Diabetes

TOPLINE:

A higher intake of lignans (found in plant-based foods such as seeds, whole grains, some fruits and vegetables, and coffee, tea, and cocoa) is linked to a reduced risk for type 2 diabetes (T2D), especially in individuals with obesity or premenopausal women.

METHODOLOGY:

• Lignans, polyphenolic compounds abundant in plant-based foods, are the primary dietary source of phytoestrogens in Western diets and are associated with a reduced risk for cardiometabolic conditions, but the relative associations of individual lignans with T2D are unknown.
• Researchers assessed the associations between the risk for T2D and the intake of total and four primary lignans using the data of 201,111 participants (mean age, 44.7 years; 80.2% women; 96.7% White individuals) from three large prospective US cohorts with over 30 years of follow-up, as well as the association between lignan intake and hemoglobin A1c in 496 participants from the Men’s Lifestyle Validation Study (MLVS).
• For the three large cohorts, lignan intake (total, secoisolariciresinol, matairesinol, pinoresinol, and lariciresinol) was assessed using a validated food frequency questionnaire updated every 2-4 years and categorized into quintiles. For MLVS, diet was assessed by two sets of 7-day diet records and presented as percentage changes in A1c for linear increases in lignan intake.
• Incident T2D was confirmed using diagnostic tests, symptoms, hypoglycemic medication, elevated glucose by several measures.

TAKEAWAY:

• Across the three cohorts, 20,291 cases of T2D were recorded in the full follow-up.
• Higher intakes of total and individual ligands, except for lariciresinol, were associated with about 8%-27% lower T2D incidents (approximate hazard ratio [HR], 0.72-0.93)
• Of the individual lignans, secoisolariciresinol (but not others) showed a significant inverse association with the risk for T2D among those with a body mass index ≥ 30 (HR, 0.75; 95% CI, 0.71-0.79) and premenopausal women (HR, 0.67; 95% CI, 0.65-0.69).
• The dietary intake of lignans assessed using the 7-day diet records in MLVS was associated with lower levels of A1c (percentage changes ranging from −0.92% to −1.50%.

IN PRACTICE:

“Our findings underscore the importance of a healthy plant-based diet rich in lignan-containing foods, including flaxseed products, whole grains, and coffee for the primary prevention of T2D,” the authors wrote.

SOURCE:

The study, led by Siyue Wang, PhD, Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts, and the School of Public Health, Peking University, Beijing, China, was published online in JAMA Network Open.

LIMITATIONS:

The study’s limitations include the potential for measurement errors in dietary assessments. Flax seed, the most concentrated source of lignans, was not assessed until midway through the three large cohort follow-ups, and this may have resulted in misclassification of the intake levels of secoisolariciresinol. The lack of diversity in the socioeconomic status and race within the population may restrict the generalizability of the findings. Despite making multivariable adjustments, residual confounding cannot be fully ruled out.

DISCLOSURES:

The three cohort studies were supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

A higher intake of lignans (found in plant-based foods such as seeds, whole grains, some fruits and vegetables, and coffee, tea, and cocoa) is linked to a reduced risk for type 2 diabetes (T2D), especially in individuals with obesity or premenopausal women.

METHODOLOGY:

• Lignans, polyphenolic compounds abundant in plant-based foods, are the primary dietary source of phytoestrogens in Western diets and are associated with a reduced risk for cardiometabolic conditions, but the relative associations of individual lignans with T2D are unknown.
• Researchers assessed the associations between the risk for T2D and the intake of total and four primary lignans using the data of 201,111 participants (mean age, 44.7 years; 80.2% women; 96.7% White individuals) from three large prospective US cohorts with over 30 years of follow-up, as well as the association between lignan intake and hemoglobin A1c in 496 participants from the Men’s Lifestyle Validation Study (MLVS).
• For the three large cohorts, lignan intake (total, secoisolariciresinol, matairesinol, pinoresinol, and lariciresinol) was assessed using a validated food frequency questionnaire updated every 2-4 years and categorized into quintiles. For MLVS, diet was assessed by two sets of 7-day diet records and presented as percentage changes in A1c for linear increases in lignan intake.
• Incident T2D was confirmed using diagnostic tests, symptoms, hypoglycemic medication, elevated glucose by several measures.

TAKEAWAY:

• Across the three cohorts, 20,291 cases of T2D were recorded in the full follow-up.
• Higher intakes of total and individual ligands, except for lariciresinol, were associated with about 8%-27% lower T2D incidents (approximate hazard ratio [HR], 0.72-0.93)
• Of the individual lignans, secoisolariciresinol (but not others) showed a significant inverse association with the risk for T2D among those with a body mass index ≥ 30 (HR, 0.75; 95% CI, 0.71-0.79) and premenopausal women (HR, 0.67; 95% CI, 0.65-0.69).
• The dietary intake of lignans assessed using the 7-day diet records in MLVS was associated with lower levels of A1c (percentage changes ranging from −0.92% to −1.50%.

IN PRACTICE:

“Our findings underscore the importance of a healthy plant-based diet rich in lignan-containing foods, including flaxseed products, whole grains, and coffee for the primary prevention of T2D,” the authors wrote.

SOURCE:

The study, led by Siyue Wang, PhD, Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts, and the School of Public Health, Peking University, Beijing, China, was published online in JAMA Network Open.

LIMITATIONS:

The study’s limitations include the potential for measurement errors in dietary assessments. Flax seed, the most concentrated source of lignans, was not assessed until midway through the three large cohort follow-ups, and this may have resulted in misclassification of the intake levels of secoisolariciresinol. The lack of diversity in the socioeconomic status and race within the population may restrict the generalizability of the findings. Despite making multivariable adjustments, residual confounding cannot be fully ruled out.

DISCLOSURES:

The three cohort studies were supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

A higher intake of lignans (found in plant-based foods such as seeds, whole grains, some fruits and vegetables, and coffee, tea, and cocoa) is linked to a reduced risk for type 2 diabetes (T2D), especially in individuals with obesity or premenopausal women.

METHODOLOGY:

• Lignans, polyphenolic compounds abundant in plant-based foods, are the primary dietary source of phytoestrogens in Western diets and are associated with a reduced risk for cardiometabolic conditions, but the relative associations of individual lignans with T2D are unknown.
• Researchers assessed the associations between the risk for T2D and the intake of total and four primary lignans using the data of 201,111 participants (mean age, 44.7 years; 80.2% women; 96.7% White individuals) from three large prospective US cohorts with over 30 years of follow-up, as well as the association between lignan intake and hemoglobin A1c in 496 participants from the Men’s Lifestyle Validation Study (MLVS).
• For the three large cohorts, lignan intake (total, secoisolariciresinol, matairesinol, pinoresinol, and lariciresinol) was assessed using a validated food frequency questionnaire updated every 2-4 years and categorized into quintiles. For MLVS, diet was assessed by two sets of 7-day diet records and presented as percentage changes in A1c for linear increases in lignan intake.
• Incident T2D was confirmed using diagnostic tests, symptoms, hypoglycemic medication, elevated glucose by several measures.

TAKEAWAY:

• Across the three cohorts, 20,291 cases of T2D were recorded in the full follow-up.
• Higher intakes of total and individual ligands, except for lariciresinol, were associated with about 8%-27% lower T2D incidents (approximate hazard ratio [HR], 0.72-0.93)
• Of the individual lignans, secoisolariciresinol (but not others) showed a significant inverse association with the risk for T2D among those with a body mass index ≥ 30 (HR, 0.75; 95% CI, 0.71-0.79) and premenopausal women (HR, 0.67; 95% CI, 0.65-0.69).
• The dietary intake of lignans assessed using the 7-day diet records in MLVS was associated with lower levels of A1c (percentage changes ranging from −0.92% to −1.50%.

IN PRACTICE:

“Our findings underscore the importance of a healthy plant-based diet rich in lignan-containing foods, including flaxseed products, whole grains, and coffee for the primary prevention of T2D,” the authors wrote.

SOURCE:

The study, led by Siyue Wang, PhD, Department of Nutrition, Harvard TH Chan School of Public Health, Boston, Massachusetts, and the School of Public Health, Peking University, Beijing, China, was published online in JAMA Network Open.

LIMITATIONS:

The study’s limitations include the potential for measurement errors in dietary assessments. Flax seed, the most concentrated source of lignans, was not assessed until midway through the three large cohort follow-ups, and this may have resulted in misclassification of the intake levels of secoisolariciresinol. The lack of diversity in the socioeconomic status and race within the population may restrict the generalizability of the findings. Despite making multivariable adjustments, residual confounding cannot be fully ruled out.

DISCLOSURES:

The three cohort studies were supported by grants from the National Institutes of Health. The authors declared no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Akshay B. Jain, MD: I’m Dr. Akshay Jain, an endocrinologist from Vancouver, and I’m joined by Dr. James Kim, a primary care physician from Calgary, Canada. 

Both Dr. Kim and I attended ADA 2024. We went over all our learnings and decided that there was a whole heap of clinical pearls that we learned from the conference. We thought it would be awesome if we could share our learnings with all of you, both from a primary care lens and from an endocrinology perspective.

One study Dr. Kim and I learned about, and we think has some definite nuances in management of people living with diabetes, regards inhaled insulin. When we have patients in our clinic who have perhaps failed multiple oral agents or have very high blood sugars, we obviously want to consider starting them on insulin for type 2 diabetes.

Sometimes there is a significant barrier, which is related to the needles. There’s an actual term for this: trypanophobia — a fear of needles. For the longest time, people have not wanted to take insulin or injectables because there’s only one way of administering it, which is subcutaneous.

Enter now inhaled insulin. We saw studies at the ADA 2024 conference that looked at a new inhaled insulin called Afrezza. Afrezza essentially is a short-acting insulin, so it’s kind of like a prandial insulin derivative, where it can be inhaled by an individual and it will work for mealtime control of blood sugars.

Dr. Kim, in your practice, how often do you see people not wanting to take shots, and has this been a big barrier for you in starting insulin? 

James W. Kim, MBBCh, PgDip, MScCH: Thank you for having me. To answer your question, absolutely I encounter this on a weekly basis — and I’m not even an endocrinologist. I just have an interest in diabetes. There are a number of patients that I think will benefit massively with insulin but they’re needle-phobic. You taught me that word, but I can never pronounce it, so my apologies for not remembering that phobia. I’m just going to call it needle phobia because I’m a simple-minded person.

The needle phobia is massive. I think there’s a definite fear of the needle, but there’s also a fear of failure. As soon as an injection is mentioned, many patients feel they failed miserably. There’s an emotional roller coaster that happens.

I’m sure, Dr. Jain, you have seen many patients, especially from Asia, who would say: “Oh, my auntie got on insulin and 3 months later, she got a kidney transplant.” “My uncle started on insulin and he unfortunately passed away a couple of months later.” Unfortunately, they’re blaming many of those things on insulin.

I also have a number of patients who said they were on insulin before many years ago, and they experienced some severe hypoglycemic events, and they don’t want to get on the insulin ever again. This is unfortunate because you know that if those patients, those aunties and uncles, were on insulin long before, maybe we could have saved their legs and kidneys, and potentially death.

Now we have advanced so much with insulin that hypoglycemia does occur, but much less than before. We still have many barriers when it comes to insulin initiations. Therefore, having this idea of inhaled insulin is fantastic, and I think we can get many more patients on insulin — the medication they actually need.

Dr. Jain: Absolutely. From the studies on inhaled insulin at ADA 2024, the key thing I found very interesting, regarding the pharmacokinetics of the insulin, was that it’s working very quickly. It starts working within minutes of administering it.

Additionally, it lasts in the body only for a shorter duration of time, compared with other injectable short-acting insulins, so it lasts in the body. The active insulin time is roughly about 2 hours or so, based on the studies, which in my mind opens up a whole world of possibilities because it means that people can take another correctional insulin if the blood sugars are still high after taking their first inhaled dose. You can take another dose subsequently without worrying about stacking of insulin. 

Many of us are familiar with this term, which is if you take two shots of short-acting insulin too close to each other, the insulin doses might add up and there can be a big drop in the blood sugars; it’s called stacking of insulin. This can be potentially avoided. 

Similarly, if you take your dinnertime inhaled insulin and the sugars are still high around bedtime, you could take a smaller dose of the inhaled insulin and not worry about middle-of-the-night hypoglycemia because the effect of the insulin would be only for a little while.

That’s one key learning that I found very helpful. The other important thing that I found was that this is not for everyone, so there are some restrictions. Essentially, the contraindication is that people who have asthma or COPD cannot be prescribed an inhaled insulin.

What are your thoughts, Dr. Kim, based on this for your practice in primary care? 

Dr. Kim: It is very fascinating, for sure. I cannot wait to get hold of this insulin. I can already think of some patients who may benefit. You’ve mentioned the asthma and COPD patients, and that makes more sense because there is an actual airway problem.

I also wonder what will happen to patients who have restrictive airway disease, where asthma and COPD fall under obstructive airway disease. What if they have obesity, where it’s really pressing into the diaphragm, and where they may not be able to take the deep breath in? How will they react?

What about someone who’s got a cold, someone who has postnasal drip, or someone who tends to cough frequently? What about egg allergies? There are many question marks around this insulin before initiating these medications. There is excitement, but there are also many questions at the same time.

Dr. Jain: I think these are very important, practical considerations that we’ll uncover as we start using more of this in clinical practice. The other important thing to note is that the presenters told us it’s important to monitor pulmonary function tests. It’s important to get a baseline pulmonary function test, and then we have to do another one in 6 months, followed by annually thereafter.

If, at any point of time, the FEV1 drops by 20% or more, then that would be an indication for discontinuation of the inhaled insulin. The pulmonary function test does not need to be one of those fancier ones. The study group would just do office spirometries. I’m wondering, Dr. Kim, in primary care, do you think this could potentially be a rate-limiting factor?

Dr. Kim: In Alberta, where I reside, no. Spirometry is very easily accessible in the province. For example, in Calgary alone, we have a population of about 1.3 million people. We have over 13 or 15 companies that can do this spirometry. We can get these things done literally within a week or 2.

However, I am aware that, in other provinces in Canada, it can definitely be a huge rate-limiting factor. Not everyone has the office-based spirometry, and definitely not within the primary care office. It has to be referred out to these private companies, most likely, and some of the rural areas will have to rely on the provincial hospitals, where the access can be even more challenging. 

On the day of the actual spirometry, if the person has a cough or is not feeling well, it’s going to be a problem because you don’t want the spirometry to be infected with a whole bunch of viruses. You’ll have to cancel that and it can be a bit of an issue.

Dr. Jain: Many of our viewers are from the United States and other parts of the world, and spirometry is quite easily accessible in most places. As an endocrinologist, I must confess that it’s been a long time since I’ve even ordered a spirometry or any clinical form of pulmonary function test. Once I start using the inhaled insulin, I’ll need to start brushing up on my pulmonary function test knowledge. 

I think these are exciting times. At least we’ve got something to offer to people who would have otherwise not taken any insulin at all. There’s certainly that hope that now there’s a different way to administer this, and hopefully it can only get better from here on.
 

Dr. Jain is a clinical instructor, Department of Endocrinology, University of British Columbia, Vancouver. Dr. Kim is a clinical assistant professor, Department of Family Medicine, University of Calgary in Alberta. Both disclosed conflicts of interest with numerous pharmaceutical companies.

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

This transcript has been edited for clarity. 

Akshay B. Jain, MD: I’m Dr. Akshay Jain, an endocrinologist from Vancouver, and I’m joined by Dr. James Kim, a primary care physician from Calgary, Canada. 

Both Dr. Kim and I attended ADA 2024. We went over all our learnings and decided that there was a whole heap of clinical pearls that we learned from the conference. We thought it would be awesome if we could share our learnings with all of you, both from a primary care lens and from an endocrinology perspective.

One study Dr. Kim and I learned about, and we think has some definite nuances in management of people living with diabetes, regards inhaled insulin. When we have patients in our clinic who have perhaps failed multiple oral agents or have very high blood sugars, we obviously want to consider starting them on insulin for type 2 diabetes.

Sometimes there is a significant barrier, which is related to the needles. There’s an actual term for this: trypanophobia — a fear of needles. For the longest time, people have not wanted to take insulin or injectables because there’s only one way of administering it, which is subcutaneous.

Enter now inhaled insulin. We saw studies at the ADA 2024 conference that looked at a new inhaled insulin called Afrezza. Afrezza essentially is a short-acting insulin, so it’s kind of like a prandial insulin derivative, where it can be inhaled by an individual and it will work for mealtime control of blood sugars.

Dr. Kim, in your practice, how often do you see people not wanting to take shots, and has this been a big barrier for you in starting insulin? 

James W. Kim, MBBCh, PgDip, MScCH: Thank you for having me. To answer your question, absolutely I encounter this on a weekly basis — and I’m not even an endocrinologist. I just have an interest in diabetes. There are a number of patients that I think will benefit massively with insulin but they’re needle-phobic. You taught me that word, but I can never pronounce it, so my apologies for not remembering that phobia. I’m just going to call it needle phobia because I’m a simple-minded person.

The needle phobia is massive. I think there’s a definite fear of the needle, but there’s also a fear of failure. As soon as an injection is mentioned, many patients feel they failed miserably. There’s an emotional roller coaster that happens.

I’m sure, Dr. Jain, you have seen many patients, especially from Asia, who would say: “Oh, my auntie got on insulin and 3 months later, she got a kidney transplant.” “My uncle started on insulin and he unfortunately passed away a couple of months later.” Unfortunately, they’re blaming many of those things on insulin.

I also have a number of patients who said they were on insulin before many years ago, and they experienced some severe hypoglycemic events, and they don’t want to get on the insulin ever again. This is unfortunate because you know that if those patients, those aunties and uncles, were on insulin long before, maybe we could have saved their legs and kidneys, and potentially death.

Now we have advanced so much with insulin that hypoglycemia does occur, but much less than before. We still have many barriers when it comes to insulin initiations. Therefore, having this idea of inhaled insulin is fantastic, and I think we can get many more patients on insulin — the medication they actually need.

Dr. Jain: Absolutely. From the studies on inhaled insulin at ADA 2024, the key thing I found very interesting, regarding the pharmacokinetics of the insulin, was that it’s working very quickly. It starts working within minutes of administering it.

Additionally, it lasts in the body only for a shorter duration of time, compared with other injectable short-acting insulins, so it lasts in the body. The active insulin time is roughly about 2 hours or so, based on the studies, which in my mind opens up a whole world of possibilities because it means that people can take another correctional insulin if the blood sugars are still high after taking their first inhaled dose. You can take another dose subsequently without worrying about stacking of insulin. 

Many of us are familiar with this term, which is if you take two shots of short-acting insulin too close to each other, the insulin doses might add up and there can be a big drop in the blood sugars; it’s called stacking of insulin. This can be potentially avoided. 

Similarly, if you take your dinnertime inhaled insulin and the sugars are still high around bedtime, you could take a smaller dose of the inhaled insulin and not worry about middle-of-the-night hypoglycemia because the effect of the insulin would be only for a little while.

That’s one key learning that I found very helpful. The other important thing that I found was that this is not for everyone, so there are some restrictions. Essentially, the contraindication is that people who have asthma or COPD cannot be prescribed an inhaled insulin.

What are your thoughts, Dr. Kim, based on this for your practice in primary care? 

Dr. Kim: It is very fascinating, for sure. I cannot wait to get hold of this insulin. I can already think of some patients who may benefit. You’ve mentioned the asthma and COPD patients, and that makes more sense because there is an actual airway problem.

I also wonder what will happen to patients who have restrictive airway disease, where asthma and COPD fall under obstructive airway disease. What if they have obesity, where it’s really pressing into the diaphragm, and where they may not be able to take the deep breath in? How will they react?

What about someone who’s got a cold, someone who has postnasal drip, or someone who tends to cough frequently? What about egg allergies? There are many question marks around this insulin before initiating these medications. There is excitement, but there are also many questions at the same time.

Dr. Jain: I think these are very important, practical considerations that we’ll uncover as we start using more of this in clinical practice. The other important thing to note is that the presenters told us it’s important to monitor pulmonary function tests. It’s important to get a baseline pulmonary function test, and then we have to do another one in 6 months, followed by annually thereafter.

If, at any point of time, the FEV1 drops by 20% or more, then that would be an indication for discontinuation of the inhaled insulin. The pulmonary function test does not need to be one of those fancier ones. The study group would just do office spirometries. I’m wondering, Dr. Kim, in primary care, do you think this could potentially be a rate-limiting factor?

Dr. Kim: In Alberta, where I reside, no. Spirometry is very easily accessible in the province. For example, in Calgary alone, we have a population of about 1.3 million people. We have over 13 or 15 companies that can do this spirometry. We can get these things done literally within a week or 2.

However, I am aware that, in other provinces in Canada, it can definitely be a huge rate-limiting factor. Not everyone has the office-based spirometry, and definitely not within the primary care office. It has to be referred out to these private companies, most likely, and some of the rural areas will have to rely on the provincial hospitals, where the access can be even more challenging. 

On the day of the actual spirometry, if the person has a cough or is not feeling well, it’s going to be a problem because you don’t want the spirometry to be infected with a whole bunch of viruses. You’ll have to cancel that and it can be a bit of an issue.

Dr. Jain: Many of our viewers are from the United States and other parts of the world, and spirometry is quite easily accessible in most places. As an endocrinologist, I must confess that it’s been a long time since I’ve even ordered a spirometry or any clinical form of pulmonary function test. Once I start using the inhaled insulin, I’ll need to start brushing up on my pulmonary function test knowledge. 

I think these are exciting times. At least we’ve got something to offer to people who would have otherwise not taken any insulin at all. There’s certainly that hope that now there’s a different way to administer this, and hopefully it can only get better from here on.
 

Dr. Jain is a clinical instructor, Department of Endocrinology, University of British Columbia, Vancouver. Dr. Kim is a clinical assistant professor, Department of Family Medicine, University of Calgary in Alberta. Both disclosed conflicts of interest with numerous pharmaceutical companies.

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

This transcript has been edited for clarity. 

Akshay B. Jain, MD: I’m Dr. Akshay Jain, an endocrinologist from Vancouver, and I’m joined by Dr. James Kim, a primary care physician from Calgary, Canada. 

Both Dr. Kim and I attended ADA 2024. We went over all our learnings and decided that there was a whole heap of clinical pearls that we learned from the conference. We thought it would be awesome if we could share our learnings with all of you, both from a primary care lens and from an endocrinology perspective.

One study Dr. Kim and I learned about, and we think has some definite nuances in management of people living with diabetes, regards inhaled insulin. When we have patients in our clinic who have perhaps failed multiple oral agents or have very high blood sugars, we obviously want to consider starting them on insulin for type 2 diabetes.

Sometimes there is a significant barrier, which is related to the needles. There’s an actual term for this: trypanophobia — a fear of needles. For the longest time, people have not wanted to take insulin or injectables because there’s only one way of administering it, which is subcutaneous.

Enter now inhaled insulin. We saw studies at the ADA 2024 conference that looked at a new inhaled insulin called Afrezza. Afrezza essentially is a short-acting insulin, so it’s kind of like a prandial insulin derivative, where it can be inhaled by an individual and it will work for mealtime control of blood sugars.

Dr. Kim, in your practice, how often do you see people not wanting to take shots, and has this been a big barrier for you in starting insulin? 

James W. Kim, MBBCh, PgDip, MScCH: Thank you for having me. To answer your question, absolutely I encounter this on a weekly basis — and I’m not even an endocrinologist. I just have an interest in diabetes. There are a number of patients that I think will benefit massively with insulin but they’re needle-phobic. You taught me that word, but I can never pronounce it, so my apologies for not remembering that phobia. I’m just going to call it needle phobia because I’m a simple-minded person.

The needle phobia is massive. I think there’s a definite fear of the needle, but there’s also a fear of failure. As soon as an injection is mentioned, many patients feel they failed miserably. There’s an emotional roller coaster that happens.

I’m sure, Dr. Jain, you have seen many patients, especially from Asia, who would say: “Oh, my auntie got on insulin and 3 months later, she got a kidney transplant.” “My uncle started on insulin and he unfortunately passed away a couple of months later.” Unfortunately, they’re blaming many of those things on insulin.

I also have a number of patients who said they were on insulin before many years ago, and they experienced some severe hypoglycemic events, and they don’t want to get on the insulin ever again. This is unfortunate because you know that if those patients, those aunties and uncles, were on insulin long before, maybe we could have saved their legs and kidneys, and potentially death.

Now we have advanced so much with insulin that hypoglycemia does occur, but much less than before. We still have many barriers when it comes to insulin initiations. Therefore, having this idea of inhaled insulin is fantastic, and I think we can get many more patients on insulin — the medication they actually need.

Dr. Jain: Absolutely. From the studies on inhaled insulin at ADA 2024, the key thing I found very interesting, regarding the pharmacokinetics of the insulin, was that it’s working very quickly. It starts working within minutes of administering it.

Additionally, it lasts in the body only for a shorter duration of time, compared with other injectable short-acting insulins, so it lasts in the body. The active insulin time is roughly about 2 hours or so, based on the studies, which in my mind opens up a whole world of possibilities because it means that people can take another correctional insulin if the blood sugars are still high after taking their first inhaled dose. You can take another dose subsequently without worrying about stacking of insulin. 

Many of us are familiar with this term, which is if you take two shots of short-acting insulin too close to each other, the insulin doses might add up and there can be a big drop in the blood sugars; it’s called stacking of insulin. This can be potentially avoided. 

Similarly, if you take your dinnertime inhaled insulin and the sugars are still high around bedtime, you could take a smaller dose of the inhaled insulin and not worry about middle-of-the-night hypoglycemia because the effect of the insulin would be only for a little while.

That’s one key learning that I found very helpful. The other important thing that I found was that this is not for everyone, so there are some restrictions. Essentially, the contraindication is that people who have asthma or COPD cannot be prescribed an inhaled insulin.

What are your thoughts, Dr. Kim, based on this for your practice in primary care? 

Dr. Kim: It is very fascinating, for sure. I cannot wait to get hold of this insulin. I can already think of some patients who may benefit. You’ve mentioned the asthma and COPD patients, and that makes more sense because there is an actual airway problem.

I also wonder what will happen to patients who have restrictive airway disease, where asthma and COPD fall under obstructive airway disease. What if they have obesity, where it’s really pressing into the diaphragm, and where they may not be able to take the deep breath in? How will they react?

What about someone who’s got a cold, someone who has postnasal drip, or someone who tends to cough frequently? What about egg allergies? There are many question marks around this insulin before initiating these medications. There is excitement, but there are also many questions at the same time.

Dr. Jain: I think these are very important, practical considerations that we’ll uncover as we start using more of this in clinical practice. The other important thing to note is that the presenters told us it’s important to monitor pulmonary function tests. It’s important to get a baseline pulmonary function test, and then we have to do another one in 6 months, followed by annually thereafter.

If, at any point of time, the FEV1 drops by 20% or more, then that would be an indication for discontinuation of the inhaled insulin. The pulmonary function test does not need to be one of those fancier ones. The study group would just do office spirometries. I’m wondering, Dr. Kim, in primary care, do you think this could potentially be a rate-limiting factor?

Dr. Kim: In Alberta, where I reside, no. Spirometry is very easily accessible in the province. For example, in Calgary alone, we have a population of about 1.3 million people. We have over 13 or 15 companies that can do this spirometry. We can get these things done literally within a week or 2.

However, I am aware that, in other provinces in Canada, it can definitely be a huge rate-limiting factor. Not everyone has the office-based spirometry, and definitely not within the primary care office. It has to be referred out to these private companies, most likely, and some of the rural areas will have to rely on the provincial hospitals, where the access can be even more challenging. 

On the day of the actual spirometry, if the person has a cough or is not feeling well, it’s going to be a problem because you don’t want the spirometry to be infected with a whole bunch of viruses. You’ll have to cancel that and it can be a bit of an issue.

Dr. Jain: Many of our viewers are from the United States and other parts of the world, and spirometry is quite easily accessible in most places. As an endocrinologist, I must confess that it’s been a long time since I’ve even ordered a spirometry or any clinical form of pulmonary function test. Once I start using the inhaled insulin, I’ll need to start brushing up on my pulmonary function test knowledge. 

I think these are exciting times. At least we’ve got something to offer to people who would have otherwise not taken any insulin at all. There’s certainly that hope that now there’s a different way to administer this, and hopefully it can only get better from here on.
 

Dr. Jain is a clinical instructor, Department of Endocrinology, University of British Columbia, Vancouver. Dr. Kim is a clinical assistant professor, Department of Family Medicine, University of Calgary in Alberta. Both disclosed conflicts of interest with numerous pharmaceutical companies.

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

TOPLINE:

When starting a regular exercise program, the skeletal muscle of sedentary men and women with overweight and obesity differs in burning sugar and fatty acids, but regular training can lessen these differences and promote similar positive metabolic changes in both biological sexes.

METHODOLOGY:

• By stimulating skeletal muscle, exercise can help prevent muscle loss associated with weight loss and improve insulin sensitivity and glucose control in type 2 diabetes, but biological sex-based differences have been reported for many measures.
• This study of sedentary men and women evaluated the molecular differences in skeletal muscle in response to a training program.
• Researchers collected muscle biopsies from 16 women and nine men with overweight or obesity (average age, 30 years) at three time points — baseline, after the first exercise session, and after the last session at the end of training.
• Training involved 1 hour of moderate to intense endurance exercise under supervision (30 minutes cycling on an ergometer and 30 minutes walking on a treadmill) thrice a week for 8 weeks.
• The biopsies were profiled for patterns of three sets of omics data — DNA methylation for insight into genes switched on and off (epigenomics), RNA molecules transcribed from genes (transcriptomics), and proteins (proteomics).

TAKEAWAY:

• At baseline, sex-specific differences were observed most tellingly in 120 proteins and also in DNA methylation sites of 16,012 genes and in 1366 RNA transcripts.
• Men displayed a higher abundance of glycolysis-related proteins and other fast-twitch fiber–type proteins, which are involved in the processing of glucose, while women showed more proteins responsible for regulating fatty acid metabolism.
• The response to the first exercise session differed between men and women, with the cellular stress response upregulated predominantly in men.
• The 8-week exercise training mitigated these sex-specific differences in the skeletal muscle, leading to an upregulation of mitochondrial proteins responsible for substrate oxidation and ATP generation in both men and women.

IN PRACTICE:

“This is important because the increased capacity after exercise to use glucose and lipids for energy production is generally regarded as key to prevent type 2 diabetes,” study leader Professor Cora Weigert from the University of Tübingen, Germany, said in a news release from the meeting organizers. “While initial response of skeletal muscles to exercise differs between females and males, repeated exercise appears to cancel out these differences and trigger beneficial metabolic changes in both sexes,” she added.

SOURCE:

The study was led by Simon I. Dreher, PhD, Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Tübingen, Germany. It was published on August 15, 2024, as an early release from the annual meeting of the European Association for the Study of Diabetes 2024, Madrid, September 9-13.

LIMITATIONS:

This abstract did not discuss any limitations.

DISCLOSURES:

The authors did not disclose any funding information. The authors declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

When starting a regular exercise program, the skeletal muscle of sedentary men and women with overweight and obesity differs in burning sugar and fatty acids, but regular training can lessen these differences and promote similar positive metabolic changes in both biological sexes.

METHODOLOGY:

• By stimulating skeletal muscle, exercise can help prevent muscle loss associated with weight loss and improve insulin sensitivity and glucose control in type 2 diabetes, but biological sex-based differences have been reported for many measures.
• This study of sedentary men and women evaluated the molecular differences in skeletal muscle in response to a training program.
• Researchers collected muscle biopsies from 16 women and nine men with overweight or obesity (average age, 30 years) at three time points — baseline, after the first exercise session, and after the last session at the end of training.
• Training involved 1 hour of moderate to intense endurance exercise under supervision (30 minutes cycling on an ergometer and 30 minutes walking on a treadmill) thrice a week for 8 weeks.
• The biopsies were profiled for patterns of three sets of omics data — DNA methylation for insight into genes switched on and off (epigenomics), RNA molecules transcribed from genes (transcriptomics), and proteins (proteomics).

TAKEAWAY:

• At baseline, sex-specific differences were observed most tellingly in 120 proteins and also in DNA methylation sites of 16,012 genes and in 1366 RNA transcripts.
• Men displayed a higher abundance of glycolysis-related proteins and other fast-twitch fiber–type proteins, which are involved in the processing of glucose, while women showed more proteins responsible for regulating fatty acid metabolism.
• The response to the first exercise session differed between men and women, with the cellular stress response upregulated predominantly in men.
• The 8-week exercise training mitigated these sex-specific differences in the skeletal muscle, leading to an upregulation of mitochondrial proteins responsible for substrate oxidation and ATP generation in both men and women.

IN PRACTICE:

“This is important because the increased capacity after exercise to use glucose and lipids for energy production is generally regarded as key to prevent type 2 diabetes,” study leader Professor Cora Weigert from the University of Tübingen, Germany, said in a news release from the meeting organizers. “While initial response of skeletal muscles to exercise differs between females and males, repeated exercise appears to cancel out these differences and trigger beneficial metabolic changes in both sexes,” she added.

SOURCE:

The study was led by Simon I. Dreher, PhD, Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Tübingen, Germany. It was published on August 15, 2024, as an early release from the annual meeting of the European Association for the Study of Diabetes 2024, Madrid, September 9-13.

LIMITATIONS:

This abstract did not discuss any limitations.

DISCLOSURES:

The authors did not disclose any funding information. The authors declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

When starting a regular exercise program, the skeletal muscle of sedentary men and women with overweight and obesity differs in burning sugar and fatty acids, but regular training can lessen these differences and promote similar positive metabolic changes in both biological sexes.

METHODOLOGY:

• By stimulating skeletal muscle, exercise can help prevent muscle loss associated with weight loss and improve insulin sensitivity and glucose control in type 2 diabetes, but biological sex-based differences have been reported for many measures.
• This study of sedentary men and women evaluated the molecular differences in skeletal muscle in response to a training program.
• Researchers collected muscle biopsies from 16 women and nine men with overweight or obesity (average age, 30 years) at three time points — baseline, after the first exercise session, and after the last session at the end of training.
• Training involved 1 hour of moderate to intense endurance exercise under supervision (30 minutes cycling on an ergometer and 30 minutes walking on a treadmill) thrice a week for 8 weeks.
• The biopsies were profiled for patterns of three sets of omics data — DNA methylation for insight into genes switched on and off (epigenomics), RNA molecules transcribed from genes (transcriptomics), and proteins (proteomics).

TAKEAWAY:

• At baseline, sex-specific differences were observed most tellingly in 120 proteins and also in DNA methylation sites of 16,012 genes and in 1366 RNA transcripts.
• Men displayed a higher abundance of glycolysis-related proteins and other fast-twitch fiber–type proteins, which are involved in the processing of glucose, while women showed more proteins responsible for regulating fatty acid metabolism.
• The response to the first exercise session differed between men and women, with the cellular stress response upregulated predominantly in men.
• The 8-week exercise training mitigated these sex-specific differences in the skeletal muscle, leading to an upregulation of mitochondrial proteins responsible for substrate oxidation and ATP generation in both men and women.

IN PRACTICE:

“This is important because the increased capacity after exercise to use glucose and lipids for energy production is generally regarded as key to prevent type 2 diabetes,” study leader Professor Cora Weigert from the University of Tübingen, Germany, said in a news release from the meeting organizers. “While initial response of skeletal muscles to exercise differs between females and males, repeated exercise appears to cancel out these differences and trigger beneficial metabolic changes in both sexes,” she added.

SOURCE:

The study was led by Simon I. Dreher, PhD, Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, Tübingen, Germany. It was published on August 15, 2024, as an early release from the annual meeting of the European Association for the Study of Diabetes 2024, Madrid, September 9-13.

LIMITATIONS:

This abstract did not discuss any limitations.

DISCLOSURES:

The authors did not disclose any funding information. The authors declared no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines. 

However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations. 

“Clinicians should not interpret these results as proof of causal relationship between suicidal ideation and semaglutide, as our pharmacovigilance study showed an association between the use of semaglutide and reports of suicidal ideation,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.

Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said. 

“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added. 

The study was published online on August 20 in JAMA Network Open. 
 

Emerging Concerns

GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe. 

Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs). 

They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. 

Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women). 

The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs. 

This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote. 

No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04). 

However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%). 
 

More Research Needed 

GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said. 

“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.

The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.

This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France. 

Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible. 

“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie. 

Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre. 

The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”

Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”

“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said. 

The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest. 
 

A version of this article appeared on Medscape.com.

A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines. 

However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations. 

“Clinicians should not interpret these results as proof of causal relationship between suicidal ideation and semaglutide, as our pharmacovigilance study showed an association between the use of semaglutide and reports of suicidal ideation,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.

Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said. 

“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added. 

The study was published online on August 20 in JAMA Network Open. 
 

Emerging Concerns

GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe. 

Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs). 

They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. 

Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women). 

The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs. 

This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote. 

No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04). 

However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%). 
 

More Research Needed 

GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said. 

“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.

The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.

This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France. 

Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible. 

“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie. 

Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre. 

The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”

Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”

“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said. 

The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest. 
 

A version of this article appeared on Medscape.com.

A new analysis has detected a signal of suicidal ideation associated with the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide, especially among individuals concurrently using antidepressants or benzodiazepines. 

However, the investigators and outside experts urge caution in drawing any firm conclusions based on the study’s observations. 

“Clinicians should not interpret these results as proof of causal relationship between suicidal ideation and semaglutide, as our pharmacovigilance study showed an association between the use of semaglutide and reports of suicidal ideation,” study investigator Georgios Schoretsanitis, MD, PhD, Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, New York, told this news organization.

Nonetheless, “physicians prescribing semaglutide should inform their patients about the medications’ risks and assess the psychiatric history and evaluate the mental state of patients before starting treatment with semaglutide,” Dr. Schoretsanitis said. 

“For patients with history of mental disorders or suicidal ideation/behaviors/attempts, physicians should be cautious and regularly monitor their mental state while taking semaglutide. If needed, the treating physician should involve different specialists, including a psychiatrist and/or clinical psychologists,” he added. 

The study was published online on August 20 in JAMA Network Open. 
 

Emerging Concerns

GLP-1 RAs are increasingly prescribed not only for type 2 diabetes but also for weight loss. However, concerns have emerged about a potential association with suicidality, which has prompted a closer look by regulators in the United States and Europe. 

Dr. Schoretsanitis and colleagues evaluated potential signals of suicidality related to semaglutide and liraglutide using data from global World Health Organization database of suspected adverse drug reactions (ADRs). 

They conducted sensitivity analyses including patients with co-reported use of antidepressants and benzodiazepines and using dapagliflozin, metformin, and orlistat as comparators. 

Between November 2000 and August 2023, there were 107 cases of suicidal and/or self-injurious ADRs reported with semaglutide (median age, 48 years; 55% women) and 162 reported with liraglutide (median age 47 years; 61% women). 

The researchers noted that a “significant disproportionality” signal emerged for semaglutide-associated suicidal ideation (reporting odds ratio [ROR], 1.45), when compared with comparator drugs. 

This signal remained significant in sensitivity analyses that included patients on concurrent antidepressants (ROR, 4.45) and benzodiazepines (ROR, 4.07), “suggesting that people with anxiety and depressive disorders may be at higher probability of reporting suicidal ideation when medicated with semaglutide,” the authors wrote. 

No significant disproportionality signal was detected for liraglutide regarding suicidal ideation (ROR, 1.04). 

However, the authors noted that pooled data from previous phase 2 and 3 trials on liraglutide vs placebo for weight management identified a potential risk for suicidal ideation, with nine of 3384 participants in the liraglutide group vs two of 1941 in the placebo group reporting suicidal ideation or behavior during the trial (0.27% vs 0.10%). 
 

More Research Needed 

GLP-1 RAs “should be used cautiously until further data are available on this topic,” Dr. Schoretsanitis said. 

“Further real-world studies should investigate the risk of suicidal ideation or behavior in people treated with these drugs in every-day clinical practice. We categorically discourage off-label use of GLP1-RA and without any medical supervision,” he added.

The coauthors of an invited commentary published with the study note that between 2020 and 2023, GLP-1 RA use rose 594% in younger people, particularly in women.

This “timely and well-conducted study” by Dr. Schoretsanitis and colleagues adds “an important piece to the very relevant safety issue” related to GLP-1 RAs, wrote Francesco Salvo, MD, PhD, with Université de Bordeaux, and Jean-Luc Faillie, MD, PhD, with Université de Montpellier, both in France. 

Pending further studies, the position of the US Food and Drug Administration (FDA) recommending caution “continues to be reasonable. Whatever the cause, depression or suicidality are rare but extremely severe events and need to be prevented and managed as much as possible. 

“Waiting for more precise data, GPL-1 receptor agonists, and appetite suppressants in general, should be prescribed with great caution in patients with a history of depression or suicidal attempts, while in patients with new onset of depression without other apparent precipitants, immediate discontinuation of GLP-1 receptor agonists should be considered,” wrote Dr. Salvo and Dr. Faillie. 

Outside experts also weighed in on the study in a statement from the UK nonprofit Science Media Centre. 

The paper presents, “at best, weak evidence of an association between semaglutide and suicidality,” Ian Douglas, PhD, professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, United Kingdom, said in the statement. “Signal detection studies in pharmacovigilance databases are good for generating hypotheses but are not suitable for assessing whether there is a causal association between a drug and an outcome.”

Stephen Evans, MSc, emeritus professor of pharmacoepidemiology, London School of Hygiene & Tropical Medicine, cautioned that the study has “major limitations.”

“This paper is based just on spontaneous reports which are sent to regulatory authorities in the country of the person reporting a suspected adverse reaction. These are sent by health professionals and patients to authorities, but are very subject to bias, including effects of media reporting. The evidence is extremely weak for a genuine effect in this instance,” Mr. Evans said. 

The study had no specific funding. Dr. Schoretsanitis reported receiving personal fees from HLS, Dexcel, Saladax, and Thermo Fisher outside the submitted work. Dr. Salvo and Dr. Faillie have no conflicts of interest. Dr. Douglas has received research grants from GSK and AstraZeneca. Mr. Evans has no conflicts of interest. 
 

A version of this article appeared on Medscape.com.

The first — but not the last — over-the-counter continuous glucose monitor (CGM) is now available for people older than 18 years who don’t use insulin and who aren’t at a risk for hypoglycemia.

Dexcom’s Stelo is designed specifically for people with type 2 diabetes who don’t use insulin or who have prediabetes but is now available over the counter for anyone for $99 a month or $89 per month with a subscription. It won’t be covered by insurance and there are no financial assistance programs as of now, but people can use healthcare spending accounts to pay for the devices.

As with current CGMs used by people with diabetes who take insulin, the waterproof device is worn on the back of the upper arm and sends real-time glucose values to a smartphone. No finger sticks are required. Each sensor lasts 15 days. Unlike current CGMs, Stelo does not issue low blood sugar alarms.

“We’re excited to empower people to have access to their glucose readings, which we know studies have been done time and time again that giving people continuous glucose monitors helps improve their time in range, their A1c, and their sense of well-being living with diabetes. ... We expect the same improvements with this product that we’ve had with the G series products,” Thomas Grace, MD, Dexcom’s head of Clinical Advocacy and Outcomes, said in an interview at a product launch event held on August 21, 2024.

Dr. Grace is a family physician and medical director of the Diabetes Center, Blanchard Valley Health System, in Findlay, Ohio, where he uses technology extensively in managing patients with diabetes, prediabetes, and obesity. For example, he always starts patients on a CGM before prescribing a glucagon-like peptide 1 (GLP-1) receptor agonist to help them see the effects of both type and quantity of the food they’re eating. “On the back end of that, people are more successful getting off of medications when they have data to support their behaviors and decisions,” he said.

He anticipates the availability of Stelo will help make inroads in bringing CGM technology to primary care. “My hope is that for the places where it hasn’t taken off yet, that patients that now have access to this are the cornerstone for clinicians to see how well people can do when they have the access to that data and that will lead to some impetus for change. In the United States, roughly less than 10% of people with diabetes have CGMs right now.”

The Stelo will soon have competition, as Abbott Diabetes Care will be launching two new over-the-counter CGMs in the coming months. “Since there isn’t a one-size-fits-all approach to glucose monitoring, Abbott has designed two different products. Lingo is designed for general consumers looking to enhance their overall health and wellness, while Libre Rio is designed for people with type 2 diabetes who do not use insulin and typically manage their condition through lifestyle changes,” an Abbott spokesperson said in an interview.

Aaron Neinstein, MD, chief medical officer of Notable, a company that applies artificial intelligence to healthcare, sees a “diminishing debate” regarding the value of CGMs for people beyond those who use insulin. “Metabolic health exists on a wide spectrum, from people who are completely healthy to those at high risk for diabetes due to family history or other medical conditions, to those with insulin resistance, those with prediabetes, those with diabetes not on insulin, and those with diabetes on insulin. So when we talk and think about CGM, we need to consider this wide range of people. The question is in which specific population do the benefits of CGM outweigh costs and any potential harms? Clearly, the farther you go into poor metabolic health, the stronger is the case for CGM.” 

Dr. Neinstein added that “thankfully,” there is no more debate about the value of CGM use for people who use insulin and are therefore at a risk for hypoglycemia. But there is less debate now about even those who don’t take insulin, with emerging evidence that a “CGM provides biofeedback and helps them as a tool to support behavior changes and learning. I hope we will see insurance coverage broaden over time to cover CGM for more of these people who can benefit and who can improve their metabolic health through the use of CGM.”

However, Dr. Neinstein cautioned, “If you go to people who have no medical problems, no insulin resistance, no family history of diabetes, at that point, we do not have evidence that CGM is of health benefit.”

Moreover, he said, “ultimately if you have to choose whether a healthcare dollar goes to CGM or a GLP-1, the GLP-1 is a more impactful choice. In an ideal world, we would be able to support patients in having both, but with the profound benefits from GLP-1s on weight loss, cardiovascular outcomes, and [hemoglobin] A1c reduction and more, they are more potent than using a CGM.”

Dr. Grace is a Dexcom employee. Dr. Neinstein is a full-time employee at Notable, with no current further disclosures.

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

The first — but not the last — over-the-counter continuous glucose monitor (CGM) is now available for people older than 18 years who don’t use insulin and who aren’t at a risk for hypoglycemia.

Dexcom’s Stelo is designed specifically for people with type 2 diabetes who don’t use insulin or who have prediabetes but is now available over the counter for anyone for $99 a month or $89 per month with a subscription. It won’t be covered by insurance and there are no financial assistance programs as of now, but people can use healthcare spending accounts to pay for the devices.

As with current CGMs used by people with diabetes who take insulin, the waterproof device is worn on the back of the upper arm and sends real-time glucose values to a smartphone. No finger sticks are required. Each sensor lasts 15 days. Unlike current CGMs, Stelo does not issue low blood sugar alarms.

“We’re excited to empower people to have access to their glucose readings, which we know studies have been done time and time again that giving people continuous glucose monitors helps improve their time in range, their A1c, and their sense of well-being living with diabetes. ... We expect the same improvements with this product that we’ve had with the G series products,” Thomas Grace, MD, Dexcom’s head of Clinical Advocacy and Outcomes, said in an interview at a product launch event held on August 21, 2024.

Dr. Grace is a family physician and medical director of the Diabetes Center, Blanchard Valley Health System, in Findlay, Ohio, where he uses technology extensively in managing patients with diabetes, prediabetes, and obesity. For example, he always starts patients on a CGM before prescribing a glucagon-like peptide 1 (GLP-1) receptor agonist to help them see the effects of both type and quantity of the food they’re eating. “On the back end of that, people are more successful getting off of medications when they have data to support their behaviors and decisions,” he said.

He anticipates the availability of Stelo will help make inroads in bringing CGM technology to primary care. “My hope is that for the places where it hasn’t taken off yet, that patients that now have access to this are the cornerstone for clinicians to see how well people can do when they have the access to that data and that will lead to some impetus for change. In the United States, roughly less than 10% of people with diabetes have CGMs right now.”

The Stelo will soon have competition, as Abbott Diabetes Care will be launching two new over-the-counter CGMs in the coming months. “Since there isn’t a one-size-fits-all approach to glucose monitoring, Abbott has designed two different products. Lingo is designed for general consumers looking to enhance their overall health and wellness, while Libre Rio is designed for people with type 2 diabetes who do not use insulin and typically manage their condition through lifestyle changes,” an Abbott spokesperson said in an interview.

Aaron Neinstein, MD, chief medical officer of Notable, a company that applies artificial intelligence to healthcare, sees a “diminishing debate” regarding the value of CGMs for people beyond those who use insulin. “Metabolic health exists on a wide spectrum, from people who are completely healthy to those at high risk for diabetes due to family history or other medical conditions, to those with insulin resistance, those with prediabetes, those with diabetes not on insulin, and those with diabetes on insulin. So when we talk and think about CGM, we need to consider this wide range of people. The question is in which specific population do the benefits of CGM outweigh costs and any potential harms? Clearly, the farther you go into poor metabolic health, the stronger is the case for CGM.” 

Dr. Neinstein added that “thankfully,” there is no more debate about the value of CGM use for people who use insulin and are therefore at a risk for hypoglycemia. But there is less debate now about even those who don’t take insulin, with emerging evidence that a “CGM provides biofeedback and helps them as a tool to support behavior changes and learning. I hope we will see insurance coverage broaden over time to cover CGM for more of these people who can benefit and who can improve their metabolic health through the use of CGM.”

However, Dr. Neinstein cautioned, “If you go to people who have no medical problems, no insulin resistance, no family history of diabetes, at that point, we do not have evidence that CGM is of health benefit.”

Moreover, he said, “ultimately if you have to choose whether a healthcare dollar goes to CGM or a GLP-1, the GLP-1 is a more impactful choice. In an ideal world, we would be able to support patients in having both, but with the profound benefits from GLP-1s on weight loss, cardiovascular outcomes, and [hemoglobin] A1c reduction and more, they are more potent than using a CGM.”

Dr. Grace is a Dexcom employee. Dr. Neinstein is a full-time employee at Notable, with no current further disclosures.

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

The first — but not the last — over-the-counter continuous glucose monitor (CGM) is now available for people older than 18 years who don’t use insulin and who aren’t at a risk for hypoglycemia.

Dexcom’s Stelo is designed specifically for people with type 2 diabetes who don’t use insulin or who have prediabetes but is now available over the counter for anyone for $99 a month or $89 per month with a subscription. It won’t be covered by insurance and there are no financial assistance programs as of now, but people can use healthcare spending accounts to pay for the devices.

As with current CGMs used by people with diabetes who take insulin, the waterproof device is worn on the back of the upper arm and sends real-time glucose values to a smartphone. No finger sticks are required. Each sensor lasts 15 days. Unlike current CGMs, Stelo does not issue low blood sugar alarms.

“We’re excited to empower people to have access to their glucose readings, which we know studies have been done time and time again that giving people continuous glucose monitors helps improve their time in range, their A1c, and their sense of well-being living with diabetes. ... We expect the same improvements with this product that we’ve had with the G series products,” Thomas Grace, MD, Dexcom’s head of Clinical Advocacy and Outcomes, said in an interview at a product launch event held on August 21, 2024.

Dr. Grace is a family physician and medical director of the Diabetes Center, Blanchard Valley Health System, in Findlay, Ohio, where he uses technology extensively in managing patients with diabetes, prediabetes, and obesity. For example, he always starts patients on a CGM before prescribing a glucagon-like peptide 1 (GLP-1) receptor agonist to help them see the effects of both type and quantity of the food they’re eating. “On the back end of that, people are more successful getting off of medications when they have data to support their behaviors and decisions,” he said.

He anticipates the availability of Stelo will help make inroads in bringing CGM technology to primary care. “My hope is that for the places where it hasn’t taken off yet, that patients that now have access to this are the cornerstone for clinicians to see how well people can do when they have the access to that data and that will lead to some impetus for change. In the United States, roughly less than 10% of people with diabetes have CGMs right now.”

The Stelo will soon have competition, as Abbott Diabetes Care will be launching two new over-the-counter CGMs in the coming months. “Since there isn’t a one-size-fits-all approach to glucose monitoring, Abbott has designed two different products. Lingo is designed for general consumers looking to enhance their overall health and wellness, while Libre Rio is designed for people with type 2 diabetes who do not use insulin and typically manage their condition through lifestyle changes,” an Abbott spokesperson said in an interview.

Aaron Neinstein, MD, chief medical officer of Notable, a company that applies artificial intelligence to healthcare, sees a “diminishing debate” regarding the value of CGMs for people beyond those who use insulin. “Metabolic health exists on a wide spectrum, from people who are completely healthy to those at high risk for diabetes due to family history or other medical conditions, to those with insulin resistance, those with prediabetes, those with diabetes not on insulin, and those with diabetes on insulin. So when we talk and think about CGM, we need to consider this wide range of people. The question is in which specific population do the benefits of CGM outweigh costs and any potential harms? Clearly, the farther you go into poor metabolic health, the stronger is the case for CGM.” 

Dr. Neinstein added that “thankfully,” there is no more debate about the value of CGM use for people who use insulin and are therefore at a risk for hypoglycemia. But there is less debate now about even those who don’t take insulin, with emerging evidence that a “CGM provides biofeedback and helps them as a tool to support behavior changes and learning. I hope we will see insurance coverage broaden over time to cover CGM for more of these people who can benefit and who can improve their metabolic health through the use of CGM.”

However, Dr. Neinstein cautioned, “If you go to people who have no medical problems, no insulin resistance, no family history of diabetes, at that point, we do not have evidence that CGM is of health benefit.”

Moreover, he said, “ultimately if you have to choose whether a healthcare dollar goes to CGM or a GLP-1, the GLP-1 is a more impactful choice. In an ideal world, we would be able to support patients in having both, but with the profound benefits from GLP-1s on weight loss, cardiovascular outcomes, and [hemoglobin] A1c reduction and more, they are more potent than using a CGM.”

Dr. Grace is a Dexcom employee. Dr. Neinstein is a full-time employee at Notable, with no current further disclosures.

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

TOPLINE:

Compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are associated with a lower risk for all-cause mortality and major adverse cardiovascular events (MACE) in patients with immune-mediated inflammatory diseases (IMIDs) and type 2 diabetes (T2D).

METHODOLOGY:

• GLP-1 RAs reduce the risk for all-cause mortality, cardiovascular mortality, and stroke in patients with diabetes. However, previous trials have excluded those with IMIDs, leaving a gap in understanding the cardioprotective effects of GLP-1 RAs in this population.
• Researchers conducted a population-based cohort study to assess if patients with an IMID derive greater benefits from GLP-1 RAs than DPP-4 inhibitors.
• They used administrative health data from British Columbia, Canada, to include 10,855 patients with IMIDs (rheumatoid arthritis, psoriatic disease, ankylosing spondylitis, inflammatory bowel disease, or systemic autoimmune rheumatic disease) and T2D who initiated either GLP-1 RA (n = 3570) or DPP-4 inhibitor (n = 7285).
• The mean follow-up was 1.46 and 1.88 years in the GLP-1 RA and DPP-4 inhibitor cohorts, respectively.
• The primary outcome was all-cause mortality, and the secondary outcome was MACE, including cardiovascular death, myocardial infarction, and ischemic stroke.

TAKEAWAY:

• The risk for all-cause mortality was 52% lower in patients who initiated GLP-1 RAs than in those who initiated DPP-4 inhibitors (weighted hazard ratio [HR], 0.48; 95% CI, 0.31-0.75).
• Additionally, patients initiating DPP-4 inhibitors.
• In the subgroup of patients with GLP-1 RAs had a significantly lower risk for MACE (weighted HR, 0.66; 95% CI, 0.50-0.88), particularly myocardial infarction (weighted HR, 0.62; 95% CI, 0.40-0.96), than those initiating rheumatoid arthritis and T2D, those who initiated GLP-1 RAs had a 55% lower risk for all-cause mortality and 61% lower risk for MACE than those who initiated DPP-4 inhibitors.

IN PRACTICE:

“This corresponds to nine fewer deaths and 11 fewer MACE per 1000 person-years, respectively, supporting the hypothesis that these agents have a cardioprotective effect in this high-risk population,” the authors wrote.

SOURCE:

This study was led by Derin Karacabeyli, MD, Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, Canada, and was published online on August 8, 2024, in PLOS ONE.

LIMITATIONS:

The study’s dependence on administrative health data might have resulted in incomplete capture of comorbidities, particularly obesity. The mean follow-up period was relatively short, which might have limited the long-term applicability of these findings. The accuracy of the case definitions for IMIDs and T2D, according to International Classification of Diseases codes, could not be fully ascertained.

DISCLOSURES:

The study was supported by grants from the Canadian Institutes of Health Research. Two authors declared receiving research support, consulting fees, or participating in advisory boards outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are associated with a lower risk for all-cause mortality and major adverse cardiovascular events (MACE) in patients with immune-mediated inflammatory diseases (IMIDs) and type 2 diabetes (T2D).

METHODOLOGY:

• GLP-1 RAs reduce the risk for all-cause mortality, cardiovascular mortality, and stroke in patients with diabetes. However, previous trials have excluded those with IMIDs, leaving a gap in understanding the cardioprotective effects of GLP-1 RAs in this population.
• Researchers conducted a population-based cohort study to assess if patients with an IMID derive greater benefits from GLP-1 RAs than DPP-4 inhibitors.
• They used administrative health data from British Columbia, Canada, to include 10,855 patients with IMIDs (rheumatoid arthritis, psoriatic disease, ankylosing spondylitis, inflammatory bowel disease, or systemic autoimmune rheumatic disease) and T2D who initiated either GLP-1 RA (n = 3570) or DPP-4 inhibitor (n = 7285).
• The mean follow-up was 1.46 and 1.88 years in the GLP-1 RA and DPP-4 inhibitor cohorts, respectively.
• The primary outcome was all-cause mortality, and the secondary outcome was MACE, including cardiovascular death, myocardial infarction, and ischemic stroke.

TAKEAWAY:

• The risk for all-cause mortality was 52% lower in patients who initiated GLP-1 RAs than in those who initiated DPP-4 inhibitors (weighted hazard ratio [HR], 0.48; 95% CI, 0.31-0.75).
• Additionally, patients initiating DPP-4 inhibitors.
• In the subgroup of patients with GLP-1 RAs had a significantly lower risk for MACE (weighted HR, 0.66; 95% CI, 0.50-0.88), particularly myocardial infarction (weighted HR, 0.62; 95% CI, 0.40-0.96), than those initiating rheumatoid arthritis and T2D, those who initiated GLP-1 RAs had a 55% lower risk for all-cause mortality and 61% lower risk for MACE than those who initiated DPP-4 inhibitors.

IN PRACTICE:

“This corresponds to nine fewer deaths and 11 fewer MACE per 1000 person-years, respectively, supporting the hypothesis that these agents have a cardioprotective effect in this high-risk population,” the authors wrote.

SOURCE:

This study was led by Derin Karacabeyli, MD, Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, Canada, and was published online on August 8, 2024, in PLOS ONE.

LIMITATIONS:

The study’s dependence on administrative health data might have resulted in incomplete capture of comorbidities, particularly obesity. The mean follow-up period was relatively short, which might have limited the long-term applicability of these findings. The accuracy of the case definitions for IMIDs and T2D, according to International Classification of Diseases codes, could not be fully ascertained.

DISCLOSURES:

The study was supported by grants from the Canadian Institutes of Health Research. Two authors declared receiving research support, consulting fees, or participating in advisory boards outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Compared with dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are associated with a lower risk for all-cause mortality and major adverse cardiovascular events (MACE) in patients with immune-mediated inflammatory diseases (IMIDs) and type 2 diabetes (T2D).

METHODOLOGY:

• GLP-1 RAs reduce the risk for all-cause mortality, cardiovascular mortality, and stroke in patients with diabetes. However, previous trials have excluded those with IMIDs, leaving a gap in understanding the cardioprotective effects of GLP-1 RAs in this population.
• Researchers conducted a population-based cohort study to assess if patients with an IMID derive greater benefits from GLP-1 RAs than DPP-4 inhibitors.
• They used administrative health data from British Columbia, Canada, to include 10,855 patients with IMIDs (rheumatoid arthritis, psoriatic disease, ankylosing spondylitis, inflammatory bowel disease, or systemic autoimmune rheumatic disease) and T2D who initiated either GLP-1 RA (n = 3570) or DPP-4 inhibitor (n = 7285).
• The mean follow-up was 1.46 and 1.88 years in the GLP-1 RA and DPP-4 inhibitor cohorts, respectively.
• The primary outcome was all-cause mortality, and the secondary outcome was MACE, including cardiovascular death, myocardial infarction, and ischemic stroke.

TAKEAWAY:

• The risk for all-cause mortality was 52% lower in patients who initiated GLP-1 RAs than in those who initiated DPP-4 inhibitors (weighted hazard ratio [HR], 0.48; 95% CI, 0.31-0.75).
• Additionally, patients initiating DPP-4 inhibitors.
• In the subgroup of patients with GLP-1 RAs had a significantly lower risk for MACE (weighted HR, 0.66; 95% CI, 0.50-0.88), particularly myocardial infarction (weighted HR, 0.62; 95% CI, 0.40-0.96), than those initiating rheumatoid arthritis and T2D, those who initiated GLP-1 RAs had a 55% lower risk for all-cause mortality and 61% lower risk for MACE than those who initiated DPP-4 inhibitors.

IN PRACTICE:

“This corresponds to nine fewer deaths and 11 fewer MACE per 1000 person-years, respectively, supporting the hypothesis that these agents have a cardioprotective effect in this high-risk population,” the authors wrote.

SOURCE:

This study was led by Derin Karacabeyli, MD, Division of Rheumatology, Department of Medicine, University of British Columbia, Vancouver, Canada, and was published online on August 8, 2024, in PLOS ONE.

LIMITATIONS:

The study’s dependence on administrative health data might have resulted in incomplete capture of comorbidities, particularly obesity. The mean follow-up period was relatively short, which might have limited the long-term applicability of these findings. The accuracy of the case definitions for IMIDs and T2D, according to International Classification of Diseases codes, could not be fully ascertained.

DISCLOSURES:

The study was supported by grants from the Canadian Institutes of Health Research. Two authors declared receiving research support, consulting fees, or participating in advisory boards outside the submitted work.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Edema in the feet and legs is a common complaint in our practices. It can cause pain, weakness, heaviness, discomfort, limited movement, and a negative body image. Medications can contribute to edema, either alone or in combination with other health issues.

Edema is also associated with advanced age, female sex, obesity, diabetes, hypertension, pain, lack of physical activity, and mobility limitations. These factors often necessitate medication prescriptions, which can aggravate the problem. Therefore, it is important to know how to treat or prevent medication-induced edema.

There are four main causes of edema, and all can facilitate medication-induced edema.

• Increased capillary pressure. Conditions such as heart failure, renal dysfunction, venous insufficiency, deep vein thrombosis, and cirrhosis can increase capillary pressure, leading to edema.
• Decreased oncotic pressure. Hypoalbuminemia, a primary cause of reduced colloid oncotic pressure, can result from nephrotic syndrome, diabetic nephropathy, lupus nephropathy, amyloidosis, nephropathies, cirrhosis, chronic liver disease, and malabsorption or malnutrition.
• Increased capillary permeability. Vascular injury, often associated with diabetes, can increase capillary permeability and contribute to edema.
• Impaired lymphatic drainage. Lymphatic obstruction is common in patients with lymphedema, tumors, inflammation, fibrosis, certain infections, surgery, and congenital anomalies. Conditions such as thyroid disorders can also cause an increase in interstitial albumin and other proteins without a corresponding increase in lymphatic flow, leading to lymphedema.

Medications That Can Cause Edema

• Calcium channel blockers (CCBs). Drugs such as nifedipine and amlodipine can increase hydrostatic pressure by causing selective vasodilation of precapillary vessels, leading to increased intracapillary pressures. Newer lipophilic CCBs (eg, levamlodipine) exhibit lower rates of edema. Reducing the dose is often effective. Diuretics are not very effective for vasodilation-induced edema. Combining CCBs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which induce postcapillary dilation and normalize intracapillary pressure, may reduce fluid leakage into the interstitial space. This combination may be more beneficial than high-dose CCB monotherapy.
• Thiazolidinedione (eg, pioglitazone). These increase vascular permeability and hydrostatic pressure. They work by stimulating the peroxisome proliferator–activated gamma receptor, increasing vascular endothelial permeability, vascular endothelial growth factor secretion, and renal retention of sodium and fluids. Because of other adverse effects, their use is now limited.
• Agents for neuropathic pain (gabapentin and pregabalin). These drugs can induce selective vasodilation of arterioles through a mechanism similar to that of CCBs, causing increased intracapillary pressures. Edema usually begins within the first month of treatment or dose increase and often regresses after dose reduction or drug discontinuation.
• Antiparkinsonian dopamine agonists. These increase hydrostatic pressure by reducing sympathetic tone and dilating arterioles through alpha-2 adrenergic receptor activity.
• New antipsychotics. Drugs like clozapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone can increase hydrostatic pressure through antagonistic effects on alpha-1 adrenergic receptors, causing vasodilation.
• Nitrates. These drugs increase hydrostatic pressure by causing preferential venous dilation, leading to increased venous pooling.
• Nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs can increase hydrostatic pressure by inhibiting vasodilation of afferent renal arterioles, decreasing the glomerular filtration rate, and stimulating the renin-angiotensin-aldosterone system, which leads to sodium and water retention. These adverse effects warrant cautious use of these agents.
• ACE inhibitors. Drugs such as enalapril and ramipril can increase vascular permeability. They reduce the metabolism and accumulation of bradykinin, which increases vascular permeability and fluid leakage. These effects are rare and are usually related to allergic responses.
• Insulin. Insulin decreases capillary oncotic pressure and increases vascular permeability. Rapid correction of hyperglycemia can cause a loss of oncotic pressure, while chronic hyperglycemia can damage vascular membranes, increasing permeability. These effects are generally benign and can be managed with careful dose titration, sodium restriction, or diuretics.
• Steroids. Steroids with mineralocorticoid activity can increase renal sodium and water retention, leading to increased blood volume. Fludrocortisone has the highest mineralocorticoid activity, while dexamethasone and methylprednisolone have negligible activity.

Implications

Understanding how these medications cause edema is important for effective management. For example, in the case of those causing edema due to reduced oncotic pressure, like insulin, slow dose titrations can help adapt to osmolarity changes. For drugs causing edema due to increased hydrostatic pressure, diuretics are more effective in acute management.

The key takeaways from this review are:

• Awareness of drug-induced edema. Many drugs besides CCBs can cause edema.
• Combination therapy. Combining ACE inhibitors or ARBs with CCBs can prevent or reduce CCB-induced edema.
• Edema management strategies. Strategies to manage or prevent edema should include dose reductions or replacement of the problematic medication, especially in severe or refractory cases.

Dr. Wajngarten, professor of cardiology, University of São Paulo, Brazil, has disclosed no relevant financial relationships.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Edema in the feet and legs is a common complaint in our practices. It can cause pain, weakness, heaviness, discomfort, limited movement, and a negative body image. Medications can contribute to edema, either alone or in combination with other health issues.

Edema is also associated with advanced age, female sex, obesity, diabetes, hypertension, pain, lack of physical activity, and mobility limitations. These factors often necessitate medication prescriptions, which can aggravate the problem. Therefore, it is important to know how to treat or prevent medication-induced edema.

There are four main causes of edema, and all can facilitate medication-induced edema.

• Increased capillary pressure. Conditions such as heart failure, renal dysfunction, venous insufficiency, deep vein thrombosis, and cirrhosis can increase capillary pressure, leading to edema.
• Decreased oncotic pressure. Hypoalbuminemia, a primary cause of reduced colloid oncotic pressure, can result from nephrotic syndrome, diabetic nephropathy, lupus nephropathy, amyloidosis, nephropathies, cirrhosis, chronic liver disease, and malabsorption or malnutrition.
• Increased capillary permeability. Vascular injury, often associated with diabetes, can increase capillary permeability and contribute to edema.
• Impaired lymphatic drainage. Lymphatic obstruction is common in patients with lymphedema, tumors, inflammation, fibrosis, certain infections, surgery, and congenital anomalies. Conditions such as thyroid disorders can also cause an increase in interstitial albumin and other proteins without a corresponding increase in lymphatic flow, leading to lymphedema.

Medications That Can Cause Edema

• Calcium channel blockers (CCBs). Drugs such as nifedipine and amlodipine can increase hydrostatic pressure by causing selective vasodilation of precapillary vessels, leading to increased intracapillary pressures. Newer lipophilic CCBs (eg, levamlodipine) exhibit lower rates of edema. Reducing the dose is often effective. Diuretics are not very effective for vasodilation-induced edema. Combining CCBs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which induce postcapillary dilation and normalize intracapillary pressure, may reduce fluid leakage into the interstitial space. This combination may be more beneficial than high-dose CCB monotherapy.
• Thiazolidinedione (eg, pioglitazone). These increase vascular permeability and hydrostatic pressure. They work by stimulating the peroxisome proliferator–activated gamma receptor, increasing vascular endothelial permeability, vascular endothelial growth factor secretion, and renal retention of sodium and fluids. Because of other adverse effects, their use is now limited.
• Agents for neuropathic pain (gabapentin and pregabalin). These drugs can induce selective vasodilation of arterioles through a mechanism similar to that of CCBs, causing increased intracapillary pressures. Edema usually begins within the first month of treatment or dose increase and often regresses after dose reduction or drug discontinuation.
• Antiparkinsonian dopamine agonists. These increase hydrostatic pressure by reducing sympathetic tone and dilating arterioles through alpha-2 adrenergic receptor activity.
• New antipsychotics. Drugs like clozapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone can increase hydrostatic pressure through antagonistic effects on alpha-1 adrenergic receptors, causing vasodilation.
• Nitrates. These drugs increase hydrostatic pressure by causing preferential venous dilation, leading to increased venous pooling.
• Nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs can increase hydrostatic pressure by inhibiting vasodilation of afferent renal arterioles, decreasing the glomerular filtration rate, and stimulating the renin-angiotensin-aldosterone system, which leads to sodium and water retention. These adverse effects warrant cautious use of these agents.
• ACE inhibitors. Drugs such as enalapril and ramipril can increase vascular permeability. They reduce the metabolism and accumulation of bradykinin, which increases vascular permeability and fluid leakage. These effects are rare and are usually related to allergic responses.
• Insulin. Insulin decreases capillary oncotic pressure and increases vascular permeability. Rapid correction of hyperglycemia can cause a loss of oncotic pressure, while chronic hyperglycemia can damage vascular membranes, increasing permeability. These effects are generally benign and can be managed with careful dose titration, sodium restriction, or diuretics.
• Steroids. Steroids with mineralocorticoid activity can increase renal sodium and water retention, leading to increased blood volume. Fludrocortisone has the highest mineralocorticoid activity, while dexamethasone and methylprednisolone have negligible activity.

Implications

Understanding how these medications cause edema is important for effective management. For example, in the case of those causing edema due to reduced oncotic pressure, like insulin, slow dose titrations can help adapt to osmolarity changes. For drugs causing edema due to increased hydrostatic pressure, diuretics are more effective in acute management.

The key takeaways from this review are:

• Awareness of drug-induced edema. Many drugs besides CCBs can cause edema.
• Combination therapy. Combining ACE inhibitors or ARBs with CCBs can prevent or reduce CCB-induced edema.
• Edema management strategies. Strategies to manage or prevent edema should include dose reductions or replacement of the problematic medication, especially in severe or refractory cases.

Dr. Wajngarten, professor of cardiology, University of São Paulo, Brazil, has disclosed no relevant financial relationships.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Edema in the feet and legs is a common complaint in our practices. It can cause pain, weakness, heaviness, discomfort, limited movement, and a negative body image. Medications can contribute to edema, either alone or in combination with other health issues.

Edema is also associated with advanced age, female sex, obesity, diabetes, hypertension, pain, lack of physical activity, and mobility limitations. These factors often necessitate medication prescriptions, which can aggravate the problem. Therefore, it is important to know how to treat or prevent medication-induced edema.

There are four main causes of edema, and all can facilitate medication-induced edema.

• Increased capillary pressure. Conditions such as heart failure, renal dysfunction, venous insufficiency, deep vein thrombosis, and cirrhosis can increase capillary pressure, leading to edema.
• Decreased oncotic pressure. Hypoalbuminemia, a primary cause of reduced colloid oncotic pressure, can result from nephrotic syndrome, diabetic nephropathy, lupus nephropathy, amyloidosis, nephropathies, cirrhosis, chronic liver disease, and malabsorption or malnutrition.
• Increased capillary permeability. Vascular injury, often associated with diabetes, can increase capillary permeability and contribute to edema.
• Impaired lymphatic drainage. Lymphatic obstruction is common in patients with lymphedema, tumors, inflammation, fibrosis, certain infections, surgery, and congenital anomalies. Conditions such as thyroid disorders can also cause an increase in interstitial albumin and other proteins without a corresponding increase in lymphatic flow, leading to lymphedema.

Medications That Can Cause Edema

• Calcium channel blockers (CCBs). Drugs such as nifedipine and amlodipine can increase hydrostatic pressure by causing selective vasodilation of precapillary vessels, leading to increased intracapillary pressures. Newer lipophilic CCBs (eg, levamlodipine) exhibit lower rates of edema. Reducing the dose is often effective. Diuretics are not very effective for vasodilation-induced edema. Combining CCBs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), which induce postcapillary dilation and normalize intracapillary pressure, may reduce fluid leakage into the interstitial space. This combination may be more beneficial than high-dose CCB monotherapy.
• Thiazolidinedione (eg, pioglitazone). These increase vascular permeability and hydrostatic pressure. They work by stimulating the peroxisome proliferator–activated gamma receptor, increasing vascular endothelial permeability, vascular endothelial growth factor secretion, and renal retention of sodium and fluids. Because of other adverse effects, their use is now limited.
• Agents for neuropathic pain (gabapentin and pregabalin). These drugs can induce selective vasodilation of arterioles through a mechanism similar to that of CCBs, causing increased intracapillary pressures. Edema usually begins within the first month of treatment or dose increase and often regresses after dose reduction or drug discontinuation.
• Antiparkinsonian dopamine agonists. These increase hydrostatic pressure by reducing sympathetic tone and dilating arterioles through alpha-2 adrenergic receptor activity.
• New antipsychotics. Drugs like clozapine, iloperidone, lurasidone, olanzapine, quetiapine, risperidone, and ziprasidone can increase hydrostatic pressure through antagonistic effects on alpha-1 adrenergic receptors, causing vasodilation.
• Nitrates. These drugs increase hydrostatic pressure by causing preferential venous dilation, leading to increased venous pooling.
• Nonsteroidal anti-inflammatory drugs (NSAIDs). These drugs can increase hydrostatic pressure by inhibiting vasodilation of afferent renal arterioles, decreasing the glomerular filtration rate, and stimulating the renin-angiotensin-aldosterone system, which leads to sodium and water retention. These adverse effects warrant cautious use of these agents.
• ACE inhibitors. Drugs such as enalapril and ramipril can increase vascular permeability. They reduce the metabolism and accumulation of bradykinin, which increases vascular permeability and fluid leakage. These effects are rare and are usually related to allergic responses.
• Insulin. Insulin decreases capillary oncotic pressure and increases vascular permeability. Rapid correction of hyperglycemia can cause a loss of oncotic pressure, while chronic hyperglycemia can damage vascular membranes, increasing permeability. These effects are generally benign and can be managed with careful dose titration, sodium restriction, or diuretics.
• Steroids. Steroids with mineralocorticoid activity can increase renal sodium and water retention, leading to increased blood volume. Fludrocortisone has the highest mineralocorticoid activity, while dexamethasone and methylprednisolone have negligible activity.

Implications

Understanding how these medications cause edema is important for effective management. For example, in the case of those causing edema due to reduced oncotic pressure, like insulin, slow dose titrations can help adapt to osmolarity changes. For drugs causing edema due to increased hydrostatic pressure, diuretics are more effective in acute management.

The key takeaways from this review are:

• Awareness of drug-induced edema. Many drugs besides CCBs can cause edema.
• Combination therapy. Combining ACE inhibitors or ARBs with CCBs can prevent or reduce CCB-induced edema.
• Edema management strategies. Strategies to manage or prevent edema should include dose reductions or replacement of the problematic medication, especially in severe or refractory cases.

Dr. Wajngarten, professor of cardiology, University of São Paulo, Brazil, has disclosed no relevant financial relationships.

This story was translated from the Medscape Portuguese edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

STOCKHOLM — At the American Society of Retina Specialists (ASRS) 2024 Annual Meeting, researchers discussed how insights into potential risk factors and new treatments could improve outcomes for patients with diabetic retinopathy.

Jennifer Lim, MD, an ophthalmologist and director of the Retina Service at the University of Illinois Hospital & Health Sciences System in Chicago, told this news organization that emerging approaches to treating diabetic retinopathy offer hope because they address the root causes of the disease beyond just targeting vascular endothelial growth factor (VEGF). She said innovative methods and add-on treatments could lead to more durable and effective drugs.

Exploration of risk factors and treatment options for diabetic retinopathy could lead to more effective management strategies for the condition, agreed David Boyer, MD, an ophthalmologist at Retina Vitreous Associates Medical Group in Los Angeles, speaking with this news organization.
 

Risk Factors for Diabetic Retinopathy

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have gained popularity because of their benefits beyond glycemic control, including weight loss, and cardiovascular and kidney protection. However, the impact of these medications on vision-threatening retinal complications is not fully understood. “There has always been a question about whether these newer diabetes medications might exacerbate diabetic eye disease,” said Dr. Boyer.

In a retrospective observational study, researchers included adults with type 2 diabetes and moderate cardiovascular disease risk who had no history of advanced diabetic retinal complications. These patients initiated treatment with GLP-1 RA, SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas. The study used inverse probability of treatment weighting to mimic randomization and compared the time to the first treatment for diabetic macular edema or proliferative diabetic retinopathy across the treatment groups.

Results, presented by Andrew J. Barkmeier, MD, an associate professor of ophthalmology at the Mayo Clinic, showed that among 371,698 patients, those who initiated therapy with SGLT2 inhibitors had a lower risk of requiring treatment for sight-threatening retinopathy compared with those using other medication classes. GLP-1 RA did not increase retinopathy risk relative to dipeptidyl peptidase 4 inhibitors and sulfonylurea medications.

“[This study] told us that we do have to keep an eye on patients’ retinopathy when they start on these new inhibitors. But the progression is minimal and, overall, I think most people today favor keeping blood sugar levels as good as possible,” said Dr. Boyer, who was not involved in the study.

Another factor that might increase diabetic retinopathy progression is obstructive sleep apnea. This underdiagnosed condition is linked to several health issues, including dementia, stroke, and myocardial infarctions. Although not easily treated, obstructive sleep apnea is manageable, Dr. Boyer explained.

Researchers utilized the TriNetX electronic health records research network to identify patients with nonproliferative diabetic retinopathy, both with and without obstructive sleep apnea. 

The results, presented by Ehsan Rahimy, MD, a retinal specialist at Palo Alto Medical Foundation and a professor at Stanford University, showed that patients with obstructive sleep apnea had a significantly higher risk of progressing to proliferative diabetic retinopathy and developing new-onset diabetic macular edema. These patients were more likely to require ocular interventions, such as intravitreal injections and laser photocoagulation. They also had greater risks for stroke, myocardial infarction, and death compared with those who did not have obstructive sleep apnea.

“It was good to bring this to everybody’s attention,” said Dr. Boyer, who was not involved in the study. “It’s an easy question to ask someone if they snore.”
 

New Treatments on the Horizon

In another presentation, Nathan C. Steinle, MD, of California Retina Consultants, presented a study that assessed the durability of response to sozinibercept in patients with retinal vascular diseases. This novel therapeutic agent is designed to inhibit VEGF-C and VEGF-D in conditions where VEGF-A suppression alone is insufficient. 

Sozinibercept was combined with standard anti–VEGF-A therapies such as ranibizumab or aflibercept. It involved a prospective, post hoc analysis of two phase 1b, open-label, dose-escalation studies, including 40 patients with neovascular age-related macular degeneration (nAMD; 31 patients) or diabetic macular edema (nine patients). These patients, either treatment-naive or previously treated, received three intravitreal injections of ranibizumab or aflibercept in combination with sozinibercept at various doses.

Results indicated that sozinibercept combination therapy was well tolerated, with no dose-limiting toxicities. In treatment-naive nAMD patients, the mean best-corrected visual acuity (BCVA) improved significantly from baseline at months 3 and 6. Previously treated nAMD patients also showed BCVA improvements, although to a lesser extent. For patients with persistent diabetic macular edema, switching to sozinibercept plus aflibercept resulted in notable BCVA gains. The mean time to requiring retreatment was longer in treatment-naive patients than in those previously treated, indicating a durable response. 

“Combination therapy with sozinibercept is going to be really important,” said Dr. Lim, who was not involved in the study, “because it attacks with a dual mechanism of action.”

Oral agents promise a potentially easier alternative for patients compared with frequent injections. CU06-1004 is a novel orally administered endothelial dysfunction blocker that has shown promise in stabilizing damaged capillaries, reducing abnormal angiogenesis, and inhibiting inflammatory activation in preclinical studies. “CU06 is very interesting to me because by preventing endothelial loss, it gets to the pathophysiology of why the blood vessels break down,” Dr. Lim said.

In a proof-of-concept phase 2a, multicenter, open-label, parallel-group trial, investigators randomly assigned 67 patients with diabetic macular edema to receive 100 mg, 200 mg, or 300 mg of CU06-1004 once daily for 12 weeks, followed by a 4-week follow-up. 

Results presented by Victor Gonzalez, MD, of Valley Retina Institute in Texas, indicated that the oral agent improved BCVA, stabilized central subfield thickness, and showed positive anatomical changes in optical coherence tomography images. CU06-1004 was well tolerated, with no drug-related serious adverse events. 

“The number [of patients] was very small, and we will need a much longer, larger trial to see if [CU06-1004] has benefits long term,” said Dr. Boyer, who was not involved in the study. “But I think we’re all very excited if we can find an oral agent for treating diabetic retinopathy. It would be easier for the patient to take a pill than having to come in for injections.” 

The sustained-release axitinib implant, OTX-TKI, is also generating significant interest, particularly for nonproliferative diabetic retinopathy. Axitinib, a tyrosine kinase inhibitor (TKI), targets signaling pathways crucial in cellular processes, providing a novel approach to managing diseases where traditional therapies might fall short. Unlike traditional anti-VEGF treatments that focus solely on cytokine levels, TKIs block the activation of signaling pathways, preventing downstream signaling regardless of cytokine levels. This mechanism is particularly important because it effectively inhibits disease progression even if levels of VEGF are high, Dr. Lim explained.

In the phase 1 HELIOS trial, OTX-TKI was assessed in patients with nonproliferative diabetic retinopathy. This multicenter, double-masked, parallel-group clinical study included 21 patients who had not received anti-VEGF treatment, dexamethasone intravitreal implants in the previous 12 months, or intraocular steroid injections in the prior 4 months. Patients were randomly assigned to receive either OTX-TKI or sham treatment.

Results presented by Dilsher S. Dhoot, MD, of California Retina Consultants, indicated that OTX-TKI was generally well tolerated, with no serious ocular adverse events. At 48 weeks, 46.2% of eyes treated with OTX-TKI showed a 1- or 2-step improvement on the Diabetic Retinopathy Severity Scale (DRSS) compared with none in the sham arm. Additionally, no eyes treated with OTX-TKI experienced a worsening on the DRSS, whereas 25% of eyes in the sham arm did. Vision-threatening complications, such as proliferative diabetic retinopathy or diabetic macular edema, developed in 37.5% of the sham group but in none of the OTX-TKI treated eyes. A single injection of OTX-TKI provided durable DRSS improvement for up to 48 weeks, with no patients in either arm requiring rescue therapy.

“This is a really exciting add-on treatment,” Dr. Lim said, who was not involved in the study. She explained that it is initially necessary to control the disease with standard treatments, because TKIs may take longer to exhibit their effects. Once the disease is stabilized, TKIs can be used alongside other therapies, potentially reducing the reliance on frequent anti-VEGF injections. “These are preliminary results, but that’s the hope going forward.”

Dr. Lim and Dr. Boyer report no relevant financial relationships.

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

STOCKHOLM — At the American Society of Retina Specialists (ASRS) 2024 Annual Meeting, researchers discussed how insights into potential risk factors and new treatments could improve outcomes for patients with diabetic retinopathy.

Jennifer Lim, MD, an ophthalmologist and director of the Retina Service at the University of Illinois Hospital & Health Sciences System in Chicago, told this news organization that emerging approaches to treating diabetic retinopathy offer hope because they address the root causes of the disease beyond just targeting vascular endothelial growth factor (VEGF). She said innovative methods and add-on treatments could lead to more durable and effective drugs.

Exploration of risk factors and treatment options for diabetic retinopathy could lead to more effective management strategies for the condition, agreed David Boyer, MD, an ophthalmologist at Retina Vitreous Associates Medical Group in Los Angeles, speaking with this news organization.
 

Risk Factors for Diabetic Retinopathy

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have gained popularity because of their benefits beyond glycemic control, including weight loss, and cardiovascular and kidney protection. However, the impact of these medications on vision-threatening retinal complications is not fully understood. “There has always been a question about whether these newer diabetes medications might exacerbate diabetic eye disease,” said Dr. Boyer.

In a retrospective observational study, researchers included adults with type 2 diabetes and moderate cardiovascular disease risk who had no history of advanced diabetic retinal complications. These patients initiated treatment with GLP-1 RA, SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas. The study used inverse probability of treatment weighting to mimic randomization and compared the time to the first treatment for diabetic macular edema or proliferative diabetic retinopathy across the treatment groups.

Results, presented by Andrew J. Barkmeier, MD, an associate professor of ophthalmology at the Mayo Clinic, showed that among 371,698 patients, those who initiated therapy with SGLT2 inhibitors had a lower risk of requiring treatment for sight-threatening retinopathy compared with those using other medication classes. GLP-1 RA did not increase retinopathy risk relative to dipeptidyl peptidase 4 inhibitors and sulfonylurea medications.

“[This study] told us that we do have to keep an eye on patients’ retinopathy when they start on these new inhibitors. But the progression is minimal and, overall, I think most people today favor keeping blood sugar levels as good as possible,” said Dr. Boyer, who was not involved in the study.

Another factor that might increase diabetic retinopathy progression is obstructive sleep apnea. This underdiagnosed condition is linked to several health issues, including dementia, stroke, and myocardial infarctions. Although not easily treated, obstructive sleep apnea is manageable, Dr. Boyer explained.

Researchers utilized the TriNetX electronic health records research network to identify patients with nonproliferative diabetic retinopathy, both with and without obstructive sleep apnea. 

The results, presented by Ehsan Rahimy, MD, a retinal specialist at Palo Alto Medical Foundation and a professor at Stanford University, showed that patients with obstructive sleep apnea had a significantly higher risk of progressing to proliferative diabetic retinopathy and developing new-onset diabetic macular edema. These patients were more likely to require ocular interventions, such as intravitreal injections and laser photocoagulation. They also had greater risks for stroke, myocardial infarction, and death compared with those who did not have obstructive sleep apnea.

“It was good to bring this to everybody’s attention,” said Dr. Boyer, who was not involved in the study. “It’s an easy question to ask someone if they snore.”
 

New Treatments on the Horizon

In another presentation, Nathan C. Steinle, MD, of California Retina Consultants, presented a study that assessed the durability of response to sozinibercept in patients with retinal vascular diseases. This novel therapeutic agent is designed to inhibit VEGF-C and VEGF-D in conditions where VEGF-A suppression alone is insufficient. 

Sozinibercept was combined with standard anti–VEGF-A therapies such as ranibizumab or aflibercept. It involved a prospective, post hoc analysis of two phase 1b, open-label, dose-escalation studies, including 40 patients with neovascular age-related macular degeneration (nAMD; 31 patients) or diabetic macular edema (nine patients). These patients, either treatment-naive or previously treated, received three intravitreal injections of ranibizumab or aflibercept in combination with sozinibercept at various doses.

Results indicated that sozinibercept combination therapy was well tolerated, with no dose-limiting toxicities. In treatment-naive nAMD patients, the mean best-corrected visual acuity (BCVA) improved significantly from baseline at months 3 and 6. Previously treated nAMD patients also showed BCVA improvements, although to a lesser extent. For patients with persistent diabetic macular edema, switching to sozinibercept plus aflibercept resulted in notable BCVA gains. The mean time to requiring retreatment was longer in treatment-naive patients than in those previously treated, indicating a durable response. 

“Combination therapy with sozinibercept is going to be really important,” said Dr. Lim, who was not involved in the study, “because it attacks with a dual mechanism of action.”

Oral agents promise a potentially easier alternative for patients compared with frequent injections. CU06-1004 is a novel orally administered endothelial dysfunction blocker that has shown promise in stabilizing damaged capillaries, reducing abnormal angiogenesis, and inhibiting inflammatory activation in preclinical studies. “CU06 is very interesting to me because by preventing endothelial loss, it gets to the pathophysiology of why the blood vessels break down,” Dr. Lim said.

In a proof-of-concept phase 2a, multicenter, open-label, parallel-group trial, investigators randomly assigned 67 patients with diabetic macular edema to receive 100 mg, 200 mg, or 300 mg of CU06-1004 once daily for 12 weeks, followed by a 4-week follow-up. 

Results presented by Victor Gonzalez, MD, of Valley Retina Institute in Texas, indicated that the oral agent improved BCVA, stabilized central subfield thickness, and showed positive anatomical changes in optical coherence tomography images. CU06-1004 was well tolerated, with no drug-related serious adverse events. 

“The number [of patients] was very small, and we will need a much longer, larger trial to see if [CU06-1004] has benefits long term,” said Dr. Boyer, who was not involved in the study. “But I think we’re all very excited if we can find an oral agent for treating diabetic retinopathy. It would be easier for the patient to take a pill than having to come in for injections.” 

The sustained-release axitinib implant, OTX-TKI, is also generating significant interest, particularly for nonproliferative diabetic retinopathy. Axitinib, a tyrosine kinase inhibitor (TKI), targets signaling pathways crucial in cellular processes, providing a novel approach to managing diseases where traditional therapies might fall short. Unlike traditional anti-VEGF treatments that focus solely on cytokine levels, TKIs block the activation of signaling pathways, preventing downstream signaling regardless of cytokine levels. This mechanism is particularly important because it effectively inhibits disease progression even if levels of VEGF are high, Dr. Lim explained.

In the phase 1 HELIOS trial, OTX-TKI was assessed in patients with nonproliferative diabetic retinopathy. This multicenter, double-masked, parallel-group clinical study included 21 patients who had not received anti-VEGF treatment, dexamethasone intravitreal implants in the previous 12 months, or intraocular steroid injections in the prior 4 months. Patients were randomly assigned to receive either OTX-TKI or sham treatment.

Results presented by Dilsher S. Dhoot, MD, of California Retina Consultants, indicated that OTX-TKI was generally well tolerated, with no serious ocular adverse events. At 48 weeks, 46.2% of eyes treated with OTX-TKI showed a 1- or 2-step improvement on the Diabetic Retinopathy Severity Scale (DRSS) compared with none in the sham arm. Additionally, no eyes treated with OTX-TKI experienced a worsening on the DRSS, whereas 25% of eyes in the sham arm did. Vision-threatening complications, such as proliferative diabetic retinopathy or diabetic macular edema, developed in 37.5% of the sham group but in none of the OTX-TKI treated eyes. A single injection of OTX-TKI provided durable DRSS improvement for up to 48 weeks, with no patients in either arm requiring rescue therapy.

“This is a really exciting add-on treatment,” Dr. Lim said, who was not involved in the study. She explained that it is initially necessary to control the disease with standard treatments, because TKIs may take longer to exhibit their effects. Once the disease is stabilized, TKIs can be used alongside other therapies, potentially reducing the reliance on frequent anti-VEGF injections. “These are preliminary results, but that’s the hope going forward.”

Dr. Lim and Dr. Boyer report no relevant financial relationships.

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

STOCKHOLM — At the American Society of Retina Specialists (ASRS) 2024 Annual Meeting, researchers discussed how insights into potential risk factors and new treatments could improve outcomes for patients with diabetic retinopathy.

Jennifer Lim, MD, an ophthalmologist and director of the Retina Service at the University of Illinois Hospital & Health Sciences System in Chicago, told this news organization that emerging approaches to treating diabetic retinopathy offer hope because they address the root causes of the disease beyond just targeting vascular endothelial growth factor (VEGF). She said innovative methods and add-on treatments could lead to more durable and effective drugs.

Exploration of risk factors and treatment options for diabetic retinopathy could lead to more effective management strategies for the condition, agreed David Boyer, MD, an ophthalmologist at Retina Vitreous Associates Medical Group in Los Angeles, speaking with this news organization.
 

Risk Factors for Diabetic Retinopathy

Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have gained popularity because of their benefits beyond glycemic control, including weight loss, and cardiovascular and kidney protection. However, the impact of these medications on vision-threatening retinal complications is not fully understood. “There has always been a question about whether these newer diabetes medications might exacerbate diabetic eye disease,” said Dr. Boyer.

In a retrospective observational study, researchers included adults with type 2 diabetes and moderate cardiovascular disease risk who had no history of advanced diabetic retinal complications. These patients initiated treatment with GLP-1 RA, SGLT2 inhibitors, DPP-4 inhibitors, or sulfonylureas. The study used inverse probability of treatment weighting to mimic randomization and compared the time to the first treatment for diabetic macular edema or proliferative diabetic retinopathy across the treatment groups.

Results, presented by Andrew J. Barkmeier, MD, an associate professor of ophthalmology at the Mayo Clinic, showed that among 371,698 patients, those who initiated therapy with SGLT2 inhibitors had a lower risk of requiring treatment for sight-threatening retinopathy compared with those using other medication classes. GLP-1 RA did not increase retinopathy risk relative to dipeptidyl peptidase 4 inhibitors and sulfonylurea medications.

“[This study] told us that we do have to keep an eye on patients’ retinopathy when they start on these new inhibitors. But the progression is minimal and, overall, I think most people today favor keeping blood sugar levels as good as possible,” said Dr. Boyer, who was not involved in the study.

Another factor that might increase diabetic retinopathy progression is obstructive sleep apnea. This underdiagnosed condition is linked to several health issues, including dementia, stroke, and myocardial infarctions. Although not easily treated, obstructive sleep apnea is manageable, Dr. Boyer explained.

Researchers utilized the TriNetX electronic health records research network to identify patients with nonproliferative diabetic retinopathy, both with and without obstructive sleep apnea. 

The results, presented by Ehsan Rahimy, MD, a retinal specialist at Palo Alto Medical Foundation and a professor at Stanford University, showed that patients with obstructive sleep apnea had a significantly higher risk of progressing to proliferative diabetic retinopathy and developing new-onset diabetic macular edema. These patients were more likely to require ocular interventions, such as intravitreal injections and laser photocoagulation. They also had greater risks for stroke, myocardial infarction, and death compared with those who did not have obstructive sleep apnea.

“It was good to bring this to everybody’s attention,” said Dr. Boyer, who was not involved in the study. “It’s an easy question to ask someone if they snore.”
 

New Treatments on the Horizon

In another presentation, Nathan C. Steinle, MD, of California Retina Consultants, presented a study that assessed the durability of response to sozinibercept in patients with retinal vascular diseases. This novel therapeutic agent is designed to inhibit VEGF-C and VEGF-D in conditions where VEGF-A suppression alone is insufficient. 

Sozinibercept was combined with standard anti–VEGF-A therapies such as ranibizumab or aflibercept. It involved a prospective, post hoc analysis of two phase 1b, open-label, dose-escalation studies, including 40 patients with neovascular age-related macular degeneration (nAMD; 31 patients) or diabetic macular edema (nine patients). These patients, either treatment-naive or previously treated, received three intravitreal injections of ranibizumab or aflibercept in combination with sozinibercept at various doses.

Results indicated that sozinibercept combination therapy was well tolerated, with no dose-limiting toxicities. In treatment-naive nAMD patients, the mean best-corrected visual acuity (BCVA) improved significantly from baseline at months 3 and 6. Previously treated nAMD patients also showed BCVA improvements, although to a lesser extent. For patients with persistent diabetic macular edema, switching to sozinibercept plus aflibercept resulted in notable BCVA gains. The mean time to requiring retreatment was longer in treatment-naive patients than in those previously treated, indicating a durable response. 

“Combination therapy with sozinibercept is going to be really important,” said Dr. Lim, who was not involved in the study, “because it attacks with a dual mechanism of action.”

Oral agents promise a potentially easier alternative for patients compared with frequent injections. CU06-1004 is a novel orally administered endothelial dysfunction blocker that has shown promise in stabilizing damaged capillaries, reducing abnormal angiogenesis, and inhibiting inflammatory activation in preclinical studies. “CU06 is very interesting to me because by preventing endothelial loss, it gets to the pathophysiology of why the blood vessels break down,” Dr. Lim said.

In a proof-of-concept phase 2a, multicenter, open-label, parallel-group trial, investigators randomly assigned 67 patients with diabetic macular edema to receive 100 mg, 200 mg, or 300 mg of CU06-1004 once daily for 12 weeks, followed by a 4-week follow-up. 

Results presented by Victor Gonzalez, MD, of Valley Retina Institute in Texas, indicated that the oral agent improved BCVA, stabilized central subfield thickness, and showed positive anatomical changes in optical coherence tomography images. CU06-1004 was well tolerated, with no drug-related serious adverse events. 

“The number [of patients] was very small, and we will need a much longer, larger trial to see if [CU06-1004] has benefits long term,” said Dr. Boyer, who was not involved in the study. “But I think we’re all very excited if we can find an oral agent for treating diabetic retinopathy. It would be easier for the patient to take a pill than having to come in for injections.” 

The sustained-release axitinib implant, OTX-TKI, is also generating significant interest, particularly for nonproliferative diabetic retinopathy. Axitinib, a tyrosine kinase inhibitor (TKI), targets signaling pathways crucial in cellular processes, providing a novel approach to managing diseases where traditional therapies might fall short. Unlike traditional anti-VEGF treatments that focus solely on cytokine levels, TKIs block the activation of signaling pathways, preventing downstream signaling regardless of cytokine levels. This mechanism is particularly important because it effectively inhibits disease progression even if levels of VEGF are high, Dr. Lim explained.

In the phase 1 HELIOS trial, OTX-TKI was assessed in patients with nonproliferative diabetic retinopathy. This multicenter, double-masked, parallel-group clinical study included 21 patients who had not received anti-VEGF treatment, dexamethasone intravitreal implants in the previous 12 months, or intraocular steroid injections in the prior 4 months. Patients were randomly assigned to receive either OTX-TKI or sham treatment.

Results presented by Dilsher S. Dhoot, MD, of California Retina Consultants, indicated that OTX-TKI was generally well tolerated, with no serious ocular adverse events. At 48 weeks, 46.2% of eyes treated with OTX-TKI showed a 1- or 2-step improvement on the Diabetic Retinopathy Severity Scale (DRSS) compared with none in the sham arm. Additionally, no eyes treated with OTX-TKI experienced a worsening on the DRSS, whereas 25% of eyes in the sham arm did. Vision-threatening complications, such as proliferative diabetic retinopathy or diabetic macular edema, developed in 37.5% of the sham group but in none of the OTX-TKI treated eyes. A single injection of OTX-TKI provided durable DRSS improvement for up to 48 weeks, with no patients in either arm requiring rescue therapy.

“This is a really exciting add-on treatment,” Dr. Lim said, who was not involved in the study. She explained that it is initially necessary to control the disease with standard treatments, because TKIs may take longer to exhibit their effects. Once the disease is stabilized, TKIs can be used alongside other therapies, potentially reducing the reliance on frequent anti-VEGF injections. “These are preliminary results, but that’s the hope going forward.”

Dr. Lim and Dr. Boyer report no relevant financial relationships.

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

Take a look at any of the evidence-based US obesity treatment guidelines. The key criteria for diagnosing overweight and obesity is based on the body mass index (BMI). 

The guidelines also use BMI to stratify care options to decrease cardiovascular risk. For example, persons with BMI ≥30 are classified as having obesity, and antiobesity medications are recommended. Those with BMI ≥ 40 are classified as having severe obesity, and metabolic bariatric surgery may be appropriate. 

But where did these cutoff points for more and less aggressive treatments come from? These BMI cutoffs are based primarily on mortality data collected from large non-Hispanic White populations, without data on potential differences by gender and ethnicity. In fact, by itself, BMI is an incomplete measure of cardiometabolic risk, especially in a multiethnic clinic with all genders represented.

For example, it is certainly true that those with BMI ≥ 30 have more cardiovascular risk factors than those with BMI < 30. But Asian American individuals have more risk factors at lower BMIs than do White or African American individuals likely because of more visceral fat accumulation at lower BMIs.

Besides the variation in gender and ethnicity, BMI does not take the type and location of body fat into consideration. Adipose tissue in visceral or ectopic areas have much higher risks for disease than subcutaneous adipose tissue because of the associated inflammation. Measures such as waist circumference, waist-to-hip ratio, and skinfold measurements aim to capture this aspect but often fall short because of variation in techniques.

BMI does not account for muscle mass either, so fit athletes and bodybuilders can be classified as having obesity by BMI alone. More accurate body fat percent measures, such as dual-energy X-ray absorptiometry or MRI specifically for ectopic fat, are labor intensive, expensive, and not feasible to perform in a busy primary care or endocrinology clinic.
 

Assessing Risks From Obesity Beyond BMI

Clearly, better risk measures than BMI are needed, but until they are available, supplemental clinical tools can aid diagnosis and treatment decisions at obesity medicine specialty centers, endocrinology and diabetes centers, and those centers that focus on the treatment of obesity.

For example, a seca scale can measure percent body fat by bioelectric impedance analysis. This technique also has its limitations, but for persons who are well hydrated, it can be used as a baseline to determine efficacy of behavioral interventions, such as resistance-exercise training and a high-protein diet to protect muscle mass as the patient loses weight.

A lot also can be gleaned from diet and exercise history, social history, family history, and physical exam as well as laboratory analyses. For example, an Asian American patient with a BMI of 26 who has been gaining weight mostly in the abdominal region after age 35 years is likely to have cardiometabolic risk, and a family history can solidify that. An exam can show signs of acanthosis nigricans or an enlarged liver and generous abdominal adipose tissue. This would be the patient in whom you would want to obtain a hemoglobin A1c measurement in the chance that it is elevated at > 5.7 mg/dL, suggesting high risk for type 2 diabetes. 

A Fibrosis-4 score can assess the risk for liver disease from aspartate transaminase and alanine aminotransferase and platelet count and age, providing clues to cardiometabolic disease risk.

In the next 10, years there may be a better measure for cardiometabolic risk that is more accurate than BMI is. It could be the sagittal abdominal diameter, which has been purported to more accurately measure visceral abdominal fat. But this has not made it to be one of the vital signs in a busy primary care clinic, however. 
 

Will New Body Fat Tools Change Practice?

In the next 10 years, there may be an affordable gadget to scan the body to determine visceral vs subcutaneous deposition of fat — like radiography for tissue. Now, three-dimensional (3D) total-body scanners can obtain body composition, but they are extremely expensive. The more important clinical question is: How will the use of these imaging modalities change your practice protocol for a particular patient? 

Think about the FibroScan, a type of ultrasound used to determine fatty liver disease and fibrosis. We order the test for those patients in whom we already have a strong suspicion for liver disease and, in obesity practices, for fatty liver and metabolic-associated fatty liver disease or metabolic associated steatohepatitis.

The test results do much to educate the patient and help the patient understand the need for aggressive treatment for their obesity. But it doesn’t necessarily change the clinician’s practice protocols and decisions. We would still recommend weight management and medications or surgery to patients regardless of the findings. 

A FibroScan is an expense, and not all primary care or endocrine practitioners may feel it necessary to purchase one for the added benefit of patient education. And I would argue that a 3D body scanner is a great tool but more for educational purposes than to really determine practice decision-making or outcomes. 

In the meantime, an old-fashioned physical examination, along with a thorough medical, social, and family history should give even the busiest primary care provider enough information to decide whether their patient is a candidate for preventive measures to reduce body fat with diet, exercise, and medication as well as whether the patient is a candidate for metabolic bariatric surgery. Higher suspicion of cardiovascular risk at lower BMI ranges for various ethnicities can help primary care providers pick up on the patients with low BMI but who are at higher risk for type 2 diabetes or prediabetes and cardiovascular disease. 

So the answer to whether we need a better measure than the BMI: Yes, we do. We need a physical examination on all patients.

Dr. Apovian, professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, both in Boston, Massachusetts, disclosed ties with Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, L-Nutra, NeuroBo Pharm, Novo, OptumRx, Pain Script, Palatin, Pursuit by You, Roman Health, Xeno, and Riverview School.

A version of this article appeared on Medscape.com.

Take a look at any of the evidence-based US obesity treatment guidelines. The key criteria for diagnosing overweight and obesity is based on the body mass index (BMI). 

The guidelines also use BMI to stratify care options to decrease cardiovascular risk. For example, persons with BMI ≥30 are classified as having obesity, and antiobesity medications are recommended. Those with BMI ≥ 40 are classified as having severe obesity, and metabolic bariatric surgery may be appropriate. 

But where did these cutoff points for more and less aggressive treatments come from? These BMI cutoffs are based primarily on mortality data collected from large non-Hispanic White populations, without data on potential differences by gender and ethnicity. In fact, by itself, BMI is an incomplete measure of cardiometabolic risk, especially in a multiethnic clinic with all genders represented.

For example, it is certainly true that those with BMI ≥ 30 have more cardiovascular risk factors than those with BMI < 30. But Asian American individuals have more risk factors at lower BMIs than do White or African American individuals likely because of more visceral fat accumulation at lower BMIs.

Besides the variation in gender and ethnicity, BMI does not take the type and location of body fat into consideration. Adipose tissue in visceral or ectopic areas have much higher risks for disease than subcutaneous adipose tissue because of the associated inflammation. Measures such as waist circumference, waist-to-hip ratio, and skinfold measurements aim to capture this aspect but often fall short because of variation in techniques.

BMI does not account for muscle mass either, so fit athletes and bodybuilders can be classified as having obesity by BMI alone. More accurate body fat percent measures, such as dual-energy X-ray absorptiometry or MRI specifically for ectopic fat, are labor intensive, expensive, and not feasible to perform in a busy primary care or endocrinology clinic.
 

Assessing Risks From Obesity Beyond BMI

Clearly, better risk measures than BMI are needed, but until they are available, supplemental clinical tools can aid diagnosis and treatment decisions at obesity medicine specialty centers, endocrinology and diabetes centers, and those centers that focus on the treatment of obesity.

For example, a seca scale can measure percent body fat by bioelectric impedance analysis. This technique also has its limitations, but for persons who are well hydrated, it can be used as a baseline to determine efficacy of behavioral interventions, such as resistance-exercise training and a high-protein diet to protect muscle mass as the patient loses weight.

A lot also can be gleaned from diet and exercise history, social history, family history, and physical exam as well as laboratory analyses. For example, an Asian American patient with a BMI of 26 who has been gaining weight mostly in the abdominal region after age 35 years is likely to have cardiometabolic risk, and a family history can solidify that. An exam can show signs of acanthosis nigricans or an enlarged liver and generous abdominal adipose tissue. This would be the patient in whom you would want to obtain a hemoglobin A1c measurement in the chance that it is elevated at > 5.7 mg/dL, suggesting high risk for type 2 diabetes. 

A Fibrosis-4 score can assess the risk for liver disease from aspartate transaminase and alanine aminotransferase and platelet count and age, providing clues to cardiometabolic disease risk.

In the next 10, years there may be a better measure for cardiometabolic risk that is more accurate than BMI is. It could be the sagittal abdominal diameter, which has been purported to more accurately measure visceral abdominal fat. But this has not made it to be one of the vital signs in a busy primary care clinic, however. 
 

Will New Body Fat Tools Change Practice?

In the next 10 years, there may be an affordable gadget to scan the body to determine visceral vs subcutaneous deposition of fat — like radiography for tissue. Now, three-dimensional (3D) total-body scanners can obtain body composition, but they are extremely expensive. The more important clinical question is: How will the use of these imaging modalities change your practice protocol for a particular patient? 

Think about the FibroScan, a type of ultrasound used to determine fatty liver disease and fibrosis. We order the test for those patients in whom we already have a strong suspicion for liver disease and, in obesity practices, for fatty liver and metabolic-associated fatty liver disease or metabolic associated steatohepatitis.

The test results do much to educate the patient and help the patient understand the need for aggressive treatment for their obesity. But it doesn’t necessarily change the clinician’s practice protocols and decisions. We would still recommend weight management and medications or surgery to patients regardless of the findings. 

A FibroScan is an expense, and not all primary care or endocrine practitioners may feel it necessary to purchase one for the added benefit of patient education. And I would argue that a 3D body scanner is a great tool but more for educational purposes than to really determine practice decision-making or outcomes. 

In the meantime, an old-fashioned physical examination, along with a thorough medical, social, and family history should give even the busiest primary care provider enough information to decide whether their patient is a candidate for preventive measures to reduce body fat with diet, exercise, and medication as well as whether the patient is a candidate for metabolic bariatric surgery. Higher suspicion of cardiovascular risk at lower BMI ranges for various ethnicities can help primary care providers pick up on the patients with low BMI but who are at higher risk for type 2 diabetes or prediabetes and cardiovascular disease. 

So the answer to whether we need a better measure than the BMI: Yes, we do. We need a physical examination on all patients.

Dr. Apovian, professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, both in Boston, Massachusetts, disclosed ties with Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, L-Nutra, NeuroBo Pharm, Novo, OptumRx, Pain Script, Palatin, Pursuit by You, Roman Health, Xeno, and Riverview School.

A version of this article appeared on Medscape.com.

Take a look at any of the evidence-based US obesity treatment guidelines. The key criteria for diagnosing overweight and obesity is based on the body mass index (BMI). 

The guidelines also use BMI to stratify care options to decrease cardiovascular risk. For example, persons with BMI ≥30 are classified as having obesity, and antiobesity medications are recommended. Those with BMI ≥ 40 are classified as having severe obesity, and metabolic bariatric surgery may be appropriate. 

But where did these cutoff points for more and less aggressive treatments come from? These BMI cutoffs are based primarily on mortality data collected from large non-Hispanic White populations, without data on potential differences by gender and ethnicity. In fact, by itself, BMI is an incomplete measure of cardiometabolic risk, especially in a multiethnic clinic with all genders represented.

For example, it is certainly true that those with BMI ≥ 30 have more cardiovascular risk factors than those with BMI < 30. But Asian American individuals have more risk factors at lower BMIs than do White or African American individuals likely because of more visceral fat accumulation at lower BMIs.

Besides the variation in gender and ethnicity, BMI does not take the type and location of body fat into consideration. Adipose tissue in visceral or ectopic areas have much higher risks for disease than subcutaneous adipose tissue because of the associated inflammation. Measures such as waist circumference, waist-to-hip ratio, and skinfold measurements aim to capture this aspect but often fall short because of variation in techniques.

BMI does not account for muscle mass either, so fit athletes and bodybuilders can be classified as having obesity by BMI alone. More accurate body fat percent measures, such as dual-energy X-ray absorptiometry or MRI specifically for ectopic fat, are labor intensive, expensive, and not feasible to perform in a busy primary care or endocrinology clinic.
 

Assessing Risks From Obesity Beyond BMI

Clearly, better risk measures than BMI are needed, but until they are available, supplemental clinical tools can aid diagnosis and treatment decisions at obesity medicine specialty centers, endocrinology and diabetes centers, and those centers that focus on the treatment of obesity.

For example, a seca scale can measure percent body fat by bioelectric impedance analysis. This technique also has its limitations, but for persons who are well hydrated, it can be used as a baseline to determine efficacy of behavioral interventions, such as resistance-exercise training and a high-protein diet to protect muscle mass as the patient loses weight.

A lot also can be gleaned from diet and exercise history, social history, family history, and physical exam as well as laboratory analyses. For example, an Asian American patient with a BMI of 26 who has been gaining weight mostly in the abdominal region after age 35 years is likely to have cardiometabolic risk, and a family history can solidify that. An exam can show signs of acanthosis nigricans or an enlarged liver and generous abdominal adipose tissue. This would be the patient in whom you would want to obtain a hemoglobin A1c measurement in the chance that it is elevated at > 5.7 mg/dL, suggesting high risk for type 2 diabetes. 

A Fibrosis-4 score can assess the risk for liver disease from aspartate transaminase and alanine aminotransferase and platelet count and age, providing clues to cardiometabolic disease risk.

In the next 10, years there may be a better measure for cardiometabolic risk that is more accurate than BMI is. It could be the sagittal abdominal diameter, which has been purported to more accurately measure visceral abdominal fat. But this has not made it to be one of the vital signs in a busy primary care clinic, however. 
 

Will New Body Fat Tools Change Practice?

In the next 10 years, there may be an affordable gadget to scan the body to determine visceral vs subcutaneous deposition of fat — like radiography for tissue. Now, three-dimensional (3D) total-body scanners can obtain body composition, but they are extremely expensive. The more important clinical question is: How will the use of these imaging modalities change your practice protocol for a particular patient? 

Think about the FibroScan, a type of ultrasound used to determine fatty liver disease and fibrosis. We order the test for those patients in whom we already have a strong suspicion for liver disease and, in obesity practices, for fatty liver and metabolic-associated fatty liver disease or metabolic associated steatohepatitis.

The test results do much to educate the patient and help the patient understand the need for aggressive treatment for their obesity. But it doesn’t necessarily change the clinician’s practice protocols and decisions. We would still recommend weight management and medications or surgery to patients regardless of the findings. 

A FibroScan is an expense, and not all primary care or endocrine practitioners may feel it necessary to purchase one for the added benefit of patient education. And I would argue that a 3D body scanner is a great tool but more for educational purposes than to really determine practice decision-making or outcomes. 

In the meantime, an old-fashioned physical examination, along with a thorough medical, social, and family history should give even the busiest primary care provider enough information to decide whether their patient is a candidate for preventive measures to reduce body fat with diet, exercise, and medication as well as whether the patient is a candidate for metabolic bariatric surgery. Higher suspicion of cardiovascular risk at lower BMI ranges for various ethnicities can help primary care providers pick up on the patients with low BMI but who are at higher risk for type 2 diabetes or prediabetes and cardiovascular disease. 

So the answer to whether we need a better measure than the BMI: Yes, we do. We need a physical examination on all patients.

Dr. Apovian, professor of medicine, Harvard Medical School, and codirector, Center for Weight Management and Wellness, Brigham and Women’s Hospital, both in Boston, Massachusetts, disclosed ties with Altimmune, CinFina Pharma, Cowen and Company, EPG Communication Holdings, Form Health, Gelesis, L-Nutra, NeuroBo Pharm, Novo, OptumRx, Pain Script, Palatin, Pursuit by You, Roman Health, Xeno, and Riverview School.

A version of this article appeared on Medscape.com.

A multi-institutional partnership has funded six new research projects aimed at developing novel insulin analogs that more closely mimic the action of a healthy pancreas. 

The Type 1 Diabetes Grand Challenge comprises Diabetes UK, JDRF (now called “Breakthrough T1D” in the United States), and the Steve Morgan Foundation. It will provide a total of £50 million (about $64 million in US dollars) for type 1 diabetes research, including £15 million (~$19 million) for six separate projects on novel insulins to be conducted at universities in the United States, Australia, and China. Four will aim to develop glucose-responsive “smart” insulins, another one ultrafast-acting insulin, and the sixth a product combining insulin and glucagon. 

“Even with the currently available modern insulins, people living with type 1 diabetes put lots of effort into managing their diabetes every day to find a good balance between acceptable glycemic control on the one hand and avoiding hypoglycemia on the other. The funded six new research projects address major shortcomings in insulin therapy,” Tim Heise, MD, vice-chair of the project’s Novel Insulins Scientific Advisory Panel, said in a statement from the Steve Morgan Foundation. 

All six projects are currently in the preclinical stage, Dr. Heise said, noting that “the idea behind the funding program is to help the most promising research initiatives to reach the clinical stage.”

Glucose-responsive, or so-called “smart,” insulins are considered the holy grail because they would become active only to prevent hyperglycemia and remain dormant otherwise, thereby not causing hypoglycemia as current insulin analogs can. The idea isn’t new. In 2010, there was excitement in the type 1 diabetes community when the pharmaceutical company Merck acquired a smaller company called SmartCells that had been working on a “smart insulin” for several years. But nothing came of that. 

“The challenges then and today are pretty similar. In particular, it is quite difficult to find a glucose-sensing moiety that is safe, reacts sufficiently to relatively small changes in the human body in both falling and increasing glucose, and can be produced in large quantities,” Dr. Heise, lead scientist and co-founder of the diabetes contract research organization Profil, based in Neuss, Germany, told this news organization.

Several papers since have reported proof-of-concept in rodents, but there are no published data thus far in humans. However, in recent years the major insulin manufacturers Novo Nordisk and Eli Lilly have acquired smaller companies with the aim of smart insulin development. 

It will still take some time, Dr. Heise said. “The challenges are well understood, although difficult to overcome. There has been quite some progress in the development of glucose-sensing moieties including, but not limited to, nanotechnological approaches.”

Applications for the newly funded projects “were thoroughly reviewed by a large panel of scientists with different areas of expertise. At the end, there was agreement in the review panel that these projects deserved further investigation, although considering their early stage, there still is a substantial risk of failure for all these projects,” he said. 

The development path might be a bit more straightforward for the other two projects. Ultra–fast-acting insulin is needed because the action of the current ones, Novo Nordisk’s Fiasp and Eli Lilly and Company’s Lyumjev, is still delayed, potentially leading to postmeal hyperglycemia if administered after or immediately prior to eating. “A truly rapid short-acting insulin might make it finally possible to progress from hybrid to fully closed loop systems, allowing a technological ‘cure’ for people with diabetes,” Dr. Heise said in the statement. 

And a protein combining insulin with glucagon could help minimize the risk for hypoglycemia, which still exists for current insulin analogs and remains “one of the major concerns associated with insulin therapy today,” he noted. 

Dr. Heise told this news organization that compared with “smart” insulin, development of the other two products “might be a bit faster if they succeed. But none of these approaches will make it to market in the next 5 years, and if one entered clinic within the next 2 years, that would be a huge success.” Nonetheless, “these research projects, if successful, might do no less than heralding a new era in insulin therapy.”

Dr. Heise is an employee of Profil, which has worked with a large number of the major diabetes industry manufacturers.

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

A multi-institutional partnership has funded six new research projects aimed at developing novel insulin analogs that more closely mimic the action of a healthy pancreas. 

The Type 1 Diabetes Grand Challenge comprises Diabetes UK, JDRF (now called “Breakthrough T1D” in the United States), and the Steve Morgan Foundation. It will provide a total of £50 million (about $64 million in US dollars) for type 1 diabetes research, including £15 million (~$19 million) for six separate projects on novel insulins to be conducted at universities in the United States, Australia, and China. Four will aim to develop glucose-responsive “smart” insulins, another one ultrafast-acting insulin, and the sixth a product combining insulin and glucagon. 

“Even with the currently available modern insulins, people living with type 1 diabetes put lots of effort into managing their diabetes every day to find a good balance between acceptable glycemic control on the one hand and avoiding hypoglycemia on the other. The funded six new research projects address major shortcomings in insulin therapy,” Tim Heise, MD, vice-chair of the project’s Novel Insulins Scientific Advisory Panel, said in a statement from the Steve Morgan Foundation. 

All six projects are currently in the preclinical stage, Dr. Heise said, noting that “the idea behind the funding program is to help the most promising research initiatives to reach the clinical stage.”

Glucose-responsive, or so-called “smart,” insulins are considered the holy grail because they would become active only to prevent hyperglycemia and remain dormant otherwise, thereby not causing hypoglycemia as current insulin analogs can. The idea isn’t new. In 2010, there was excitement in the type 1 diabetes community when the pharmaceutical company Merck acquired a smaller company called SmartCells that had been working on a “smart insulin” for several years. But nothing came of that. 

“The challenges then and today are pretty similar. In particular, it is quite difficult to find a glucose-sensing moiety that is safe, reacts sufficiently to relatively small changes in the human body in both falling and increasing glucose, and can be produced in large quantities,” Dr. Heise, lead scientist and co-founder of the diabetes contract research organization Profil, based in Neuss, Germany, told this news organization.

Several papers since have reported proof-of-concept in rodents, but there are no published data thus far in humans. However, in recent years the major insulin manufacturers Novo Nordisk and Eli Lilly have acquired smaller companies with the aim of smart insulin development. 

It will still take some time, Dr. Heise said. “The challenges are well understood, although difficult to overcome. There has been quite some progress in the development of glucose-sensing moieties including, but not limited to, nanotechnological approaches.”

Applications for the newly funded projects “were thoroughly reviewed by a large panel of scientists with different areas of expertise. At the end, there was agreement in the review panel that these projects deserved further investigation, although considering their early stage, there still is a substantial risk of failure for all these projects,” he said. 

The development path might be a bit more straightforward for the other two projects. Ultra–fast-acting insulin is needed because the action of the current ones, Novo Nordisk’s Fiasp and Eli Lilly and Company’s Lyumjev, is still delayed, potentially leading to postmeal hyperglycemia if administered after or immediately prior to eating. “A truly rapid short-acting insulin might make it finally possible to progress from hybrid to fully closed loop systems, allowing a technological ‘cure’ for people with diabetes,” Dr. Heise said in the statement. 

And a protein combining insulin with glucagon could help minimize the risk for hypoglycemia, which still exists for current insulin analogs and remains “one of the major concerns associated with insulin therapy today,” he noted. 

Dr. Heise told this news organization that compared with “smart” insulin, development of the other two products “might be a bit faster if they succeed. But none of these approaches will make it to market in the next 5 years, and if one entered clinic within the next 2 years, that would be a huge success.” Nonetheless, “these research projects, if successful, might do no less than heralding a new era in insulin therapy.”

Dr. Heise is an employee of Profil, which has worked with a large number of the major diabetes industry manufacturers.

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

A multi-institutional partnership has funded six new research projects aimed at developing novel insulin analogs that more closely mimic the action of a healthy pancreas. 

The Type 1 Diabetes Grand Challenge comprises Diabetes UK, JDRF (now called “Breakthrough T1D” in the United States), and the Steve Morgan Foundation. It will provide a total of £50 million (about $64 million in US dollars) for type 1 diabetes research, including £15 million (~$19 million) for six separate projects on novel insulins to be conducted at universities in the United States, Australia, and China. Four will aim to develop glucose-responsive “smart” insulins, another one ultrafast-acting insulin, and the sixth a product combining insulin and glucagon. 

“Even with the currently available modern insulins, people living with type 1 diabetes put lots of effort into managing their diabetes every day to find a good balance between acceptable glycemic control on the one hand and avoiding hypoglycemia on the other. The funded six new research projects address major shortcomings in insulin therapy,” Tim Heise, MD, vice-chair of the project’s Novel Insulins Scientific Advisory Panel, said in a statement from the Steve Morgan Foundation. 

All six projects are currently in the preclinical stage, Dr. Heise said, noting that “the idea behind the funding program is to help the most promising research initiatives to reach the clinical stage.”

Glucose-responsive, or so-called “smart,” insulins are considered the holy grail because they would become active only to prevent hyperglycemia and remain dormant otherwise, thereby not causing hypoglycemia as current insulin analogs can. The idea isn’t new. In 2010, there was excitement in the type 1 diabetes community when the pharmaceutical company Merck acquired a smaller company called SmartCells that had been working on a “smart insulin” for several years. But nothing came of that. 

“The challenges then and today are pretty similar. In particular, it is quite difficult to find a glucose-sensing moiety that is safe, reacts sufficiently to relatively small changes in the human body in both falling and increasing glucose, and can be produced in large quantities,” Dr. Heise, lead scientist and co-founder of the diabetes contract research organization Profil, based in Neuss, Germany, told this news organization.

Several papers since have reported proof-of-concept in rodents, but there are no published data thus far in humans. However, in recent years the major insulin manufacturers Novo Nordisk and Eli Lilly have acquired smaller companies with the aim of smart insulin development. 

It will still take some time, Dr. Heise said. “The challenges are well understood, although difficult to overcome. There has been quite some progress in the development of glucose-sensing moieties including, but not limited to, nanotechnological approaches.”

Applications for the newly funded projects “were thoroughly reviewed by a large panel of scientists with different areas of expertise. At the end, there was agreement in the review panel that these projects deserved further investigation, although considering their early stage, there still is a substantial risk of failure for all these projects,” he said. 

The development path might be a bit more straightforward for the other two projects. Ultra–fast-acting insulin is needed because the action of the current ones, Novo Nordisk’s Fiasp and Eli Lilly and Company’s Lyumjev, is still delayed, potentially leading to postmeal hyperglycemia if administered after or immediately prior to eating. “A truly rapid short-acting insulin might make it finally possible to progress from hybrid to fully closed loop systems, allowing a technological ‘cure’ for people with diabetes,” Dr. Heise said in the statement. 

And a protein combining insulin with glucagon could help minimize the risk for hypoglycemia, which still exists for current insulin analogs and remains “one of the major concerns associated with insulin therapy today,” he noted. 

Dr. Heise told this news organization that compared with “smart” insulin, development of the other two products “might be a bit faster if they succeed. But none of these approaches will make it to market in the next 5 years, and if one entered clinic within the next 2 years, that would be a huge success.” Nonetheless, “these research projects, if successful, might do no less than heralding a new era in insulin therapy.”

Dr. Heise is an employee of Profil, which has worked with a large number of the major diabetes industry manufacturers.

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