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Some, not all, ultraprocessed foods linked to type 2 diabetes
High total intake of ultraprocessed food (UPF) is associated with an increased risk of developing type 2 diabetes, suggests a large-scale analysis that nevertheless revealed that the risk applies only to certain such foods.
The research was recently published in Diabetes Care by Zhangling Chen, PhD, Erasmus MC Rotterdam, Netherlands, and colleagues.
Examining almost 200,000 participants in three U.S. studies, yielding more than 5 million person-years of follow-up, the scientists found that high intake of UPF was associated with a 28% increased risk of type 2 diabetes, after statistical adjustments.
However, the increased risk was restricted to certain UPFs, including ready meals, refined breads, sweetened beverages, and sauces and condiments, with other foods considered UPFs, such as cereals, dark- and whole grain breads, and packaged sweet and savory snacks, among others, associated with a reduced risk of diabetes.
Senior author Jean-Philippe Drouin-Chartier, PhD, Nutrition Center, Laval University, Quebec City, told this news organization: “While whole grain breads can be considered as ultraprocessed foods, their consumption should not be discouraged. In our study, we observed that whole grain breads consumption is inversely associated with type 2 diabetes risk. This is supported by many studies linking dietary fiber consumption to better cardiometabolic health.”
Ultraprocessed food intake higher in the U.S. than in Europe
The researchers note that a handful of European studies have also reported an association between UPF consumption and increased type 2 diabetes risk, with the effect ranging from 15% to 53%, depending on the level of intake and the cohort of patients studied.
They note, however, that total UPF intake in the U.S. is “much higher than in Europe,” particularly in the case of ultraprocessed breads and cereals and artificially or sugar-sweetened beverages.
In the current study, they examined data on 71,781 women from the Nurses’ Health Study, 87,918 women from the NHS II, and 38,847 men from the Health Professional Follow-up Study, none of whom had cardiovascular disease, cancer, or diabetes at baseline.
In all three studies, questionnaires were administered every 2 years to collect demographic, lifestyle, and medical information, and a validated food frequency questionnaire was used every 2-4 years to assess participants’ diets over 30 years of follow-up.
Using the NOVA Food Classification system, the items on the food frequency questionnaire were categorized into one of four groups: unprocessed or minimally processed foods; processed culinary ingredients; processed foods; or UPFs, which were subdivided into nine mutually exclusive subgroups.
Servings per day were then used to determine individual UPF intake.
Higher total UPF intake was associated with a greater total energy intake, body mass index, and prevalence of hypercholesterolemia and/or hypertension, as well as lower healthy eating scores and physical activity.
The researchers calculated that, over 5,187,678 person-years of follow-up, there were 19,503 cases of type 2 diabetes across the three study cohorts.
Multivariate analysis taking into consideration a range of potential risk factors, including BMI, revealed that, across the three study cohorts, the highest quintile of UPF intake was associated with a significantly increased risk of type 2 diabetes.
Compared with the lowest quintile of UPF intake, the hazard ratio for incident type 2 diabetes was 1.28 (P < .0001), with an increase in risk per additional serving per day of 3%.
The UPFs associated with a higher type 2 diabetes risk were as previously described and also included animal-based products and ready-to-eat mixed dishes.
In contrast, intake of UPFs including cereals, dark and whole grain breads, packaged sweet and savory snacks, fruit-based products, and yogurt and dairy-based desserts were linked to a reduced risk of type 2 diabetes.
Then to further validate their findings, the researchers conducted a meta-analysis of their own and four additional studies, comprising 415,554 participants and 21,932 events, with a follow-up of 3.4-32.0 years.
They determined that the pooled relative risk of type 2 diabetes with the highest versus lowest levels of UPF consumption was 1.40, with each 10% increase in total UPF intake associated with a 12% increase in diabetes risk.
Ideal is to have access to minimally processed foods
The NOVA food classification system states that UPFs are industrial formulations “made mostly or entirely with substances extracted from foods, often chemically modified, with additives and with little, if any, whole foods added.”
A recent study questioned the value of the NOVA classification after finding that it had “low consistency” when assigning foods.
Previous studies have nevertheless revealed that UPFs and their constituents negatively affect the gut microbiota and can cause systemic inflammation, insulin resistance, and increased body weight.
Dr. Drouin-Chartier concluded: “There is a need to facilitate ... access to minimally processed foods. This encompasses [appropriate] pricing and physical access [to such foods], that is, addressing the issue of food deserts.”
The NHS I and II and HPFS studies are supported by National Institutes of Health. Dr. Drouin-Chartier has reported a relationship with the Dairy Farmers of Canada. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
High total intake of ultraprocessed food (UPF) is associated with an increased risk of developing type 2 diabetes, suggests a large-scale analysis that nevertheless revealed that the risk applies only to certain such foods.
The research was recently published in Diabetes Care by Zhangling Chen, PhD, Erasmus MC Rotterdam, Netherlands, and colleagues.
Examining almost 200,000 participants in three U.S. studies, yielding more than 5 million person-years of follow-up, the scientists found that high intake of UPF was associated with a 28% increased risk of type 2 diabetes, after statistical adjustments.
However, the increased risk was restricted to certain UPFs, including ready meals, refined breads, sweetened beverages, and sauces and condiments, with other foods considered UPFs, such as cereals, dark- and whole grain breads, and packaged sweet and savory snacks, among others, associated with a reduced risk of diabetes.
Senior author Jean-Philippe Drouin-Chartier, PhD, Nutrition Center, Laval University, Quebec City, told this news organization: “While whole grain breads can be considered as ultraprocessed foods, their consumption should not be discouraged. In our study, we observed that whole grain breads consumption is inversely associated with type 2 diabetes risk. This is supported by many studies linking dietary fiber consumption to better cardiometabolic health.”
Ultraprocessed food intake higher in the U.S. than in Europe
The researchers note that a handful of European studies have also reported an association between UPF consumption and increased type 2 diabetes risk, with the effect ranging from 15% to 53%, depending on the level of intake and the cohort of patients studied.
They note, however, that total UPF intake in the U.S. is “much higher than in Europe,” particularly in the case of ultraprocessed breads and cereals and artificially or sugar-sweetened beverages.
In the current study, they examined data on 71,781 women from the Nurses’ Health Study, 87,918 women from the NHS II, and 38,847 men from the Health Professional Follow-up Study, none of whom had cardiovascular disease, cancer, or diabetes at baseline.
In all three studies, questionnaires were administered every 2 years to collect demographic, lifestyle, and medical information, and a validated food frequency questionnaire was used every 2-4 years to assess participants’ diets over 30 years of follow-up.
Using the NOVA Food Classification system, the items on the food frequency questionnaire were categorized into one of four groups: unprocessed or minimally processed foods; processed culinary ingredients; processed foods; or UPFs, which were subdivided into nine mutually exclusive subgroups.
Servings per day were then used to determine individual UPF intake.
Higher total UPF intake was associated with a greater total energy intake, body mass index, and prevalence of hypercholesterolemia and/or hypertension, as well as lower healthy eating scores and physical activity.
The researchers calculated that, over 5,187,678 person-years of follow-up, there were 19,503 cases of type 2 diabetes across the three study cohorts.
Multivariate analysis taking into consideration a range of potential risk factors, including BMI, revealed that, across the three study cohorts, the highest quintile of UPF intake was associated with a significantly increased risk of type 2 diabetes.
Compared with the lowest quintile of UPF intake, the hazard ratio for incident type 2 diabetes was 1.28 (P < .0001), with an increase in risk per additional serving per day of 3%.
The UPFs associated with a higher type 2 diabetes risk were as previously described and also included animal-based products and ready-to-eat mixed dishes.
In contrast, intake of UPFs including cereals, dark and whole grain breads, packaged sweet and savory snacks, fruit-based products, and yogurt and dairy-based desserts were linked to a reduced risk of type 2 diabetes.
Then to further validate their findings, the researchers conducted a meta-analysis of their own and four additional studies, comprising 415,554 participants and 21,932 events, with a follow-up of 3.4-32.0 years.
They determined that the pooled relative risk of type 2 diabetes with the highest versus lowest levels of UPF consumption was 1.40, with each 10% increase in total UPF intake associated with a 12% increase in diabetes risk.
Ideal is to have access to minimally processed foods
The NOVA food classification system states that UPFs are industrial formulations “made mostly or entirely with substances extracted from foods, often chemically modified, with additives and with little, if any, whole foods added.”
A recent study questioned the value of the NOVA classification after finding that it had “low consistency” when assigning foods.
Previous studies have nevertheless revealed that UPFs and their constituents negatively affect the gut microbiota and can cause systemic inflammation, insulin resistance, and increased body weight.
Dr. Drouin-Chartier concluded: “There is a need to facilitate ... access to minimally processed foods. This encompasses [appropriate] pricing and physical access [to such foods], that is, addressing the issue of food deserts.”
The NHS I and II and HPFS studies are supported by National Institutes of Health. Dr. Drouin-Chartier has reported a relationship with the Dairy Farmers of Canada. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
High total intake of ultraprocessed food (UPF) is associated with an increased risk of developing type 2 diabetes, suggests a large-scale analysis that nevertheless revealed that the risk applies only to certain such foods.
The research was recently published in Diabetes Care by Zhangling Chen, PhD, Erasmus MC Rotterdam, Netherlands, and colleagues.
Examining almost 200,000 participants in three U.S. studies, yielding more than 5 million person-years of follow-up, the scientists found that high intake of UPF was associated with a 28% increased risk of type 2 diabetes, after statistical adjustments.
However, the increased risk was restricted to certain UPFs, including ready meals, refined breads, sweetened beverages, and sauces and condiments, with other foods considered UPFs, such as cereals, dark- and whole grain breads, and packaged sweet and savory snacks, among others, associated with a reduced risk of diabetes.
Senior author Jean-Philippe Drouin-Chartier, PhD, Nutrition Center, Laval University, Quebec City, told this news organization: “While whole grain breads can be considered as ultraprocessed foods, their consumption should not be discouraged. In our study, we observed that whole grain breads consumption is inversely associated with type 2 diabetes risk. This is supported by many studies linking dietary fiber consumption to better cardiometabolic health.”
Ultraprocessed food intake higher in the U.S. than in Europe
The researchers note that a handful of European studies have also reported an association between UPF consumption and increased type 2 diabetes risk, with the effect ranging from 15% to 53%, depending on the level of intake and the cohort of patients studied.
They note, however, that total UPF intake in the U.S. is “much higher than in Europe,” particularly in the case of ultraprocessed breads and cereals and artificially or sugar-sweetened beverages.
In the current study, they examined data on 71,781 women from the Nurses’ Health Study, 87,918 women from the NHS II, and 38,847 men from the Health Professional Follow-up Study, none of whom had cardiovascular disease, cancer, or diabetes at baseline.
In all three studies, questionnaires were administered every 2 years to collect demographic, lifestyle, and medical information, and a validated food frequency questionnaire was used every 2-4 years to assess participants’ diets over 30 years of follow-up.
Using the NOVA Food Classification system, the items on the food frequency questionnaire were categorized into one of four groups: unprocessed or minimally processed foods; processed culinary ingredients; processed foods; or UPFs, which were subdivided into nine mutually exclusive subgroups.
Servings per day were then used to determine individual UPF intake.
Higher total UPF intake was associated with a greater total energy intake, body mass index, and prevalence of hypercholesterolemia and/or hypertension, as well as lower healthy eating scores and physical activity.
The researchers calculated that, over 5,187,678 person-years of follow-up, there were 19,503 cases of type 2 diabetes across the three study cohorts.
Multivariate analysis taking into consideration a range of potential risk factors, including BMI, revealed that, across the three study cohorts, the highest quintile of UPF intake was associated with a significantly increased risk of type 2 diabetes.
Compared with the lowest quintile of UPF intake, the hazard ratio for incident type 2 diabetes was 1.28 (P < .0001), with an increase in risk per additional serving per day of 3%.
The UPFs associated with a higher type 2 diabetes risk were as previously described and also included animal-based products and ready-to-eat mixed dishes.
In contrast, intake of UPFs including cereals, dark and whole grain breads, packaged sweet and savory snacks, fruit-based products, and yogurt and dairy-based desserts were linked to a reduced risk of type 2 diabetes.
Then to further validate their findings, the researchers conducted a meta-analysis of their own and four additional studies, comprising 415,554 participants and 21,932 events, with a follow-up of 3.4-32.0 years.
They determined that the pooled relative risk of type 2 diabetes with the highest versus lowest levels of UPF consumption was 1.40, with each 10% increase in total UPF intake associated with a 12% increase in diabetes risk.
Ideal is to have access to minimally processed foods
The NOVA food classification system states that UPFs are industrial formulations “made mostly or entirely with substances extracted from foods, often chemically modified, with additives and with little, if any, whole foods added.”
A recent study questioned the value of the NOVA classification after finding that it had “low consistency” when assigning foods.
Previous studies have nevertheless revealed that UPFs and their constituents negatively affect the gut microbiota and can cause systemic inflammation, insulin resistance, and increased body weight.
Dr. Drouin-Chartier concluded: “There is a need to facilitate ... access to minimally processed foods. This encompasses [appropriate] pricing and physical access [to such foods], that is, addressing the issue of food deserts.”
The NHS I and II and HPFS studies are supported by National Institutes of Health. Dr. Drouin-Chartier has reported a relationship with the Dairy Farmers of Canada. No other financial relationships were declared.
A version of this article first appeared on Medscape.com.
FROM DIABETES CARE
TikTok’s fave weight loss drugs: Link to thyroid cancer?
With #Ozempic and #ozempicweightloss continuing to trend on social media, along with the mainstream media focusing on celebrities who rely on Ozempic (semaglutide) for weight loss, the daily requests for this new medication have been increasing.
Accompanying these requests are concerns and questions about potential risks, including this most recent message from one of my patients: “Dr. P – I saw the warnings. Is this medication going to make me get thyroid cancer? Please let me know!”
Let’s look at what we know to date, including recent studies, and how to advise our patients on this very hot topic.
Using GLP-1 receptor agonists for obesity
We have extensive prior experience with glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide, for treating type 2 diabetes and now recently as agents for weight loss.
Large clinical trials have documented the benefits of this medication class not only for weight reduction but also for cardiovascular and renal benefits in patients with diabetes. The subcutaneously injectable medications work by promoting insulin secretion, slowing gastric emptying, and suppressing glucagon secretion, with a low risk for hypoglycemia.
The Food and Drug Administration approved daily-injection GLP-1 agonist liraglutide for weight loss in 2014, and weekly-injection semaglutide for chronic weight management in 2021, in patients with a body mass index ≥ 27 with at least one weight-related condition or a BMI ≥ 30.
The brand name for semaglutide approved for weight loss is Wegovy, and the dose is slightly higher (maximum 2.4 mg/wk) than that of Ozempic (maximum 2.0 mg/wk), which is semaglutide approved for type 2 diabetes.
In trials for weight loss, data showed a mean change in body weight of almost 15% in the semaglutide group at week 68 compared with placebo, which is very impressive, particularly compared with other FDA-approved oral long-term weight loss medications.
The newest synthetic dual-acting agent is tirzepatide, which targets GLP-1 but is also a glucose-dependent insulinotropic polypeptide (GIP) agonist. The weekly subcutaneous injection was approved in May 2022 as Mounjaro for treating type 2 diabetes and produced even greater weight loss than semaglutide in clinical trials. Tirzepatide is now in trials for obesity and is under expedited review by the FDA for weight loss.
Why the concern about thyroid cancer?
Early on with the FDA approvals of GLP-1 agonists, a warning accompanied the products’ labels to not use this class of medications in patients with medullary thyroid cancer, a family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome type 2. This warning was based on data from animal studies.
Human pancreatic cells aren’t the only cells that express GLP-1 receptors. These receptors are also expressed by parafollicular cells (C cells) of the thyroid, which secrete calcitonin and are the cells involved in medullary thyroid cancer. A dose-related and duration-dependent increase in thyroid C-cell tumor incidence was noted in rodents. The same relationship was not demonstrated in monkeys. Humans have far fewer C cells than rats, and human C cells have very low expression of the GLP-1 receptor.
Over a decade ago, a study examining the FDA’s database of reported adverse events found an increased risk for thyroid cancer in patients treated with exenatide, another GLP-1 agonist. The reporting system wasn’t designed to distinguish thyroid cancer subtypes.
Numerous subsequent studies didn’t confirm this relationship. The LEADER trial looked at liraglutide in patients with type 2 diabetes and showed no effect of GLP-1 receptor activation on human serum calcitonin levels, C-cell proliferation, or C-cell malignancy. Similarly, a large meta-analysis in patients with type 2 diabetes didn’t find a statistically increased risk for thyroid cancer with liraglutide, and no thyroid malignancies were reported with exenatide.
Two U.S. administrative databases from commercial health plans (a retrospective cohort study and a nested case-control study) compared type 2 diabetes patients who were taking exenatide vs. other antidiabetic drugs and found that exenatide was not significantly associated with an increased risk for thyroid cancer.
And a recent meta-analysis of 45 trials showed no significant effects on the occurrence of thyroid cancer with GLP-1 receptor agonists. Of note, it did find an increased risk for overall thyroid disorders, although there was no clear statistically significant finding pointing to a specific thyroid disorder.
Differing from prior studies, a recent nationwide French health care system study provided newer data suggesting a moderate increased risk for thyroid cancer in a cohort of patients with type 2 diabetes who were taking GLP-1 agonists. The increase in relative risk was noted for all types of thyroid cancer in patients using GLP-1 receptor agonists for 1-3 years.
An accompanying commentary by Caroline A. Thompson, PhD, and Til Stürmer, MD, provides perspective on this study’s potential limitations. These include detection bias, as the study results focused only on the statistically significant data. Also discussed were limitations to the case-control design, issues with claims-based tumor type classification (unavailability of surgical pathology), and an inability to adjust for family history and obesity, which is a risk factor alone for thyroid cancer. There was also no adjustment for exposure to head/neck radiation.
While this study has important findings to consider, it deserves further investigation, with future studies linking data to tumor registry data before a change is made in clinical practice.
No clear relationship has been drawn between GLP-1 receptor agonists and thyroid cancer in humans. Numerous confounding factors limit the data. Studies generally don’t specify the type of thyroid cancer, and they lump medullary thyroid cancer, the rarest form, with papillary thyroid cancer.
Is a detection bias present where weight loss makes nodules more visible on the neck among those treated with GLP-1 agonists? And/or are patients treated with GLP-1 agonists being screened more stringently for thyroid nodules and/or cancer?
How to advise our patients and respond to the EMR messages
The TikTok videos may continue, the celebrity chatter may increase, and we, as physicians, will continue to look to real-world data with randomized controlled trials to tailor our decision-making and guide our patients.
Thyroid cancer remains a rare outcome, and GLP-1 receptor agonists remain a very important and beneficial treatment option for the right patient.
A version of this article first appeared on Medscape.com.
With #Ozempic and #ozempicweightloss continuing to trend on social media, along with the mainstream media focusing on celebrities who rely on Ozempic (semaglutide) for weight loss, the daily requests for this new medication have been increasing.
Accompanying these requests are concerns and questions about potential risks, including this most recent message from one of my patients: “Dr. P – I saw the warnings. Is this medication going to make me get thyroid cancer? Please let me know!”
Let’s look at what we know to date, including recent studies, and how to advise our patients on this very hot topic.
Using GLP-1 receptor agonists for obesity
We have extensive prior experience with glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide, for treating type 2 diabetes and now recently as agents for weight loss.
Large clinical trials have documented the benefits of this medication class not only for weight reduction but also for cardiovascular and renal benefits in patients with diabetes. The subcutaneously injectable medications work by promoting insulin secretion, slowing gastric emptying, and suppressing glucagon secretion, with a low risk for hypoglycemia.
The Food and Drug Administration approved daily-injection GLP-1 agonist liraglutide for weight loss in 2014, and weekly-injection semaglutide for chronic weight management in 2021, in patients with a body mass index ≥ 27 with at least one weight-related condition or a BMI ≥ 30.
The brand name for semaglutide approved for weight loss is Wegovy, and the dose is slightly higher (maximum 2.4 mg/wk) than that of Ozempic (maximum 2.0 mg/wk), which is semaglutide approved for type 2 diabetes.
In trials for weight loss, data showed a mean change in body weight of almost 15% in the semaglutide group at week 68 compared with placebo, which is very impressive, particularly compared with other FDA-approved oral long-term weight loss medications.
The newest synthetic dual-acting agent is tirzepatide, which targets GLP-1 but is also a glucose-dependent insulinotropic polypeptide (GIP) agonist. The weekly subcutaneous injection was approved in May 2022 as Mounjaro for treating type 2 diabetes and produced even greater weight loss than semaglutide in clinical trials. Tirzepatide is now in trials for obesity and is under expedited review by the FDA for weight loss.
Why the concern about thyroid cancer?
Early on with the FDA approvals of GLP-1 agonists, a warning accompanied the products’ labels to not use this class of medications in patients with medullary thyroid cancer, a family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome type 2. This warning was based on data from animal studies.
Human pancreatic cells aren’t the only cells that express GLP-1 receptors. These receptors are also expressed by parafollicular cells (C cells) of the thyroid, which secrete calcitonin and are the cells involved in medullary thyroid cancer. A dose-related and duration-dependent increase in thyroid C-cell tumor incidence was noted in rodents. The same relationship was not demonstrated in monkeys. Humans have far fewer C cells than rats, and human C cells have very low expression of the GLP-1 receptor.
Over a decade ago, a study examining the FDA’s database of reported adverse events found an increased risk for thyroid cancer in patients treated with exenatide, another GLP-1 agonist. The reporting system wasn’t designed to distinguish thyroid cancer subtypes.
Numerous subsequent studies didn’t confirm this relationship. The LEADER trial looked at liraglutide in patients with type 2 diabetes and showed no effect of GLP-1 receptor activation on human serum calcitonin levels, C-cell proliferation, or C-cell malignancy. Similarly, a large meta-analysis in patients with type 2 diabetes didn’t find a statistically increased risk for thyroid cancer with liraglutide, and no thyroid malignancies were reported with exenatide.
Two U.S. administrative databases from commercial health plans (a retrospective cohort study and a nested case-control study) compared type 2 diabetes patients who were taking exenatide vs. other antidiabetic drugs and found that exenatide was not significantly associated with an increased risk for thyroid cancer.
And a recent meta-analysis of 45 trials showed no significant effects on the occurrence of thyroid cancer with GLP-1 receptor agonists. Of note, it did find an increased risk for overall thyroid disorders, although there was no clear statistically significant finding pointing to a specific thyroid disorder.
Differing from prior studies, a recent nationwide French health care system study provided newer data suggesting a moderate increased risk for thyroid cancer in a cohort of patients with type 2 diabetes who were taking GLP-1 agonists. The increase in relative risk was noted for all types of thyroid cancer in patients using GLP-1 receptor agonists for 1-3 years.
An accompanying commentary by Caroline A. Thompson, PhD, and Til Stürmer, MD, provides perspective on this study’s potential limitations. These include detection bias, as the study results focused only on the statistically significant data. Also discussed were limitations to the case-control design, issues with claims-based tumor type classification (unavailability of surgical pathology), and an inability to adjust for family history and obesity, which is a risk factor alone for thyroid cancer. There was also no adjustment for exposure to head/neck radiation.
While this study has important findings to consider, it deserves further investigation, with future studies linking data to tumor registry data before a change is made in clinical practice.
No clear relationship has been drawn between GLP-1 receptor agonists and thyroid cancer in humans. Numerous confounding factors limit the data. Studies generally don’t specify the type of thyroid cancer, and they lump medullary thyroid cancer, the rarest form, with papillary thyroid cancer.
Is a detection bias present where weight loss makes nodules more visible on the neck among those treated with GLP-1 agonists? And/or are patients treated with GLP-1 agonists being screened more stringently for thyroid nodules and/or cancer?
How to advise our patients and respond to the EMR messages
The TikTok videos may continue, the celebrity chatter may increase, and we, as physicians, will continue to look to real-world data with randomized controlled trials to tailor our decision-making and guide our patients.
Thyroid cancer remains a rare outcome, and GLP-1 receptor agonists remain a very important and beneficial treatment option for the right patient.
A version of this article first appeared on Medscape.com.
With #Ozempic and #ozempicweightloss continuing to trend on social media, along with the mainstream media focusing on celebrities who rely on Ozempic (semaglutide) for weight loss, the daily requests for this new medication have been increasing.
Accompanying these requests are concerns and questions about potential risks, including this most recent message from one of my patients: “Dr. P – I saw the warnings. Is this medication going to make me get thyroid cancer? Please let me know!”
Let’s look at what we know to date, including recent studies, and how to advise our patients on this very hot topic.
Using GLP-1 receptor agonists for obesity
We have extensive prior experience with glucagon-like peptide 1 (GLP-1) receptor agonists, such as semaglutide, for treating type 2 diabetes and now recently as agents for weight loss.
Large clinical trials have documented the benefits of this medication class not only for weight reduction but also for cardiovascular and renal benefits in patients with diabetes. The subcutaneously injectable medications work by promoting insulin secretion, slowing gastric emptying, and suppressing glucagon secretion, with a low risk for hypoglycemia.
The Food and Drug Administration approved daily-injection GLP-1 agonist liraglutide for weight loss in 2014, and weekly-injection semaglutide for chronic weight management in 2021, in patients with a body mass index ≥ 27 with at least one weight-related condition or a BMI ≥ 30.
The brand name for semaglutide approved for weight loss is Wegovy, and the dose is slightly higher (maximum 2.4 mg/wk) than that of Ozempic (maximum 2.0 mg/wk), which is semaglutide approved for type 2 diabetes.
In trials for weight loss, data showed a mean change in body weight of almost 15% in the semaglutide group at week 68 compared with placebo, which is very impressive, particularly compared with other FDA-approved oral long-term weight loss medications.
The newest synthetic dual-acting agent is tirzepatide, which targets GLP-1 but is also a glucose-dependent insulinotropic polypeptide (GIP) agonist. The weekly subcutaneous injection was approved in May 2022 as Mounjaro for treating type 2 diabetes and produced even greater weight loss than semaglutide in clinical trials. Tirzepatide is now in trials for obesity and is under expedited review by the FDA for weight loss.
Why the concern about thyroid cancer?
Early on with the FDA approvals of GLP-1 agonists, a warning accompanied the products’ labels to not use this class of medications in patients with medullary thyroid cancer, a family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome type 2. This warning was based on data from animal studies.
Human pancreatic cells aren’t the only cells that express GLP-1 receptors. These receptors are also expressed by parafollicular cells (C cells) of the thyroid, which secrete calcitonin and are the cells involved in medullary thyroid cancer. A dose-related and duration-dependent increase in thyroid C-cell tumor incidence was noted in rodents. The same relationship was not demonstrated in monkeys. Humans have far fewer C cells than rats, and human C cells have very low expression of the GLP-1 receptor.
Over a decade ago, a study examining the FDA’s database of reported adverse events found an increased risk for thyroid cancer in patients treated with exenatide, another GLP-1 agonist. The reporting system wasn’t designed to distinguish thyroid cancer subtypes.
Numerous subsequent studies didn’t confirm this relationship. The LEADER trial looked at liraglutide in patients with type 2 diabetes and showed no effect of GLP-1 receptor activation on human serum calcitonin levels, C-cell proliferation, or C-cell malignancy. Similarly, a large meta-analysis in patients with type 2 diabetes didn’t find a statistically increased risk for thyroid cancer with liraglutide, and no thyroid malignancies were reported with exenatide.
Two U.S. administrative databases from commercial health plans (a retrospective cohort study and a nested case-control study) compared type 2 diabetes patients who were taking exenatide vs. other antidiabetic drugs and found that exenatide was not significantly associated with an increased risk for thyroid cancer.
And a recent meta-analysis of 45 trials showed no significant effects on the occurrence of thyroid cancer with GLP-1 receptor agonists. Of note, it did find an increased risk for overall thyroid disorders, although there was no clear statistically significant finding pointing to a specific thyroid disorder.
Differing from prior studies, a recent nationwide French health care system study provided newer data suggesting a moderate increased risk for thyroid cancer in a cohort of patients with type 2 diabetes who were taking GLP-1 agonists. The increase in relative risk was noted for all types of thyroid cancer in patients using GLP-1 receptor agonists for 1-3 years.
An accompanying commentary by Caroline A. Thompson, PhD, and Til Stürmer, MD, provides perspective on this study’s potential limitations. These include detection bias, as the study results focused only on the statistically significant data. Also discussed were limitations to the case-control design, issues with claims-based tumor type classification (unavailability of surgical pathology), and an inability to adjust for family history and obesity, which is a risk factor alone for thyroid cancer. There was also no adjustment for exposure to head/neck radiation.
While this study has important findings to consider, it deserves further investigation, with future studies linking data to tumor registry data before a change is made in clinical practice.
No clear relationship has been drawn between GLP-1 receptor agonists and thyroid cancer in humans. Numerous confounding factors limit the data. Studies generally don’t specify the type of thyroid cancer, and they lump medullary thyroid cancer, the rarest form, with papillary thyroid cancer.
Is a detection bias present where weight loss makes nodules more visible on the neck among those treated with GLP-1 agonists? And/or are patients treated with GLP-1 agonists being screened more stringently for thyroid nodules and/or cancer?
How to advise our patients and respond to the EMR messages
The TikTok videos may continue, the celebrity chatter may increase, and we, as physicians, will continue to look to real-world data with randomized controlled trials to tailor our decision-making and guide our patients.
Thyroid cancer remains a rare outcome, and GLP-1 receptor agonists remain a very important and beneficial treatment option for the right patient.
A version of this article first appeared on Medscape.com.
High caffeine levels may lower body fat, type 2 diabetes risks
the results of a new study suggest.
Explaining that caffeine has thermogenic effects, the researchers note that previous short-term studies have linked caffeine intake with reductions in weight and fat mass. And observational data have shown associations between coffee consumption and lower risks of type 2 diabetes and cardiovascular disease.
In an effort to isolate the effects of caffeine from those of other food and drink components, Susanna C. Larsson, PhD, of the Karolinska Institute, Stockholm, and colleagues used data from studies of mainly European populations to examine two specific genetic mutations that have been linked to a slower speed of caffeine metabolism.
The two gene variants resulted in “genetically predicted, lifelong, higher plasma caffeine concentrations,” the researchers note “and were associated with lower body mass index and fat mass, as well as a lower risk of type 2 diabetes.”
Approximately half of the effect of caffeine on type 2 diabetes was estimated to be mediated through body mass index (BMI) reduction.
The work was published online March 14 in BMJ Medicine.
“This publication supports existing studies suggesting a link between caffeine consumption and increased fat burn,” notes Stephen Lawrence, MBChB, Warwick (England) University. “The big leap of faith that the authors have made is to assume that the weight loss brought about by increased caffeine consumption is sufficient to reduce the risk of developing type 2 diabetes,” he told the UK Science Media Centre.
“It does not, however, prove cause and effect.”
The researchers agree, noting: “Further clinical study is warranted to investigate the translational potential of these findings towards reducing the burden of metabolic disease.”
Katarina Kos, MD, PhD, a senior lecturer in diabetes and obesity at the University of Exeter (England), emphasized that this genetic study “shows links and potential health benefits for people with certain genes attributed to a faster [caffeine] metabolism as a hereditary trait and potentially a better metabolism.”
“It does not study or recommend drinking more coffee, which was not the purpose of this research,” she told the UK Science Media Centre.
Using Mendelian randomization, Dr. Larsson and colleagues examined data that came from a genomewide association meta-analysis of 9,876 individuals of European ancestry from six population-based studies.
Genetically predicted higher plasma caffeine concentrations in those carrying the two gene variants were associated with a lower BMI, with one standard deviation increase in predicted plasma caffeine equaling about 4.8 kg/m2 in BMI (P < .001).
For whole-body fat mass, one standard deviation increase in plasma caffeine equaled a reduction of about 9.5 kg (P < .001). However, there was no significant association with fat-free body mass (P = .17).
Genetically predicted higher plasma caffeine concentrations were also associated with a lower risk for type 2 diabetes in the FinnGen study (odds ratio, 0.77 per standard deviation increase; P < .001) and the DIAMANTE consortia (0.84, P < .001).
Combined, the odds ratio of type 2 diabetes per standard deviation of plasma caffeine increase was 0.81 (P < .001).
Dr. Larsson and colleagues calculated that approximately 43% of the protective effect of plasma caffeine on type 2 diabetes was mediated through BMI.
They did not find any strong associations between genetically predicted plasma caffeine concentrations and risk of any of the studied cardiovascular disease outcomes (ischemic heart disease, atrial fibrillation, heart failure, and stroke).
The thermogenic response to caffeine has been previously quantified as an approximate 100 kcal increase in energy expenditure per 100 mg daily caffeine intake, an amount that could result in reduced obesity risk. Another possible mechanism is enhanced satiety and suppressed energy intake with higher caffeine levels, the researchers say.
“Long-term clinical studies investigating the effect of caffeine intake on fat mass and type 2 diabetes risk are warranted,” they note. “Randomized controlled trials are warranted to assess whether noncaloric caffeine-containing beverages might play a role in reducing the risk of obesity and type 2 diabetes.”
The study was supported by the Swedish Research Council for Health, Working Life and Welfare, Swedish Heart Lung Foundation, and Swedish Research Council. Dr. Larsson, Dr. Lawrence, and Dr. Kos have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
the results of a new study suggest.
Explaining that caffeine has thermogenic effects, the researchers note that previous short-term studies have linked caffeine intake with reductions in weight and fat mass. And observational data have shown associations between coffee consumption and lower risks of type 2 diabetes and cardiovascular disease.
In an effort to isolate the effects of caffeine from those of other food and drink components, Susanna C. Larsson, PhD, of the Karolinska Institute, Stockholm, and colleagues used data from studies of mainly European populations to examine two specific genetic mutations that have been linked to a slower speed of caffeine metabolism.
The two gene variants resulted in “genetically predicted, lifelong, higher plasma caffeine concentrations,” the researchers note “and were associated with lower body mass index and fat mass, as well as a lower risk of type 2 diabetes.”
Approximately half of the effect of caffeine on type 2 diabetes was estimated to be mediated through body mass index (BMI) reduction.
The work was published online March 14 in BMJ Medicine.
“This publication supports existing studies suggesting a link between caffeine consumption and increased fat burn,” notes Stephen Lawrence, MBChB, Warwick (England) University. “The big leap of faith that the authors have made is to assume that the weight loss brought about by increased caffeine consumption is sufficient to reduce the risk of developing type 2 diabetes,” he told the UK Science Media Centre.
“It does not, however, prove cause and effect.”
The researchers agree, noting: “Further clinical study is warranted to investigate the translational potential of these findings towards reducing the burden of metabolic disease.”
Katarina Kos, MD, PhD, a senior lecturer in diabetes and obesity at the University of Exeter (England), emphasized that this genetic study “shows links and potential health benefits for people with certain genes attributed to a faster [caffeine] metabolism as a hereditary trait and potentially a better metabolism.”
“It does not study or recommend drinking more coffee, which was not the purpose of this research,” she told the UK Science Media Centre.
Using Mendelian randomization, Dr. Larsson and colleagues examined data that came from a genomewide association meta-analysis of 9,876 individuals of European ancestry from six population-based studies.
Genetically predicted higher plasma caffeine concentrations in those carrying the two gene variants were associated with a lower BMI, with one standard deviation increase in predicted plasma caffeine equaling about 4.8 kg/m2 in BMI (P < .001).
For whole-body fat mass, one standard deviation increase in plasma caffeine equaled a reduction of about 9.5 kg (P < .001). However, there was no significant association with fat-free body mass (P = .17).
Genetically predicted higher plasma caffeine concentrations were also associated with a lower risk for type 2 diabetes in the FinnGen study (odds ratio, 0.77 per standard deviation increase; P < .001) and the DIAMANTE consortia (0.84, P < .001).
Combined, the odds ratio of type 2 diabetes per standard deviation of plasma caffeine increase was 0.81 (P < .001).
Dr. Larsson and colleagues calculated that approximately 43% of the protective effect of plasma caffeine on type 2 diabetes was mediated through BMI.
They did not find any strong associations between genetically predicted plasma caffeine concentrations and risk of any of the studied cardiovascular disease outcomes (ischemic heart disease, atrial fibrillation, heart failure, and stroke).
The thermogenic response to caffeine has been previously quantified as an approximate 100 kcal increase in energy expenditure per 100 mg daily caffeine intake, an amount that could result in reduced obesity risk. Another possible mechanism is enhanced satiety and suppressed energy intake with higher caffeine levels, the researchers say.
“Long-term clinical studies investigating the effect of caffeine intake on fat mass and type 2 diabetes risk are warranted,” they note. “Randomized controlled trials are warranted to assess whether noncaloric caffeine-containing beverages might play a role in reducing the risk of obesity and type 2 diabetes.”
The study was supported by the Swedish Research Council for Health, Working Life and Welfare, Swedish Heart Lung Foundation, and Swedish Research Council. Dr. Larsson, Dr. Lawrence, and Dr. Kos have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
the results of a new study suggest.
Explaining that caffeine has thermogenic effects, the researchers note that previous short-term studies have linked caffeine intake with reductions in weight and fat mass. And observational data have shown associations between coffee consumption and lower risks of type 2 diabetes and cardiovascular disease.
In an effort to isolate the effects of caffeine from those of other food and drink components, Susanna C. Larsson, PhD, of the Karolinska Institute, Stockholm, and colleagues used data from studies of mainly European populations to examine two specific genetic mutations that have been linked to a slower speed of caffeine metabolism.
The two gene variants resulted in “genetically predicted, lifelong, higher plasma caffeine concentrations,” the researchers note “and were associated with lower body mass index and fat mass, as well as a lower risk of type 2 diabetes.”
Approximately half of the effect of caffeine on type 2 diabetes was estimated to be mediated through body mass index (BMI) reduction.
The work was published online March 14 in BMJ Medicine.
“This publication supports existing studies suggesting a link between caffeine consumption and increased fat burn,” notes Stephen Lawrence, MBChB, Warwick (England) University. “The big leap of faith that the authors have made is to assume that the weight loss brought about by increased caffeine consumption is sufficient to reduce the risk of developing type 2 diabetes,” he told the UK Science Media Centre.
“It does not, however, prove cause and effect.”
The researchers agree, noting: “Further clinical study is warranted to investigate the translational potential of these findings towards reducing the burden of metabolic disease.”
Katarina Kos, MD, PhD, a senior lecturer in diabetes and obesity at the University of Exeter (England), emphasized that this genetic study “shows links and potential health benefits for people with certain genes attributed to a faster [caffeine] metabolism as a hereditary trait and potentially a better metabolism.”
“It does not study or recommend drinking more coffee, which was not the purpose of this research,” she told the UK Science Media Centre.
Using Mendelian randomization, Dr. Larsson and colleagues examined data that came from a genomewide association meta-analysis of 9,876 individuals of European ancestry from six population-based studies.
Genetically predicted higher plasma caffeine concentrations in those carrying the two gene variants were associated with a lower BMI, with one standard deviation increase in predicted plasma caffeine equaling about 4.8 kg/m2 in BMI (P < .001).
For whole-body fat mass, one standard deviation increase in plasma caffeine equaled a reduction of about 9.5 kg (P < .001). However, there was no significant association with fat-free body mass (P = .17).
Genetically predicted higher plasma caffeine concentrations were also associated with a lower risk for type 2 diabetes in the FinnGen study (odds ratio, 0.77 per standard deviation increase; P < .001) and the DIAMANTE consortia (0.84, P < .001).
Combined, the odds ratio of type 2 diabetes per standard deviation of plasma caffeine increase was 0.81 (P < .001).
Dr. Larsson and colleagues calculated that approximately 43% of the protective effect of plasma caffeine on type 2 diabetes was mediated through BMI.
They did not find any strong associations between genetically predicted plasma caffeine concentrations and risk of any of the studied cardiovascular disease outcomes (ischemic heart disease, atrial fibrillation, heart failure, and stroke).
The thermogenic response to caffeine has been previously quantified as an approximate 100 kcal increase in energy expenditure per 100 mg daily caffeine intake, an amount that could result in reduced obesity risk. Another possible mechanism is enhanced satiety and suppressed energy intake with higher caffeine levels, the researchers say.
“Long-term clinical studies investigating the effect of caffeine intake on fat mass and type 2 diabetes risk are warranted,” they note. “Randomized controlled trials are warranted to assess whether noncaloric caffeine-containing beverages might play a role in reducing the risk of obesity and type 2 diabetes.”
The study was supported by the Swedish Research Council for Health, Working Life and Welfare, Swedish Heart Lung Foundation, and Swedish Research Council. Dr. Larsson, Dr. Lawrence, and Dr. Kos have reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM BMJ MEDICINE
Can particles in dairy and beef cause cancer and MS?
In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?
However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.
In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.
Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
Acid radicals
However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.
According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
Viral progeny
In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.
The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
‘Breast milk is healthy’
Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.
The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
Colon cancer
To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.
The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
Institutional skepticism
When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?
The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.
BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.
Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
Association with MS?
Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”
However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.
Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.
This article was translated from the Medscape German Edition. A version appeared on Medscape.com.
In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?
However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.
In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.
Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
Acid radicals
However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.
According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
Viral progeny
In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.
The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
‘Breast milk is healthy’
Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.
The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
Colon cancer
To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.
The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
Institutional skepticism
When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?
The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.
BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.
Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
Association with MS?
Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”
However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.
Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.
This article was translated from the Medscape German Edition. A version appeared on Medscape.com.
In Western diets, dairy and beef are ubiquitous: Milk goes with coffee, melted cheese with pizza, and chili with rice. But what if dairy products and beef contained a new kind of pathogen that could infect you as a child and trigger cancer or multiple sclerosis (MS) 40-70 years later?
However, in two joint statements, the German Federal Institute for Risk Assessment (BfR) and the Max Rubner Institute (MRI) have rejected such theories.
In 2008, Harald zur Hausen, MD, DSc, received the Nobel Prize in Medicine for his discovery that human papillomaviruses cause cervical cancer. His starting point was the observation that sexually abstinent women, such as nuns, rarely develop this cancer. So it was possible to draw the conclusion that pathogens are transmitted during sexual intercourse, explain Dr. zur Hausen and his wife Ethel-Michele de Villiers, PhD, both of DKFZ Heidelberg.
Papillomaviruses, as well as human herpes and Epstein-Barr viruses (EBV), polyomaviruses, and retroviruses, cause cancer in a direct way: by inserting their genes into the DNA of human cells. With a latency of a few years to a few decades, the proteins formed through expression stimulate malignant growth by altering the regulating host gene.
Acid radicals
However, viruses – just like bacteria and parasites – can also indirectly trigger cancer. One mechanism for this triggering is the disruption of immune defenses, as shown by the sometimes drastically increased tumor incidence with AIDS or with immunosuppressants after transplants. Chronic inflammation is a second mechanism that generates acid radicals and thereby causes random mutations in replicating cells. Examples include stomach cancer caused by Helicobacter pylori and liver cancer caused by Schistosoma, liver fluke, and hepatitis B and C viruses.
According to Dr. de Villiers and Dr. zur Hausen, there are good reasons to believe that other pathogens could cause chronic inflammation and thereby lead to cancer. Epidemiologic data suggest that dairy and meat products from European cows (Bos taurus) are a potential source. This is because colon cancer and breast cancer commonly occur in places where these foods are heavily consumed (that is, in North America, Argentina, Europe, and Australia). In contrast, the rate is low in India, where cows are revered as holy animals. Also noteworthy is that women with a lactose intolerance rarely develop breast cancer.
Viral progeny
In fact, the researchers found single-stranded DNA rings that originated in viruses, which they named bovine meat and milk factors (BMMF), in the intestines of patients with colon cancer. They reported, “This new class of pathogen deserves, in our opinion at least, to become the focus of cancer development and further chronic diseases.” They also detected elevated levels of acid radicals in these areas (that is, oxidative stress), which is typical for chronic inflammation.
The researchers assume that infants, whose immune system is not yet fully matured, ingest the BMMF as soon as they have dairy. Therefore, there is no need for adults to avoid dairy or beef because everyone is infected anyway, said Dr. zur Hausen.
‘Breast milk is healthy’
Dr. De Villiers and Dr. zur Hausen outlined more evidence of cancer-triggering pathogens. Mothers who have breastfed are less likely, especially after multiple pregnancies, to develop tumors in various organs or to have MS and type 2 diabetes. The authors attribute the protective effect to oligosaccharides in breast milk, which begin to be formed midway through the pregnancy. They bind to lectin receptors and, in so doing, mask the terminal molecule onto which the viruses need to dock. As a result, their port of entry into the cells is blocked.
The oligosaccharides also protect the baby against life-threatening infections by blocking access by rotaviruses and noroviruses. In this way, especially if breastfeeding lasts a long time – around 1 year – the period of incomplete immunocompetence is bridged.
Colon cancer
To date, it has been assumed that around 20% of all cancerous diseases globally are caused by infections, said the researchers. But if the suspected BMMF cases are included, this figure rises to 50%, even to around 80%, for colon cancer. If the suspicion is confirmed, the consequences for prevention and therapy would be significant.
The voice of a Nobel prize winner undoubtedly carries weight, but at the time, Dr. zur Hausen still had to convince a host of skeptics with his discovery that a viral infection is a major cause of cervical cancer. Nonetheless, some indicators suggest that he and his wife have found a dead end this time.
Institutional skepticism
When his working group made the results public in February 2019, the DKFZ felt the need to give an all-clear signal in response to alarmed press reports. There is no reason to see dairy and meat consumption as something negative. Similarly, in their first joint statement, the BfR and the MRI judged the data to be insufficient and called for further studies. Multiple research teams began to focus on BMMF as a result. In what foods can they be found? Are they more common in patients with cancer than in healthy people? Are they infectious? Do they cause inflammation and cancer?
The findings presented in a second statement by the BfR and MRI at the end of November 2022 contradicted the claims made by the DKFZ scientists across the board. In no way do BMMF represent new pathogens. They are variants of already known DNA sequences. In addition, they are present in numerous animal-based and plant-based foods, including pork, fish, fruit, vegetables, and nuts.
BMMF do not possess the ability to infect human cells, the institutes said. The proof that they are damaging to one’s health was also absent. It is true that the incidence of intestinal tumors correlates positively with the consumption of red and processed meat – which in no way signifies causality – but dairy products are linked to a reduced risk. On the other hand, breast cancer cannot be associated with the consumption of beef or dairy.
Therefore, both institutes recommend continuing to use these products as supplementary diet for infants because of their micronutrients. They further stated that the products are safe for people of all ages.
Association with MS?
Unperturbed, Dr. de Villiers and Dr. zur Hausen went one step further in their current article. They posited that MS is also associated with the consumption of dairy products and beef. Here too geographic distribution prompted the idea to look for BMMF in the brain lesions of patients with MS. The researchers isolated ring-shaped DNA molecules that proved to be closely related to BMMF from dairy and cattle blood. “The result was electrifying for us.”
However, there are several other factors to consider, such as vitamin D3 deficiency. This is because the incidence of MS decreases the further you travel from the poles toward the equator (that is, as solar radiation increases). Also, EBV clearly plays a role because patients with MS display increased titers of EBV antibodies. One study also showed that people in Antarctica excreted reactivated EBV in their saliva during winter and that vitamin D3 stopped the viral secretion.
Under these conditions, the researchers hypothesized that MS is caused by a double infection of brain cells by EBV and BMMF. EBV is reactivated by a lack of vitamin D3, and the BMMF multiply and are eventually converted into proteins. A focal immunoreaction causes the Schwann cells and oligodendrocytes to malfunction, which leads to the destruction of the myelin sheaths around the nerve fibers.
This article was translated from the Medscape German Edition. A version appeared on Medscape.com.
Gestational diabetes affects fetal lung development
Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.
Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.
Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.
In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.
“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.
Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.
The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.
The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.
The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.
However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.
“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.
Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.
Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.
In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.
“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.
Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.
The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.
The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.
The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.
However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.
“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
Lung development in the fetus may be adversely affected by a mother’s gestational diabetes, based on data from in vivo, in vitro, and ex vivo studies.
Gestational diabetes mellitus (GDM) has recently been associated with fetal lung underdevelopment (FLUD) and delayed lung maturation that may lead to immediate respiratory distress in newborns and later chronic lung disease, Pengzheng Chen, PhD, of Shandong University, Jinan, China, and colleagues wrote.
Antenatal corticosteroids are considered an effective treatment for gestational fetal lung underdevelopment, but recent studies have shown adverse effects of these medications, and therefore more research is needed to identify the etiology and pathogenesis of FLUD induced by GDM, they said.
In a study published in the International Journal of Nanomedicine, the researchers collected umbilical cord blood samples from patients with GDM and matched controls at a single hospital in China.
“Using an ex vivo exosome exposure model of fetal lung explants, we observed the morphological alteration of lung explants and evaluated the expression of molecules involved in lung development,” the researchers wrote.
Fetal lung underdevelopment was more common after exposure to exosomes from the umbilical cord plasma of individuals with gestational diabetes mellitus, compared with exosomes from healthy controls.
The researchers also used mouse models to examine the effects of exosomes on fetal lung development in vivo. They found that exosomes associated with GDM impeded the growth, branching morphogenesis, and maturation of fetal lungs in mouse models. In addition, the expression of the apoptotic biomarkers known as BAX, BIM, and cleaved CASPASE-3 was up-regulated in GDMUB-exosomes and HG-exos groups, but the antiapoptotic protein BCL-2 was down-regulated; this further supported the negative impact of GDM exomes on fetal lung development, the researchers said.
The researchers then conducted miRNA sequencing, which showed that the miRNA in placenta-derived exosomes from GDM pregnancies were distinct from the miRNA in exosomes from healthy control pregnancies.
The study findings were limited by several factors including the impurity of the isolated placenta-derived exosomes from the umbilical cord blood plasma, which were not placenta specific, the researchers noted. Other limitations included the lack of data on different stages of lung development, and more research is needed to validate miRNAs and to explore the signally pathways involved in fetal lung development.
However, the study is the first known to demonstrate an adverse effect of GDM on fetal lung development via in vitro, ex vivo, and in vitro models, they said.
“These data highlight an emerging role of placenta-derived exosomes in the pathogenesis of fetal lung underdevelopment in GDM pregnancies, and provide a novel strategy for maternal-fetal communication,” they concluded.
The study received no outside funding. The researchers had no financial conflicts to disclose.
FROM THE INTERNATIONAL JOURNAL OF NANOMEDICINE
Can SGLT2 inhibitors limit acute kidney injury in type 2 diabetes?
Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.
The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.
The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.
Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.
Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.
More recent experience has calmed AKI concerns, however.
Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.
The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).
Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk
“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.
Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.
Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.
One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.
Early AKI concern has diminished
Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.
In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.
Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.
The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.
During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.
A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.
The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.
He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.
The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.
A version of this article originally appeared on Medscape.com.
Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.
The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.
The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.
Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.
Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.
More recent experience has calmed AKI concerns, however.
Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.
The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).
Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk
“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.
Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.
Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.
One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.
Early AKI concern has diminished
Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.
In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.
Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.
The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.
During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.
A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.
The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.
He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.
The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.
A version of this article originally appeared on Medscape.com.
Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor, in an analysis of health insurance data from more than 100,000 Taiwan residents during 2016-2018.
The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.
The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor “appears to be quite low” compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.
Treatment with an SGLT2 inhibitor – such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) – causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.
Indeed, canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.
More recent experience has calmed AKI concerns, however.
Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale University, New Haven, Conn., said: “It’s a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low.” Dr. Wilson was not involved with the new study.
The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1,000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1,000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).
Main barrier to SGLT2 inhibitor use is unfamiliarity, not AKI risk
“My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class,” Dr. Wilson said in an interview.
Although he sees “relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists,” routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.
Clinicians in primary care “still perceive the SGLT2 inhibitor class as something of a ‘specialty drug,’ and they defer initiating it on that basis,” Dr. Wilson observed. “That’s probably not a good thing,” as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.
One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative U.S. sample of 1,330 adults with type 2 diabetes studied in depth during 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.
Early AKI concern has diminished
Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.
In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.
Despite accumulated evidence exonerating AKI risk, U.S. labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.
The new Taiwan study used data from the country’s National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.
During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.
A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, reported the authors from several medical institutions in Taiwan.
The study’s main limitation was its reliance on “quite insensitive” administrative coding data to identify AKI cases, said Dr. Wilson.
He noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among U.S. clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.
The study received no commercial funding, and none of the authors had disclosures. Dr. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.
A version of this article originally appeared on Medscape.com.
‘Breakthrough’ study: Diabetes drug helps prevent long COVID
with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.
In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection.
“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.
Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.
The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.
The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.
The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.
Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant.
The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.
Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.
The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.
When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.
Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.
At the same time, the study authors caution that more research is needed.
“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”
Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.
Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.
The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.
“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals.
Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.
“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”
Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19.
Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”
“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”
A version of this article first appeared on WebMD.com.
with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.
In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection.
“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.
Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.
The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.
The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.
The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.
Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant.
The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.
Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.
The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.
When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.
Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.
At the same time, the study authors caution that more research is needed.
“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”
Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.
Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.
The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.
“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals.
Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.
“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”
Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19.
Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”
“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”
A version of this article first appeared on WebMD.com.
with The Lancet on SSRN. The preprint hasn’t yet been peer-reviewed or published in a journal.
In particular, metformin led to a 42% drop in long COVID among people who had a mild to moderate COVID-19 infection.
“Long COVID affects millions of people, and preventing long COVID through a treatment like metformin could prevent significant disruptions in people’s lives,” said lead author Carolyn Bramante, MD, assistant professor of internal medicine and pediatrics at the University of Minnesota, Minneapolis.
Between January 2021 and February 2022, Dr. Bramante and colleagues tested three oral medications – metformin (typically used to treat type 2 diabetes), ivermectin (an antiparasitic), and fluvoxamine (an antidepressant) – in a clinical trial across the United States called COVID-OUT. The people being studied, investigators, care providers, and others involved in the study were blinded to the randomized treatments. The trial was decentralized, with no in-person contact with participants.
The researchers included patients who were aged 30-85 with overweight or obesity, had documentation of a confirmed COVID-19 infection, had fewer than 7 days of symptoms, had no known prior infection, and joined the study within 3 days of their positive test. The study included monthly follow-up for 300 days, and participants indicated whether they received a long COVID diagnosis from a medical doctor, which the researchers confirmed in medical records after participants gave consent.
The medications were prepackaged into pill boxes for fast delivery to participants and to ensure they took the correct number of each type of pill. The packages were sent via same-day courier or overnight shipping.
The metformin doses were doled out over 14 days, with 500 milligrams on the first day, 500 milligrams twice a day for the next 4 days, and then 500 milligrams in the morning and 1,000 milligrams in the evening for the remaining 9 days.
Among the 1,323 people studied, 1,125 agreed to do long-term follow-up for long COVID: 564 in the metformin group and 561 in the blinded placebo group. The average age was 45, and 56% were women, including 7% who were pregnant.
The average time from the start of symptoms to starting medication was 5 days, and 47% began taking the drug within 4 days or less. About 55% had received the primary COVID-19 vaccination series, including 5.1% who received an initial booster, before enrolling in the study.
Overall, 8.4% of participants reported that a medical provider diagnosed them with long COVID. Of those who took metformin, 6.3% developed long COVID, compared to 10.6% among those who took the identical-matched placebo.
The risk reduction for metformin was 42% versus the placebo, which was consistent across subgroups, including vaccination status and different COVID-19 variants.
When metformin was started less than 4 days after COVID-19 symptoms started, the effect was potentially even greater, with a 64% reduction, as compared with a 36% reduction among those who started metformin after 4 or more days after symptoms.
Neither ivermectin nor fluvoxamine showed any benefits for preventing long COVID.
At the same time, the study authors caution that more research is needed.
“The COVID-OUT trial does not indicate whether or not metformin would be effective at preventing long COVID if started at the time of emergency department visit or hospitalization for COVID-19, nor whether metformin would be effective as treatment in persons who already have long COVID,” they wrote. “With the burden of long COVID on society, confirmation is urgently needed in a trial that addresses our study’s limitations in order to translate these results into practice and policy.”
Several risk factors for long COVID emerged in the analysis. About 11.1% of the women had a long COVID diagnosis, compared with 4.9% of the men. Also, those who had received at least the primary vaccine series had a lower risk of developing long COVID, at 6.6%, as compared with 10.5% among the unvaccinated. Only 1 of the 57 people who received a booster shot developed long COVID.
Notably, pregnant and lactating people were included in this study, which is important given that pregnant people face higher risks for poor COVID-19 outcomes and are excluded from most nonobstetric clinical trials, the study authors wrote. In this study, they were randomized to metformin or placebo but not ivermectin or fluvoxamine due to limited research about the safety of those drugs during pregnancy and lactation.
The results are now under journal review but show findings consistent with those from other recent studies. Also, in August 2022, the authors published results from COVID-OUT that showed metformin led to a 42% reduction in hospital visits, emergency department visits, and deaths related to severe COVID-19.
“Given the lack of side effects and cost for a 2-week course, I think these data support use of metformin now,” said Eric Topol, MD, founder and director of the Scripps Research Translational Institute and editor-in-chief of Medscape, WebMD’s sister site for health care professionals.
Dr. Topol, who wasn’t involved with this study, has been a leading voice on COVID-19 research throughout the pandemic. He noted the need for more studies, including a factorial design trial to test metformin and Paxlovid, which has shown promise in preventing long COVID. Dr. Topol also wrote about the preprint in Ground Truths, his online newsletter.
“As I’ve written in the past, I don’t use the term ‘breakthrough’ lightly,” he wrote. “But to see such a pronounced benefit in the current randomized trial of metformin, in the context of its being so safe and low cost, I’d give it a breakthrough categorization.”
Another way to put it, Dr. Topol wrote, is that based on this study, he would take metformin if he became infected with COVID-19.
Jeremy Faust, MD, an emergency medicine doctor at Brigham and Women’s Hospital in Boston, also wrote about the study in his newsletter, Inside Medicine. He noted that the 42% reduction in long COVID means that 23 COVID-19 patients need to be treated with metformin to prevent one long COVID diagnosis, which is an “important reduction.”
“Bottom line: If a person who meets criteria for obesity or overweight status were to ask me if they should take metformin (for 2 weeks) starting as soon as they learn they have COVID-19, I would say yes in many if not most cases, based on this new data,” he wrote. “This is starting to look like a real win.”
A version of this article first appeared on WebMD.com.
What’s it like to take Ozempic? A doctor’s own story
With the rising popularity of weight-loss drug injections, I’ve received many questions from patients about the pros, cons, and costs. While Ozempic (semaglutide) is perhaps the best known, it’s technically an agent approved only for type 2 diabetes that has been used off label for obesity. The same substance, semaglutide, is approved for use in obesity, but at a higher dose, under the brand name Wegovy. Alternatives are available, and results will vary depending on the specific agent used and the individual.
Ultimately, I decided to try these new injections for myself. I am not a paid representative for, nor an advocate of, any of these medications; I’m here only to share my personal experience.
In my discussions with patients about weight, I sometimes felt like an imposter. While I was overweight by medical standards, I fortunately had none of the underlying health problems. I wasn’t on medications for blood pressure nor did I have diabetes, but I was counseling people to lose weight and eat better while not always following my own advice.
Since having children and turning 40, my metabolism, like many other women’s, seems to have plummeted. I tried a number of older weight-loss medications, like phentermine and phendimetrazine, under the supervision of medical professionals.
Each time, the efforts worked for a short while, particularly when I followed good portion control and practiced moderate exercise. Once the side effects (that is, tachycardia, palpitations, mood changes, constipation) became intolerable, or I became tired or fearful of being on the medications too long, I’d stop and I would regain some of the weight.
When the newer subcutaneous injectable medications arrived on the scene and I started to talk to my patients about them, I was intrigued by their novel mode of action and seeming benefits.
These medications, glucagonlike peptide–1 (GLP-1) receptor agonists, were first approved for type 2 diabetes, and it soon became apparent that patients were losing significant amounts of weight taking them, so manufacturers conducted further trials in obesity patients without type 2 diabetes.
The first of these, liraglutide, is injected daily and was first approved as Victoza for type 2 diabetes; it later received an additional approval for obesity, in December 2014, as Saxenda.
Semaglutide, another of the new GLP-1 agonists, was first approved for type 2 diabetes as Ozempic but again was found to lead to substantial weight loss, so a subsequent approval of the drug for obesity, as Wegovy, came in June 2021. Semaglutide is injected once a week.
Semaglutide was branded a “game changer” when it was licensed for obesity because the mean weight loss seen in trials was around 15%, more than for any other drug and approaching what could be achieved with bariatric surgery, some doctors said.
These medications work in a different way from the older weight loss drugs, which had focused on the use of amphetamines. The newer medications became very popular because treating obesity helps lower blood glucose, blood pressure, cholesterol, kidney disease risk, and other comorbidities that occur with diabetes. Plus, for most people, there were fewer side effects.
I first tried Saxenda when it arrived on the market, via some samples that our pharmaceutical representative brought, both out of curiosity and to see if it would help me lose the stubborn baby weight. I ended up stopping the daily injections after my second or third week because of nausea and vomiting. I took a break, got a prescription for antinausea medicine, and tried again because it did indeed decrease my appetite. However, when I took my prescription to the pharmacy, my insurance wouldn’t cover it. It happens to doctors, too.
Fast-forward to 2017-2018. The baby weight was still holding on despite lifestyle changes, diet, and exercising. The newer drug classes hit the market, and again we had samples from our reps.
When Ozempic was on backorder, I switched to a low dose of Mounjaro (tirzepatide), a new dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, approved for type 2 diabetes in May 2022, again using it off label as a weekly injection, as it isn’t currently approved for weight loss. However, it does produce significant weight loss and is awaiting approval for obesity.
With these new medications, I noticed that both my patients and I didn’t complain as much about nausea and vomiting, but I did experience stomach upset, constipation, and acid reflux.
The appetite suppression is effective. It slows down the emptying of the gut so I feel full longer. I’ve lost 30 lb with these weekly injections and would like to lose another 20 lb. I follow a routine of reasonable, portion-controlled eating and moderate exercise (30 minutes of cardiovascular activity at least two to three times a week).
Discontinuing the medications may cause rebound weight gain, especially if I’m no longer following a routine of healthy eating and/or moderate exercise. I deal with minimal constipation by taking stool softeners, and I take antacids for acid reflux.
Here’s what I recommend applying when working with patients who have obesity: First, explain how these medications work. Then conduct a health history to make sure these injections are right for them. Patients with a family history of pancreatic cancer can’t take these medications. You also want to monitor use in patients with a history of hypoglycemia so their blood sugar doesn’t drop too low. It’s also important to make sure your patients are able to afford the medication. My husband takes Ozempic for diabetes, and recently we were told that a refill would cost about $1,500 a month, even with insurance. “Covered” doesn’t necessarily mean affordable.
Take a baseline hemoglobin A1c and repeat it after the patient has been on the medication for 2-3 weeks. Also remind them that they can’t rely solely on the medication but need to practice portion control and healthier eating and to exercise more.
For myself, I want to lose those remaining 20 lb or so by eating healthy and being physically active without having to rely on medication for the rest of my life. Research on these medications is still early so we don’t know the long-term effects yet.
As clinicians, I feel it’s okay to be honest with our patients about our own personal struggles to help them understand that they are not alone and that losing weight is a challenge for everyone.
Dr. Swiner is a family physician in Durham, N.C. She reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
With the rising popularity of weight-loss drug injections, I’ve received many questions from patients about the pros, cons, and costs. While Ozempic (semaglutide) is perhaps the best known, it’s technically an agent approved only for type 2 diabetes that has been used off label for obesity. The same substance, semaglutide, is approved for use in obesity, but at a higher dose, under the brand name Wegovy. Alternatives are available, and results will vary depending on the specific agent used and the individual.
Ultimately, I decided to try these new injections for myself. I am not a paid representative for, nor an advocate of, any of these medications; I’m here only to share my personal experience.
In my discussions with patients about weight, I sometimes felt like an imposter. While I was overweight by medical standards, I fortunately had none of the underlying health problems. I wasn’t on medications for blood pressure nor did I have diabetes, but I was counseling people to lose weight and eat better while not always following my own advice.
Since having children and turning 40, my metabolism, like many other women’s, seems to have plummeted. I tried a number of older weight-loss medications, like phentermine and phendimetrazine, under the supervision of medical professionals.
Each time, the efforts worked for a short while, particularly when I followed good portion control and practiced moderate exercise. Once the side effects (that is, tachycardia, palpitations, mood changes, constipation) became intolerable, or I became tired or fearful of being on the medications too long, I’d stop and I would regain some of the weight.
When the newer subcutaneous injectable medications arrived on the scene and I started to talk to my patients about them, I was intrigued by their novel mode of action and seeming benefits.
These medications, glucagonlike peptide–1 (GLP-1) receptor agonists, were first approved for type 2 diabetes, and it soon became apparent that patients were losing significant amounts of weight taking them, so manufacturers conducted further trials in obesity patients without type 2 diabetes.
The first of these, liraglutide, is injected daily and was first approved as Victoza for type 2 diabetes; it later received an additional approval for obesity, in December 2014, as Saxenda.
Semaglutide, another of the new GLP-1 agonists, was first approved for type 2 diabetes as Ozempic but again was found to lead to substantial weight loss, so a subsequent approval of the drug for obesity, as Wegovy, came in June 2021. Semaglutide is injected once a week.
Semaglutide was branded a “game changer” when it was licensed for obesity because the mean weight loss seen in trials was around 15%, more than for any other drug and approaching what could be achieved with bariatric surgery, some doctors said.
These medications work in a different way from the older weight loss drugs, which had focused on the use of amphetamines. The newer medications became very popular because treating obesity helps lower blood glucose, blood pressure, cholesterol, kidney disease risk, and other comorbidities that occur with diabetes. Plus, for most people, there were fewer side effects.
I first tried Saxenda when it arrived on the market, via some samples that our pharmaceutical representative brought, both out of curiosity and to see if it would help me lose the stubborn baby weight. I ended up stopping the daily injections after my second or third week because of nausea and vomiting. I took a break, got a prescription for antinausea medicine, and tried again because it did indeed decrease my appetite. However, when I took my prescription to the pharmacy, my insurance wouldn’t cover it. It happens to doctors, too.
Fast-forward to 2017-2018. The baby weight was still holding on despite lifestyle changes, diet, and exercising. The newer drug classes hit the market, and again we had samples from our reps.
When Ozempic was on backorder, I switched to a low dose of Mounjaro (tirzepatide), a new dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, approved for type 2 diabetes in May 2022, again using it off label as a weekly injection, as it isn’t currently approved for weight loss. However, it does produce significant weight loss and is awaiting approval for obesity.
With these new medications, I noticed that both my patients and I didn’t complain as much about nausea and vomiting, but I did experience stomach upset, constipation, and acid reflux.
The appetite suppression is effective. It slows down the emptying of the gut so I feel full longer. I’ve lost 30 lb with these weekly injections and would like to lose another 20 lb. I follow a routine of reasonable, portion-controlled eating and moderate exercise (30 minutes of cardiovascular activity at least two to three times a week).
Discontinuing the medications may cause rebound weight gain, especially if I’m no longer following a routine of healthy eating and/or moderate exercise. I deal with minimal constipation by taking stool softeners, and I take antacids for acid reflux.
Here’s what I recommend applying when working with patients who have obesity: First, explain how these medications work. Then conduct a health history to make sure these injections are right for them. Patients with a family history of pancreatic cancer can’t take these medications. You also want to monitor use in patients with a history of hypoglycemia so their blood sugar doesn’t drop too low. It’s also important to make sure your patients are able to afford the medication. My husband takes Ozempic for diabetes, and recently we were told that a refill would cost about $1,500 a month, even with insurance. “Covered” doesn’t necessarily mean affordable.
Take a baseline hemoglobin A1c and repeat it after the patient has been on the medication for 2-3 weeks. Also remind them that they can’t rely solely on the medication but need to practice portion control and healthier eating and to exercise more.
For myself, I want to lose those remaining 20 lb or so by eating healthy and being physically active without having to rely on medication for the rest of my life. Research on these medications is still early so we don’t know the long-term effects yet.
As clinicians, I feel it’s okay to be honest with our patients about our own personal struggles to help them understand that they are not alone and that losing weight is a challenge for everyone.
Dr. Swiner is a family physician in Durham, N.C. She reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
With the rising popularity of weight-loss drug injections, I’ve received many questions from patients about the pros, cons, and costs. While Ozempic (semaglutide) is perhaps the best known, it’s technically an agent approved only for type 2 diabetes that has been used off label for obesity. The same substance, semaglutide, is approved for use in obesity, but at a higher dose, under the brand name Wegovy. Alternatives are available, and results will vary depending on the specific agent used and the individual.
Ultimately, I decided to try these new injections for myself. I am not a paid representative for, nor an advocate of, any of these medications; I’m here only to share my personal experience.
In my discussions with patients about weight, I sometimes felt like an imposter. While I was overweight by medical standards, I fortunately had none of the underlying health problems. I wasn’t on medications for blood pressure nor did I have diabetes, but I was counseling people to lose weight and eat better while not always following my own advice.
Since having children and turning 40, my metabolism, like many other women’s, seems to have plummeted. I tried a number of older weight-loss medications, like phentermine and phendimetrazine, under the supervision of medical professionals.
Each time, the efforts worked for a short while, particularly when I followed good portion control and practiced moderate exercise. Once the side effects (that is, tachycardia, palpitations, mood changes, constipation) became intolerable, or I became tired or fearful of being on the medications too long, I’d stop and I would regain some of the weight.
When the newer subcutaneous injectable medications arrived on the scene and I started to talk to my patients about them, I was intrigued by their novel mode of action and seeming benefits.
These medications, glucagonlike peptide–1 (GLP-1) receptor agonists, were first approved for type 2 diabetes, and it soon became apparent that patients were losing significant amounts of weight taking them, so manufacturers conducted further trials in obesity patients without type 2 diabetes.
The first of these, liraglutide, is injected daily and was first approved as Victoza for type 2 diabetes; it later received an additional approval for obesity, in December 2014, as Saxenda.
Semaglutide, another of the new GLP-1 agonists, was first approved for type 2 diabetes as Ozempic but again was found to lead to substantial weight loss, so a subsequent approval of the drug for obesity, as Wegovy, came in June 2021. Semaglutide is injected once a week.
Semaglutide was branded a “game changer” when it was licensed for obesity because the mean weight loss seen in trials was around 15%, more than for any other drug and approaching what could be achieved with bariatric surgery, some doctors said.
These medications work in a different way from the older weight loss drugs, which had focused on the use of amphetamines. The newer medications became very popular because treating obesity helps lower blood glucose, blood pressure, cholesterol, kidney disease risk, and other comorbidities that occur with diabetes. Plus, for most people, there were fewer side effects.
I first tried Saxenda when it arrived on the market, via some samples that our pharmaceutical representative brought, both out of curiosity and to see if it would help me lose the stubborn baby weight. I ended up stopping the daily injections after my second or third week because of nausea and vomiting. I took a break, got a prescription for antinausea medicine, and tried again because it did indeed decrease my appetite. However, when I took my prescription to the pharmacy, my insurance wouldn’t cover it. It happens to doctors, too.
Fast-forward to 2017-2018. The baby weight was still holding on despite lifestyle changes, diet, and exercising. The newer drug classes hit the market, and again we had samples from our reps.
When Ozempic was on backorder, I switched to a low dose of Mounjaro (tirzepatide), a new dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, approved for type 2 diabetes in May 2022, again using it off label as a weekly injection, as it isn’t currently approved for weight loss. However, it does produce significant weight loss and is awaiting approval for obesity.
With these new medications, I noticed that both my patients and I didn’t complain as much about nausea and vomiting, but I did experience stomach upset, constipation, and acid reflux.
The appetite suppression is effective. It slows down the emptying of the gut so I feel full longer. I’ve lost 30 lb with these weekly injections and would like to lose another 20 lb. I follow a routine of reasonable, portion-controlled eating and moderate exercise (30 minutes of cardiovascular activity at least two to three times a week).
Discontinuing the medications may cause rebound weight gain, especially if I’m no longer following a routine of healthy eating and/or moderate exercise. I deal with minimal constipation by taking stool softeners, and I take antacids for acid reflux.
Here’s what I recommend applying when working with patients who have obesity: First, explain how these medications work. Then conduct a health history to make sure these injections are right for them. Patients with a family history of pancreatic cancer can’t take these medications. You also want to monitor use in patients with a history of hypoglycemia so their blood sugar doesn’t drop too low. It’s also important to make sure your patients are able to afford the medication. My husband takes Ozempic for diabetes, and recently we were told that a refill would cost about $1,500 a month, even with insurance. “Covered” doesn’t necessarily mean affordable.
Take a baseline hemoglobin A1c and repeat it after the patient has been on the medication for 2-3 weeks. Also remind them that they can’t rely solely on the medication but need to practice portion control and healthier eating and to exercise more.
For myself, I want to lose those remaining 20 lb or so by eating healthy and being physically active without having to rely on medication for the rest of my life. Research on these medications is still early so we don’t know the long-term effects yet.
As clinicians, I feel it’s okay to be honest with our patients about our own personal struggles to help them understand that they are not alone and that losing weight is a challenge for everyone.
Dr. Swiner is a family physician in Durham, N.C. She reported no conflicts of interest.
A version of this article first appeared on Medscape.com.
New documentary highlights human toll of high insulin cost
A new documentary premiering at the 2023 South by Southwest (SXSW) Festival illustrates the human consequences of insulin’s high cost in the United States. Its creators hope that it will help spur action toward overall prescription pricing reform.
Pay or Die: A Documentary is scheduled to premiere March 11. It will be shown twice more during the festival, which runs from March 10 to 19 in Austin, Texas. The documentary was co-created and directed by filmmaker and cinematographer Scott Alexander Ruderman, who has type 1 diabetes, and his partner, producer and journalist Rachael Dyer. One of the executive producers is Sarah Silverman, a comic, actor, producer, and health care reform advocate.
The 90-minute film follows three human stories: A mother and young daughter who both have type 1 diabetes and become homeless after spending their rent money on insulin, a young adult diagnosed during the COVID-19 pandemic, and a mother whose 26-year-old son died from diabetic ketoacidosis (DKA) after his insulin was rationed.
“As an Australian now living in the U.S. and seeing how the health care system works here, especially for people with type 1 diabetes like Scott, and how access to insulin is a life-or-death situation, has been very eye-opening for me. I’m also half Canadian, and both are countries where access to health care is a human right, not a business,” Ms. Dyer said in an interview.
In response to the March 1 announcement from Eli Lilly about its insulin price cut, the film’s team told this news organization: “While we commend Eli Lilly in taking this first step and hope that Novo Nordisk and Sanofi [the two other major insulin manufacturers] follow suit, it is important to remember that the key issue is not about these companies voluntarily slashing prices; it’s about changing laws so the insulin manufacturers do not have the ability to raise the prices again.
“This is the life-or-death issue that we focus on in our documentary Pay or Die. It’s also important to note that insulin is just one of the many expensive prescription drugs in the U.S., which is why we need to call for reform. Affordable medication needs to be a basic human right within reach for all Americans.”
Physician perspective: Good news on insulin, but broader issues
The film features four physicians. One, Mayo Clinic oncologist/hematologist S. Vincent Rajkumar, MD, has spoken and published widely on insulin prices specifically and U.S. drug costs more broadly.
The other three are Joslin Clinic endocrinologist Elizabeth Halprin, MD, Massachusetts General Hospital internist Leigh Simmons, MD, and New York University physician and essayist Danielle Ofri, MD, PhD.
In an interview after the Lilly announcement, Dr. Rajkumar said, “I think this is very, very good news for patients. ... The fact that they’re doing it means they’re listening to us and listening to patients, which is good. And I do hope that other insulin manufacturers do the same shortly.”
However, he added, “for prescription drug prices and particularly cancer drug prices, there’s more reform that’s needed, and that’s at the policy level. ... The goal of the film was to use insulin to highlight the prescription drug price problem in the U.S.”
‘Then life changed’
The filmmaker, Mr. Ruderman, was diagnosed at age 19, during his freshman year in college. He spent several days hospitalized with DKA, and “then life changed,” he said in an interview. He went into photography first and later filmmaking, always with the uneasy knowledge that he could lose access to insulin at any time.
The impetus for the film came after he and Ms. Dyer walked into a pharmacy while visiting Canada in 2018 and discovered how much cheaper insulin was compared to the United States – roughly $20 per vial, compared to $300 in the U.S.
“When Rachael [Dyer] and I came back to the U.S., we were actually quite shocked about how many people are struggling to afford their medication ... the uninsured, those aging off their parents’ health insurance. So that was really the kickoff to us going into the field for the last 4 years making this documentary.”
As a freelancer, Mr. Ruderman has been personally paying for expensive “premium” health insurance that covers the pump and glucose monitors he uses. He buys insulin overseas as often as possible.
“Fortunately, I haven’t been in a situation where I’ve had to ration my insulin, but the fear is instilled in me. What if there’s a month when I can’t afford it? What am I going to do?” (Note: The writer of this article is in the same situation, which could be alleviated by Lilly’s action.)
Timing is everything
To be sure, even before Lilly’s announcement, some progress had been made since work on the film began.
The issue of insulin pricing has received wide media attention. More than 20 states have passed copay caps on insulin, and a new law capping the cost of insulin for Medicare beneficiaries at $35/month went into effect in January 2023. President Biden mentioned insulin during his State of the Union address, and Georgia Senator Raphael Warnock made the issue a centerpiece of his campaign.
But there have also been losses, including the failure thus far to pass a nationwide copay cap.
These recent developments make this a good time for the film’s debut, producer Yael Melamede said in an interview. “There’s a lot happening in the space, but also a lot of incredible disappointments along the way, so we are really interested in getting this film out now.”
Ms. Melamede, who owns a film production company, said, “I’ve done a lot of films that have some issue advocacy side to them. I love this film because it’s grounded in the stories of real people. ... We feel this is a perfect catalyst to keep the energy going and for people to say this is super-important and not get distracted.”
While the film doesn’t advocate for specific policies, there is a “call to action” at the end that points viewers to resources on the website for writing to their members of Congress along with additional ways to become personally involved.
Ms. Dyer told this news organization, “This film is not only focusing on type 1 diabetes. That is obviously the crux of the issue, but it is a broader health care message for everyone wanting to make a change for health care in this country, the richest country in the world.”
At SXSW, Pay or Die will be competing with seven other films in the documentary feature competition, and it is eligible to win other awards.
Several other activities at the festival will address the topics of diabetes and U.S. health care costs, including a panel discussion titled Crushing: The Burden of Diabetes on Patients, featuring musician and actor Nick Jonas, who has type 1 diabetes, and a representative from the continuous glucose monitor manufacturer Dexcom.
Another panel, Young and Uninsured: Pay or Die, will include Dr. Rajkumar, Mr. Ruderman, Texas Representative James Talarico, who is advancing an insulin cap bill in that state, and Nicole Smith-Holt, the Minnesota mother of the young man who died because he couldn’t afford his insulin.
Mr. Ruderman, Ms. Dyer, Ms. Melamede, and Dr. Rajkumar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A new documentary premiering at the 2023 South by Southwest (SXSW) Festival illustrates the human consequences of insulin’s high cost in the United States. Its creators hope that it will help spur action toward overall prescription pricing reform.
Pay or Die: A Documentary is scheduled to premiere March 11. It will be shown twice more during the festival, which runs from March 10 to 19 in Austin, Texas. The documentary was co-created and directed by filmmaker and cinematographer Scott Alexander Ruderman, who has type 1 diabetes, and his partner, producer and journalist Rachael Dyer. One of the executive producers is Sarah Silverman, a comic, actor, producer, and health care reform advocate.
The 90-minute film follows three human stories: A mother and young daughter who both have type 1 diabetes and become homeless after spending their rent money on insulin, a young adult diagnosed during the COVID-19 pandemic, and a mother whose 26-year-old son died from diabetic ketoacidosis (DKA) after his insulin was rationed.
“As an Australian now living in the U.S. and seeing how the health care system works here, especially for people with type 1 diabetes like Scott, and how access to insulin is a life-or-death situation, has been very eye-opening for me. I’m also half Canadian, and both are countries where access to health care is a human right, not a business,” Ms. Dyer said in an interview.
In response to the March 1 announcement from Eli Lilly about its insulin price cut, the film’s team told this news organization: “While we commend Eli Lilly in taking this first step and hope that Novo Nordisk and Sanofi [the two other major insulin manufacturers] follow suit, it is important to remember that the key issue is not about these companies voluntarily slashing prices; it’s about changing laws so the insulin manufacturers do not have the ability to raise the prices again.
“This is the life-or-death issue that we focus on in our documentary Pay or Die. It’s also important to note that insulin is just one of the many expensive prescription drugs in the U.S., which is why we need to call for reform. Affordable medication needs to be a basic human right within reach for all Americans.”
Physician perspective: Good news on insulin, but broader issues
The film features four physicians. One, Mayo Clinic oncologist/hematologist S. Vincent Rajkumar, MD, has spoken and published widely on insulin prices specifically and U.S. drug costs more broadly.
The other three are Joslin Clinic endocrinologist Elizabeth Halprin, MD, Massachusetts General Hospital internist Leigh Simmons, MD, and New York University physician and essayist Danielle Ofri, MD, PhD.
In an interview after the Lilly announcement, Dr. Rajkumar said, “I think this is very, very good news for patients. ... The fact that they’re doing it means they’re listening to us and listening to patients, which is good. And I do hope that other insulin manufacturers do the same shortly.”
However, he added, “for prescription drug prices and particularly cancer drug prices, there’s more reform that’s needed, and that’s at the policy level. ... The goal of the film was to use insulin to highlight the prescription drug price problem in the U.S.”
‘Then life changed’
The filmmaker, Mr. Ruderman, was diagnosed at age 19, during his freshman year in college. He spent several days hospitalized with DKA, and “then life changed,” he said in an interview. He went into photography first and later filmmaking, always with the uneasy knowledge that he could lose access to insulin at any time.
The impetus for the film came after he and Ms. Dyer walked into a pharmacy while visiting Canada in 2018 and discovered how much cheaper insulin was compared to the United States – roughly $20 per vial, compared to $300 in the U.S.
“When Rachael [Dyer] and I came back to the U.S., we were actually quite shocked about how many people are struggling to afford their medication ... the uninsured, those aging off their parents’ health insurance. So that was really the kickoff to us going into the field for the last 4 years making this documentary.”
As a freelancer, Mr. Ruderman has been personally paying for expensive “premium” health insurance that covers the pump and glucose monitors he uses. He buys insulin overseas as often as possible.
“Fortunately, I haven’t been in a situation where I’ve had to ration my insulin, but the fear is instilled in me. What if there’s a month when I can’t afford it? What am I going to do?” (Note: The writer of this article is in the same situation, which could be alleviated by Lilly’s action.)
Timing is everything
To be sure, even before Lilly’s announcement, some progress had been made since work on the film began.
The issue of insulin pricing has received wide media attention. More than 20 states have passed copay caps on insulin, and a new law capping the cost of insulin for Medicare beneficiaries at $35/month went into effect in January 2023. President Biden mentioned insulin during his State of the Union address, and Georgia Senator Raphael Warnock made the issue a centerpiece of his campaign.
But there have also been losses, including the failure thus far to pass a nationwide copay cap.
These recent developments make this a good time for the film’s debut, producer Yael Melamede said in an interview. “There’s a lot happening in the space, but also a lot of incredible disappointments along the way, so we are really interested in getting this film out now.”
Ms. Melamede, who owns a film production company, said, “I’ve done a lot of films that have some issue advocacy side to them. I love this film because it’s grounded in the stories of real people. ... We feel this is a perfect catalyst to keep the energy going and for people to say this is super-important and not get distracted.”
While the film doesn’t advocate for specific policies, there is a “call to action” at the end that points viewers to resources on the website for writing to their members of Congress along with additional ways to become personally involved.
Ms. Dyer told this news organization, “This film is not only focusing on type 1 diabetes. That is obviously the crux of the issue, but it is a broader health care message for everyone wanting to make a change for health care in this country, the richest country in the world.”
At SXSW, Pay or Die will be competing with seven other films in the documentary feature competition, and it is eligible to win other awards.
Several other activities at the festival will address the topics of diabetes and U.S. health care costs, including a panel discussion titled Crushing: The Burden of Diabetes on Patients, featuring musician and actor Nick Jonas, who has type 1 diabetes, and a representative from the continuous glucose monitor manufacturer Dexcom.
Another panel, Young and Uninsured: Pay or Die, will include Dr. Rajkumar, Mr. Ruderman, Texas Representative James Talarico, who is advancing an insulin cap bill in that state, and Nicole Smith-Holt, the Minnesota mother of the young man who died because he couldn’t afford his insulin.
Mr. Ruderman, Ms. Dyer, Ms. Melamede, and Dr. Rajkumar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
A new documentary premiering at the 2023 South by Southwest (SXSW) Festival illustrates the human consequences of insulin’s high cost in the United States. Its creators hope that it will help spur action toward overall prescription pricing reform.
Pay or Die: A Documentary is scheduled to premiere March 11. It will be shown twice more during the festival, which runs from March 10 to 19 in Austin, Texas. The documentary was co-created and directed by filmmaker and cinematographer Scott Alexander Ruderman, who has type 1 diabetes, and his partner, producer and journalist Rachael Dyer. One of the executive producers is Sarah Silverman, a comic, actor, producer, and health care reform advocate.
The 90-minute film follows three human stories: A mother and young daughter who both have type 1 diabetes and become homeless after spending their rent money on insulin, a young adult diagnosed during the COVID-19 pandemic, and a mother whose 26-year-old son died from diabetic ketoacidosis (DKA) after his insulin was rationed.
“As an Australian now living in the U.S. and seeing how the health care system works here, especially for people with type 1 diabetes like Scott, and how access to insulin is a life-or-death situation, has been very eye-opening for me. I’m also half Canadian, and both are countries where access to health care is a human right, not a business,” Ms. Dyer said in an interview.
In response to the March 1 announcement from Eli Lilly about its insulin price cut, the film’s team told this news organization: “While we commend Eli Lilly in taking this first step and hope that Novo Nordisk and Sanofi [the two other major insulin manufacturers] follow suit, it is important to remember that the key issue is not about these companies voluntarily slashing prices; it’s about changing laws so the insulin manufacturers do not have the ability to raise the prices again.
“This is the life-or-death issue that we focus on in our documentary Pay or Die. It’s also important to note that insulin is just one of the many expensive prescription drugs in the U.S., which is why we need to call for reform. Affordable medication needs to be a basic human right within reach for all Americans.”
Physician perspective: Good news on insulin, but broader issues
The film features four physicians. One, Mayo Clinic oncologist/hematologist S. Vincent Rajkumar, MD, has spoken and published widely on insulin prices specifically and U.S. drug costs more broadly.
The other three are Joslin Clinic endocrinologist Elizabeth Halprin, MD, Massachusetts General Hospital internist Leigh Simmons, MD, and New York University physician and essayist Danielle Ofri, MD, PhD.
In an interview after the Lilly announcement, Dr. Rajkumar said, “I think this is very, very good news for patients. ... The fact that they’re doing it means they’re listening to us and listening to patients, which is good. And I do hope that other insulin manufacturers do the same shortly.”
However, he added, “for prescription drug prices and particularly cancer drug prices, there’s more reform that’s needed, and that’s at the policy level. ... The goal of the film was to use insulin to highlight the prescription drug price problem in the U.S.”
‘Then life changed’
The filmmaker, Mr. Ruderman, was diagnosed at age 19, during his freshman year in college. He spent several days hospitalized with DKA, and “then life changed,” he said in an interview. He went into photography first and later filmmaking, always with the uneasy knowledge that he could lose access to insulin at any time.
The impetus for the film came after he and Ms. Dyer walked into a pharmacy while visiting Canada in 2018 and discovered how much cheaper insulin was compared to the United States – roughly $20 per vial, compared to $300 in the U.S.
“When Rachael [Dyer] and I came back to the U.S., we were actually quite shocked about how many people are struggling to afford their medication ... the uninsured, those aging off their parents’ health insurance. So that was really the kickoff to us going into the field for the last 4 years making this documentary.”
As a freelancer, Mr. Ruderman has been personally paying for expensive “premium” health insurance that covers the pump and glucose monitors he uses. He buys insulin overseas as often as possible.
“Fortunately, I haven’t been in a situation where I’ve had to ration my insulin, but the fear is instilled in me. What if there’s a month when I can’t afford it? What am I going to do?” (Note: The writer of this article is in the same situation, which could be alleviated by Lilly’s action.)
Timing is everything
To be sure, even before Lilly’s announcement, some progress had been made since work on the film began.
The issue of insulin pricing has received wide media attention. More than 20 states have passed copay caps on insulin, and a new law capping the cost of insulin for Medicare beneficiaries at $35/month went into effect in January 2023. President Biden mentioned insulin during his State of the Union address, and Georgia Senator Raphael Warnock made the issue a centerpiece of his campaign.
But there have also been losses, including the failure thus far to pass a nationwide copay cap.
These recent developments make this a good time for the film’s debut, producer Yael Melamede said in an interview. “There’s a lot happening in the space, but also a lot of incredible disappointments along the way, so we are really interested in getting this film out now.”
Ms. Melamede, who owns a film production company, said, “I’ve done a lot of films that have some issue advocacy side to them. I love this film because it’s grounded in the stories of real people. ... We feel this is a perfect catalyst to keep the energy going and for people to say this is super-important and not get distracted.”
While the film doesn’t advocate for specific policies, there is a “call to action” at the end that points viewers to resources on the website for writing to their members of Congress along with additional ways to become personally involved.
Ms. Dyer told this news organization, “This film is not only focusing on type 1 diabetes. That is obviously the crux of the issue, but it is a broader health care message for everyone wanting to make a change for health care in this country, the richest country in the world.”
At SXSW, Pay or Die will be competing with seven other films in the documentary feature competition, and it is eligible to win other awards.
Several other activities at the festival will address the topics of diabetes and U.S. health care costs, including a panel discussion titled Crushing: The Burden of Diabetes on Patients, featuring musician and actor Nick Jonas, who has type 1 diabetes, and a representative from the continuous glucose monitor manufacturer Dexcom.
Another panel, Young and Uninsured: Pay or Die, will include Dr. Rajkumar, Mr. Ruderman, Texas Representative James Talarico, who is advancing an insulin cap bill in that state, and Nicole Smith-Holt, the Minnesota mother of the young man who died because he couldn’t afford his insulin.
Mr. Ruderman, Ms. Dyer, Ms. Melamede, and Dr. Rajkumar have disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Causal link found between childhood obesity and adult-onset diabetes
Childhood obesity is a risk factor for four of the five subtypes of adult-onset diabetes, emphasizing the importance of childhood weight control, according to a collaborative study from the Karolinska Institutet in Stockholm, the University of Bristol (England), and Sun Yat-Sen University in China.
“Our finding is that children who have a bigger body size than the average have increased risks of developing almost all subtypes of adult-onset diabetes, except for the mild age-related subtype,” lead author Yuxia Wei, a PhD student from the Karolinska Institutet, said in an interview. “This tells us that it is important to prevent overweight/obesity in children and important for pediatric patients to lose weight if they have already been overweight/obese,” she added, while acknowledging that the study did not examine whether childhood weight loss would prevent adult-onset diabetes.
The study, published online in Diabetologia, used Mendelian randomization (MR), with data from genome-wide association studies (GWAS) of childhood obesity and the five subtypes of adult-onset diabetes: latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). MR is “a rather new but commonly used and established technique that uses genetic information to study the causal link between an environmental risk factor and a disease, while accounting for the influence of other risk factors,” Ms. Wei explained.
To identify genetic variations associated with obesity, the study used statistics from a GWAS of 453,169 Europeans who self-reported body size at age 10 years in the UK Biobank study. After adjustment for sex, age at baseline, type of genotyping array, and month of birth, they identified 295 independent single nucleotide polymorphisms (SNPs) for childhood body size.
The researchers also used data from two GWAS of European adults with newly diagnosed diabetes, or without diabetes, to identify SNPs in 8,581 individuals with LADA, 3,937 with SIDD, 3,874 with SIRD, 4,118 with MOD, and 5,605 with MARD.
They then used MR to assess the association of genetically predicted childhood body size with the different diabetes subtypes.
The analysis showed that, with the exception of MARD, all other adult-onset diabetes subtypes were causally associated with childhood obesity, with odds ratio of 1.62 for LADA, 2.11 for SIDD, 2.76 for SIRD, and 7.30 for MOD. However, a genetic correlation between childhood obesity and adult-onset diabetes was found only for MOD, and no other subtypes. “The weak genetic correlation between childhood obesity and adult diabetes indicates that the genes promoting childhood adiposity are largely distinct from those promoting diabetes during adulthood,” noted the authors.
The findings indicate that “childhood body size and MOD may share some genetic mutations,” added Ms. Wei. “That is to say, some genes may affect childhood body size and MOD simultaneously.” But the shared genes do demonstrate the causal effect of childhood obesity on MOD, she explained. The causal effect is demonstrated through the MR analysis.
Additionally, they noted that while “the link between childhood body size and SIRD is expected, given the adverse effects of adiposity on insulin sensitivity ... the smaller OR for SIRD than for MOD suggests that non–obesity-related and/or nongenetic effects may be the main factors underlying the development of SIRD.” Asked for her theory on how childhood body size could affect diabetes subtypes characterized by autoimmunity (LADA) or impaired insulin secretion (SIDD), Ms. Wei speculated that “excess fat around the pancreas can affect insulin secretion and that impaired insulin secretion is also an important problem for LADA.”
Another theory is that it might be “metabolic memory,” suggested Jordi Merino, PhD, of the University of Copenhagen and Harvard University, Boston, who was not involved in the research. “Being exposed to obesity during childhood will tell the body to produce more insulin/aberrant immunity responses later in life.”
Dr. Merino said that, overall, the study’s findings “highlight the long and lasting effect of early-life adiposity and metabolic alterations on different forms of adult-onset diabetes,” adding that this is the first evidence “that childhood adiposity is not only linked to the more traditional diabetes subtype consequence of increased insulin resistance but also subtypes driven by autoimmunity or impaired insulin secretion.” He explained that genetics is “only part of the story” driving increased diabetes risk and “we do not know much about other factors interacting with genetics, but the results from this Mendelian randomization analysis suggest that childhood obesity is a causal factor for all adult-onset diabetes subtypes. Identifying causal factors instead of associative factors is critical to implement more targeted preventive and therapeutic strategies.”
He acknowledged, “There is a long path for these results to be eventually implemented in clinical practice, but they can support early weight control strategies for preventing different diabetes subtypes.”
The study was supported by the Swedish Research Council, Research Council for Health, Working Life and Welfare, and Novo Nordisk Foundation. Ms. Wei received a scholarship from the China Scholarship Council. One coauthor is an employee of GlaxoSmithKline. Dr. Merino reported no conflicts of interest.
Childhood obesity is a risk factor for four of the five subtypes of adult-onset diabetes, emphasizing the importance of childhood weight control, according to a collaborative study from the Karolinska Institutet in Stockholm, the University of Bristol (England), and Sun Yat-Sen University in China.
“Our finding is that children who have a bigger body size than the average have increased risks of developing almost all subtypes of adult-onset diabetes, except for the mild age-related subtype,” lead author Yuxia Wei, a PhD student from the Karolinska Institutet, said in an interview. “This tells us that it is important to prevent overweight/obesity in children and important for pediatric patients to lose weight if they have already been overweight/obese,” she added, while acknowledging that the study did not examine whether childhood weight loss would prevent adult-onset diabetes.
The study, published online in Diabetologia, used Mendelian randomization (MR), with data from genome-wide association studies (GWAS) of childhood obesity and the five subtypes of adult-onset diabetes: latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). MR is “a rather new but commonly used and established technique that uses genetic information to study the causal link between an environmental risk factor and a disease, while accounting for the influence of other risk factors,” Ms. Wei explained.
To identify genetic variations associated with obesity, the study used statistics from a GWAS of 453,169 Europeans who self-reported body size at age 10 years in the UK Biobank study. After adjustment for sex, age at baseline, type of genotyping array, and month of birth, they identified 295 independent single nucleotide polymorphisms (SNPs) for childhood body size.
The researchers also used data from two GWAS of European adults with newly diagnosed diabetes, or without diabetes, to identify SNPs in 8,581 individuals with LADA, 3,937 with SIDD, 3,874 with SIRD, 4,118 with MOD, and 5,605 with MARD.
They then used MR to assess the association of genetically predicted childhood body size with the different diabetes subtypes.
The analysis showed that, with the exception of MARD, all other adult-onset diabetes subtypes were causally associated with childhood obesity, with odds ratio of 1.62 for LADA, 2.11 for SIDD, 2.76 for SIRD, and 7.30 for MOD. However, a genetic correlation between childhood obesity and adult-onset diabetes was found only for MOD, and no other subtypes. “The weak genetic correlation between childhood obesity and adult diabetes indicates that the genes promoting childhood adiposity are largely distinct from those promoting diabetes during adulthood,” noted the authors.
The findings indicate that “childhood body size and MOD may share some genetic mutations,” added Ms. Wei. “That is to say, some genes may affect childhood body size and MOD simultaneously.” But the shared genes do demonstrate the causal effect of childhood obesity on MOD, she explained. The causal effect is demonstrated through the MR analysis.
Additionally, they noted that while “the link between childhood body size and SIRD is expected, given the adverse effects of adiposity on insulin sensitivity ... the smaller OR for SIRD than for MOD suggests that non–obesity-related and/or nongenetic effects may be the main factors underlying the development of SIRD.” Asked for her theory on how childhood body size could affect diabetes subtypes characterized by autoimmunity (LADA) or impaired insulin secretion (SIDD), Ms. Wei speculated that “excess fat around the pancreas can affect insulin secretion and that impaired insulin secretion is also an important problem for LADA.”
Another theory is that it might be “metabolic memory,” suggested Jordi Merino, PhD, of the University of Copenhagen and Harvard University, Boston, who was not involved in the research. “Being exposed to obesity during childhood will tell the body to produce more insulin/aberrant immunity responses later in life.”
Dr. Merino said that, overall, the study’s findings “highlight the long and lasting effect of early-life adiposity and metabolic alterations on different forms of adult-onset diabetes,” adding that this is the first evidence “that childhood adiposity is not only linked to the more traditional diabetes subtype consequence of increased insulin resistance but also subtypes driven by autoimmunity or impaired insulin secretion.” He explained that genetics is “only part of the story” driving increased diabetes risk and “we do not know much about other factors interacting with genetics, but the results from this Mendelian randomization analysis suggest that childhood obesity is a causal factor for all adult-onset diabetes subtypes. Identifying causal factors instead of associative factors is critical to implement more targeted preventive and therapeutic strategies.”
He acknowledged, “There is a long path for these results to be eventually implemented in clinical practice, but they can support early weight control strategies for preventing different diabetes subtypes.”
The study was supported by the Swedish Research Council, Research Council for Health, Working Life and Welfare, and Novo Nordisk Foundation. Ms. Wei received a scholarship from the China Scholarship Council. One coauthor is an employee of GlaxoSmithKline. Dr. Merino reported no conflicts of interest.
Childhood obesity is a risk factor for four of the five subtypes of adult-onset diabetes, emphasizing the importance of childhood weight control, according to a collaborative study from the Karolinska Institutet in Stockholm, the University of Bristol (England), and Sun Yat-Sen University in China.
“Our finding is that children who have a bigger body size than the average have increased risks of developing almost all subtypes of adult-onset diabetes, except for the mild age-related subtype,” lead author Yuxia Wei, a PhD student from the Karolinska Institutet, said in an interview. “This tells us that it is important to prevent overweight/obesity in children and important for pediatric patients to lose weight if they have already been overweight/obese,” she added, while acknowledging that the study did not examine whether childhood weight loss would prevent adult-onset diabetes.
The study, published online in Diabetologia, used Mendelian randomization (MR), with data from genome-wide association studies (GWAS) of childhood obesity and the five subtypes of adult-onset diabetes: latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). MR is “a rather new but commonly used and established technique that uses genetic information to study the causal link between an environmental risk factor and a disease, while accounting for the influence of other risk factors,” Ms. Wei explained.
To identify genetic variations associated with obesity, the study used statistics from a GWAS of 453,169 Europeans who self-reported body size at age 10 years in the UK Biobank study. After adjustment for sex, age at baseline, type of genotyping array, and month of birth, they identified 295 independent single nucleotide polymorphisms (SNPs) for childhood body size.
The researchers also used data from two GWAS of European adults with newly diagnosed diabetes, or without diabetes, to identify SNPs in 8,581 individuals with LADA, 3,937 with SIDD, 3,874 with SIRD, 4,118 with MOD, and 5,605 with MARD.
They then used MR to assess the association of genetically predicted childhood body size with the different diabetes subtypes.
The analysis showed that, with the exception of MARD, all other adult-onset diabetes subtypes were causally associated with childhood obesity, with odds ratio of 1.62 for LADA, 2.11 for SIDD, 2.76 for SIRD, and 7.30 for MOD. However, a genetic correlation between childhood obesity and adult-onset diabetes was found only for MOD, and no other subtypes. “The weak genetic correlation between childhood obesity and adult diabetes indicates that the genes promoting childhood adiposity are largely distinct from those promoting diabetes during adulthood,” noted the authors.
The findings indicate that “childhood body size and MOD may share some genetic mutations,” added Ms. Wei. “That is to say, some genes may affect childhood body size and MOD simultaneously.” But the shared genes do demonstrate the causal effect of childhood obesity on MOD, she explained. The causal effect is demonstrated through the MR analysis.
Additionally, they noted that while “the link between childhood body size and SIRD is expected, given the adverse effects of adiposity on insulin sensitivity ... the smaller OR for SIRD than for MOD suggests that non–obesity-related and/or nongenetic effects may be the main factors underlying the development of SIRD.” Asked for her theory on how childhood body size could affect diabetes subtypes characterized by autoimmunity (LADA) or impaired insulin secretion (SIDD), Ms. Wei speculated that “excess fat around the pancreas can affect insulin secretion and that impaired insulin secretion is also an important problem for LADA.”
Another theory is that it might be “metabolic memory,” suggested Jordi Merino, PhD, of the University of Copenhagen and Harvard University, Boston, who was not involved in the research. “Being exposed to obesity during childhood will tell the body to produce more insulin/aberrant immunity responses later in life.”
Dr. Merino said that, overall, the study’s findings “highlight the long and lasting effect of early-life adiposity and metabolic alterations on different forms of adult-onset diabetes,” adding that this is the first evidence “that childhood adiposity is not only linked to the more traditional diabetes subtype consequence of increased insulin resistance but also subtypes driven by autoimmunity or impaired insulin secretion.” He explained that genetics is “only part of the story” driving increased diabetes risk and “we do not know much about other factors interacting with genetics, but the results from this Mendelian randomization analysis suggest that childhood obesity is a causal factor for all adult-onset diabetes subtypes. Identifying causal factors instead of associative factors is critical to implement more targeted preventive and therapeutic strategies.”
He acknowledged, “There is a long path for these results to be eventually implemented in clinical practice, but they can support early weight control strategies for preventing different diabetes subtypes.”
The study was supported by the Swedish Research Council, Research Council for Health, Working Life and Welfare, and Novo Nordisk Foundation. Ms. Wei received a scholarship from the China Scholarship Council. One coauthor is an employee of GlaxoSmithKline. Dr. Merino reported no conflicts of interest.
FROM DIABETOLOGIA