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The Cause of All That Stress: Tonsillectomy?
This transcript has been edited for clarity.
You know those times in your life when you’re just feeling ... stressed? You’re on the edge; you have no chill; everything just sort of gets to you. If you can step away from the anxiety for a moment, you might ask yourself where it’s all coming from. Is it really the stuff in your inbox at work or is it money issues at home? Is it something with your relationship, or maybe it’s your sleep quality or your diet? One thing you probably won’t blame for those acute stress reactions is the tonsillectomy you had as a kid. But according to new research, maybe you should.
Tonsillectomy and adenoidectomy are among the most common surgical procedures young people in the United States undergo, with about 300,000 cases a year, according to recent numbers. That’s down a bit from numbers a decade or so ago, but suffice it to say, a good chunk of the population is walking around right now without their tonsils.
The data supporting tonsillectomy have never been great. The two big indications for the surgery are recurrent sore throat — data show that tonsillectomy reduces this by about 0.7 sore throats per year— and obstructive sleep apnea (OSA). The data for improvement of OSA are a bit better than the data for sore throats.
Also, tonsillectomy is a relatively quick, relatively well-reimbursed surgery with indications that are — let’s be honest — somewhat subjective, and so variation is high. One study found that in a single Vermont town, nearly 60% of the population had had their tonsils removed by the time they turned 18. A few towns over, the rate was 20%.
A few factors have led to the decline of tonsillectomy in recent years. Reimbursement rates have gone down a bit. Additionally, better data collection and statistical analysis have shown that the benefits of the procedure are relatively modest.
And then there is a body of medical literature that at first struck me as surprising and almost bizarre: data linking tonsillectomy to subsequent physical and psychiatric disorders.
I teach a course on interpretation of the medical literature, and one of the first things I teach my students is to check their gut when they see the conclusion of a study.
Basically, even before you read the data, have a sense in your own mind if the hypothesis seems reasonable. If a paper is going to conclude that smoking leads to increased risk for bone cancer, I’d say that seems like a reasonable thing to study. If a paper purports to show a link between eating poultry and bone cancer, I’m going to be reading it with quite a bit more skepticism.
The technical term for that process is assessing “biologic plausibility.” If we’re talking tonsils, we have to ask ourselves: Is it plausible that removing someone’s tonsils when they are young should lead to major problems in the future?
At first blush, it didn’t seem very plausible to me.
But the truth is, there are quite a few studies out there demonstrating links like this: links between tonsillectomy and irritable bowel syndrome; links between tonsillectomy and cancer; links between tonsillectomy and depression.
And this week, appearing in JAMA Network Open, is a study linking tonsillectomy with stress disorders.
Researchers leveraged Sweden’s health database, which contains longitudinal data on basically every person who has lived in Sweden since 1981. This database let them know who had a tonsillectomy or adenoidectomy, and when, and what happened to them later in life.
I think the best way to present these data is to show you what they found, and then challenge that finding, and then show you what they did in anticipation of the challenges we would have to their findings. It’s a pretty thorough study.
So, topline results here. The researchers first identified 83,957 individuals who had their tonsils removed. They matched each of them with 10 controls who did not have their tonsils removed but were the same age and sex.
Over around 30 years of follow-up, those people who had their tonsils removed were 43% more likely to develop a stress-related disorder. Among the specific disorders, the risk for PTSD was substantially higher: 55% higher in the tonsillectomy group.
That’s pretty surprising, but I bet you already want to push back against this. Sure, the control group was the same age and sex, but other factors might be different between the two groups. You’d be right to think so. People who got their tonsils out were more likely to have parents with a history of stress-related disorders and who had lower educational attainment. But the primary results were adjusted for those factors.
There’s more to a family than parental educational attainment, of course. To account for household factors that might be harder to measure, the researchers created a second control group, this one comprising the siblings of people who had their tonsils removed but who hadn’t themselves had their tonsils removed.
The relationship between tonsillectomy and stress disorders in this population was not quite as robust but still present: a 34% increase in any stress disorder and a 41% increase in the risk for PTSD.
Maybe kids who get their tonsils out are just followed more closely thereafter, so doctors might notice a stress disorder and document it in the medical record; whereas with other kids it might go unnoticed. This is known as ascertainment bias. The researchers addressed this in a sensitivity analysis where they excluded new diagnoses of stress disorders that occurred in the first 3 years after tonsillectomy. The results were largely unchanged.
So how do we explain these data? We observe a correlation between tonsillectomy in youth and stress disorders in later life. But correlation is not causation. One possibility, perhaps even the most likely possibility, is that tonsillectomy is a marker of some other problem. Maybe these kids are more prone to infections and are therefore more likely to need their tonsils removed. Then, after a lifetime of more infections than average, their stress responses are higher. Or maybe kids with a higher BMI are more likely to have their tonsils removed due to sleep apnea concerns, and it’s that elevated BMI that leads to higher stress in later life.
Or maybe this is causal. Maybe there actually is biological plausibility here. The authors suggest that removal of tonsils might lead to broader changes in the immune system; after all, tonsillar tissue is on the front line of our defense against pathogens that might enter our bodies through our mouths or noses. Immunologic changes lead to greater inflammation over time, and there is decent evidence to link chronic inflammation to a variety of physical and psychological disorders.
In support of this, the authors show that the kids with tonsillectomy were more likely to be hospitalized for an infectious disease in the future as well, in magnitudes similar to the increased risk for stress. But they don’t actually show that the relationship between tonsillectomy and stress is mediated by that increased risk for infectious disease.
In the end, I find these data really intriguing. Before I dug into the literature, it seemed highly unlikely that removal of these small lumps of tissue would have much of an effect on anything. Now I’m not so sure. A few things can be removed from the human body without any consequences, but it can be hard to know exactly what those consequences are.
That said, given the rather marginal benefits of tonsillectomy and the growing number of studies expanding on the risks, I expect that we’ll see the rates of the surgery decline even further in the future.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
You know those times in your life when you’re just feeling ... stressed? You’re on the edge; you have no chill; everything just sort of gets to you. If you can step away from the anxiety for a moment, you might ask yourself where it’s all coming from. Is it really the stuff in your inbox at work or is it money issues at home? Is it something with your relationship, or maybe it’s your sleep quality or your diet? One thing you probably won’t blame for those acute stress reactions is the tonsillectomy you had as a kid. But according to new research, maybe you should.
Tonsillectomy and adenoidectomy are among the most common surgical procedures young people in the United States undergo, with about 300,000 cases a year, according to recent numbers. That’s down a bit from numbers a decade or so ago, but suffice it to say, a good chunk of the population is walking around right now without their tonsils.
The data supporting tonsillectomy have never been great. The two big indications for the surgery are recurrent sore throat — data show that tonsillectomy reduces this by about 0.7 sore throats per year— and obstructive sleep apnea (OSA). The data for improvement of OSA are a bit better than the data for sore throats.
Also, tonsillectomy is a relatively quick, relatively well-reimbursed surgery with indications that are — let’s be honest — somewhat subjective, and so variation is high. One study found that in a single Vermont town, nearly 60% of the population had had their tonsils removed by the time they turned 18. A few towns over, the rate was 20%.
A few factors have led to the decline of tonsillectomy in recent years. Reimbursement rates have gone down a bit. Additionally, better data collection and statistical analysis have shown that the benefits of the procedure are relatively modest.
And then there is a body of medical literature that at first struck me as surprising and almost bizarre: data linking tonsillectomy to subsequent physical and psychiatric disorders.
I teach a course on interpretation of the medical literature, and one of the first things I teach my students is to check their gut when they see the conclusion of a study.
Basically, even before you read the data, have a sense in your own mind if the hypothesis seems reasonable. If a paper is going to conclude that smoking leads to increased risk for bone cancer, I’d say that seems like a reasonable thing to study. If a paper purports to show a link between eating poultry and bone cancer, I’m going to be reading it with quite a bit more skepticism.
The technical term for that process is assessing “biologic plausibility.” If we’re talking tonsils, we have to ask ourselves: Is it plausible that removing someone’s tonsils when they are young should lead to major problems in the future?
At first blush, it didn’t seem very plausible to me.
But the truth is, there are quite a few studies out there demonstrating links like this: links between tonsillectomy and irritable bowel syndrome; links between tonsillectomy and cancer; links between tonsillectomy and depression.
And this week, appearing in JAMA Network Open, is a study linking tonsillectomy with stress disorders.
Researchers leveraged Sweden’s health database, which contains longitudinal data on basically every person who has lived in Sweden since 1981. This database let them know who had a tonsillectomy or adenoidectomy, and when, and what happened to them later in life.
I think the best way to present these data is to show you what they found, and then challenge that finding, and then show you what they did in anticipation of the challenges we would have to their findings. It’s a pretty thorough study.
So, topline results here. The researchers first identified 83,957 individuals who had their tonsils removed. They matched each of them with 10 controls who did not have their tonsils removed but were the same age and sex.
Over around 30 years of follow-up, those people who had their tonsils removed were 43% more likely to develop a stress-related disorder. Among the specific disorders, the risk for PTSD was substantially higher: 55% higher in the tonsillectomy group.
That’s pretty surprising, but I bet you already want to push back against this. Sure, the control group was the same age and sex, but other factors might be different between the two groups. You’d be right to think so. People who got their tonsils out were more likely to have parents with a history of stress-related disorders and who had lower educational attainment. But the primary results were adjusted for those factors.
There’s more to a family than parental educational attainment, of course. To account for household factors that might be harder to measure, the researchers created a second control group, this one comprising the siblings of people who had their tonsils removed but who hadn’t themselves had their tonsils removed.
The relationship between tonsillectomy and stress disorders in this population was not quite as robust but still present: a 34% increase in any stress disorder and a 41% increase in the risk for PTSD.
Maybe kids who get their tonsils out are just followed more closely thereafter, so doctors might notice a stress disorder and document it in the medical record; whereas with other kids it might go unnoticed. This is known as ascertainment bias. The researchers addressed this in a sensitivity analysis where they excluded new diagnoses of stress disorders that occurred in the first 3 years after tonsillectomy. The results were largely unchanged.
So how do we explain these data? We observe a correlation between tonsillectomy in youth and stress disorders in later life. But correlation is not causation. One possibility, perhaps even the most likely possibility, is that tonsillectomy is a marker of some other problem. Maybe these kids are more prone to infections and are therefore more likely to need their tonsils removed. Then, after a lifetime of more infections than average, their stress responses are higher. Or maybe kids with a higher BMI are more likely to have their tonsils removed due to sleep apnea concerns, and it’s that elevated BMI that leads to higher stress in later life.
Or maybe this is causal. Maybe there actually is biological plausibility here. The authors suggest that removal of tonsils might lead to broader changes in the immune system; after all, tonsillar tissue is on the front line of our defense against pathogens that might enter our bodies through our mouths or noses. Immunologic changes lead to greater inflammation over time, and there is decent evidence to link chronic inflammation to a variety of physical and psychological disorders.
In support of this, the authors show that the kids with tonsillectomy were more likely to be hospitalized for an infectious disease in the future as well, in magnitudes similar to the increased risk for stress. But they don’t actually show that the relationship between tonsillectomy and stress is mediated by that increased risk for infectious disease.
In the end, I find these data really intriguing. Before I dug into the literature, it seemed highly unlikely that removal of these small lumps of tissue would have much of an effect on anything. Now I’m not so sure. A few things can be removed from the human body without any consequences, but it can be hard to know exactly what those consequences are.
That said, given the rather marginal benefits of tonsillectomy and the growing number of studies expanding on the risks, I expect that we’ll see the rates of the surgery decline even further in the future.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
You know those times in your life when you’re just feeling ... stressed? You’re on the edge; you have no chill; everything just sort of gets to you. If you can step away from the anxiety for a moment, you might ask yourself where it’s all coming from. Is it really the stuff in your inbox at work or is it money issues at home? Is it something with your relationship, or maybe it’s your sleep quality or your diet? One thing you probably won’t blame for those acute stress reactions is the tonsillectomy you had as a kid. But according to new research, maybe you should.
Tonsillectomy and adenoidectomy are among the most common surgical procedures young people in the United States undergo, with about 300,000 cases a year, according to recent numbers. That’s down a bit from numbers a decade or so ago, but suffice it to say, a good chunk of the population is walking around right now without their tonsils.
The data supporting tonsillectomy have never been great. The two big indications for the surgery are recurrent sore throat — data show that tonsillectomy reduces this by about 0.7 sore throats per year— and obstructive sleep apnea (OSA). The data for improvement of OSA are a bit better than the data for sore throats.
Also, tonsillectomy is a relatively quick, relatively well-reimbursed surgery with indications that are — let’s be honest — somewhat subjective, and so variation is high. One study found that in a single Vermont town, nearly 60% of the population had had their tonsils removed by the time they turned 18. A few towns over, the rate was 20%.
A few factors have led to the decline of tonsillectomy in recent years. Reimbursement rates have gone down a bit. Additionally, better data collection and statistical analysis have shown that the benefits of the procedure are relatively modest.
And then there is a body of medical literature that at first struck me as surprising and almost bizarre: data linking tonsillectomy to subsequent physical and psychiatric disorders.
I teach a course on interpretation of the medical literature, and one of the first things I teach my students is to check their gut when they see the conclusion of a study.
Basically, even before you read the data, have a sense in your own mind if the hypothesis seems reasonable. If a paper is going to conclude that smoking leads to increased risk for bone cancer, I’d say that seems like a reasonable thing to study. If a paper purports to show a link between eating poultry and bone cancer, I’m going to be reading it with quite a bit more skepticism.
The technical term for that process is assessing “biologic plausibility.” If we’re talking tonsils, we have to ask ourselves: Is it plausible that removing someone’s tonsils when they are young should lead to major problems in the future?
At first blush, it didn’t seem very plausible to me.
But the truth is, there are quite a few studies out there demonstrating links like this: links between tonsillectomy and irritable bowel syndrome; links between tonsillectomy and cancer; links between tonsillectomy and depression.
And this week, appearing in JAMA Network Open, is a study linking tonsillectomy with stress disorders.
Researchers leveraged Sweden’s health database, which contains longitudinal data on basically every person who has lived in Sweden since 1981. This database let them know who had a tonsillectomy or adenoidectomy, and when, and what happened to them later in life.
I think the best way to present these data is to show you what they found, and then challenge that finding, and then show you what they did in anticipation of the challenges we would have to their findings. It’s a pretty thorough study.
So, topline results here. The researchers first identified 83,957 individuals who had their tonsils removed. They matched each of them with 10 controls who did not have their tonsils removed but were the same age and sex.
Over around 30 years of follow-up, those people who had their tonsils removed were 43% more likely to develop a stress-related disorder. Among the specific disorders, the risk for PTSD was substantially higher: 55% higher in the tonsillectomy group.
That’s pretty surprising, but I bet you already want to push back against this. Sure, the control group was the same age and sex, but other factors might be different between the two groups. You’d be right to think so. People who got their tonsils out were more likely to have parents with a history of stress-related disorders and who had lower educational attainment. But the primary results were adjusted for those factors.
There’s more to a family than parental educational attainment, of course. To account for household factors that might be harder to measure, the researchers created a second control group, this one comprising the siblings of people who had their tonsils removed but who hadn’t themselves had their tonsils removed.
The relationship between tonsillectomy and stress disorders in this population was not quite as robust but still present: a 34% increase in any stress disorder and a 41% increase in the risk for PTSD.
Maybe kids who get their tonsils out are just followed more closely thereafter, so doctors might notice a stress disorder and document it in the medical record; whereas with other kids it might go unnoticed. This is known as ascertainment bias. The researchers addressed this in a sensitivity analysis where they excluded new diagnoses of stress disorders that occurred in the first 3 years after tonsillectomy. The results were largely unchanged.
So how do we explain these data? We observe a correlation between tonsillectomy in youth and stress disorders in later life. But correlation is not causation. One possibility, perhaps even the most likely possibility, is that tonsillectomy is a marker of some other problem. Maybe these kids are more prone to infections and are therefore more likely to need their tonsils removed. Then, after a lifetime of more infections than average, their stress responses are higher. Or maybe kids with a higher BMI are more likely to have their tonsils removed due to sleep apnea concerns, and it’s that elevated BMI that leads to higher stress in later life.
Or maybe this is causal. Maybe there actually is biological plausibility here. The authors suggest that removal of tonsils might lead to broader changes in the immune system; after all, tonsillar tissue is on the front line of our defense against pathogens that might enter our bodies through our mouths or noses. Immunologic changes lead to greater inflammation over time, and there is decent evidence to link chronic inflammation to a variety of physical and psychological disorders.
In support of this, the authors show that the kids with tonsillectomy were more likely to be hospitalized for an infectious disease in the future as well, in magnitudes similar to the increased risk for stress. But they don’t actually show that the relationship between tonsillectomy and stress is mediated by that increased risk for infectious disease.
In the end, I find these data really intriguing. Before I dug into the literature, it seemed highly unlikely that removal of these small lumps of tissue would have much of an effect on anything. Now I’m not so sure. A few things can be removed from the human body without any consequences, but it can be hard to know exactly what those consequences are.
That said, given the rather marginal benefits of tonsillectomy and the growing number of studies expanding on the risks, I expect that we’ll see the rates of the surgery decline even further in the future.
F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator in New Haven, Connecticut. He reported no relevant conflicts of interest.
A version of this article first appeared on Medscape.com.
Transdermal Beats Oral Estrogen for CVD Safety of Hormone Therapy
I’d like to talk with you about a recent report in the British Medical Journal (BMJ) on different forms of contemporary menopausal hormone therapy and risks for cardiovascular disease (CVD).
This is a very large-scale and comprehensive study from Sweden that looked at more than 900,000 women, including more than 77,000 users of hormone therapy. The women were aged 50-58 years and the study leveraged the nationwide register system, where they have information on prescription medications as well as health outcomes that can be linked.
This study looked at the different forms of hormone therapy: oral vs transdermal, estrogen with and without a progestogen, and also tibolone (which is not available in the United States). The endpoints included myocardial infarction (MI), total ischemic heart disease, stroke, a composite of CVD, as well as venous thromboembolism (VTE).
They found that tibolone was associated with the greatest increased risk for CVD; there was actually an increase in both ischemic heart disease and stroke as well as composite CVD. They did not see an increased risk for VTE. This may be related to the unique pharmacologic profile of tibolone, which has estrogenic, progestogenic, and androgenic properties.
The estrogens tested in the estrogen plus progestin and estrogen alone formulations were not conjugated equine estrogen as tested in the Women’s Health Initiative (WHI) and HERS trials, but mostly oral or transdermal estradiol. With combination estrogen plus progestin, they saw a small (about 20%) increase in ischemic heart disease, similar to what was seen in the WHI. And they saw about a doubling in the risk for VTE, also similar to what was seen in the WHI. With estrogen alone there was no increase in ischemic heart disease or MI, but there was about a 50% increase in VTE — again, similar to the WHI findings.
With transdermal estradiol (transdermal forms of estrogen), in contrast, there was no clear increase in any of these CVD outcomes. In fact, there was a borderline reduction in both MI and composite CVD.
So overall, this study suggests greater cardiovascular safety with transdermal compared with oral estrogen. This would be expected, given the first-pass metabolism and increased clotting associated with oral estrogens.
On the basis of a large body of evidence, we know that for women in early menopause who have bothersome vasomotor symptoms, if they’re healthy, oral or transdermal estrogen could be used according to the preference of the woman. But this study suggests that, especially in women who do have cardiovascular risk factors, it may be very reasonable to lean toward the use of transdermal over oral estrogen among those who are choosing to use hormone therapy.
We certainly need more research on transdermal estradiol, micronized progesterone, and these contemporary formulations that are being used. But in the meantime, this study in the BMJ does provide very useful information for women and their clinicians.
Dr Manson, Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School; Chief, Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston, Massachusetts; Past President, North American Menopause Society, 2011-2012, has disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).
A version of this article appeared on Medscape.com.
I’d like to talk with you about a recent report in the British Medical Journal (BMJ) on different forms of contemporary menopausal hormone therapy and risks for cardiovascular disease (CVD).
This is a very large-scale and comprehensive study from Sweden that looked at more than 900,000 women, including more than 77,000 users of hormone therapy. The women were aged 50-58 years and the study leveraged the nationwide register system, where they have information on prescription medications as well as health outcomes that can be linked.
This study looked at the different forms of hormone therapy: oral vs transdermal, estrogen with and without a progestogen, and also tibolone (which is not available in the United States). The endpoints included myocardial infarction (MI), total ischemic heart disease, stroke, a composite of CVD, as well as venous thromboembolism (VTE).
They found that tibolone was associated with the greatest increased risk for CVD; there was actually an increase in both ischemic heart disease and stroke as well as composite CVD. They did not see an increased risk for VTE. This may be related to the unique pharmacologic profile of tibolone, which has estrogenic, progestogenic, and androgenic properties.
The estrogens tested in the estrogen plus progestin and estrogen alone formulations were not conjugated equine estrogen as tested in the Women’s Health Initiative (WHI) and HERS trials, but mostly oral or transdermal estradiol. With combination estrogen plus progestin, they saw a small (about 20%) increase in ischemic heart disease, similar to what was seen in the WHI. And they saw about a doubling in the risk for VTE, also similar to what was seen in the WHI. With estrogen alone there was no increase in ischemic heart disease or MI, but there was about a 50% increase in VTE — again, similar to the WHI findings.
With transdermal estradiol (transdermal forms of estrogen), in contrast, there was no clear increase in any of these CVD outcomes. In fact, there was a borderline reduction in both MI and composite CVD.
So overall, this study suggests greater cardiovascular safety with transdermal compared with oral estrogen. This would be expected, given the first-pass metabolism and increased clotting associated with oral estrogens.
On the basis of a large body of evidence, we know that for women in early menopause who have bothersome vasomotor symptoms, if they’re healthy, oral or transdermal estrogen could be used according to the preference of the woman. But this study suggests that, especially in women who do have cardiovascular risk factors, it may be very reasonable to lean toward the use of transdermal over oral estrogen among those who are choosing to use hormone therapy.
We certainly need more research on transdermal estradiol, micronized progesterone, and these contemporary formulations that are being used. But in the meantime, this study in the BMJ does provide very useful information for women and their clinicians.
Dr Manson, Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School; Chief, Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston, Massachusetts; Past President, North American Menopause Society, 2011-2012, has disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).
A version of this article appeared on Medscape.com.
I’d like to talk with you about a recent report in the British Medical Journal (BMJ) on different forms of contemporary menopausal hormone therapy and risks for cardiovascular disease (CVD).
This is a very large-scale and comprehensive study from Sweden that looked at more than 900,000 women, including more than 77,000 users of hormone therapy. The women were aged 50-58 years and the study leveraged the nationwide register system, where they have information on prescription medications as well as health outcomes that can be linked.
This study looked at the different forms of hormone therapy: oral vs transdermal, estrogen with and without a progestogen, and also tibolone (which is not available in the United States). The endpoints included myocardial infarction (MI), total ischemic heart disease, stroke, a composite of CVD, as well as venous thromboembolism (VTE).
They found that tibolone was associated with the greatest increased risk for CVD; there was actually an increase in both ischemic heart disease and stroke as well as composite CVD. They did not see an increased risk for VTE. This may be related to the unique pharmacologic profile of tibolone, which has estrogenic, progestogenic, and androgenic properties.
The estrogens tested in the estrogen plus progestin and estrogen alone formulations were not conjugated equine estrogen as tested in the Women’s Health Initiative (WHI) and HERS trials, but mostly oral or transdermal estradiol. With combination estrogen plus progestin, they saw a small (about 20%) increase in ischemic heart disease, similar to what was seen in the WHI. And they saw about a doubling in the risk for VTE, also similar to what was seen in the WHI. With estrogen alone there was no increase in ischemic heart disease or MI, but there was about a 50% increase in VTE — again, similar to the WHI findings.
With transdermal estradiol (transdermal forms of estrogen), in contrast, there was no clear increase in any of these CVD outcomes. In fact, there was a borderline reduction in both MI and composite CVD.
So overall, this study suggests greater cardiovascular safety with transdermal compared with oral estrogen. This would be expected, given the first-pass metabolism and increased clotting associated with oral estrogens.
On the basis of a large body of evidence, we know that for women in early menopause who have bothersome vasomotor symptoms, if they’re healthy, oral or transdermal estrogen could be used according to the preference of the woman. But this study suggests that, especially in women who do have cardiovascular risk factors, it may be very reasonable to lean toward the use of transdermal over oral estrogen among those who are choosing to use hormone therapy.
We certainly need more research on transdermal estradiol, micronized progesterone, and these contemporary formulations that are being used. But in the meantime, this study in the BMJ does provide very useful information for women and their clinicians.
Dr Manson, Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School; Chief, Division of Preventive Medicine, Brigham and Women’s Hospital, both in Boston, Massachusetts; Past President, North American Menopause Society, 2011-2012, has disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).
A version of this article appeared on Medscape.com.
Is Vitamin E Beneficial for Bone Health?
Vitamin E may be best known for boosting skin and eye health as well as immune function. In recent years, researchers have explored the potential benefits of vitamin E on bone loss, especially in women with menopause-related osteoporosis. While data are beginning to roll in from these studies, evidence supporting a positive impact of vitamin E on osteoporosis and hip fracture risk in perimenopausal women remains elusive.
For osteoporosis, the rationale for using vitamin E is based on its antioxidant activity, which can scavenge potentially damaging free radicals. Researchers have asked whether vitamin E can help maintain the integrity of bone matrix and stimulate bone formation while minimizing bone resorption, particularly in trabecular (spongy) bone, the bone compartment preferentially affected in perimenopausal bone loss.
Vitamin E mostly consists of two isomers: alpha-tocopherol and gamma-tocopherol. Alpha-tocopherol has higher antioxidant activity and is found in nuts, seeds, vegetable oils, green leafy vegetables, fortified cereals, and vitamin E supplements. Gamma-tocopherol is known for its superior anti-inflammatory properties and accounts for about 70% of the total vitamin E intake in a typical American diet, largely sourced from soybean and other vegetable oils.
Benefits and Risks in Bone Loss Studies
Perimenopausal bone loss is caused, to a great extent, by the decrease in sex hormones. Studies of vitamin E in ovariectomized rats have yielded mixed results. This animal model lacks sex hormones and has similar bone changes to those of postmenopausal women. Some animal studies have suggested a positive effect of vitamin E on bone while others have reported no effect.
Studies in humans also have produced conflicting reports of positive, neutral, and negative associations of vitamin E with bone health. For example, the Women’s Health Initiative examined the relationship between vitamin and mineral antioxidants and bone health in postmenopausal women and found no significant association between antioxidants and bone mineral density.
Another study examining data from children and adolescents enrolled in the National Health and Nutrition Examination Survey (NHANES) database found an inverse association between alpha-tocopherol and lumbar spine bone density, suggesting a deleterious effect on bone. Inverse associations also have been reported in certain studies of postmenopausal women.
High doses of alpha-tocopherol have been linked to a risk for impaired bone health through a variety of mechanisms, such as interference with vitamin K metabolism; competitive binding for alpha-tocopherol transfer protein, inhibiting the entry of beneficial vitamin E isomers, including gamma-tocopherol; and pro-oxidant effects that harm bone. Thus, postmenopausal women taking vitamin E supplements primarily as high doses of alpha-tocopherol might be hindering their bone health.
Data for gamma-tocopherol are more promising. Some studies hypothesize that gamma-tocopherol might uncouple bone turnover, leading to increased bone formation without affecting bone resorption. Further, a randomized controlled study of mixed tocopherols (rather than alpha-tocopherol) vs placebo reported a protective effect of this preparation on bone outcomes by suppressing bone resorption. This raises the importance of considering the specific forms of vitamin E when evaluating its role in bone health.
Limitations of Current Studies
Researchers acknowledge several limitations in studies to date. For example, there are very few randomized controlled trials assessing the impact of vitamin E on bone health. Most studies are cross-sectional or observational, even when longitudinal. Cross-sectional and observational designs prevent us from establishing a causal relationship between vitamin E and bone endpoints.
Such designs also run the risk of additional confounders that may affect associations between vitamin E and bone, or the lack thereof. These could include both known and unknown confounders. Of note, gamma-tocopherol intake data were not available for certain NHANES studies.
Further, people often consume multiple nutrients and supplements, complicating the identification of specific nutrient-disease associations. Most human studies estimate tocopherol intake by dietary questionnaires or measure serum tocopherol levels, which reflect short-term dietary intake, while bone mineral density is probably influenced by long-term dietary patterns.
Too Soon to Prescribe Vitamin E for Bone Health
Some nutrition experts advocate for vitamin E supplements containing mixed tocopherols, specifically suggesting a ratio of 50-100 IU of gamma-tocopherol per 400 IU of D-alpha-tocopherol. Additional research is essential to confirm and further clarify the role of gamma-tocopherol in bone formation and resorption. In fact, it is also important to explore the influence of other compounds in the vitamin E family on skeletal health.
Until more data are available, we would recommend following the Institute of Medicine’s guidelines for the recommended daily allowance (RDA) of vitamin E. This is age dependent, ranging from 4 to 11 mg/d between the ages of 0 and 13 years, and 15 mg/d thereafter.
Overall, evidence of vitamin E’s impact on osteoporosis and hip fracture risk in perimenopausal women remains inconclusive. Although some observational and interventional studies suggest potential benefits, more interventional studies, particularly randomized controlled trials, are necessary to explore the risks and benefits of vitamin E supplementation and serum vitamin E levels on bone density and fracture risk more thoroughly.
Dr. Pani, Assistant Professor, Department of Internal Medicine, UVA School of Medicine; Medical Director, Department of General Medicine, Same Day Care Clinic, both in Charlottesville, has disclosed no relevant financial relationships. Dr. Misra, Professor, Chair, Physician-in-Chief, Department of Pediatrics, University of Virginia, and UVA Health Children’s, Charlottesville, has disclosed being a key opinion leader for Lumos Pharma.
A version of this article appeared on Medscape.com.
Vitamin E may be best known for boosting skin and eye health as well as immune function. In recent years, researchers have explored the potential benefits of vitamin E on bone loss, especially in women with menopause-related osteoporosis. While data are beginning to roll in from these studies, evidence supporting a positive impact of vitamin E on osteoporosis and hip fracture risk in perimenopausal women remains elusive.
For osteoporosis, the rationale for using vitamin E is based on its antioxidant activity, which can scavenge potentially damaging free radicals. Researchers have asked whether vitamin E can help maintain the integrity of bone matrix and stimulate bone formation while minimizing bone resorption, particularly in trabecular (spongy) bone, the bone compartment preferentially affected in perimenopausal bone loss.
Vitamin E mostly consists of two isomers: alpha-tocopherol and gamma-tocopherol. Alpha-tocopherol has higher antioxidant activity and is found in nuts, seeds, vegetable oils, green leafy vegetables, fortified cereals, and vitamin E supplements. Gamma-tocopherol is known for its superior anti-inflammatory properties and accounts for about 70% of the total vitamin E intake in a typical American diet, largely sourced from soybean and other vegetable oils.
Benefits and Risks in Bone Loss Studies
Perimenopausal bone loss is caused, to a great extent, by the decrease in sex hormones. Studies of vitamin E in ovariectomized rats have yielded mixed results. This animal model lacks sex hormones and has similar bone changes to those of postmenopausal women. Some animal studies have suggested a positive effect of vitamin E on bone while others have reported no effect.
Studies in humans also have produced conflicting reports of positive, neutral, and negative associations of vitamin E with bone health. For example, the Women’s Health Initiative examined the relationship between vitamin and mineral antioxidants and bone health in postmenopausal women and found no significant association between antioxidants and bone mineral density.
Another study examining data from children and adolescents enrolled in the National Health and Nutrition Examination Survey (NHANES) database found an inverse association between alpha-tocopherol and lumbar spine bone density, suggesting a deleterious effect on bone. Inverse associations also have been reported in certain studies of postmenopausal women.
High doses of alpha-tocopherol have been linked to a risk for impaired bone health through a variety of mechanisms, such as interference with vitamin K metabolism; competitive binding for alpha-tocopherol transfer protein, inhibiting the entry of beneficial vitamin E isomers, including gamma-tocopherol; and pro-oxidant effects that harm bone. Thus, postmenopausal women taking vitamin E supplements primarily as high doses of alpha-tocopherol might be hindering their bone health.
Data for gamma-tocopherol are more promising. Some studies hypothesize that gamma-tocopherol might uncouple bone turnover, leading to increased bone formation without affecting bone resorption. Further, a randomized controlled study of mixed tocopherols (rather than alpha-tocopherol) vs placebo reported a protective effect of this preparation on bone outcomes by suppressing bone resorption. This raises the importance of considering the specific forms of vitamin E when evaluating its role in bone health.
Limitations of Current Studies
Researchers acknowledge several limitations in studies to date. For example, there are very few randomized controlled trials assessing the impact of vitamin E on bone health. Most studies are cross-sectional or observational, even when longitudinal. Cross-sectional and observational designs prevent us from establishing a causal relationship between vitamin E and bone endpoints.
Such designs also run the risk of additional confounders that may affect associations between vitamin E and bone, or the lack thereof. These could include both known and unknown confounders. Of note, gamma-tocopherol intake data were not available for certain NHANES studies.
Further, people often consume multiple nutrients and supplements, complicating the identification of specific nutrient-disease associations. Most human studies estimate tocopherol intake by dietary questionnaires or measure serum tocopherol levels, which reflect short-term dietary intake, while bone mineral density is probably influenced by long-term dietary patterns.
Too Soon to Prescribe Vitamin E for Bone Health
Some nutrition experts advocate for vitamin E supplements containing mixed tocopherols, specifically suggesting a ratio of 50-100 IU of gamma-tocopherol per 400 IU of D-alpha-tocopherol. Additional research is essential to confirm and further clarify the role of gamma-tocopherol in bone formation and resorption. In fact, it is also important to explore the influence of other compounds in the vitamin E family on skeletal health.
Until more data are available, we would recommend following the Institute of Medicine’s guidelines for the recommended daily allowance (RDA) of vitamin E. This is age dependent, ranging from 4 to 11 mg/d between the ages of 0 and 13 years, and 15 mg/d thereafter.
Overall, evidence of vitamin E’s impact on osteoporosis and hip fracture risk in perimenopausal women remains inconclusive. Although some observational and interventional studies suggest potential benefits, more interventional studies, particularly randomized controlled trials, are necessary to explore the risks and benefits of vitamin E supplementation and serum vitamin E levels on bone density and fracture risk more thoroughly.
Dr. Pani, Assistant Professor, Department of Internal Medicine, UVA School of Medicine; Medical Director, Department of General Medicine, Same Day Care Clinic, both in Charlottesville, has disclosed no relevant financial relationships. Dr. Misra, Professor, Chair, Physician-in-Chief, Department of Pediatrics, University of Virginia, and UVA Health Children’s, Charlottesville, has disclosed being a key opinion leader for Lumos Pharma.
A version of this article appeared on Medscape.com.
Vitamin E may be best known for boosting skin and eye health as well as immune function. In recent years, researchers have explored the potential benefits of vitamin E on bone loss, especially in women with menopause-related osteoporosis. While data are beginning to roll in from these studies, evidence supporting a positive impact of vitamin E on osteoporosis and hip fracture risk in perimenopausal women remains elusive.
For osteoporosis, the rationale for using vitamin E is based on its antioxidant activity, which can scavenge potentially damaging free radicals. Researchers have asked whether vitamin E can help maintain the integrity of bone matrix and stimulate bone formation while minimizing bone resorption, particularly in trabecular (spongy) bone, the bone compartment preferentially affected in perimenopausal bone loss.
Vitamin E mostly consists of two isomers: alpha-tocopherol and gamma-tocopherol. Alpha-tocopherol has higher antioxidant activity and is found in nuts, seeds, vegetable oils, green leafy vegetables, fortified cereals, and vitamin E supplements. Gamma-tocopherol is known for its superior anti-inflammatory properties and accounts for about 70% of the total vitamin E intake in a typical American diet, largely sourced from soybean and other vegetable oils.
Benefits and Risks in Bone Loss Studies
Perimenopausal bone loss is caused, to a great extent, by the decrease in sex hormones. Studies of vitamin E in ovariectomized rats have yielded mixed results. This animal model lacks sex hormones and has similar bone changes to those of postmenopausal women. Some animal studies have suggested a positive effect of vitamin E on bone while others have reported no effect.
Studies in humans also have produced conflicting reports of positive, neutral, and negative associations of vitamin E with bone health. For example, the Women’s Health Initiative examined the relationship between vitamin and mineral antioxidants and bone health in postmenopausal women and found no significant association between antioxidants and bone mineral density.
Another study examining data from children and adolescents enrolled in the National Health and Nutrition Examination Survey (NHANES) database found an inverse association between alpha-tocopherol and lumbar spine bone density, suggesting a deleterious effect on bone. Inverse associations also have been reported in certain studies of postmenopausal women.
High doses of alpha-tocopherol have been linked to a risk for impaired bone health through a variety of mechanisms, such as interference with vitamin K metabolism; competitive binding for alpha-tocopherol transfer protein, inhibiting the entry of beneficial vitamin E isomers, including gamma-tocopherol; and pro-oxidant effects that harm bone. Thus, postmenopausal women taking vitamin E supplements primarily as high doses of alpha-tocopherol might be hindering their bone health.
Data for gamma-tocopherol are more promising. Some studies hypothesize that gamma-tocopherol might uncouple bone turnover, leading to increased bone formation without affecting bone resorption. Further, a randomized controlled study of mixed tocopherols (rather than alpha-tocopherol) vs placebo reported a protective effect of this preparation on bone outcomes by suppressing bone resorption. This raises the importance of considering the specific forms of vitamin E when evaluating its role in bone health.
Limitations of Current Studies
Researchers acknowledge several limitations in studies to date. For example, there are very few randomized controlled trials assessing the impact of vitamin E on bone health. Most studies are cross-sectional or observational, even when longitudinal. Cross-sectional and observational designs prevent us from establishing a causal relationship between vitamin E and bone endpoints.
Such designs also run the risk of additional confounders that may affect associations between vitamin E and bone, or the lack thereof. These could include both known and unknown confounders. Of note, gamma-tocopherol intake data were not available for certain NHANES studies.
Further, people often consume multiple nutrients and supplements, complicating the identification of specific nutrient-disease associations. Most human studies estimate tocopherol intake by dietary questionnaires or measure serum tocopherol levels, which reflect short-term dietary intake, while bone mineral density is probably influenced by long-term dietary patterns.
Too Soon to Prescribe Vitamin E for Bone Health
Some nutrition experts advocate for vitamin E supplements containing mixed tocopherols, specifically suggesting a ratio of 50-100 IU of gamma-tocopherol per 400 IU of D-alpha-tocopherol. Additional research is essential to confirm and further clarify the role of gamma-tocopherol in bone formation and resorption. In fact, it is also important to explore the influence of other compounds in the vitamin E family on skeletal health.
Until more data are available, we would recommend following the Institute of Medicine’s guidelines for the recommended daily allowance (RDA) of vitamin E. This is age dependent, ranging from 4 to 11 mg/d between the ages of 0 and 13 years, and 15 mg/d thereafter.
Overall, evidence of vitamin E’s impact on osteoporosis and hip fracture risk in perimenopausal women remains inconclusive. Although some observational and interventional studies suggest potential benefits, more interventional studies, particularly randomized controlled trials, are necessary to explore the risks and benefits of vitamin E supplementation and serum vitamin E levels on bone density and fracture risk more thoroughly.
Dr. Pani, Assistant Professor, Department of Internal Medicine, UVA School of Medicine; Medical Director, Department of General Medicine, Same Day Care Clinic, both in Charlottesville, has disclosed no relevant financial relationships. Dr. Misra, Professor, Chair, Physician-in-Chief, Department of Pediatrics, University of Virginia, and UVA Health Children’s, Charlottesville, has disclosed being a key opinion leader for Lumos Pharma.
A version of this article appeared on Medscape.com.
Could Diet and Gut Bacteria Be Fueling Early CRC?
This transcript has been edited for clarity.
I’d like to reflect a little on the ever-rising incidence of early-onset colorectal cancer. I saw two patients in the clinic on Friday, both in their early thirties, presenting with stage IV disease. Both had young families — a disaster.
This is an issue that we must address, I think, epidemiologically. We know that and currently, around 200,000 such cases are diagnosed every year, but it is said to increase unquestionably.
The epidemiologists, I think, correctly have identified that this sharp, rapid increase does imply that there is a new environmental change that is underpinning or underscoring this rise in early-onset disease.
There’s a fantastic team that has been put together by Paul Brennan, Mike Stratton, and colleagues, a collaborative group of epidemiologists, geneticists, and bioinformaticians, who are looking at a global study to try to understand the basis of early-onset colorectal cancer. Their approach is to combine conventional epidemiology, genomics, and fantastic computational support to try to unpick the mutational signatures involved.
The dominant hypothesis is that, over the past 20-25 years or so, there has been a change in diet that has allowed an alteration in the gut microbiome such that we now harbor, in some cases, more bacteria capable of manufacturing, synthesizing, and releasing mutagenic chemicals. There’s a subtype of Escherichia coli which manufactures one such mutagen called colibactin.
Again, through some of the painstaking, extraordinary work that Mike Stratton and colleagues have done at the Sanger Institute, they have managed to, using a variety of different techniques — in vitro, observational, and so on — relate exposure to the mutagen colibactin to a particular mutational signature.
They plan to do a large global study — one of the strengths — involving many different countries around the globe, collect material from older colorectal cancer patients and early-onset colorectal cancer patients, and undertake a staggeringly large mutational study to see if the mutational signature associated with colibactin is more highly represented in these early-onset cases. The hypothesis is that, if you’re exposed to this mutagen in childhood, then it increases the tumor mutational burden and therefore the likelihood of developing cancer at an earlier age.
All of us believe that converting a normal cell into a tumor cell usually requires five or six or seven separate mutational events occurring at random. The earlier these occur, the greater the tumor, the greater the normal single-cellular mutational burden, and the more likely it is to develop cancer sooner rather than later.
This is a fantastically interesting study, and it’s the way ahead with modern genetic epidemiology, one would say. We wish them well. This will be a 3- to 5-year truly international effort, bringing together a genuinely internationally outstanding research team. We hope that they are able to shed more light on the epidemiology of this early-onset disease, because only by understanding can we deflect and deal with it.
Knowledge is power, as I’ve said many times before. If we understand the underlying epidemiology, that will allow us to intervene, one would hope, and avoid the chaotic disaster of my clinic on Friday, with these two young patients with an extremely limited lifespan and large families who will be left bereft in having lost a parent.
More power to the team. We wish them well with the study, but again, this is a pointer to the future, one would hope, of modern genetic computational epidemiology.
I’d be really interested in any ideas or comments that you might have. Are you in the field? Are you seeing more young patients? Do you have any ideas or hypotheses of your own around the microbiome and what bugs might be involved and so on?
Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, England; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, has disclosed relevant financial relationships with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
I’d like to reflect a little on the ever-rising incidence of early-onset colorectal cancer. I saw two patients in the clinic on Friday, both in their early thirties, presenting with stage IV disease. Both had young families — a disaster.
This is an issue that we must address, I think, epidemiologically. We know that and currently, around 200,000 such cases are diagnosed every year, but it is said to increase unquestionably.
The epidemiologists, I think, correctly have identified that this sharp, rapid increase does imply that there is a new environmental change that is underpinning or underscoring this rise in early-onset disease.
There’s a fantastic team that has been put together by Paul Brennan, Mike Stratton, and colleagues, a collaborative group of epidemiologists, geneticists, and bioinformaticians, who are looking at a global study to try to understand the basis of early-onset colorectal cancer. Their approach is to combine conventional epidemiology, genomics, and fantastic computational support to try to unpick the mutational signatures involved.
The dominant hypothesis is that, over the past 20-25 years or so, there has been a change in diet that has allowed an alteration in the gut microbiome such that we now harbor, in some cases, more bacteria capable of manufacturing, synthesizing, and releasing mutagenic chemicals. There’s a subtype of Escherichia coli which manufactures one such mutagen called colibactin.
Again, through some of the painstaking, extraordinary work that Mike Stratton and colleagues have done at the Sanger Institute, they have managed to, using a variety of different techniques — in vitro, observational, and so on — relate exposure to the mutagen colibactin to a particular mutational signature.
They plan to do a large global study — one of the strengths — involving many different countries around the globe, collect material from older colorectal cancer patients and early-onset colorectal cancer patients, and undertake a staggeringly large mutational study to see if the mutational signature associated with colibactin is more highly represented in these early-onset cases. The hypothesis is that, if you’re exposed to this mutagen in childhood, then it increases the tumor mutational burden and therefore the likelihood of developing cancer at an earlier age.
All of us believe that converting a normal cell into a tumor cell usually requires five or six or seven separate mutational events occurring at random. The earlier these occur, the greater the tumor, the greater the normal single-cellular mutational burden, and the more likely it is to develop cancer sooner rather than later.
This is a fantastically interesting study, and it’s the way ahead with modern genetic epidemiology, one would say. We wish them well. This will be a 3- to 5-year truly international effort, bringing together a genuinely internationally outstanding research team. We hope that they are able to shed more light on the epidemiology of this early-onset disease, because only by understanding can we deflect and deal with it.
Knowledge is power, as I’ve said many times before. If we understand the underlying epidemiology, that will allow us to intervene, one would hope, and avoid the chaotic disaster of my clinic on Friday, with these two young patients with an extremely limited lifespan and large families who will be left bereft in having lost a parent.
More power to the team. We wish them well with the study, but again, this is a pointer to the future, one would hope, of modern genetic computational epidemiology.
I’d be really interested in any ideas or comments that you might have. Are you in the field? Are you seeing more young patients? Do you have any ideas or hypotheses of your own around the microbiome and what bugs might be involved and so on?
Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, England; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, has disclosed relevant financial relationships with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
I’d like to reflect a little on the ever-rising incidence of early-onset colorectal cancer. I saw two patients in the clinic on Friday, both in their early thirties, presenting with stage IV disease. Both had young families — a disaster.
This is an issue that we must address, I think, epidemiologically. We know that and currently, around 200,000 such cases are diagnosed every year, but it is said to increase unquestionably.
The epidemiologists, I think, correctly have identified that this sharp, rapid increase does imply that there is a new environmental change that is underpinning or underscoring this rise in early-onset disease.
There’s a fantastic team that has been put together by Paul Brennan, Mike Stratton, and colleagues, a collaborative group of epidemiologists, geneticists, and bioinformaticians, who are looking at a global study to try to understand the basis of early-onset colorectal cancer. Their approach is to combine conventional epidemiology, genomics, and fantastic computational support to try to unpick the mutational signatures involved.
The dominant hypothesis is that, over the past 20-25 years or so, there has been a change in diet that has allowed an alteration in the gut microbiome such that we now harbor, in some cases, more bacteria capable of manufacturing, synthesizing, and releasing mutagenic chemicals. There’s a subtype of Escherichia coli which manufactures one such mutagen called colibactin.
Again, through some of the painstaking, extraordinary work that Mike Stratton and colleagues have done at the Sanger Institute, they have managed to, using a variety of different techniques — in vitro, observational, and so on — relate exposure to the mutagen colibactin to a particular mutational signature.
They plan to do a large global study — one of the strengths — involving many different countries around the globe, collect material from older colorectal cancer patients and early-onset colorectal cancer patients, and undertake a staggeringly large mutational study to see if the mutational signature associated with colibactin is more highly represented in these early-onset cases. The hypothesis is that, if you’re exposed to this mutagen in childhood, then it increases the tumor mutational burden and therefore the likelihood of developing cancer at an earlier age.
All of us believe that converting a normal cell into a tumor cell usually requires five or six or seven separate mutational events occurring at random. The earlier these occur, the greater the tumor, the greater the normal single-cellular mutational burden, and the more likely it is to develop cancer sooner rather than later.
This is a fantastically interesting study, and it’s the way ahead with modern genetic epidemiology, one would say. We wish them well. This will be a 3- to 5-year truly international effort, bringing together a genuinely internationally outstanding research team. We hope that they are able to shed more light on the epidemiology of this early-onset disease, because only by understanding can we deflect and deal with it.
Knowledge is power, as I’ve said many times before. If we understand the underlying epidemiology, that will allow us to intervene, one would hope, and avoid the chaotic disaster of my clinic on Friday, with these two young patients with an extremely limited lifespan and large families who will be left bereft in having lost a parent.
More power to the team. We wish them well with the study, but again, this is a pointer to the future, one would hope, of modern genetic computational epidemiology.
I’d be really interested in any ideas or comments that you might have. Are you in the field? Are you seeing more young patients? Do you have any ideas or hypotheses of your own around the microbiome and what bugs might be involved and so on?
Dr. Kerr, Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, England; Professor of Cancer Medicine, Oxford Cancer Centre, Oxford, United Kingdom, has disclosed relevant financial relationships with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer, Genomic Health, Merck Serono, and Roche.
A version of this article appeared on Medscape.com.
On the Murder of UnitedHealthcare’s CEO
On December 4, UnitedHealthcare CEO Brian Thompson was assassinated in New York City outside of a hotel. As of the time of this writing, the shooter is still at large.
I suppose I could write about how this shows that Americans are fed up with the way modern commercial healthcare companies operate. Who gets care and who doesn’t.
I could write about how industry trends of “Delay, Deny, Defend” lead to the suffering of millions of people who need healthcare that they thought they were paying for.
I could write about the callousness of the way people online are celebrating the cold-blooded murder of a married man with two children.
I might write about how insurance companies intentionally, and routinely, drag out (or deny) reimbursements for physicians (including small solo practice ones, like myself) who are legitimately caring for their patients.
I suppose I could write something about how gun violence is so pervasive in our society that it scarcely merits a second glance at the news story. If the headline just said, “Unknown Assailant Kills Man Outside Hotel,” would you have even read beyond that?
I could write about how the lack of regulations, and accelerating attempts to scrap them, can lead to insider trading.
I could write about how having insurance companies and medical facilities more beholden to shareholders than to patients is a serious conflict of interest.
I could try to make points about how the widespread availability of firearms (in this case one with a built-in silencer) in America means that anyone with a vendetta, or serious mental illness, or just a short temper, can get one — and use it.
I could talk about how “greed is good” in healthcare settings rewards a few and hurts many — no matter how much the PR spinners try to make it sound like it’s a great win-win situation all-around.
I could argue that the jubilant “good riddance” and “eat the rich” responses of many — both medical and nonmedical people — to the killing shows that, as a society, we’re losing the qualities that make us human.
I could also argue that putting financial gain for executive bonuses and stockholder dividends ahead of the health and well-being of others shows that, as a society, we’re losing the qualities that make us human.
I could make a point that , provided the target is someone they have a difference of opinion with. Which is, honestly, pretty damn scary.
I could talk about how policies of arbitrarily changing the rules about anesthesia coverage, or letting a computer decide how long a hospital stay should be, or to deny rehabilitation care, are unethical, unjust, and just plain wrong.
I could write about a lot of things based on what happened outside that New York Hilton Midtown in early December.
But as I stare at my screen, I’m well aware that no matter what I write it won’t change any opinions, solve anything, or even lead to people trying to find a solution.
Because that’s just the world we live in.
Block has a solo neurology practice in Scottsdale, Arizona.
On December 4, UnitedHealthcare CEO Brian Thompson was assassinated in New York City outside of a hotel. As of the time of this writing, the shooter is still at large.
I suppose I could write about how this shows that Americans are fed up with the way modern commercial healthcare companies operate. Who gets care and who doesn’t.
I could write about how industry trends of “Delay, Deny, Defend” lead to the suffering of millions of people who need healthcare that they thought they were paying for.
I could write about the callousness of the way people online are celebrating the cold-blooded murder of a married man with two children.
I might write about how insurance companies intentionally, and routinely, drag out (or deny) reimbursements for physicians (including small solo practice ones, like myself) who are legitimately caring for their patients.
I suppose I could write something about how gun violence is so pervasive in our society that it scarcely merits a second glance at the news story. If the headline just said, “Unknown Assailant Kills Man Outside Hotel,” would you have even read beyond that?
I could write about how the lack of regulations, and accelerating attempts to scrap them, can lead to insider trading.
I could write about how having insurance companies and medical facilities more beholden to shareholders than to patients is a serious conflict of interest.
I could try to make points about how the widespread availability of firearms (in this case one with a built-in silencer) in America means that anyone with a vendetta, or serious mental illness, or just a short temper, can get one — and use it.
I could talk about how “greed is good” in healthcare settings rewards a few and hurts many — no matter how much the PR spinners try to make it sound like it’s a great win-win situation all-around.
I could argue that the jubilant “good riddance” and “eat the rich” responses of many — both medical and nonmedical people — to the killing shows that, as a society, we’re losing the qualities that make us human.
I could also argue that putting financial gain for executive bonuses and stockholder dividends ahead of the health and well-being of others shows that, as a society, we’re losing the qualities that make us human.
I could make a point that , provided the target is someone they have a difference of opinion with. Which is, honestly, pretty damn scary.
I could talk about how policies of arbitrarily changing the rules about anesthesia coverage, or letting a computer decide how long a hospital stay should be, or to deny rehabilitation care, are unethical, unjust, and just plain wrong.
I could write about a lot of things based on what happened outside that New York Hilton Midtown in early December.
But as I stare at my screen, I’m well aware that no matter what I write it won’t change any opinions, solve anything, or even lead to people trying to find a solution.
Because that’s just the world we live in.
Block has a solo neurology practice in Scottsdale, Arizona.
On December 4, UnitedHealthcare CEO Brian Thompson was assassinated in New York City outside of a hotel. As of the time of this writing, the shooter is still at large.
I suppose I could write about how this shows that Americans are fed up with the way modern commercial healthcare companies operate. Who gets care and who doesn’t.
I could write about how industry trends of “Delay, Deny, Defend” lead to the suffering of millions of people who need healthcare that they thought they were paying for.
I could write about the callousness of the way people online are celebrating the cold-blooded murder of a married man with two children.
I might write about how insurance companies intentionally, and routinely, drag out (or deny) reimbursements for physicians (including small solo practice ones, like myself) who are legitimately caring for their patients.
I suppose I could write something about how gun violence is so pervasive in our society that it scarcely merits a second glance at the news story. If the headline just said, “Unknown Assailant Kills Man Outside Hotel,” would you have even read beyond that?
I could write about how the lack of regulations, and accelerating attempts to scrap them, can lead to insider trading.
I could write about how having insurance companies and medical facilities more beholden to shareholders than to patients is a serious conflict of interest.
I could try to make points about how the widespread availability of firearms (in this case one with a built-in silencer) in America means that anyone with a vendetta, or serious mental illness, or just a short temper, can get one — and use it.
I could talk about how “greed is good” in healthcare settings rewards a few and hurts many — no matter how much the PR spinners try to make it sound like it’s a great win-win situation all-around.
I could argue that the jubilant “good riddance” and “eat the rich” responses of many — both medical and nonmedical people — to the killing shows that, as a society, we’re losing the qualities that make us human.
I could also argue that putting financial gain for executive bonuses and stockholder dividends ahead of the health and well-being of others shows that, as a society, we’re losing the qualities that make us human.
I could make a point that , provided the target is someone they have a difference of opinion with. Which is, honestly, pretty damn scary.
I could talk about how policies of arbitrarily changing the rules about anesthesia coverage, or letting a computer decide how long a hospital stay should be, or to deny rehabilitation care, are unethical, unjust, and just plain wrong.
I could write about a lot of things based on what happened outside that New York Hilton Midtown in early December.
But as I stare at my screen, I’m well aware that no matter what I write it won’t change any opinions, solve anything, or even lead to people trying to find a solution.
Because that’s just the world we live in.
Block has a solo neurology practice in Scottsdale, Arizona.
Can We Fight Social Media’s Promotion of Junk Food?
Of those three truths, the one that tends to get more public health attention is advertising. More specifically, advertising junk food to kids.
Back in the days when cable television was king of all free time, study after study tried to quantify junk- and fast-food advertising to kids and speculated about its impact on childhood obesity rates. But as broadcast television use began fading, advertisers — and, of course, studies about advertising — turned their attention first to gaming and now to social media.
The social media numbers are quite staggering. According to a study published — probably not coincidentally — on Halloween, looking at the 40 top brands of junk- and fast food sold in Canada, those 40 brands alone were mentioned over 16 million times by social media users, reaching an estimated 42 billion total users within a 1-year period.
And unique to the challenge of junk- and fast-food advertising on social media is that it also includes “earned” advertising, the kind not paid for by manufacturers but rather the kind where friends, family, and influencers post about junk food. Occasionally, though, these lines are blurred by initiatives from fast-food manufacturers explicitly encouraging social sharing. Consequently, even were there a desire, there isn’t likely to be a regulatory mechanism to markedly reduce it.
For years, here in North America, excepting Quebec, the desire has been mainly to just talk about how concerned we are about junk-food advertising to kids. Elsewhere, however, some countries tried to do more, including both Mexico and Chile, which put kid-targeted TV food advertising bans in place in 2014 and 2016, respectively.
Did they work? It depends on what outcome you’re considering. If the question is, did they work in regard to obesity? — which is how everyone tends to frame the question — by themselves, probably not. No one sandbag stops a flood, and though junk-food advertising is certainly a sandbag, we’re still facing a torrential downpour of obesity contributors. No doubt they did work to reduce kids’ exposure to junk-food advertising on television, but what remains to be seen is whether there is a means to now tackle social media’s generous servings of the same. Moreover, the obesity lens is the wrong one. Ultraprocessed food consumption isn’t good for anyone, regardless of weight, and its reduced marketing and consumption is a worthy goal of its own.
But Chile and Mexico are filling more than single sandbags, as both countries have rolled out a suite of interventions they are hoping will help improve nutrition: from front-of–package labeling reforms and warnings, to the banning of advertising geared specifically to appeal to children (like sugary cereal cartoon mascots), to implementing sugar-sweetened-beverage taxes, to having blanket overall bans on food advertising during the daytime.
Mexico is even taking first steps to start addressing junk food’s ubiquity by banning its sale in schools altogether. Schools found to be selling common Mexican junk food fare, such as sugary fruit drinks; chips; artificial pork rinds; and soy-encased, salty peanuts with chili, will see their administrators facing heavy fines.
Because therein lies the biggest rub. Going back to those three simple truths, junk food is hyperpalatable and consequently tends to be what we crave when we’re hungry. So even if we miraculously one day do more than just talk about advertising reforms, and especially given that we won’t be able to do anything about social media’s earned product placements, junk food’s ubiquitous availability within arms’ reach or on our Uber Eats apps will see us be likely to continue its excessive consumption.
That’s not to say we shouldn’t emulate Mexico and Chile’s initiatives, nor that they shouldn’t continue to build upon them, but one thing is certain: Human nature and inconvenient truths around food are incredibly powerful forces that we haven’t yet figured out how to tame.
Dr. Freedhoff, Associate Professor, Department of Family Medicine, University of Ottawa; Medical Director, Bariatric Medical Institute, Ottawa, Ontario, Canada, has disclosed relevant financial relationships with Bariatric Medical Institute, Constant Health, Novo Nordisk, and Weighty Matters.
A version of this article appeared on Medscape.com.
Of those three truths, the one that tends to get more public health attention is advertising. More specifically, advertising junk food to kids.
Back in the days when cable television was king of all free time, study after study tried to quantify junk- and fast-food advertising to kids and speculated about its impact on childhood obesity rates. But as broadcast television use began fading, advertisers — and, of course, studies about advertising — turned their attention first to gaming and now to social media.
The social media numbers are quite staggering. According to a study published — probably not coincidentally — on Halloween, looking at the 40 top brands of junk- and fast food sold in Canada, those 40 brands alone were mentioned over 16 million times by social media users, reaching an estimated 42 billion total users within a 1-year period.
And unique to the challenge of junk- and fast-food advertising on social media is that it also includes “earned” advertising, the kind not paid for by manufacturers but rather the kind where friends, family, and influencers post about junk food. Occasionally, though, these lines are blurred by initiatives from fast-food manufacturers explicitly encouraging social sharing. Consequently, even were there a desire, there isn’t likely to be a regulatory mechanism to markedly reduce it.
For years, here in North America, excepting Quebec, the desire has been mainly to just talk about how concerned we are about junk-food advertising to kids. Elsewhere, however, some countries tried to do more, including both Mexico and Chile, which put kid-targeted TV food advertising bans in place in 2014 and 2016, respectively.
Did they work? It depends on what outcome you’re considering. If the question is, did they work in regard to obesity? — which is how everyone tends to frame the question — by themselves, probably not. No one sandbag stops a flood, and though junk-food advertising is certainly a sandbag, we’re still facing a torrential downpour of obesity contributors. No doubt they did work to reduce kids’ exposure to junk-food advertising on television, but what remains to be seen is whether there is a means to now tackle social media’s generous servings of the same. Moreover, the obesity lens is the wrong one. Ultraprocessed food consumption isn’t good for anyone, regardless of weight, and its reduced marketing and consumption is a worthy goal of its own.
But Chile and Mexico are filling more than single sandbags, as both countries have rolled out a suite of interventions they are hoping will help improve nutrition: from front-of–package labeling reforms and warnings, to the banning of advertising geared specifically to appeal to children (like sugary cereal cartoon mascots), to implementing sugar-sweetened-beverage taxes, to having blanket overall bans on food advertising during the daytime.
Mexico is even taking first steps to start addressing junk food’s ubiquity by banning its sale in schools altogether. Schools found to be selling common Mexican junk food fare, such as sugary fruit drinks; chips; artificial pork rinds; and soy-encased, salty peanuts with chili, will see their administrators facing heavy fines.
Because therein lies the biggest rub. Going back to those three simple truths, junk food is hyperpalatable and consequently tends to be what we crave when we’re hungry. So even if we miraculously one day do more than just talk about advertising reforms, and especially given that we won’t be able to do anything about social media’s earned product placements, junk food’s ubiquitous availability within arms’ reach or on our Uber Eats apps will see us be likely to continue its excessive consumption.
That’s not to say we shouldn’t emulate Mexico and Chile’s initiatives, nor that they shouldn’t continue to build upon them, but one thing is certain: Human nature and inconvenient truths around food are incredibly powerful forces that we haven’t yet figured out how to tame.
Dr. Freedhoff, Associate Professor, Department of Family Medicine, University of Ottawa; Medical Director, Bariatric Medical Institute, Ottawa, Ontario, Canada, has disclosed relevant financial relationships with Bariatric Medical Institute, Constant Health, Novo Nordisk, and Weighty Matters.
A version of this article appeared on Medscape.com.
Of those three truths, the one that tends to get more public health attention is advertising. More specifically, advertising junk food to kids.
Back in the days when cable television was king of all free time, study after study tried to quantify junk- and fast-food advertising to kids and speculated about its impact on childhood obesity rates. But as broadcast television use began fading, advertisers — and, of course, studies about advertising — turned their attention first to gaming and now to social media.
The social media numbers are quite staggering. According to a study published — probably not coincidentally — on Halloween, looking at the 40 top brands of junk- and fast food sold in Canada, those 40 brands alone were mentioned over 16 million times by social media users, reaching an estimated 42 billion total users within a 1-year period.
And unique to the challenge of junk- and fast-food advertising on social media is that it also includes “earned” advertising, the kind not paid for by manufacturers but rather the kind where friends, family, and influencers post about junk food. Occasionally, though, these lines are blurred by initiatives from fast-food manufacturers explicitly encouraging social sharing. Consequently, even were there a desire, there isn’t likely to be a regulatory mechanism to markedly reduce it.
For years, here in North America, excepting Quebec, the desire has been mainly to just talk about how concerned we are about junk-food advertising to kids. Elsewhere, however, some countries tried to do more, including both Mexico and Chile, which put kid-targeted TV food advertising bans in place in 2014 and 2016, respectively.
Did they work? It depends on what outcome you’re considering. If the question is, did they work in regard to obesity? — which is how everyone tends to frame the question — by themselves, probably not. No one sandbag stops a flood, and though junk-food advertising is certainly a sandbag, we’re still facing a torrential downpour of obesity contributors. No doubt they did work to reduce kids’ exposure to junk-food advertising on television, but what remains to be seen is whether there is a means to now tackle social media’s generous servings of the same. Moreover, the obesity lens is the wrong one. Ultraprocessed food consumption isn’t good for anyone, regardless of weight, and its reduced marketing and consumption is a worthy goal of its own.
But Chile and Mexico are filling more than single sandbags, as both countries have rolled out a suite of interventions they are hoping will help improve nutrition: from front-of–package labeling reforms and warnings, to the banning of advertising geared specifically to appeal to children (like sugary cereal cartoon mascots), to implementing sugar-sweetened-beverage taxes, to having blanket overall bans on food advertising during the daytime.
Mexico is even taking first steps to start addressing junk food’s ubiquity by banning its sale in schools altogether. Schools found to be selling common Mexican junk food fare, such as sugary fruit drinks; chips; artificial pork rinds; and soy-encased, salty peanuts with chili, will see their administrators facing heavy fines.
Because therein lies the biggest rub. Going back to those three simple truths, junk food is hyperpalatable and consequently tends to be what we crave when we’re hungry. So even if we miraculously one day do more than just talk about advertising reforms, and especially given that we won’t be able to do anything about social media’s earned product placements, junk food’s ubiquitous availability within arms’ reach or on our Uber Eats apps will see us be likely to continue its excessive consumption.
That’s not to say we shouldn’t emulate Mexico and Chile’s initiatives, nor that they shouldn’t continue to build upon them, but one thing is certain: Human nature and inconvenient truths around food are incredibly powerful forces that we haven’t yet figured out how to tame.
Dr. Freedhoff, Associate Professor, Department of Family Medicine, University of Ottawa; Medical Director, Bariatric Medical Institute, Ottawa, Ontario, Canada, has disclosed relevant financial relationships with Bariatric Medical Institute, Constant Health, Novo Nordisk, and Weighty Matters.
A version of this article appeared on Medscape.com.
REALIZE-K: A New Potassium Binder to Help Keep Spiro on Board
This transcript has been edited for clarity.
We have talked often in the past about potassium. Why is potassium so important in heart failure? It’s because many doctors are afraid to give some of the drugs that will raise the potassium, because then you need to deal with it —and everybody is afraid of hyperkalemia causing arrhythmias.
Calm those nerves. Just remember that arrhythmias only occur when the potassium suddenly goes up. This chronic hyperkalemia, which occurs with many of our drugs, usually — I can’t say every time — does not result in arrhythmias.
Patiromer and Zirconium Cyclosilicate
Now, we’ve got potassium binders. You’ve heard me talk about the potassium binders in several of my other chats with you, and they work. We have primarily two of them. The first one that came out was patiromer, and now I’m going to talk to you a little bit about zirconium cyclosilicate, which uses sodium as its exchange ion. Whenever you take out one ion, you have to put another one in, and in this case it’s sodium. Maybe if you use it in the higher doses, you can give the patient more edema or you can make the patient congested with more fluid.
Years ago we did the DIAMOND study; it was a patiromer study, but in essence we found that you could continue to give the drug, particularly the mineralocorticoid receptor antagonists (MRAs) such as spironolactone or eplerenone, as long as you have the patiromer as your safety net, and that the drugs were well tolerated and the adverse events were significantly less.
The REALIZE-K Trial
Now, let’s talk about the REALIZE-K trial. The researchers wanted to prove basically the same thing: that the patients could be started or kept on their spironolactone as long as you had that backup of the zirconium cyclosilicate binder.
They picked patients who had HFrEF — so, low ejection fractions, defined as less than 40% — and they were already on guideline-directed medical therapy, but not an MRA. They divided up the patients right from the beginning between those who were already hyperkalemic — in other words, they had potassiums of 5.1-5.9 mEq/L, which is when doctors start getting worried. GFRs had to be better than 30 mL/min per 1.73 m2, and if the potassium was not yet okay, they were given the zirconium cyclosilicate to normalize the potassium and then they entered the study.
The second group had some history of or were at risk for hyperkalemia. Maybe their GFRs were lower, but their potassiums were somewhere between 3.5 and 5 mEq/L.
They started with about 366 patients. These trials have not been huge, certainly not what we normally see in heart failure trials. About 95 patients had hyperkalemia initially and 271 patients were normokalemic.
Then they were randomized; about 102 patients went on the potassium binder and the other group went on the placebo. They continued the study and they continued to check whether the patient had to come off the drug or had to reduce or remove the spironolactone.
These were older patients, mostly in their early seventies. This was an international trial. There were not that many patients from North America, but they had quite a few patients from Europe and some patients from Latin America. There were many with diabetes, atrial fibrillation, and all the usual comorbidities that we typically see.
The proportions of patients classified as New York Heart Association Class III and IV were about 16% to 17% and the rest were Class II, so this is really the ambulatory population. NT-proBNP levels were elevated, at approximately 1000-1200 pg/mL, and the GFRs were either in the high 40s or about 60 mL/min per 1.73 m2. The patients were pretty well medicated, including with RAAS inhibition, beta-blockers, and even SGLT2 inhibitors.
This is a very typical population and they wanted to see what happened. Did the patients remain on the binder and were they able to tolerate the spironolactone? In fact, that was the case.
At the end of the study, more patients had been able to stay on their spironolactone, which is that one drug that we’re not doing so well on when you look at large databases. If they were on the zirconium drug, they were more likely to stay on the spironolactone. They even did a sensitivity analysis, which really showed that it was consistent across the board.
Edema and Hyperkalemia
Now we have two binders that have shown to us that patients can stay on their drugs. There were some interesting findings here, though.
There was more edema — again, everything is based on small numbers — and there seemed to be more heart failure events in the group that received the zirconium cyclosilicate. The first episode of hyperkalemia was delayed or didn’t happen at all. Again, the hyperkalemia was controlled.
What does that tell you? Well, the exchange is sodium. There had been reports before that if you gave this binder at the higher doses, you would have more retention of sodium. I think we see that in this trial, even though the numbers are very small.
According to the investigators, these were issues that could be resolved through an increase in diuretics or having the patient remember to be careful with their sodium intake so they don’t retain more fluid.
My message to you is to use these binders, whichever one of the two you want or whichever your hospital has available for you on their formulary, because it may give you that sense of comfort and self-efficacy so that you can actually start your patients on an MRA and keep them on it.
The MRAs are lifesaving drugs and the patients with HFrEF need to be on them. This is a way to do it without having to sacrifice your true guideline-directed medical therapy.
Dr. Piña, Professor of Medicine/Cardiology/Heart Failure/Transplant; Quality Officer, Cardiovascular Line, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Clinical Professor of Medicine, Central Michigan University College of Medicine, Mount Pleasant, Michigan; Adjunct Professor of Epidemiology and Biostatistics, Population & Quantitative Health Sciences, Case Western University, Cleveland, Ohio, disclosed ties with the Food and Drug Administration’s Center for Devices and Radiological Health.
A version of this article appeared on Medscape.com
This transcript has been edited for clarity.
We have talked often in the past about potassium. Why is potassium so important in heart failure? It’s because many doctors are afraid to give some of the drugs that will raise the potassium, because then you need to deal with it —and everybody is afraid of hyperkalemia causing arrhythmias.
Calm those nerves. Just remember that arrhythmias only occur when the potassium suddenly goes up. This chronic hyperkalemia, which occurs with many of our drugs, usually — I can’t say every time — does not result in arrhythmias.
Patiromer and Zirconium Cyclosilicate
Now, we’ve got potassium binders. You’ve heard me talk about the potassium binders in several of my other chats with you, and they work. We have primarily two of them. The first one that came out was patiromer, and now I’m going to talk to you a little bit about zirconium cyclosilicate, which uses sodium as its exchange ion. Whenever you take out one ion, you have to put another one in, and in this case it’s sodium. Maybe if you use it in the higher doses, you can give the patient more edema or you can make the patient congested with more fluid.
Years ago we did the DIAMOND study; it was a patiromer study, but in essence we found that you could continue to give the drug, particularly the mineralocorticoid receptor antagonists (MRAs) such as spironolactone or eplerenone, as long as you have the patiromer as your safety net, and that the drugs were well tolerated and the adverse events were significantly less.
The REALIZE-K Trial
Now, let’s talk about the REALIZE-K trial. The researchers wanted to prove basically the same thing: that the patients could be started or kept on their spironolactone as long as you had that backup of the zirconium cyclosilicate binder.
They picked patients who had HFrEF — so, low ejection fractions, defined as less than 40% — and they were already on guideline-directed medical therapy, but not an MRA. They divided up the patients right from the beginning between those who were already hyperkalemic — in other words, they had potassiums of 5.1-5.9 mEq/L, which is when doctors start getting worried. GFRs had to be better than 30 mL/min per 1.73 m2, and if the potassium was not yet okay, they were given the zirconium cyclosilicate to normalize the potassium and then they entered the study.
The second group had some history of or were at risk for hyperkalemia. Maybe their GFRs were lower, but their potassiums were somewhere between 3.5 and 5 mEq/L.
They started with about 366 patients. These trials have not been huge, certainly not what we normally see in heart failure trials. About 95 patients had hyperkalemia initially and 271 patients were normokalemic.
Then they were randomized; about 102 patients went on the potassium binder and the other group went on the placebo. They continued the study and they continued to check whether the patient had to come off the drug or had to reduce or remove the spironolactone.
These were older patients, mostly in their early seventies. This was an international trial. There were not that many patients from North America, but they had quite a few patients from Europe and some patients from Latin America. There were many with diabetes, atrial fibrillation, and all the usual comorbidities that we typically see.
The proportions of patients classified as New York Heart Association Class III and IV were about 16% to 17% and the rest were Class II, so this is really the ambulatory population. NT-proBNP levels were elevated, at approximately 1000-1200 pg/mL, and the GFRs were either in the high 40s or about 60 mL/min per 1.73 m2. The patients were pretty well medicated, including with RAAS inhibition, beta-blockers, and even SGLT2 inhibitors.
This is a very typical population and they wanted to see what happened. Did the patients remain on the binder and were they able to tolerate the spironolactone? In fact, that was the case.
At the end of the study, more patients had been able to stay on their spironolactone, which is that one drug that we’re not doing so well on when you look at large databases. If they were on the zirconium drug, they were more likely to stay on the spironolactone. They even did a sensitivity analysis, which really showed that it was consistent across the board.
Edema and Hyperkalemia
Now we have two binders that have shown to us that patients can stay on their drugs. There were some interesting findings here, though.
There was more edema — again, everything is based on small numbers — and there seemed to be more heart failure events in the group that received the zirconium cyclosilicate. The first episode of hyperkalemia was delayed or didn’t happen at all. Again, the hyperkalemia was controlled.
What does that tell you? Well, the exchange is sodium. There had been reports before that if you gave this binder at the higher doses, you would have more retention of sodium. I think we see that in this trial, even though the numbers are very small.
According to the investigators, these were issues that could be resolved through an increase in diuretics or having the patient remember to be careful with their sodium intake so they don’t retain more fluid.
My message to you is to use these binders, whichever one of the two you want or whichever your hospital has available for you on their formulary, because it may give you that sense of comfort and self-efficacy so that you can actually start your patients on an MRA and keep them on it.
The MRAs are lifesaving drugs and the patients with HFrEF need to be on them. This is a way to do it without having to sacrifice your true guideline-directed medical therapy.
Dr. Piña, Professor of Medicine/Cardiology/Heart Failure/Transplant; Quality Officer, Cardiovascular Line, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Clinical Professor of Medicine, Central Michigan University College of Medicine, Mount Pleasant, Michigan; Adjunct Professor of Epidemiology and Biostatistics, Population & Quantitative Health Sciences, Case Western University, Cleveland, Ohio, disclosed ties with the Food and Drug Administration’s Center for Devices and Radiological Health.
A version of this article appeared on Medscape.com
This transcript has been edited for clarity.
We have talked often in the past about potassium. Why is potassium so important in heart failure? It’s because many doctors are afraid to give some of the drugs that will raise the potassium, because then you need to deal with it —and everybody is afraid of hyperkalemia causing arrhythmias.
Calm those nerves. Just remember that arrhythmias only occur when the potassium suddenly goes up. This chronic hyperkalemia, which occurs with many of our drugs, usually — I can’t say every time — does not result in arrhythmias.
Patiromer and Zirconium Cyclosilicate
Now, we’ve got potassium binders. You’ve heard me talk about the potassium binders in several of my other chats with you, and they work. We have primarily two of them. The first one that came out was patiromer, and now I’m going to talk to you a little bit about zirconium cyclosilicate, which uses sodium as its exchange ion. Whenever you take out one ion, you have to put another one in, and in this case it’s sodium. Maybe if you use it in the higher doses, you can give the patient more edema or you can make the patient congested with more fluid.
Years ago we did the DIAMOND study; it was a patiromer study, but in essence we found that you could continue to give the drug, particularly the mineralocorticoid receptor antagonists (MRAs) such as spironolactone or eplerenone, as long as you have the patiromer as your safety net, and that the drugs were well tolerated and the adverse events were significantly less.
The REALIZE-K Trial
Now, let’s talk about the REALIZE-K trial. The researchers wanted to prove basically the same thing: that the patients could be started or kept on their spironolactone as long as you had that backup of the zirconium cyclosilicate binder.
They picked patients who had HFrEF — so, low ejection fractions, defined as less than 40% — and they were already on guideline-directed medical therapy, but not an MRA. They divided up the patients right from the beginning between those who were already hyperkalemic — in other words, they had potassiums of 5.1-5.9 mEq/L, which is when doctors start getting worried. GFRs had to be better than 30 mL/min per 1.73 m2, and if the potassium was not yet okay, they were given the zirconium cyclosilicate to normalize the potassium and then they entered the study.
The second group had some history of or were at risk for hyperkalemia. Maybe their GFRs were lower, but their potassiums were somewhere between 3.5 and 5 mEq/L.
They started with about 366 patients. These trials have not been huge, certainly not what we normally see in heart failure trials. About 95 patients had hyperkalemia initially and 271 patients were normokalemic.
Then they were randomized; about 102 patients went on the potassium binder and the other group went on the placebo. They continued the study and they continued to check whether the patient had to come off the drug or had to reduce or remove the spironolactone.
These were older patients, mostly in their early seventies. This was an international trial. There were not that many patients from North America, but they had quite a few patients from Europe and some patients from Latin America. There were many with diabetes, atrial fibrillation, and all the usual comorbidities that we typically see.
The proportions of patients classified as New York Heart Association Class III and IV were about 16% to 17% and the rest were Class II, so this is really the ambulatory population. NT-proBNP levels were elevated, at approximately 1000-1200 pg/mL, and the GFRs were either in the high 40s or about 60 mL/min per 1.73 m2. The patients were pretty well medicated, including with RAAS inhibition, beta-blockers, and even SGLT2 inhibitors.
This is a very typical population and they wanted to see what happened. Did the patients remain on the binder and were they able to tolerate the spironolactone? In fact, that was the case.
At the end of the study, more patients had been able to stay on their spironolactone, which is that one drug that we’re not doing so well on when you look at large databases. If they were on the zirconium drug, they were more likely to stay on the spironolactone. They even did a sensitivity analysis, which really showed that it was consistent across the board.
Edema and Hyperkalemia
Now we have two binders that have shown to us that patients can stay on their drugs. There were some interesting findings here, though.
There was more edema — again, everything is based on small numbers — and there seemed to be more heart failure events in the group that received the zirconium cyclosilicate. The first episode of hyperkalemia was delayed or didn’t happen at all. Again, the hyperkalemia was controlled.
What does that tell you? Well, the exchange is sodium. There had been reports before that if you gave this binder at the higher doses, you would have more retention of sodium. I think we see that in this trial, even though the numbers are very small.
According to the investigators, these were issues that could be resolved through an increase in diuretics or having the patient remember to be careful with their sodium intake so they don’t retain more fluid.
My message to you is to use these binders, whichever one of the two you want or whichever your hospital has available for you on their formulary, because it may give you that sense of comfort and self-efficacy so that you can actually start your patients on an MRA and keep them on it.
The MRAs are lifesaving drugs and the patients with HFrEF need to be on them. This is a way to do it without having to sacrifice your true guideline-directed medical therapy.
Dr. Piña, Professor of Medicine/Cardiology/Heart Failure/Transplant; Quality Officer, Cardiovascular Line, Sidney Kimmel College of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Clinical Professor of Medicine, Central Michigan University College of Medicine, Mount Pleasant, Michigan; Adjunct Professor of Epidemiology and Biostatistics, Population & Quantitative Health Sciences, Case Western University, Cleveland, Ohio, disclosed ties with the Food and Drug Administration’s Center for Devices and Radiological Health.
A version of this article appeared on Medscape.com
Focus on Nutrient Density Instead of Limiting Certain Foods
The word “malnutrition” probably brings to mind images of very thin patients with catabolic illness. But it really just means “poor nutrition,” which can — and often does — apply to patients with overweight or obesity.
That’s because malnutrition doesn’t occur simply because of a lack of calories, but rather because there is a gap in the nutrition the body requires and the nutrition it receives.
Each day, clinicians see patients with chronic conditions related to malnutrition. That list includes diabetes and hypertension, which can be promoted by excess intake of certain nutrients (carbohydrates and sodium) or inadequate intake of others (fiber, protein, potassium, magnesium, and calcium).
Diet Education Is Vital in Chronic Disease Management
Diet education is without a doubt a core pillar of chronic disease management. Nutrition therapy is recommended in treatment guidelines for the management of some of the most commonly seen chronic conditions such as hypertension, diabetes, and kidney disease. But in one study, only 58% of physicians, nurses and other health professionals surveyed had received formal nutrition education and only 40% were confident in their ability to provide nutrition education to patients.
As a registered dietitian, I welcome referrals for both prevention and management of chronic diseases with open arms. But medical nutrition therapy with a registered dietitian may not be realistic for all patients owing to financial, geographic, or other constraints. So, their best option may be the few minutes that a physician or physician extender has to spare at the end of their appointment.
But time constraints may result in clinicians turning to short, easy-to-remember messages such as “Don’t eat anything white” or “Only shop the edges of the grocery store.” Although catchy, this type of advice can inadvertently encourage patients to skip over foods that are actually very nutrient dense. For example, white foods such as onions, turnips, mushrooms, cauliflower, and even popcorn are low in calories and high in nutritional value. The center aisles of the grocery store may harbor high-carbohydrate breakfast cereals and potato chips, but they are also home to legumes, nuts, and canned and frozen fruits and vegetables.
What may be more effective is educating the patient on the importance of focusing on the nutrient density of foods, rather than simply limiting certain food groups or colors.
How to Work Nutrient Density into the Conversation
Nutrient density is a concept that refers to the proportion of nutrients to calories in a food item: essentially, a food’s qualitative nutritional value. It provides more depth than simply referring to foods as being high or low in calories, healthy or unhealthy, or good or bad.
Educating patients about nutrition density and encouraging a focus on foods that are low in calories and high in vitamins and minerals can help address micronutrient deficiencies, which may be more common than previously thought and linked to the chronic diseases that we see daily. It is worth noting that some foods that are not low in calories are still nutrient dense. Avocados, liver, and nuts come to mind as foods that are high in calories, but they have additional nutrients such as fiber, potassium, antioxidants, vitamin A, iron, and selenium that can still make them an excellent choice if they are part of a well-balanced diet.
I fear that we often underestimate our patients. We worry that not providing them with a list of acceptable foods will set them up for failure. But, in my experience, that list of “good” and “bad” foods may be useful for a week or so but will eventually become lost on the fridge under children’s artwork and save-the-dates.
Patients know that potato chips offer little more than fat, carbs, and salt and that they’re a poor choice for long-term health. What they might not know is that cocktail peanuts can also satisfy the craving for a salty snack, with more than four times the protein, twice the fiber, and just over half of the sodium found in the same serving size of regular salted potato chips. Peanuts have the added bonus of being high in heart-healthy monounsaturated fatty acids.
The best thing that clinicians can do with just a few minutes of time for diet education is to talk to patients about the nutrient density of whole foods and caution patients against highly processed foods, because processing can decrease nutritional content. Our most effective option is to explain why a varied diet with focus on fruits, vegetables, lean protein, nuts, legumes, and healthy fats is beneficial for cardiovascular and metabolic health. After that, all that is left is to trust the patient to make the right choices for their health.
Brandy Winfree Root, a renal dietitian in private practice in Mary Esther, Florida, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
The word “malnutrition” probably brings to mind images of very thin patients with catabolic illness. But it really just means “poor nutrition,” which can — and often does — apply to patients with overweight or obesity.
That’s because malnutrition doesn’t occur simply because of a lack of calories, but rather because there is a gap in the nutrition the body requires and the nutrition it receives.
Each day, clinicians see patients with chronic conditions related to malnutrition. That list includes diabetes and hypertension, which can be promoted by excess intake of certain nutrients (carbohydrates and sodium) or inadequate intake of others (fiber, protein, potassium, magnesium, and calcium).
Diet Education Is Vital in Chronic Disease Management
Diet education is without a doubt a core pillar of chronic disease management. Nutrition therapy is recommended in treatment guidelines for the management of some of the most commonly seen chronic conditions such as hypertension, diabetes, and kidney disease. But in one study, only 58% of physicians, nurses and other health professionals surveyed had received formal nutrition education and only 40% were confident in their ability to provide nutrition education to patients.
As a registered dietitian, I welcome referrals for both prevention and management of chronic diseases with open arms. But medical nutrition therapy with a registered dietitian may not be realistic for all patients owing to financial, geographic, or other constraints. So, their best option may be the few minutes that a physician or physician extender has to spare at the end of their appointment.
But time constraints may result in clinicians turning to short, easy-to-remember messages such as “Don’t eat anything white” or “Only shop the edges of the grocery store.” Although catchy, this type of advice can inadvertently encourage patients to skip over foods that are actually very nutrient dense. For example, white foods such as onions, turnips, mushrooms, cauliflower, and even popcorn are low in calories and high in nutritional value. The center aisles of the grocery store may harbor high-carbohydrate breakfast cereals and potato chips, but they are also home to legumes, nuts, and canned and frozen fruits and vegetables.
What may be more effective is educating the patient on the importance of focusing on the nutrient density of foods, rather than simply limiting certain food groups or colors.
How to Work Nutrient Density into the Conversation
Nutrient density is a concept that refers to the proportion of nutrients to calories in a food item: essentially, a food’s qualitative nutritional value. It provides more depth than simply referring to foods as being high or low in calories, healthy or unhealthy, or good or bad.
Educating patients about nutrition density and encouraging a focus on foods that are low in calories and high in vitamins and minerals can help address micronutrient deficiencies, which may be more common than previously thought and linked to the chronic diseases that we see daily. It is worth noting that some foods that are not low in calories are still nutrient dense. Avocados, liver, and nuts come to mind as foods that are high in calories, but they have additional nutrients such as fiber, potassium, antioxidants, vitamin A, iron, and selenium that can still make them an excellent choice if they are part of a well-balanced diet.
I fear that we often underestimate our patients. We worry that not providing them with a list of acceptable foods will set them up for failure. But, in my experience, that list of “good” and “bad” foods may be useful for a week or so but will eventually become lost on the fridge under children’s artwork and save-the-dates.
Patients know that potato chips offer little more than fat, carbs, and salt and that they’re a poor choice for long-term health. What they might not know is that cocktail peanuts can also satisfy the craving for a salty snack, with more than four times the protein, twice the fiber, and just over half of the sodium found in the same serving size of regular salted potato chips. Peanuts have the added bonus of being high in heart-healthy monounsaturated fatty acids.
The best thing that clinicians can do with just a few minutes of time for diet education is to talk to patients about the nutrient density of whole foods and caution patients against highly processed foods, because processing can decrease nutritional content. Our most effective option is to explain why a varied diet with focus on fruits, vegetables, lean protein, nuts, legumes, and healthy fats is beneficial for cardiovascular and metabolic health. After that, all that is left is to trust the patient to make the right choices for their health.
Brandy Winfree Root, a renal dietitian in private practice in Mary Esther, Florida, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
The word “malnutrition” probably brings to mind images of very thin patients with catabolic illness. But it really just means “poor nutrition,” which can — and often does — apply to patients with overweight or obesity.
That’s because malnutrition doesn’t occur simply because of a lack of calories, but rather because there is a gap in the nutrition the body requires and the nutrition it receives.
Each day, clinicians see patients with chronic conditions related to malnutrition. That list includes diabetes and hypertension, which can be promoted by excess intake of certain nutrients (carbohydrates and sodium) or inadequate intake of others (fiber, protein, potassium, magnesium, and calcium).
Diet Education Is Vital in Chronic Disease Management
Diet education is without a doubt a core pillar of chronic disease management. Nutrition therapy is recommended in treatment guidelines for the management of some of the most commonly seen chronic conditions such as hypertension, diabetes, and kidney disease. But in one study, only 58% of physicians, nurses and other health professionals surveyed had received formal nutrition education and only 40% were confident in their ability to provide nutrition education to patients.
As a registered dietitian, I welcome referrals for both prevention and management of chronic diseases with open arms. But medical nutrition therapy with a registered dietitian may not be realistic for all patients owing to financial, geographic, or other constraints. So, their best option may be the few minutes that a physician or physician extender has to spare at the end of their appointment.
But time constraints may result in clinicians turning to short, easy-to-remember messages such as “Don’t eat anything white” or “Only shop the edges of the grocery store.” Although catchy, this type of advice can inadvertently encourage patients to skip over foods that are actually very nutrient dense. For example, white foods such as onions, turnips, mushrooms, cauliflower, and even popcorn are low in calories and high in nutritional value. The center aisles of the grocery store may harbor high-carbohydrate breakfast cereals and potato chips, but they are also home to legumes, nuts, and canned and frozen fruits and vegetables.
What may be more effective is educating the patient on the importance of focusing on the nutrient density of foods, rather than simply limiting certain food groups or colors.
How to Work Nutrient Density into the Conversation
Nutrient density is a concept that refers to the proportion of nutrients to calories in a food item: essentially, a food’s qualitative nutritional value. It provides more depth than simply referring to foods as being high or low in calories, healthy or unhealthy, or good or bad.
Educating patients about nutrition density and encouraging a focus on foods that are low in calories and high in vitamins and minerals can help address micronutrient deficiencies, which may be more common than previously thought and linked to the chronic diseases that we see daily. It is worth noting that some foods that are not low in calories are still nutrient dense. Avocados, liver, and nuts come to mind as foods that are high in calories, but they have additional nutrients such as fiber, potassium, antioxidants, vitamin A, iron, and selenium that can still make them an excellent choice if they are part of a well-balanced diet.
I fear that we often underestimate our patients. We worry that not providing them with a list of acceptable foods will set them up for failure. But, in my experience, that list of “good” and “bad” foods may be useful for a week or so but will eventually become lost on the fridge under children’s artwork and save-the-dates.
Patients know that potato chips offer little more than fat, carbs, and salt and that they’re a poor choice for long-term health. What they might not know is that cocktail peanuts can also satisfy the craving for a salty snack, with more than four times the protein, twice the fiber, and just over half of the sodium found in the same serving size of regular salted potato chips. Peanuts have the added bonus of being high in heart-healthy monounsaturated fatty acids.
The best thing that clinicians can do with just a few minutes of time for diet education is to talk to patients about the nutrient density of whole foods and caution patients against highly processed foods, because processing can decrease nutritional content. Our most effective option is to explain why a varied diet with focus on fruits, vegetables, lean protein, nuts, legumes, and healthy fats is beneficial for cardiovascular and metabolic health. After that, all that is left is to trust the patient to make the right choices for their health.
Brandy Winfree Root, a renal dietitian in private practice in Mary Esther, Florida, has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Maintaining Weight Loss With GLP-1s Needs Lifestyle Changes
This transcript has been edited for clarity.
Nearly every patient I start on incretin therapy for weight loss asks me the same question, which is, will I have to stay on this forever? The answer is probably yes, but I think it’s much more nuanced than that because A) forever is a long time and B) I think there are various ways to approach this.
I want people to start just saying, let’s see how this works, because not everyone’s going to lose the same amount of weight or respond in the same way. I say let’s try it, but don’t stop it suddenly. If we decide at some point you don’t need quite the same dose, we can reduce the dose and maybe even reduce the frequency of giving it, but you don’t want to stop cold turkey because you may well regain the weight, and that’s obviously not our desired outcome.
There have been multiple clinical trials in which people started on an incretin hormone, either a glucagon-like peptide 1 (GLP-1) receptor agonist or a dual hormone, and they’ve actually shown that stopping it and then continuing patients on a placebo vs active drug results in continued weight gain over time vs either weight maintenance or weight loss when they remain on the incretin hormone. Clearly, on average, people will regain the weight, but that isn’t always true.
One of the things I think is really important is that, from the get-go on starting on these hormones, people start working with a lifestyle plan, whether it’s working with a coach or an online program. However they approach this, it’s important to start changing habits and increasing exercise.
I can’t say how important this is enough, because people need to increase their physical activity to enhance the benefits of these agents and also to help retain lean body mass. I don’t want people losing a large amount of lean body mass as they go through the process of weight loss.
I set the stage for the fact that I expect people to adhere to a lifestyle program, and maybe losing weight with the medications is going to help them do even better because they’re going to see positive outcomes.
When they get to the point of weight maintenance, I think we need to reinforce lifestyle. I either go down on the dose given weekly or I start having patients take the dose every other week, for instance, as opposed to every week, and then sometimes every month. Depending on the patient, I get them potentially to a lower dose, and then they’re able to maintain the weight as long as they improved their lifestyle along with the changes in the medication.
I tell people we’ll work with the drug, we’ll work with their metabolic needs, that there are many benefits to being on incretin hormone therapy, but I think it’s important that we can do this on an individualized basis. The thing I don’t want to happen, though, is for people to start on it and then stop it, and then start on it and stop it because they may lose weight, regain weight, get side effects, get used to the side effects, stop it, and start it.
As we know, that’s not the best way to do this, and I think it’s not healthy for people to do that either. I know it’s been somewhat problematic with supply chain issues, but hopefully we’ll be able to start these agents, reach the desired outcome in terms of weight loss, and then help patients maintain that weight with a combination of both medication and lifestyle.
Dr. Peters, professor, Department of Clinical Medicine, Keck School of Medicine; Director, University of Southern California Westside Center for Diabetes, Los Angeles, disclosed ties with Abbott Diabetes Care, Becton Dickinson; Boehringer Ingelheim Pharmaceuticals, Eli Lilly, Lexicon Pharmaceuticals, Livongo; Medscape; Merck, Novo Nordisk, Omada Health, OptumHealth, Sanofi, Zafgen, Dexcom, MannKind, and AstraZeneca.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Nearly every patient I start on incretin therapy for weight loss asks me the same question, which is, will I have to stay on this forever? The answer is probably yes, but I think it’s much more nuanced than that because A) forever is a long time and B) I think there are various ways to approach this.
I want people to start just saying, let’s see how this works, because not everyone’s going to lose the same amount of weight or respond in the same way. I say let’s try it, but don’t stop it suddenly. If we decide at some point you don’t need quite the same dose, we can reduce the dose and maybe even reduce the frequency of giving it, but you don’t want to stop cold turkey because you may well regain the weight, and that’s obviously not our desired outcome.
There have been multiple clinical trials in which people started on an incretin hormone, either a glucagon-like peptide 1 (GLP-1) receptor agonist or a dual hormone, and they’ve actually shown that stopping it and then continuing patients on a placebo vs active drug results in continued weight gain over time vs either weight maintenance or weight loss when they remain on the incretin hormone. Clearly, on average, people will regain the weight, but that isn’t always true.
One of the things I think is really important is that, from the get-go on starting on these hormones, people start working with a lifestyle plan, whether it’s working with a coach or an online program. However they approach this, it’s important to start changing habits and increasing exercise.
I can’t say how important this is enough, because people need to increase their physical activity to enhance the benefits of these agents and also to help retain lean body mass. I don’t want people losing a large amount of lean body mass as they go through the process of weight loss.
I set the stage for the fact that I expect people to adhere to a lifestyle program, and maybe losing weight with the medications is going to help them do even better because they’re going to see positive outcomes.
When they get to the point of weight maintenance, I think we need to reinforce lifestyle. I either go down on the dose given weekly or I start having patients take the dose every other week, for instance, as opposed to every week, and then sometimes every month. Depending on the patient, I get them potentially to a lower dose, and then they’re able to maintain the weight as long as they improved their lifestyle along with the changes in the medication.
I tell people we’ll work with the drug, we’ll work with their metabolic needs, that there are many benefits to being on incretin hormone therapy, but I think it’s important that we can do this on an individualized basis. The thing I don’t want to happen, though, is for people to start on it and then stop it, and then start on it and stop it because they may lose weight, regain weight, get side effects, get used to the side effects, stop it, and start it.
As we know, that’s not the best way to do this, and I think it’s not healthy for people to do that either. I know it’s been somewhat problematic with supply chain issues, but hopefully we’ll be able to start these agents, reach the desired outcome in terms of weight loss, and then help patients maintain that weight with a combination of both medication and lifestyle.
Dr. Peters, professor, Department of Clinical Medicine, Keck School of Medicine; Director, University of Southern California Westside Center for Diabetes, Los Angeles, disclosed ties with Abbott Diabetes Care, Becton Dickinson; Boehringer Ingelheim Pharmaceuticals, Eli Lilly, Lexicon Pharmaceuticals, Livongo; Medscape; Merck, Novo Nordisk, Omada Health, OptumHealth, Sanofi, Zafgen, Dexcom, MannKind, and AstraZeneca.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Nearly every patient I start on incretin therapy for weight loss asks me the same question, which is, will I have to stay on this forever? The answer is probably yes, but I think it’s much more nuanced than that because A) forever is a long time and B) I think there are various ways to approach this.
I want people to start just saying, let’s see how this works, because not everyone’s going to lose the same amount of weight or respond in the same way. I say let’s try it, but don’t stop it suddenly. If we decide at some point you don’t need quite the same dose, we can reduce the dose and maybe even reduce the frequency of giving it, but you don’t want to stop cold turkey because you may well regain the weight, and that’s obviously not our desired outcome.
There have been multiple clinical trials in which people started on an incretin hormone, either a glucagon-like peptide 1 (GLP-1) receptor agonist or a dual hormone, and they’ve actually shown that stopping it and then continuing patients on a placebo vs active drug results in continued weight gain over time vs either weight maintenance or weight loss when they remain on the incretin hormone. Clearly, on average, people will regain the weight, but that isn’t always true.
One of the things I think is really important is that, from the get-go on starting on these hormones, people start working with a lifestyle plan, whether it’s working with a coach or an online program. However they approach this, it’s important to start changing habits and increasing exercise.
I can’t say how important this is enough, because people need to increase their physical activity to enhance the benefits of these agents and also to help retain lean body mass. I don’t want people losing a large amount of lean body mass as they go through the process of weight loss.
I set the stage for the fact that I expect people to adhere to a lifestyle program, and maybe losing weight with the medications is going to help them do even better because they’re going to see positive outcomes.
When they get to the point of weight maintenance, I think we need to reinforce lifestyle. I either go down on the dose given weekly or I start having patients take the dose every other week, for instance, as opposed to every week, and then sometimes every month. Depending on the patient, I get them potentially to a lower dose, and then they’re able to maintain the weight as long as they improved their lifestyle along with the changes in the medication.
I tell people we’ll work with the drug, we’ll work with their metabolic needs, that there are many benefits to being on incretin hormone therapy, but I think it’s important that we can do this on an individualized basis. The thing I don’t want to happen, though, is for people to start on it and then stop it, and then start on it and stop it because they may lose weight, regain weight, get side effects, get used to the side effects, stop it, and start it.
As we know, that’s not the best way to do this, and I think it’s not healthy for people to do that either. I know it’s been somewhat problematic with supply chain issues, but hopefully we’ll be able to start these agents, reach the desired outcome in terms of weight loss, and then help patients maintain that weight with a combination of both medication and lifestyle.
Dr. Peters, professor, Department of Clinical Medicine, Keck School of Medicine; Director, University of Southern California Westside Center for Diabetes, Los Angeles, disclosed ties with Abbott Diabetes Care, Becton Dickinson; Boehringer Ingelheim Pharmaceuticals, Eli Lilly, Lexicon Pharmaceuticals, Livongo; Medscape; Merck, Novo Nordisk, Omada Health, OptumHealth, Sanofi, Zafgen, Dexcom, MannKind, and AstraZeneca.
A version of this article first appeared on Medscape.com.
New Approaches to Research Beyond Massive Clinical Trials
This transcript has been edited for clarity.
I want to briefly present a fascinating effort, one that needs to be applauded and applauded again, and then we need to scratch our collective heads and ask, why did we do it and what did we learn?
I’m referring to a report recently published in Annals of Internal Medicine, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial.” The title of this report does not do it justice. This was a massive effort — one could, I believe, even use the term Herculean — to ask an important question that was asked more than 20 years ago.
This was a national women’s health initiative to answer these questions. The study looked at 36,282 postmenopausal women who, at the time of agreeing to be randomized in this trial, had no history of breast or colorectal cancer. This was a 7-year randomized intervention effort, and 40 centers across the United States participated, obviously funded by the government. Randomization was one-to-one to placebo or 1000 mg calcium and 400 international units of vitamin D3 daily.
They looked at the incidence of colorectal cancer, breast cancer, and total cancer, and importantly as an endpoint, total cardiovascular disease and hip fractures. They didn’t comment on hip fractures in this particular analysis. Obviously, hip fractures relate to this question of osteoporosis in postmenopausal women.
Here’s the bottom line: With a median follow-up now of 22.3 years — that’s not 2 years, but 22.3 years — there was a 7% decrease in cancer mortality in the population that received the calcium and vitamin D3. This is nothing to snicker at, and nothing at which to say, “Wow. That’s not important.”
However, in this analysis involving several tens of thousands of women, there was a 6% increase in cardiovascular disease mortality noted and reported. Overall, there was no effect on all-cause mortality of this intervention, with a hazard ratio — you rarely see this — of 1.00.
There is much that can be said, but I will summarize my comments very briefly. Criticize this if you want. It’s not inappropriate to criticize, but what was the individual impact of the calcium vs vitamin D? If they had only used one vs the other, or used both but in separate arms of the trial, and you could have separated what might have caused the decrease in cancer mortality and not the increased cardiovascular disease… This was designed more than 20 years ago. That’s one point.
The second is, how many more tens of thousands of patients would they have had to add to do this, and at what cost? This was a massive study, a national study, and a simple study in terms of the intervention. It was low risk except if you look at the long-term outcome. You can only imagine how much it would cost to do that study today — not the cost of the calcium, the vitamin D3, but the cost of doing the trial that was concluded to have no impact.
From a societal perspective, this was an important question to answer, certainly then. What did we learn and at what cost? The bottom line is that we have to figure out a way of answering these kinds of questions.
Perhaps now they should be from real-world data, looking at electronic medical records or at a variety of other population-based data so that we can get the answer — not in 20 years but in perhaps 2 months, because we’ve looked at the data using artificial intelligence to help us to answer these questions; and maybe not 36,000 patients but 360,000 individuals looked at over this period of time.
Again, I’m proposing an alternative solution because the questions that were asked 20 years ago remain important today. This cannot be the way that we, in the future, try to answer them, certainly from the perspective of cost and also the perspective of time to get the answers.
Let me conclude by, again, applauding these researchers because of the quality of the work they started out doing and ended up doing and reporting. Also, I think we’ve learned that we have to come up with alternative ways to answer what were important questions then and are important questions today.
Dr. Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, disclosed ties with GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I want to briefly present a fascinating effort, one that needs to be applauded and applauded again, and then we need to scratch our collective heads and ask, why did we do it and what did we learn?
I’m referring to a report recently published in Annals of Internal Medicine, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial.” The title of this report does not do it justice. This was a massive effort — one could, I believe, even use the term Herculean — to ask an important question that was asked more than 20 years ago.
This was a national women’s health initiative to answer these questions. The study looked at 36,282 postmenopausal women who, at the time of agreeing to be randomized in this trial, had no history of breast or colorectal cancer. This was a 7-year randomized intervention effort, and 40 centers across the United States participated, obviously funded by the government. Randomization was one-to-one to placebo or 1000 mg calcium and 400 international units of vitamin D3 daily.
They looked at the incidence of colorectal cancer, breast cancer, and total cancer, and importantly as an endpoint, total cardiovascular disease and hip fractures. They didn’t comment on hip fractures in this particular analysis. Obviously, hip fractures relate to this question of osteoporosis in postmenopausal women.
Here’s the bottom line: With a median follow-up now of 22.3 years — that’s not 2 years, but 22.3 years — there was a 7% decrease in cancer mortality in the population that received the calcium and vitamin D3. This is nothing to snicker at, and nothing at which to say, “Wow. That’s not important.”
However, in this analysis involving several tens of thousands of women, there was a 6% increase in cardiovascular disease mortality noted and reported. Overall, there was no effect on all-cause mortality of this intervention, with a hazard ratio — you rarely see this — of 1.00.
There is much that can be said, but I will summarize my comments very briefly. Criticize this if you want. It’s not inappropriate to criticize, but what was the individual impact of the calcium vs vitamin D? If they had only used one vs the other, or used both but in separate arms of the trial, and you could have separated what might have caused the decrease in cancer mortality and not the increased cardiovascular disease… This was designed more than 20 years ago. That’s one point.
The second is, how many more tens of thousands of patients would they have had to add to do this, and at what cost? This was a massive study, a national study, and a simple study in terms of the intervention. It was low risk except if you look at the long-term outcome. You can only imagine how much it would cost to do that study today — not the cost of the calcium, the vitamin D3, but the cost of doing the trial that was concluded to have no impact.
From a societal perspective, this was an important question to answer, certainly then. What did we learn and at what cost? The bottom line is that we have to figure out a way of answering these kinds of questions.
Perhaps now they should be from real-world data, looking at electronic medical records or at a variety of other population-based data so that we can get the answer — not in 20 years but in perhaps 2 months, because we’ve looked at the data using artificial intelligence to help us to answer these questions; and maybe not 36,000 patients but 360,000 individuals looked at over this period of time.
Again, I’m proposing an alternative solution because the questions that were asked 20 years ago remain important today. This cannot be the way that we, in the future, try to answer them, certainly from the perspective of cost and also the perspective of time to get the answers.
Let me conclude by, again, applauding these researchers because of the quality of the work they started out doing and ended up doing and reporting. Also, I think we’ve learned that we have to come up with alternative ways to answer what were important questions then and are important questions today.
Dr. Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, disclosed ties with GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I want to briefly present a fascinating effort, one that needs to be applauded and applauded again, and then we need to scratch our collective heads and ask, why did we do it and what did we learn?
I’m referring to a report recently published in Annals of Internal Medicine, “Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial.” The title of this report does not do it justice. This was a massive effort — one could, I believe, even use the term Herculean — to ask an important question that was asked more than 20 years ago.
This was a national women’s health initiative to answer these questions. The study looked at 36,282 postmenopausal women who, at the time of agreeing to be randomized in this trial, had no history of breast or colorectal cancer. This was a 7-year randomized intervention effort, and 40 centers across the United States participated, obviously funded by the government. Randomization was one-to-one to placebo or 1000 mg calcium and 400 international units of vitamin D3 daily.
They looked at the incidence of colorectal cancer, breast cancer, and total cancer, and importantly as an endpoint, total cardiovascular disease and hip fractures. They didn’t comment on hip fractures in this particular analysis. Obviously, hip fractures relate to this question of osteoporosis in postmenopausal women.
Here’s the bottom line: With a median follow-up now of 22.3 years — that’s not 2 years, but 22.3 years — there was a 7% decrease in cancer mortality in the population that received the calcium and vitamin D3. This is nothing to snicker at, and nothing at which to say, “Wow. That’s not important.”
However, in this analysis involving several tens of thousands of women, there was a 6% increase in cardiovascular disease mortality noted and reported. Overall, there was no effect on all-cause mortality of this intervention, with a hazard ratio — you rarely see this — of 1.00.
There is much that can be said, but I will summarize my comments very briefly. Criticize this if you want. It’s not inappropriate to criticize, but what was the individual impact of the calcium vs vitamin D? If they had only used one vs the other, or used both but in separate arms of the trial, and you could have separated what might have caused the decrease in cancer mortality and not the increased cardiovascular disease… This was designed more than 20 years ago. That’s one point.
The second is, how many more tens of thousands of patients would they have had to add to do this, and at what cost? This was a massive study, a national study, and a simple study in terms of the intervention. It was low risk except if you look at the long-term outcome. You can only imagine how much it would cost to do that study today — not the cost of the calcium, the vitamin D3, but the cost of doing the trial that was concluded to have no impact.
From a societal perspective, this was an important question to answer, certainly then. What did we learn and at what cost? The bottom line is that we have to figure out a way of answering these kinds of questions.
Perhaps now they should be from real-world data, looking at electronic medical records or at a variety of other population-based data so that we can get the answer — not in 20 years but in perhaps 2 months, because we’ve looked at the data using artificial intelligence to help us to answer these questions; and maybe not 36,000 patients but 360,000 individuals looked at over this period of time.
Again, I’m proposing an alternative solution because the questions that were asked 20 years ago remain important today. This cannot be the way that we, in the future, try to answer them, certainly from the perspective of cost and also the perspective of time to get the answers.
Let me conclude by, again, applauding these researchers because of the quality of the work they started out doing and ended up doing and reporting. Also, I think we’ve learned that we have to come up with alternative ways to answer what were important questions then and are important questions today.
Dr. Markman, Professor of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center; President, Medicine & Science, City of Hope Atlanta, Chicago, Phoenix, disclosed ties with GlaxoSmithKline and AstraZeneca.
A version of this article first appeared on Medscape.com.