”
Transgender individuals live in every state, with the greatest percentage of both youth and adults in the Northeast and West, and lesser percentages in the Midwest and South, reported the Williams Institute.
Williams estimates as many as 3% of 13- to 17-year-olds in New York identify as trans, while just 0.6% of that age group in Wyoming is transgender. A total of 2%-2.5% of those aged 13-17 are transgender in Hawaii, New Mexico, Maryland, and Washington, D.C.
Among the states with higher percentages of trans-identifying 18- to 24-year-olds: Arizona (1.9%), Arkansas (3.6%), Colorado (2%), Delaware (2.4%), Illinois (1.9%), Maryland (1.9%), North Carolina (2.5%), Oklahoma (2.5%), Massachusetts (2.3%), Rhode Island (2.1%), and Washington (2%).
A version of this article first appeared on Medscape.com.
Two new studies point to an ever-increasing number of young people in the United States who identify as transgender and nonbinary, with the figures doubling among 18- to 24-year-olds in one institute’s research – from 0.66% of the population in 2016 to 1.3% (398,900) in 2022.
In addition, 1.4% (300,100) of 13- to 17-year-olds identify as trans or nonbinary, according to the report from that group, the Williams Institute at the University of California, Los Angeles, School of Law.
Williams, which conducts independent research on sexual orientation and gender identity law and public policy, did not contain data on 13- to 17-year-olds in its 2016 study, so the growth in that group over the past 5+ years is not as well documented.
Overall, some 1.6 million Americans older than age 13 now identify as transgender, reported the Williams researchers.
And in a new Pew Research Center survey, 2% of adults aged 18-29 identify as transgender and 3% identify as nonbinary, a far greater number than in other age cohorts.
These reports are likely underestimates. The Human Rights Campaign estimates that some 2 million Americans of all ages identify as transgender.
The Pew survey is weighted to be representative but still has limitations, said the organization. The Williams analysis, based on responses to two CDC surveys – the Behavioral Risk Factor Surveillance System (BRFSS) and Youth Risk Behavior Survey (YRBS) – is incomplete, say researchers, because not every state collects data on gender identity.
Transgender identities more predominant among youth
The Williams researchers report that 18.3% of those who identified as trans were 13- to 17-year-olds; that age group makes up 7.6% of the United States population 13 and older.
And despite not having firm figures from earlier reports, they comment: “Youth ages 13-17 comprise a larger share of the transgender-identified population than we previously estimated, currently comprising about 18% of the transgender-identified population in the United State, up from 10% previously.”
About one-quarter of those who identified as trans in the new 2022 report were aged 18-24; that age cohort accounts for 11% of Americans.
The number of older Americans who identify as trans are more proportionate to their representation in the population, according to Williams. Overall, about half of those who said they were trans were aged 25-64; that group accounts for 62% of the overall American population. Some 10% of trans-identified individuals were over age 65. About 20% of Americans are 65 or older, said the researchers.
The Pew research – based on the responses of 10,188 individuals surveyed in May – also found growing numbers of young people who identify as trans. “The share of U.S. adults who are transgender is particularly high among adults younger than 25,” reported Pew in a blog post.
In the 18- to 25-year-old group, 3.1% identified as a trans man or a trans woman, compared with just 0.5% of those ages 25-29.
That compares to 0.3% of those aged 30-49 and 0.2% of those older than 50.
Racial and state-by-state variation
Similar percentages of youth aged 13-17 of all races and ethnicities in the Williams study report they are transgender, ranging from 1% of those who are Asian, to 1.3% of White youth, 1.4% of Black youth, 1.8% of American Indian or Alaska Native, and 1.8% of Latinx youth. The institute reported that 1.5% of biracial and multiracial youth identified as transgender.
The researchers said, however, that “transgender-identified youth and adults appear more likely to report being Latinx and less likely to report being White, as compared to the United States population.”
Transgender individuals live in every state, with the greatest percentage of both youth and adults in the Northeast and West, and lesser percentages in the Midwest and South, reported the Williams Institute.
Williams estimates as many as 3% of 13- to 17-year-olds in New York identify as trans, while just 0.6% of that age group in Wyoming is transgender. A total of 2%-2.5% of those aged 13-17 are transgender in Hawaii, New Mexico, Maryland, and Washington, D.C.
Among the states with higher percentages of trans-identifying 18- to 24-year-olds: Arizona (1.9%), Arkansas (3.6%), Colorado (2%), Delaware (2.4%), Illinois (1.9%), Maryland (1.9%), North Carolina (2.5%), Oklahoma (2.5%), Massachusetts (2.3%), Rhode Island (2.1%), and Washington (2%).
A version of this article first appeared on Medscape.com.
Two new studies point to an ever-increasing number of young people in the United States who identify as transgender and nonbinary, with the figures doubling among 18- to 24-year-olds in one institute’s research – from 0.66% of the population in 2016 to 1.3% (398,900) in 2022.
In addition, 1.4% (300,100) of 13- to 17-year-olds identify as trans or nonbinary, according to the report from that group, the Williams Institute at the University of California, Los Angeles, School of Law.
Williams, which conducts independent research on sexual orientation and gender identity law and public policy, did not contain data on 13- to 17-year-olds in its 2016 study, so the growth in that group over the past 5+ years is not as well documented.
Overall, some 1.6 million Americans older than age 13 now identify as transgender, reported the Williams researchers.
And in a new Pew Research Center survey, 2% of adults aged 18-29 identify as transgender and 3% identify as nonbinary, a far greater number than in other age cohorts.
These reports are likely underestimates. The Human Rights Campaign estimates that some 2 million Americans of all ages identify as transgender.
The Pew survey is weighted to be representative but still has limitations, said the organization. The Williams analysis, based on responses to two CDC surveys – the Behavioral Risk Factor Surveillance System (BRFSS) and Youth Risk Behavior Survey (YRBS) – is incomplete, say researchers, because not every state collects data on gender identity.
Transgender identities more predominant among youth
The Williams researchers report that 18.3% of those who identified as trans were 13- to 17-year-olds; that age group makes up 7.6% of the United States population 13 and older.
And despite not having firm figures from earlier reports, they comment: “Youth ages 13-17 comprise a larger share of the transgender-identified population than we previously estimated, currently comprising about 18% of the transgender-identified population in the United State, up from 10% previously.”
About one-quarter of those who identified as trans in the new 2022 report were aged 18-24; that age cohort accounts for 11% of Americans.
The number of older Americans who identify as trans are more proportionate to their representation in the population, according to Williams. Overall, about half of those who said they were trans were aged 25-64; that group accounts for 62% of the overall American population. Some 10% of trans-identified individuals were over age 65. About 20% of Americans are 65 or older, said the researchers.
The Pew research – based on the responses of 10,188 individuals surveyed in May – also found growing numbers of young people who identify as trans. “The share of U.S. adults who are transgender is particularly high among adults younger than 25,” reported Pew in a blog post.
In the 18- to 25-year-old group, 3.1% identified as a trans man or a trans woman, compared with just 0.5% of those ages 25-29.
That compares to 0.3% of those aged 30-49 and 0.2% of those older than 50.
Racial and state-by-state variation
Similar percentages of youth aged 13-17 of all races and ethnicities in the Williams study report they are transgender, ranging from 1% of those who are Asian, to 1.3% of White youth, 1.4% of Black youth, 1.8% of American Indian or Alaska Native, and 1.8% of Latinx youth. The institute reported that 1.5% of biracial and multiracial youth identified as transgender.
The researchers said, however, that “transgender-identified youth and adults appear more likely to report being Latinx and less likely to report being White, as compared to the United States population.”
Transgender individuals live in every state, with the greatest percentage of both youth and adults in the Northeast and West, and lesser percentages in the Midwest and South, reported the Williams Institute.
Williams estimates as many as 3% of 13- to 17-year-olds in New York identify as trans, while just 0.6% of that age group in Wyoming is transgender. A total of 2%-2.5% of those aged 13-17 are transgender in Hawaii, New Mexico, Maryland, and Washington, D.C.
Among the states with higher percentages of trans-identifying 18- to 24-year-olds: Arizona (1.9%), Arkansas (3.6%), Colorado (2%), Delaware (2.4%), Illinois (1.9%), Maryland (1.9%), North Carolina (2.5%), Oklahoma (2.5%), Massachusetts (2.3%), Rhode Island (2.1%), and Washington (2%).
A version of this article first appeared on Medscape.com.
Jury still out on cardiovascular safety of testosterone
Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.
A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.
The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.
In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.
To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.
They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.
During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.
This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.
However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”
Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”
‘Trial is not definitive’
Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.
Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.
While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.
“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.
Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.
“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.
On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”
“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
Earlier data inconclusive
Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.
Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.
But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.
Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.
A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
Meta-analysis results
Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.
The men were a mean age of 65, had a mean body mass index of 30 kg/m2, and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes.
Cardiovascular and cerebrovascular outcomes were not primary outcomes.
During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).
In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.
The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.
Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.
The only detected adverse effects were edema and a modest lowering of HDL cholesterol.
“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.
However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”
“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.
The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
A version of this article first appeared on Medscape.com.
Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.
A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.
The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.
In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.
To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.
They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.
During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.
This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.
However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”
Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”
‘Trial is not definitive’
Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.
Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.
While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.
“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.
Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.
“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.
On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”
“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
Earlier data inconclusive
Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.
Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.
But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.
Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.
A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
Meta-analysis results
Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.
The men were a mean age of 65, had a mean body mass index of 30 kg/m2, and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes.
Cardiovascular and cerebrovascular outcomes were not primary outcomes.
During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).
In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.
The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.
Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.
The only detected adverse effects were edema and a modest lowering of HDL cholesterol.
“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.
However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”
“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.
The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
A version of this article first appeared on Medscape.com.
Despite a new meta-analysis claiming to show that testosterone replacement therapy for men with hypogonadism does not increase the risk of cardiovascular outcomes such as myocardial infarction or stroke, experts say the jury is still out.
A more definitive answer for cardiovascular safety of testosterone therapy will come from the TRAVERSE dedicated cardiovascular outcome trial, sponsored by AbbVie, which will have up to 5 years of follow-up, with results expected later this year.
The current meta-analysis by Jemma Hudson of Aberdeen (Scotland) University and colleagues was published online in The Lancet Healthy Longevity. The work will also be presented June 13 at ENDO 2022, the Endocrine Society’s annual meeting in Atlanta, Georgia, by senior author Channa Y. Jayasena, MD, PhD.
In 2014, the U.S. Food and Drug Administration mandated a label on testosterone products warning of possible increased cardiovascular risks and to reserve the therapy for symptomatic hypogonadism only. In contrast, the European Medicines Agency concluded that when hypogonadism is properly diagnosed and managed, there is currently no clear, consistent evidence that testosterone therapy causes increased cardiovascular risk.
To address this uncertainty, Dr. Hudson and colleagues formed a global collaborative to obtain individual patient data on cardiovascular outcomes from randomized controlled trials of testosterone therapy for men with hypogonadism.
They pooled data from 35 trials published from 1992 to Aug. 27, 2018, including 17 trials (3,431 patients) for which the researchers obtained patient-level data. The individual trials were 3-12 months long, except for one 3-year trial.
During a mean follow-up of 9.5 months, there was no significant increase in cardiovascular outcomes in men randomized to testosterone therapy versus placebo (odds ratio, 1.07; P = .62), nor were there any significantly increased risks of death, stroke, or different types of cardiovascular outcome, although those numbers were small.
This is “the most comprehensive study to date investigating the safety of testosterone treatment of hypogonadism,” according to the researchers. “The current results provide some reassurance about the short-term to medium-term safety of testosterone to treat male hypogonadism,” they conclude.
However, they also acknowledge that “long-term data are needed to fully evaluate the safety of testosterone.”
Erin D. Michos, MD, coauthor of an accompanying editorial, told this news organization, “This study doesn’t say to me that low testosterone necessarily needs to be treated. It’s still not indicated in people just for a low number [for blood testosterone] with less-severe symptoms. It really comes down to each individual person, how symptomatic they are, and their cardiovascular risk.”
‘Trial is not definitive’
Dr. Michos is not the only person to be skeptical. Together with Steven Nissen, MD, an investigator for the TRAVERSE trial, she agrees that this new evidence is not yet decisive, largely because the individual trials in the meta-analysis were short and not designed as cardiovascular outcome trials.
Dr. Nissen, a cardiologist at Cleveland Clinic, added that the individual trials were heterogeneous, with “very few real cardiovascular events,” so the meta-analysis “is not definitive,” he said in an interview.
While this meta-analysis “that pooled together a lot of smaller studies is reassuring that there’s no signal of harm, it’s really inconclusive because the follow-up was really short – a mean of only 9.5 months – and you really need a larger study with longer follow up to be more conclusive,” Dr. Michos noted.
“We should have more data soon” from TRAVERSE, said Dr. Michos, from the division of cardiology, Johns Hopkins University, Baltimore, who is not involved with that study.
Meanwhile, “I don’t think [this analysis] changes the current recommendations,” she said.
“We should continue to use caution as indicated by the FDA label and only use testosterone therapy selectively in people who have true symptoms of hypogonadism,” and be cautious about using it particularly in men at higher cardiovascular risk because of family history or known personal heart disease.
On the other hand, the meta-analysis did not show harm, she noted, “so we don’t necessarily need to pull patients off therapy if they are already taking it. But I wouldn’t right now just start new patients on it unless they had a strong indication.”
“Certainly, great caution is advised regarding the use of testosterone replacement therapy in people with established atherosclerosis due to the findings of plaque progression in the testosterone trials and the excess cardiovascular events observed in the TOM trial, write Dr. Michos and fellow editorialist Matthew J. Budoff, MD, of University of California, Los Angeles, in their editorial.
Earlier data inconclusive
Testosterone concentrations progressively decline in men with advancing age, at about 2% per year, Dr. Michos and Dr. Budoff write. In addition, men with obesity or with diabetes have low levels of testosterone, Dr. Michos noted.
Low testosterone blood levels have been associated with insulin resistance, inflammation, dyslipidemia, and atherosclerosis. Testosterone replacement therapy has been used to increase libido, improve erectile dysfunction, and boost energy levels, mood, and muscle strength.
But it is well known that testosterone increases hematocrit, which has the potential to increase the risk of venous thromboembolism.
Two large observational studies have reported increased risks of myocardial infarction, stroke, and death in men taking testosterone, compared with nonusers, but the study designs have been widely criticized, Dr. Hudson and coauthors say in their article.
A placebo-controlled trial was stopped early by its data- and safety-monitoring board following increased cardiovascular events in men aged 65 and older who received 6 months of testosterone. Other controlled trials have not observed these effects, but none was sufficiently powered.
Meta-analysis results
Dr. Hudson and colleagues performed a meta-analysis of 35 trials in 5,601 men aged 18 years and older with low baseline testosterone (≤ 350 nmol/dL) who had been randomized to testosterone replacement therapy or placebo for at least 3 months, for which there were data on mortality, stroke, and cardiovascular outcomes.
The men were a mean age of 65, had a mean body mass index of 30 kg/m2, and most (88%) were White. A quarter had angina, 8% had a previous myocardial infarction, and 27% had diabetes.
Cardiovascular and cerebrovascular outcomes were not primary outcomes.
During a mean follow-up of 9.5 months, in the 13 trials that provided this information, the rate of cardiovascular events was similar in the men who received testosterone (120/1,601, 7.5%) compared with those who received placebo (110/1,519, 7.2%).
In the 14 trials that provided this information, fewer deaths were reported during testosterone treatment (6/1,621, 0.4%) than during placebo treatment (12/1,537, 0.8%), but these numbers were too small to establish whether testosterone reduced mortality risk.
The most common cardiovascular events were arrhythmia, followed by coronary heart disease, heart failure, and myocardial infarction.
Patient age, baseline testosterone, smoking status, or diabetes status were not associated with cardiovascular risk.
The only detected adverse effects were edema and a modest lowering of HDL cholesterol.
“Men who develop sexual dysfunction, unexplained anemia, or osteoporosis should be tested for low testosterone,” senior author of the meta-analysis Dr. Jayasena said in an email to this news organization.
However, Dr. Jayasena added, “Mass screening for testosterone has no benefit in asymptomatic men.”
“Older men may still benefit from testosterone, but only if they have the clinical features [of hypogonadism] and low testosterone levels,” he concluded.
The current study is supported by the Health Technology Assessment program of the National Institute for Health Research. The TRAVERSE trial is sponsored by AbbVie. Dr. Jayasena has reported receiving research grants from LogixX Pharma. Dr. Hudson has reported no relevant financial relationships. Disclosures for the other authors are listed in the article. Dr. Michos has reported receiving support from the Amato Fund in Women’s Cardiovascular Health at Johns Hopkins School of Medicine and serving on medical advisory boards for Novartis, Esperion, Amarin, and AstraZeneca outside the submitted work. Dr. Budoff has reported receiving grant support from General Electric.
A version of this article first appeared on Medscape.com.
FROM THE LANCET HEALTHY LONGEVITY