Expert Perspective

Type 2 diabetes (T2D) has become a noncommunicable pandemic. Approximately 14.7% of the US adult population has diabetes.¹ Additionally, nearly 25% of the geriatric population has diabetes and nearly 50% has prediabetes.² Needless to say, most practices, regardless of specialty, see many patients with diabetes. We have made major advances in diabetes treatments, yet diabetes mellitus is still the leading cause of legal blindness, nontraumatic amputation, and end-stage renal disease requiring dialysis.³ 

While the prevalence of diabetes in adults is concerning, what is even more startling is the significant increase of T2D within the pediatric population. It was not too long ago that we considered T2D an “adult-only” disease. Now, 24% of children with diabetes have T2D, and 18% of adolescents have prediabetes.^4,5 This is not the end of the story. Recent studies have identified that the earlier you are diagnosed with T2D, the less responsive you are to diabetes treatments—and the disease will progress more rapidly to complications. 
 

We know that pediatric patients are not little adults. There are important physiologic and metabolic differences in our younger patients. The RISE study found that adolescents have lower insulin sensitivity than adults.^4,6 The pancreatic beta cells are more responsive at first and there is less clearance by the liver, which may indeed make insulin resistance worse. Finally, pancreatic beta cell function declines more rapidly in adolescents than in adults.^4,6 These physiologic changes can be even worse during puberty. The hormonal changes seen in puberty accelerate and amplify insulin secretion and worsen insulin resistance, which can result in hyperglycemia in those at risk.^7,8

The other complicating factor is the rapid rise in obesity in Americans. While childhood obesity is not quite at adult levels, it is a major risk factor for adult obesity. The prevalence of obesity in childhood was recently estimated to be 19.7% and is still on the rise.⁹ Obesity can be diabetogenic as we see an increase in visceral obesity. This triggers an inflammatory response that leads to worsening systemic insulin resistance and lipotoxicity from elevated circulating free fatty acids.⁸ 

Lifestyle and behavioral factors are also important in adolescents with T2D. While they are more independent than younger children, they are still largely dependent on the foods that are available in their home. Family food choices have a major impact on our youth. Further, the foods that our adolescents eat outside the home are more likely to be fast food or ultra-processed foods, which have been shown to contribute to obesity and T2D. 

Family history is a strong predictor of risk for T2D. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort, 89.4% of pediatric participants had a first-degree relative or grandparent with T2D.¹⁰ This highlights the importance of both genetic risk and living environment as risks for T2D. 

The American Diabetes Association recommends that all children with specific risk factors be screened for diabetes starting at the age 10 years or at puberty, whichever comes first.¹¹ The screening tests recommended for diabetes are currently the same as for adults, yet there are few data supporting this regimen. To diagnose diabetes, you can use any of the following screening tests: fasting glucose, glucose tolerance, or glycated hemoglobin (HbA1c).¹ 

Risk Factors That Should Prompt Diabetes Screening¹¹

Screening is recommended in children who are overweight (≥85%) or obese (≥95%) and who also have ≥1 of the following risk factors:

• Family history of T2D in a first- or second-degree relative
• Maternal history of gestational diabetes
• Low birth weight for gestational age
• Physical signs of insulin resistance or related conditions (eg, hypertension, dyslipidemia, polycystic ovary syndrome)
• High-risk race/ethnicity (Native American, African American, Pacific Islander, Latino)

Diagnostic Criteria for Diabetes Mellitus¹¹

A childhood or adolescent T2D diagnosis should be taken seriously and communicated to the patient and family in a timely manner. Treatment should start immediately. There are several factors that make managing T2D in adolescents more challenging. Children do not control key aspects of their life, including nutrition and, often, free time activity. There are a lot of social pressures to be “normal,” and having a chronic disease will definitely make the child feel “different” and potentially feel socially isolated. There are high rates of mood disorders in children with diabetes, which can make self-management even harder.¹²

As mentioned above, treatment should begin immediately upon diagnosis. This is because T2D in younger people tends to be more progressive and less responsive to treatment options, and patients are much more likely to develop.^1,13,14 These same complications can be seen in adult patients, but in younger patients they develop earlier in the disease; specifically, renal and neurologic complications occur at even higher rates.¹⁴ 

The initial treatment should include both family-based therapeutic lifestyle changes (ie, nutrition, physical activity intervention) and medication.¹¹ There are fewer US Food and Drug Administration–approved medication options for children and adolescents, and those treatments that have been approved are less durable in this population. 

Metformin and insulin are the most-used medications, but their initiation is often delayed, as therapeutic lifestyle change is tried first. This has not been shown to be an effective strategy and may even undermine the value of therapeutic lifestyle change if the family is told later that medication may still need to be added. 

Recent studies have shown the benefit of select glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as important therapeutic tools to treat T2D in adolescence. Dulaglutide, exenatide, and liraglutide have been shown to be safe and effective in trials for adolescents with T2D.^15-17 These agents reduce glucose and body weight and may be important tools to help reduce extra glycemic risks (eg, cardiovascular disease, kidney disease), but they have not been studied for this purpose yet. 

Further, there is good support for the use of bariatric surgery for adolescents. While this is a relatively new treatment option, early and mid-term results are favorable compared with medication-based strategies.¹⁸ Further studies are needed to determine the long-term benefits.

Take home points:

1. T2D is becoming increasingly common in our youth.
2. T2D, when diagnosed earlier in life, is more progressive, less responsive to treatment options, and associated with earlier complications.
3. New studies support the use of novel therapies such as GLP-1 RAs and metabolic surgery in this age group.

Dr. Shubrook and Dr. Antonia M. Molinari have written a comprehensive review on treatment options and current guidelines for the management of T2D in the pediatric population, which can supply further information.¹⁹ 

Type 2 diabetes (T2D) has become a noncommunicable pandemic. Approximately 14.7% of the US adult population has diabetes.¹ Additionally, nearly 25% of the geriatric population has diabetes and nearly 50% has prediabetes.² Needless to say, most practices, regardless of specialty, see many patients with diabetes. We have made major advances in diabetes treatments, yet diabetes mellitus is still the leading cause of legal blindness, nontraumatic amputation, and end-stage renal disease requiring dialysis.³ 

While the prevalence of diabetes in adults is concerning, what is even more startling is the significant increase of T2D within the pediatric population. It was not too long ago that we considered T2D an “adult-only” disease. Now, 24% of children with diabetes have T2D, and 18% of adolescents have prediabetes.^4,5 This is not the end of the story. Recent studies have identified that the earlier you are diagnosed with T2D, the less responsive you are to diabetes treatments—and the disease will progress more rapidly to complications. 
 

We know that pediatric patients are not little adults. There are important physiologic and metabolic differences in our younger patients. The RISE study found that adolescents have lower insulin sensitivity than adults.^4,6 The pancreatic beta cells are more responsive at first and there is less clearance by the liver, which may indeed make insulin resistance worse. Finally, pancreatic beta cell function declines more rapidly in adolescents than in adults.^4,6 These physiologic changes can be even worse during puberty. The hormonal changes seen in puberty accelerate and amplify insulin secretion and worsen insulin resistance, which can result in hyperglycemia in those at risk.^7,8

The other complicating factor is the rapid rise in obesity in Americans. While childhood obesity is not quite at adult levels, it is a major risk factor for adult obesity. The prevalence of obesity in childhood was recently estimated to be 19.7% and is still on the rise.⁹ Obesity can be diabetogenic as we see an increase in visceral obesity. This triggers an inflammatory response that leads to worsening systemic insulin resistance and lipotoxicity from elevated circulating free fatty acids.⁸ 

Lifestyle and behavioral factors are also important in adolescents with T2D. While they are more independent than younger children, they are still largely dependent on the foods that are available in their home. Family food choices have a major impact on our youth. Further, the foods that our adolescents eat outside the home are more likely to be fast food or ultra-processed foods, which have been shown to contribute to obesity and T2D. 

Family history is a strong predictor of risk for T2D. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort, 89.4% of pediatric participants had a first-degree relative or grandparent with T2D.¹⁰ This highlights the importance of both genetic risk and living environment as risks for T2D. 

The American Diabetes Association recommends that all children with specific risk factors be screened for diabetes starting at the age 10 years or at puberty, whichever comes first.¹¹ The screening tests recommended for diabetes are currently the same as for adults, yet there are few data supporting this regimen. To diagnose diabetes, you can use any of the following screening tests: fasting glucose, glucose tolerance, or glycated hemoglobin (HbA1c).¹ 

Risk Factors That Should Prompt Diabetes Screening¹¹

Screening is recommended in children who are overweight (≥85%) or obese (≥95%) and who also have ≥1 of the following risk factors:

• Family history of T2D in a first- or second-degree relative
• Maternal history of gestational diabetes
• Low birth weight for gestational age
• Physical signs of insulin resistance or related conditions (eg, hypertension, dyslipidemia, polycystic ovary syndrome)
• High-risk race/ethnicity (Native American, African American, Pacific Islander, Latino)

Diagnostic Criteria for Diabetes Mellitus¹¹

A childhood or adolescent T2D diagnosis should be taken seriously and communicated to the patient and family in a timely manner. Treatment should start immediately. There are several factors that make managing T2D in adolescents more challenging. Children do not control key aspects of their life, including nutrition and, often, free time activity. There are a lot of social pressures to be “normal,” and having a chronic disease will definitely make the child feel “different” and potentially feel socially isolated. There are high rates of mood disorders in children with diabetes, which can make self-management even harder.¹²

As mentioned above, treatment should begin immediately upon diagnosis. This is because T2D in younger people tends to be more progressive and less responsive to treatment options, and patients are much more likely to develop.^1,13,14 These same complications can be seen in adult patients, but in younger patients they develop earlier in the disease; specifically, renal and neurologic complications occur at even higher rates.¹⁴ 

The initial treatment should include both family-based therapeutic lifestyle changes (ie, nutrition, physical activity intervention) and medication.¹¹ There are fewer US Food and Drug Administration–approved medication options for children and adolescents, and those treatments that have been approved are less durable in this population. 

Metformin and insulin are the most-used medications, but their initiation is often delayed, as therapeutic lifestyle change is tried first. This has not been shown to be an effective strategy and may even undermine the value of therapeutic lifestyle change if the family is told later that medication may still need to be added. 

Recent studies have shown the benefit of select glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as important therapeutic tools to treat T2D in adolescence. Dulaglutide, exenatide, and liraglutide have been shown to be safe and effective in trials for adolescents with T2D.^15-17 These agents reduce glucose and body weight and may be important tools to help reduce extra glycemic risks (eg, cardiovascular disease, kidney disease), but they have not been studied for this purpose yet. 

Further, there is good support for the use of bariatric surgery for adolescents. While this is a relatively new treatment option, early and mid-term results are favorable compared with medication-based strategies.¹⁸ Further studies are needed to determine the long-term benefits.

Take home points:

1. T2D is becoming increasingly common in our youth.
2. T2D, when diagnosed earlier in life, is more progressive, less responsive to treatment options, and associated with earlier complications.
3. New studies support the use of novel therapies such as GLP-1 RAs and metabolic surgery in this age group.

Dr. Shubrook and Dr. Antonia M. Molinari have written a comprehensive review on treatment options and current guidelines for the management of T2D in the pediatric population, which can supply further information.¹⁹ 

Type 2 diabetes (T2D) has become a noncommunicable pandemic. Approximately 14.7% of the US adult population has diabetes.¹ Additionally, nearly 25% of the geriatric population has diabetes and nearly 50% has prediabetes.² Needless to say, most practices, regardless of specialty, see many patients with diabetes. We have made major advances in diabetes treatments, yet diabetes mellitus is still the leading cause of legal blindness, nontraumatic amputation, and end-stage renal disease requiring dialysis.³ 

While the prevalence of diabetes in adults is concerning, what is even more startling is the significant increase of T2D within the pediatric population. It was not too long ago that we considered T2D an “adult-only” disease. Now, 24% of children with diabetes have T2D, and 18% of adolescents have prediabetes.^4,5 This is not the end of the story. Recent studies have identified that the earlier you are diagnosed with T2D, the less responsive you are to diabetes treatments—and the disease will progress more rapidly to complications. 
 

We know that pediatric patients are not little adults. There are important physiologic and metabolic differences in our younger patients. The RISE study found that adolescents have lower insulin sensitivity than adults.^4,6 The pancreatic beta cells are more responsive at first and there is less clearance by the liver, which may indeed make insulin resistance worse. Finally, pancreatic beta cell function declines more rapidly in adolescents than in adults.^4,6 These physiologic changes can be even worse during puberty. The hormonal changes seen in puberty accelerate and amplify insulin secretion and worsen insulin resistance, which can result in hyperglycemia in those at risk.^7,8

The other complicating factor is the rapid rise in obesity in Americans. While childhood obesity is not quite at adult levels, it is a major risk factor for adult obesity. The prevalence of obesity in childhood was recently estimated to be 19.7% and is still on the rise.⁹ Obesity can be diabetogenic as we see an increase in visceral obesity. This triggers an inflammatory response that leads to worsening systemic insulin resistance and lipotoxicity from elevated circulating free fatty acids.⁸ 

Lifestyle and behavioral factors are also important in adolescents with T2D. While they are more independent than younger children, they are still largely dependent on the foods that are available in their home. Family food choices have a major impact on our youth. Further, the foods that our adolescents eat outside the home are more likely to be fast food or ultra-processed foods, which have been shown to contribute to obesity and T2D. 

Family history is a strong predictor of risk for T2D. In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) cohort, 89.4% of pediatric participants had a first-degree relative or grandparent with T2D.¹⁰ This highlights the importance of both genetic risk and living environment as risks for T2D. 

The American Diabetes Association recommends that all children with specific risk factors be screened for diabetes starting at the age 10 years or at puberty, whichever comes first.¹¹ The screening tests recommended for diabetes are currently the same as for adults, yet there are few data supporting this regimen. To diagnose diabetes, you can use any of the following screening tests: fasting glucose, glucose tolerance, or glycated hemoglobin (HbA1c).¹ 

Risk Factors That Should Prompt Diabetes Screening¹¹

Screening is recommended in children who are overweight (≥85%) or obese (≥95%) and who also have ≥1 of the following risk factors:

• Family history of T2D in a first- or second-degree relative
• Maternal history of gestational diabetes
• Low birth weight for gestational age
• Physical signs of insulin resistance or related conditions (eg, hypertension, dyslipidemia, polycystic ovary syndrome)
• High-risk race/ethnicity (Native American, African American, Pacific Islander, Latino)

Diagnostic Criteria for Diabetes Mellitus¹¹

A childhood or adolescent T2D diagnosis should be taken seriously and communicated to the patient and family in a timely manner. Treatment should start immediately. There are several factors that make managing T2D in adolescents more challenging. Children do not control key aspects of their life, including nutrition and, often, free time activity. There are a lot of social pressures to be “normal,” and having a chronic disease will definitely make the child feel “different” and potentially feel socially isolated. There are high rates of mood disorders in children with diabetes, which can make self-management even harder.¹²

As mentioned above, treatment should begin immediately upon diagnosis. This is because T2D in younger people tends to be more progressive and less responsive to treatment options, and patients are much more likely to develop.^1,13,14 These same complications can be seen in adult patients, but in younger patients they develop earlier in the disease; specifically, renal and neurologic complications occur at even higher rates.¹⁴ 

The initial treatment should include both family-based therapeutic lifestyle changes (ie, nutrition, physical activity intervention) and medication.¹¹ There are fewer US Food and Drug Administration–approved medication options for children and adolescents, and those treatments that have been approved are less durable in this population. 

Metformin and insulin are the most-used medications, but their initiation is often delayed, as therapeutic lifestyle change is tried first. This has not been shown to be an effective strategy and may even undermine the value of therapeutic lifestyle change if the family is told later that medication may still need to be added. 

Recent studies have shown the benefit of select glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as important therapeutic tools to treat T2D in adolescence. Dulaglutide, exenatide, and liraglutide have been shown to be safe and effective in trials for adolescents with T2D.^15-17 These agents reduce glucose and body weight and may be important tools to help reduce extra glycemic risks (eg, cardiovascular disease, kidney disease), but they have not been studied for this purpose yet. 

Further, there is good support for the use of bariatric surgery for adolescents. While this is a relatively new treatment option, early and mid-term results are favorable compared with medication-based strategies.¹⁸ Further studies are needed to determine the long-term benefits.

Take home points:

1. T2D is becoming increasingly common in our youth.
2. T2D, when diagnosed earlier in life, is more progressive, less responsive to treatment options, and associated with earlier complications.
3. New studies support the use of novel therapies such as GLP-1 RAs and metabolic surgery in this age group.

Dr. Shubrook and Dr. Antonia M. Molinari have written a comprehensive review on treatment options and current guidelines for the management of T2D in the pediatric population, which can supply further information.¹⁹ 

This transcript has been edited for clarity.

I’m David Kerr, professor of cancer medicine at Oxford. As I’m gearing up to have my autumnal COVID-19 booster vaccine, there’s a small controversy raging in the United Kingdom about access to a medicine called Evusheld.

This was developed by AstraZeneca. It’s a combination of two relatively long-acting antibodies (tixagevimab and cilgavimab) that bind to the spike protein on the outside of the SARS-CoV-2 virus, the virus that causes COVID-19. The antibody binds to the spike protein and prevents it from binding to and infecting or damaging cells, so it’s what’s called preexposure prophylaxis.

Although vaccination is still the best approach to protecting against and, one would hope, conferring a degree of herd protection to our population as a whole, there are some people who cannot mount an appropriate immune response and we have to take care of these folks. Because the vaccines don’t work very well for them, the vaccine itself is not sufficient to protect them.

Evusheld, in trials that have been done hitherto, can protect people who can’t mount an immune response from being infected. Between 75% and 80% of patients treated with Evusheld didn’t get COVID-19. The duration of effect seemed to be at least for 6 months, possibly longer, so it’s a really good result. This caused our medicines regulatory authority in the United Kingdom to approve the drug in March of this year. Although the drug has been approved, it’s not yet funded and not yet available for vulnerable patients.

These are patients who, for reasons of inborn genetic diseases, cannot mount an immune response; patients who are pharmacologically immune depleted; patients who have had transplants and are on immunosuppressive drugs; and some of our cancer patients, particularly those with blood or hematologic malignancies, who can receive very heavy treatment that can pound the immune system to bits.

These are, in the population as a whole, relatively small numbers, but an important number of people who are still vulnerable to developing COVID-19 despite vaccination.

Why isn’t the drug available? We have a two-stage process in the United Kingdom. We have the scientists and regulatory authorities looking at the evidence and data and saying, “Yes, it stacks up. This drug is effective and safe to some extent.”

The second phase is a health technology assessment undertaken by NICE, our National Institute for Health and Care Excellence – something that I’ve talked about a number of times before and the sometimes seemingly arbitrary decisions that they make. NICE hasn’t evaluated the drug yet, and the British government has held out because they are arguing that we don’t have enough data.

The trials with Evusheld were done before the Omicron variant dominated, as it does now; therefore, they are looking to try to work with AstraZeneca to generate more real-world data to show that Evusheld would prevent infection from the Omicron variant of the virus. Equally as important, how long does that protection last? Is it as protective against Omicron, and what’s the duration of that protection? Those bits of work are going on now.

Some real-world data are starting to emerge, showing that Evusheld will offer some degree of protection against Omicron, but there are still question marks about duration and the proportion of the population that would benefit.

NICE aren’t due to report on this – although the drug was approved in March of this year – until next year some time. That’s what’s caused a degree of consternation in the community of patients that we serve. Some of my clinical colleagues are beating the drum, saying, “We must have this drug now.” We’re still waiting on NICE to announce.

One obvious way to go around this is the government, which has bent over backwards in the United Kingdom to do as much as it can to protect the population from COVID-19. There was fantastic vaccine rollout and an extraordinary economic package to support individuals during lockdown to maintain the workforce, to support families and people at home. They’ve done a fantastic job.

Wanting to damp down this controversy, perhaps the sensible thing would be to ask NICE to evaluate the data that they have just now, to allow AstraZeneca to present whatever real-world evidence they have, and although it may not be perfect, it may be sufficient – we don’t know – to pass the NICE health technology assessment.

Watch this space. Let’s see what happens. If I were government, that’s what I would do. I would ask NICE to bring their appraisal forward. I would ask them to work with AstraZeneca to go over every ounce and iota of data that they have to see if this drug will be sufficiently effective and sufficiently cost-effective to be used before winter comes. I think the whole world is holding its breath, expecting another COVID-19 winter surge. Now would be the time to act.

What do you think? Here we are in the United Kingdom discussing yet another quasi–”health-rationing” problem. It’s not. This is about collecting more data and being as rational as possible. Can we accelerate that process? Perhaps.

Thanks for listening. I’d be very grateful for any comments that you might choose to make.
 

David J. Kerr, MD, DSc, is a professor of cancer medicine at the University of Oxford (England). He disclosed financial relationships with Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer HealthCare Pharmaceuticals, Genomic Health, Merck Serono, Roche, and Celleron Therapeutics.

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

This transcript has been edited for clarity.

I’m David Kerr, professor of cancer medicine at Oxford. As I’m gearing up to have my autumnal COVID-19 booster vaccine, there’s a small controversy raging in the United Kingdom about access to a medicine called Evusheld.

This was developed by AstraZeneca. It’s a combination of two relatively long-acting antibodies (tixagevimab and cilgavimab) that bind to the spike protein on the outside of the SARS-CoV-2 virus, the virus that causes COVID-19. The antibody binds to the spike protein and prevents it from binding to and infecting or damaging cells, so it’s what’s called preexposure prophylaxis.

Although vaccination is still the best approach to protecting against and, one would hope, conferring a degree of herd protection to our population as a whole, there are some people who cannot mount an appropriate immune response and we have to take care of these folks. Because the vaccines don’t work very well for them, the vaccine itself is not sufficient to protect them.

Evusheld, in trials that have been done hitherto, can protect people who can’t mount an immune response from being infected. Between 75% and 80% of patients treated with Evusheld didn’t get COVID-19. The duration of effect seemed to be at least for 6 months, possibly longer, so it’s a really good result. This caused our medicines regulatory authority in the United Kingdom to approve the drug in March of this year. Although the drug has been approved, it’s not yet funded and not yet available for vulnerable patients.

These are patients who, for reasons of inborn genetic diseases, cannot mount an immune response; patients who are pharmacologically immune depleted; patients who have had transplants and are on immunosuppressive drugs; and some of our cancer patients, particularly those with blood or hematologic malignancies, who can receive very heavy treatment that can pound the immune system to bits.

These are, in the population as a whole, relatively small numbers, but an important number of people who are still vulnerable to developing COVID-19 despite vaccination.

Why isn’t the drug available? We have a two-stage process in the United Kingdom. We have the scientists and regulatory authorities looking at the evidence and data and saying, “Yes, it stacks up. This drug is effective and safe to some extent.”

The second phase is a health technology assessment undertaken by NICE, our National Institute for Health and Care Excellence – something that I’ve talked about a number of times before and the sometimes seemingly arbitrary decisions that they make. NICE hasn’t evaluated the drug yet, and the British government has held out because they are arguing that we don’t have enough data.

The trials with Evusheld were done before the Omicron variant dominated, as it does now; therefore, they are looking to try to work with AstraZeneca to generate more real-world data to show that Evusheld would prevent infection from the Omicron variant of the virus. Equally as important, how long does that protection last? Is it as protective against Omicron, and what’s the duration of that protection? Those bits of work are going on now.

Some real-world data are starting to emerge, showing that Evusheld will offer some degree of protection against Omicron, but there are still question marks about duration and the proportion of the population that would benefit.

NICE aren’t due to report on this – although the drug was approved in March of this year – until next year some time. That’s what’s caused a degree of consternation in the community of patients that we serve. Some of my clinical colleagues are beating the drum, saying, “We must have this drug now.” We’re still waiting on NICE to announce.

One obvious way to go around this is the government, which has bent over backwards in the United Kingdom to do as much as it can to protect the population from COVID-19. There was fantastic vaccine rollout and an extraordinary economic package to support individuals during lockdown to maintain the workforce, to support families and people at home. They’ve done a fantastic job.

Wanting to damp down this controversy, perhaps the sensible thing would be to ask NICE to evaluate the data that they have just now, to allow AstraZeneca to present whatever real-world evidence they have, and although it may not be perfect, it may be sufficient – we don’t know – to pass the NICE health technology assessment.

Watch this space. Let’s see what happens. If I were government, that’s what I would do. I would ask NICE to bring their appraisal forward. I would ask them to work with AstraZeneca to go over every ounce and iota of data that they have to see if this drug will be sufficiently effective and sufficiently cost-effective to be used before winter comes. I think the whole world is holding its breath, expecting another COVID-19 winter surge. Now would be the time to act.

What do you think? Here we are in the United Kingdom discussing yet another quasi–”health-rationing” problem. It’s not. This is about collecting more data and being as rational as possible. Can we accelerate that process? Perhaps.

Thanks for listening. I’d be very grateful for any comments that you might choose to make.
 

David J. Kerr, MD, DSc, is a professor of cancer medicine at the University of Oxford (England). He disclosed financial relationships with Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer HealthCare Pharmaceuticals, Genomic Health, Merck Serono, Roche, and Celleron Therapeutics.

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

This transcript has been edited for clarity.

I’m David Kerr, professor of cancer medicine at Oxford. As I’m gearing up to have my autumnal COVID-19 booster vaccine, there’s a small controversy raging in the United Kingdom about access to a medicine called Evusheld.

This was developed by AstraZeneca. It’s a combination of two relatively long-acting antibodies (tixagevimab and cilgavimab) that bind to the spike protein on the outside of the SARS-CoV-2 virus, the virus that causes COVID-19. The antibody binds to the spike protein and prevents it from binding to and infecting or damaging cells, so it’s what’s called preexposure prophylaxis.

Although vaccination is still the best approach to protecting against and, one would hope, conferring a degree of herd protection to our population as a whole, there are some people who cannot mount an appropriate immune response and we have to take care of these folks. Because the vaccines don’t work very well for them, the vaccine itself is not sufficient to protect them.

Evusheld, in trials that have been done hitherto, can protect people who can’t mount an immune response from being infected. Between 75% and 80% of patients treated with Evusheld didn’t get COVID-19. The duration of effect seemed to be at least for 6 months, possibly longer, so it’s a really good result. This caused our medicines regulatory authority in the United Kingdom to approve the drug in March of this year. Although the drug has been approved, it’s not yet funded and not yet available for vulnerable patients.

These are patients who, for reasons of inborn genetic diseases, cannot mount an immune response; patients who are pharmacologically immune depleted; patients who have had transplants and are on immunosuppressive drugs; and some of our cancer patients, particularly those with blood or hematologic malignancies, who can receive very heavy treatment that can pound the immune system to bits.

These are, in the population as a whole, relatively small numbers, but an important number of people who are still vulnerable to developing COVID-19 despite vaccination.

Why isn’t the drug available? We have a two-stage process in the United Kingdom. We have the scientists and regulatory authorities looking at the evidence and data and saying, “Yes, it stacks up. This drug is effective and safe to some extent.”

The second phase is a health technology assessment undertaken by NICE, our National Institute for Health and Care Excellence – something that I’ve talked about a number of times before and the sometimes seemingly arbitrary decisions that they make. NICE hasn’t evaluated the drug yet, and the British government has held out because they are arguing that we don’t have enough data.

The trials with Evusheld were done before the Omicron variant dominated, as it does now; therefore, they are looking to try to work with AstraZeneca to generate more real-world data to show that Evusheld would prevent infection from the Omicron variant of the virus. Equally as important, how long does that protection last? Is it as protective against Omicron, and what’s the duration of that protection? Those bits of work are going on now.

Some real-world data are starting to emerge, showing that Evusheld will offer some degree of protection against Omicron, but there are still question marks about duration and the proportion of the population that would benefit.

NICE aren’t due to report on this – although the drug was approved in March of this year – until next year some time. That’s what’s caused a degree of consternation in the community of patients that we serve. Some of my clinical colleagues are beating the drum, saying, “We must have this drug now.” We’re still waiting on NICE to announce.

One obvious way to go around this is the government, which has bent over backwards in the United Kingdom to do as much as it can to protect the population from COVID-19. There was fantastic vaccine rollout and an extraordinary economic package to support individuals during lockdown to maintain the workforce, to support families and people at home. They’ve done a fantastic job.

Wanting to damp down this controversy, perhaps the sensible thing would be to ask NICE to evaluate the data that they have just now, to allow AstraZeneca to present whatever real-world evidence they have, and although it may not be perfect, it may be sufficient – we don’t know – to pass the NICE health technology assessment.

Watch this space. Let’s see what happens. If I were government, that’s what I would do. I would ask NICE to bring their appraisal forward. I would ask them to work with AstraZeneca to go over every ounce and iota of data that they have to see if this drug will be sufficiently effective and sufficiently cost-effective to be used before winter comes. I think the whole world is holding its breath, expecting another COVID-19 winter surge. Now would be the time to act.

What do you think? Here we are in the United Kingdom discussing yet another quasi–”health-rationing” problem. It’s not. This is about collecting more data and being as rational as possible. Can we accelerate that process? Perhaps.

Thanks for listening. I’d be very grateful for any comments that you might choose to make.
 

David J. Kerr, MD, DSc, is a professor of cancer medicine at the University of Oxford (England). He disclosed financial relationships with Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Bayer HealthCare Pharmaceuticals, Genomic Health, Merck Serono, Roche, and Celleron Therapeutics.

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

Migraine affects more than 1 in 6 US adults. This figure masks the fact that migraine is a predominantly female disorder; compared with men, 3-month migraine prevalence is more than 2-fold higher (21% vs. 10%) in women. Research by the World Health Organization has established migraine as second among the world’s causes of disability, and first among women of reproductive age.  

Despite this burden of illness, migraine is often not diagnosed or treated effectively. General lifestyle advice such as maintaining a healthy weight, sleep hygiene, regular meals, regular exercise and hydration, and management of identified predisposing or triggering factors—together with optimization of symptomatic migraine treatment—can benefit all women with migraine. However, specific hormonal events such as menstruation, hormonal contraception, pregnancy, menopause, and hormone replacement therapy have variable, but often predictable, effects on the frequency and severity of migraine. At each of these life stages, there are specific opportunities to intervene and relieve migraine burden.

Menstrual migraine

Menstruation is one of the most significant risk factors for migraine, notably migraine without aura, with increased prevalence during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation.

The International Headache Society (IHS) recognizes 2 types of menstrual migraine. There is menstrually related migraine, which is migraine without aura that regularly occurs on or between day −2 to +3 of menstruation (there is no day 0), with additional attacks of migraine with or without aura at other times of the cycle. There is also pure menstrual migraine, which is migraine without aura that occurs only on or between day −2 to +3, with no attacks at any other time of the cycle.

In women with menstrually related migraine, the diagnosis should only be made if the relationship between migraine and menstruation is greater than a chance association. To confirm this diagnosis, migraine attacks during the day −2 to +3 window must occur in at least 2 of 3 menstrual cycles. Relying on history to confirm the diagnosis can be misleading. Use of a 3-month diary can reveal the predictable patterns associated with menstrual migraine, aiding diagnosis and management. 

Menstrual migraine affects 20% to 25% of women with migraine in the general population, and 22% to 70% of women seen in headache clinics. In women diagnosed with menstrual migraine, their perimenstrual attacks have distinctive clinical features which include more associated symptoms, longer duration, greater severity, greater susceptibility to relapse, greater resistance to treatment, and greater disability than migraines occurring at other times during the menstrual cycle.

Symptomatic treatment of perimenstrual attacks of migraine is the same as for treatment of non-menstrual attacks, but due to the longer duration of perimenstrual attacks, treatment usually needs to be repeated on several consecutive days. With respect to prevention, specific consideration should be given to the presence of menstrual disorders, contraceptive requirements, pregnancy wishes, and symptoms of perimenopause.

The 2 established triggers for perimenstrual migraine attacks are prostaglandin release, which also results in dysmenorrhea, and late luteal phase estrogen "withdrawal". There are no investigations to identify the relevant mechanism(s). However, a history of dysmenorrhea is suggestive of a prostaglandin trigger and both migraine and dysmenorrhea can benefit from treatment with prostaglandin inhibitors.

Contraceptive methods can effectively manage both perimenstrual triggers. The European Headache Federation and the European Society of Contraception and Reproductive Health recommend combined hormonal contraception (CHC) in women with menstrual migraine who require contraception or who have additional menstrual disorders that use of CHC would benefit. The desogestrel progestogen-only pill is an alternative option, particularly for women with aura, but bleeding side effects are a common reason for discontinuation.

The principal barriers to effective management of menstrual migraine are lack of awareness and under-diagnosis. Although the IHS criteria facilitate research diagnosis, there continues to be important unmet needs in the clinical management of women with menstrual migraine. Improved awareness by healthcare professionals is critical; women visiting their primary care physician or who are referred to a gynecologist seldom mention migraine unless specifically asked.

Contraception

Most women use contraception at some stage in their lives. Hormonal contraception, particularly CHC, is popular and effective, with additional non-contraceptive benefits.

As with the natural menstrual cycle, estrogen “withdrawal” (in this case the consequence of stopping contraceptive hormones during the hormone-free interval) can trigger migraine without aura. Eliminating the hormone-free interval by taking CHCs continuously, without a break, eliminates the risk of estrogen withdrawal migraine. Further, continuous use of CHC increases contraceptive efficacy and there are no differential safety concerns.

Contraceptive use of CHC is contraindicated in women with migraine aura, since migraine aura and use of ethinylestradiol are independent risk factors for ischemic stroke. Effective contraception need not be compromised since progestogen-only and non-hormonal methods—

several of which are more effective than CHC—are not associated with increased risk.

Despite there being little concern regarding use of CHCs in women with migraine without aura, clinical experience suggests that many women with migraine are denied CHCs. In some cases, this stems from misdiagnosing premonitory migraine symptoms as aura. In other cases, even a clear diagnosis of menstrual migraine without aura can result in CHCs being withheld due to the misconception of risk. To ensure that women receive optimum contraceptive options, contraceptive providers need a better understanding of the Medical Eligibility Criteria for Contraceptive Use as well as simple tools to aid migraine diagnosis.

Pregnancy and breastfeeding

Around 60-70% of pregnant women with migraine experience fewer attacks compared to pre-pregnancy, with improvement more likely in women with a history of menstrual migraine. In contrast, migraine with aura tends to continue to occur throughout pregnancy and postpartum and may start for the first time during this period. Women can be reassured that migraine, both with or without aura, does not have any adverse effect on the outcome of pregnancy. However, women with aura should be monitored during pregnancy since there is an increased risk of comorbid conditions, such as arterial and venous thrombosis, pre-eclampsia, and gestational hypertension.

Healthcare professionals need to be aware of their female patients with migraine who may be planning to conceive so that strategies for treating migraine can be discussed. Most drugs and other teratogens exert their greatest effects on the fetus in the first trimester, often before pregnancy is confirmed. Symptomatic treatment with acetaminophen and metoclopramide is safe. If this is ineffective, sumatriptan is an option. Ergot derivatives are contraindicated. If prophylaxis is considered necessary, propranolol is the safest and most effective option. Valproate is contraindicated for migraine prophylaxis in women of reproductive capacity who are not using adequate contraception due to the increased risk of neural tube defects, cardiac defects, and other developmental effects associated with use of this medication.

Fertility treatment is frequently associated with increased headache and migraine. It is also important to consider that headache can be symptomatic of emotional stress, which would benefit from supportive management.

Breastfeeding generally maintains the benefits of pregnancy on migraine and should be encouraged, where possible. Recent studies suggest that the number of women choosing to breastfeed is rising, but there is also evidence that women with migraine do not initiate breastfeeding or discontinue because of their concerns about taking medication.

Unfortunately, many women and healthcare professionals rely on information in the package inserts, which may not tell the full story. Milk supply can reduce within 48 hours without full and repeated emptying of the breast, so advising a woman to interrupt breastfeeding for even a few days while treating a migraine attack can destroy her milk production. Hence, maintaining breastfeeding during drug treatment is increasingly recommended. Healthcare professionals should be informed about which treatments can safely be used at this time. For acute treatment, acetaminophen and NSAIDS are first-line options and can be combined with metoclopramide. Sumatriptan is a second-line option that allows breastfeeding to continue without the need to ‘pump and dump’.

Menopause and hormone replacement therapy

Despite increased prevalence of menstrual migraine during perimenopause, headache and migraine are under-reported by women with perimenopausal migraine. Management should be directed to treating the menopausal symptoms, which may include hormone replacement therapy (HRT). Studies suggest a significant association between migraine and current use of HRT.

Understanding the effects of different types of HRT is important, as some studies suggest that a history of worsening migraine at menopause is a factor in predicting worsening migraine with HRT. However, the regimen of HRT, route of estrogen, and type of progestogen all have differing effects on migraine. Non-oral routes of continuous estrogen/progestogen are less likely to have a negative effect on migraine than oral formulations, and continuous estrogen/progestogen appears to be better tolerated than cyclical combined HRT. Oral micronized progesterone may directly benefit migraine due to GABAergic effects. Disturbed sleep is both a common migraine trigger and the action of progesterone to restore normal sleep will also benefit migraine.   

In contrast to CHCs, physiologic doses of transdermal estradiol and progesterone used in HRT are not associated with increased risk of ischemic stroke and can be used by women with migraine aura.

Conclusion

Many questions related to these topics don't have ready answers—questions like increased prevalence of hormone-related migraine, age of onset of menstrual migraines, and multispecialty treatment of these patients. Research is either limited or yet to be done, and we may not get the answers until healthcare professionals and women are more aware of the hormonal effects of migraine.

The effects of hormonal changes on migraine provide physicians with specific opportunities to identify and manage migraine in women. Under-treatment – in addition to causing unnecessary disability and suffering – is not economically cost-effective in terms of time lost from work and burden placed on the families of these patients. More effective health care would alleviate much of the suffering and therefore reduce both the personal and financial costs of migraine. Ineffective management of migraine in women has significant implications for women, their families, and their employers.

Migraine affects more than 1 in 6 US adults. This figure masks the fact that migraine is a predominantly female disorder; compared with men, 3-month migraine prevalence is more than 2-fold higher (21% vs. 10%) in women. Research by the World Health Organization has established migraine as second among the world’s causes of disability, and first among women of reproductive age.  

Despite this burden of illness, migraine is often not diagnosed or treated effectively. General lifestyle advice such as maintaining a healthy weight, sleep hygiene, regular meals, regular exercise and hydration, and management of identified predisposing or triggering factors—together with optimization of symptomatic migraine treatment—can benefit all women with migraine. However, specific hormonal events such as menstruation, hormonal contraception, pregnancy, menopause, and hormone replacement therapy have variable, but often predictable, effects on the frequency and severity of migraine. At each of these life stages, there are specific opportunities to intervene and relieve migraine burden.

Menstrual migraine

Menstruation is one of the most significant risk factors for migraine, notably migraine without aura, with increased prevalence during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation.

The International Headache Society (IHS) recognizes 2 types of menstrual migraine. There is menstrually related migraine, which is migraine without aura that regularly occurs on or between day −2 to +3 of menstruation (there is no day 0), with additional attacks of migraine with or without aura at other times of the cycle. There is also pure menstrual migraine, which is migraine without aura that occurs only on or between day −2 to +3, with no attacks at any other time of the cycle.

In women with menstrually related migraine, the diagnosis should only be made if the relationship between migraine and menstruation is greater than a chance association. To confirm this diagnosis, migraine attacks during the day −2 to +3 window must occur in at least 2 of 3 menstrual cycles. Relying on history to confirm the diagnosis can be misleading. Use of a 3-month diary can reveal the predictable patterns associated with menstrual migraine, aiding diagnosis and management. 

Menstrual migraine affects 20% to 25% of women with migraine in the general population, and 22% to 70% of women seen in headache clinics. In women diagnosed with menstrual migraine, their perimenstrual attacks have distinctive clinical features which include more associated symptoms, longer duration, greater severity, greater susceptibility to relapse, greater resistance to treatment, and greater disability than migraines occurring at other times during the menstrual cycle.

Symptomatic treatment of perimenstrual attacks of migraine is the same as for treatment of non-menstrual attacks, but due to the longer duration of perimenstrual attacks, treatment usually needs to be repeated on several consecutive days. With respect to prevention, specific consideration should be given to the presence of menstrual disorders, contraceptive requirements, pregnancy wishes, and symptoms of perimenopause.

The 2 established triggers for perimenstrual migraine attacks are prostaglandin release, which also results in dysmenorrhea, and late luteal phase estrogen "withdrawal". There are no investigations to identify the relevant mechanism(s). However, a history of dysmenorrhea is suggestive of a prostaglandin trigger and both migraine and dysmenorrhea can benefit from treatment with prostaglandin inhibitors.

Contraceptive methods can effectively manage both perimenstrual triggers. The European Headache Federation and the European Society of Contraception and Reproductive Health recommend combined hormonal contraception (CHC) in women with menstrual migraine who require contraception or who have additional menstrual disorders that use of CHC would benefit. The desogestrel progestogen-only pill is an alternative option, particularly for women with aura, but bleeding side effects are a common reason for discontinuation.

The principal barriers to effective management of menstrual migraine are lack of awareness and under-diagnosis. Although the IHS criteria facilitate research diagnosis, there continues to be important unmet needs in the clinical management of women with menstrual migraine. Improved awareness by healthcare professionals is critical; women visiting their primary care physician or who are referred to a gynecologist seldom mention migraine unless specifically asked.

Contraception

Most women use contraception at some stage in their lives. Hormonal contraception, particularly CHC, is popular and effective, with additional non-contraceptive benefits.

As with the natural menstrual cycle, estrogen “withdrawal” (in this case the consequence of stopping contraceptive hormones during the hormone-free interval) can trigger migraine without aura. Eliminating the hormone-free interval by taking CHCs continuously, without a break, eliminates the risk of estrogen withdrawal migraine. Further, continuous use of CHC increases contraceptive efficacy and there are no differential safety concerns.

Contraceptive use of CHC is contraindicated in women with migraine aura, since migraine aura and use of ethinylestradiol are independent risk factors for ischemic stroke. Effective contraception need not be compromised since progestogen-only and non-hormonal methods—

several of which are more effective than CHC—are not associated with increased risk.

Despite there being little concern regarding use of CHCs in women with migraine without aura, clinical experience suggests that many women with migraine are denied CHCs. In some cases, this stems from misdiagnosing premonitory migraine symptoms as aura. In other cases, even a clear diagnosis of menstrual migraine without aura can result in CHCs being withheld due to the misconception of risk. To ensure that women receive optimum contraceptive options, contraceptive providers need a better understanding of the Medical Eligibility Criteria for Contraceptive Use as well as simple tools to aid migraine diagnosis.

Pregnancy and breastfeeding

Around 60-70% of pregnant women with migraine experience fewer attacks compared to pre-pregnancy, with improvement more likely in women with a history of menstrual migraine. In contrast, migraine with aura tends to continue to occur throughout pregnancy and postpartum and may start for the first time during this period. Women can be reassured that migraine, both with or without aura, does not have any adverse effect on the outcome of pregnancy. However, women with aura should be monitored during pregnancy since there is an increased risk of comorbid conditions, such as arterial and venous thrombosis, pre-eclampsia, and gestational hypertension.

Healthcare professionals need to be aware of their female patients with migraine who may be planning to conceive so that strategies for treating migraine can be discussed. Most drugs and other teratogens exert their greatest effects on the fetus in the first trimester, often before pregnancy is confirmed. Symptomatic treatment with acetaminophen and metoclopramide is safe. If this is ineffective, sumatriptan is an option. Ergot derivatives are contraindicated. If prophylaxis is considered necessary, propranolol is the safest and most effective option. Valproate is contraindicated for migraine prophylaxis in women of reproductive capacity who are not using adequate contraception due to the increased risk of neural tube defects, cardiac defects, and other developmental effects associated with use of this medication.

Fertility treatment is frequently associated with increased headache and migraine. It is also important to consider that headache can be symptomatic of emotional stress, which would benefit from supportive management.

Breastfeeding generally maintains the benefits of pregnancy on migraine and should be encouraged, where possible. Recent studies suggest that the number of women choosing to breastfeed is rising, but there is also evidence that women with migraine do not initiate breastfeeding or discontinue because of their concerns about taking medication.

Unfortunately, many women and healthcare professionals rely on information in the package inserts, which may not tell the full story. Milk supply can reduce within 48 hours without full and repeated emptying of the breast, so advising a woman to interrupt breastfeeding for even a few days while treating a migraine attack can destroy her milk production. Hence, maintaining breastfeeding during drug treatment is increasingly recommended. Healthcare professionals should be informed about which treatments can safely be used at this time. For acute treatment, acetaminophen and NSAIDS are first-line options and can be combined with metoclopramide. Sumatriptan is a second-line option that allows breastfeeding to continue without the need to ‘pump and dump’.

Menopause and hormone replacement therapy

Despite increased prevalence of menstrual migraine during perimenopause, headache and migraine are under-reported by women with perimenopausal migraine. Management should be directed to treating the menopausal symptoms, which may include hormone replacement therapy (HRT). Studies suggest a significant association between migraine and current use of HRT.

Understanding the effects of different types of HRT is important, as some studies suggest that a history of worsening migraine at menopause is a factor in predicting worsening migraine with HRT. However, the regimen of HRT, route of estrogen, and type of progestogen all have differing effects on migraine. Non-oral routes of continuous estrogen/progestogen are less likely to have a negative effect on migraine than oral formulations, and continuous estrogen/progestogen appears to be better tolerated than cyclical combined HRT. Oral micronized progesterone may directly benefit migraine due to GABAergic effects. Disturbed sleep is both a common migraine trigger and the action of progesterone to restore normal sleep will also benefit migraine.   

In contrast to CHCs, physiologic doses of transdermal estradiol and progesterone used in HRT are not associated with increased risk of ischemic stroke and can be used by women with migraine aura.

Conclusion

Many questions related to these topics don't have ready answers—questions like increased prevalence of hormone-related migraine, age of onset of menstrual migraines, and multispecialty treatment of these patients. Research is either limited or yet to be done, and we may not get the answers until healthcare professionals and women are more aware of the hormonal effects of migraine.

The effects of hormonal changes on migraine provide physicians with specific opportunities to identify and manage migraine in women. Under-treatment – in addition to causing unnecessary disability and suffering – is not economically cost-effective in terms of time lost from work and burden placed on the families of these patients. More effective health care would alleviate much of the suffering and therefore reduce both the personal and financial costs of migraine. Ineffective management of migraine in women has significant implications for women, their families, and their employers.

Migraine affects more than 1 in 6 US adults. This figure masks the fact that migraine is a predominantly female disorder; compared with men, 3-month migraine prevalence is more than 2-fold higher (21% vs. 10%) in women. Research by the World Health Organization has established migraine as second among the world’s causes of disability, and first among women of reproductive age.  

Despite this burden of illness, migraine is often not diagnosed or treated effectively. General lifestyle advice such as maintaining a healthy weight, sleep hygiene, regular meals, regular exercise and hydration, and management of identified predisposing or triggering factors—together with optimization of symptomatic migraine treatment—can benefit all women with migraine. However, specific hormonal events such as menstruation, hormonal contraception, pregnancy, menopause, and hormone replacement therapy have variable, but often predictable, effects on the frequency and severity of migraine. At each of these life stages, there are specific opportunities to intervene and relieve migraine burden.

Menstrual migraine

Menstruation is one of the most significant risk factors for migraine, notably migraine without aura, with increased prevalence during a 5-day perimenstrual window that starts 2 days before the onset of menses and continues through the first 3 days of menstruation.

The International Headache Society (IHS) recognizes 2 types of menstrual migraine. There is menstrually related migraine, which is migraine without aura that regularly occurs on or between day −2 to +3 of menstruation (there is no day 0), with additional attacks of migraine with or without aura at other times of the cycle. There is also pure menstrual migraine, which is migraine without aura that occurs only on or between day −2 to +3, with no attacks at any other time of the cycle.

In women with menstrually related migraine, the diagnosis should only be made if the relationship between migraine and menstruation is greater than a chance association. To confirm this diagnosis, migraine attacks during the day −2 to +3 window must occur in at least 2 of 3 menstrual cycles. Relying on history to confirm the diagnosis can be misleading. Use of a 3-month diary can reveal the predictable patterns associated with menstrual migraine, aiding diagnosis and management. 

Menstrual migraine affects 20% to 25% of women with migraine in the general population, and 22% to 70% of women seen in headache clinics. In women diagnosed with menstrual migraine, their perimenstrual attacks have distinctive clinical features which include more associated symptoms, longer duration, greater severity, greater susceptibility to relapse, greater resistance to treatment, and greater disability than migraines occurring at other times during the menstrual cycle.

Symptomatic treatment of perimenstrual attacks of migraine is the same as for treatment of non-menstrual attacks, but due to the longer duration of perimenstrual attacks, treatment usually needs to be repeated on several consecutive days. With respect to prevention, specific consideration should be given to the presence of menstrual disorders, contraceptive requirements, pregnancy wishes, and symptoms of perimenopause.

The 2 established triggers for perimenstrual migraine attacks are prostaglandin release, which also results in dysmenorrhea, and late luteal phase estrogen "withdrawal". There are no investigations to identify the relevant mechanism(s). However, a history of dysmenorrhea is suggestive of a prostaglandin trigger and both migraine and dysmenorrhea can benefit from treatment with prostaglandin inhibitors.

Contraceptive methods can effectively manage both perimenstrual triggers. The European Headache Federation and the European Society of Contraception and Reproductive Health recommend combined hormonal contraception (CHC) in women with menstrual migraine who require contraception or who have additional menstrual disorders that use of CHC would benefit. The desogestrel progestogen-only pill is an alternative option, particularly for women with aura, but bleeding side effects are a common reason for discontinuation.

The principal barriers to effective management of menstrual migraine are lack of awareness and under-diagnosis. Although the IHS criteria facilitate research diagnosis, there continues to be important unmet needs in the clinical management of women with menstrual migraine. Improved awareness by healthcare professionals is critical; women visiting their primary care physician or who are referred to a gynecologist seldom mention migraine unless specifically asked.

Contraception

Most women use contraception at some stage in their lives. Hormonal contraception, particularly CHC, is popular and effective, with additional non-contraceptive benefits.

As with the natural menstrual cycle, estrogen “withdrawal” (in this case the consequence of stopping contraceptive hormones during the hormone-free interval) can trigger migraine without aura. Eliminating the hormone-free interval by taking CHCs continuously, without a break, eliminates the risk of estrogen withdrawal migraine. Further, continuous use of CHC increases contraceptive efficacy and there are no differential safety concerns.

Contraceptive use of CHC is contraindicated in women with migraine aura, since migraine aura and use of ethinylestradiol are independent risk factors for ischemic stroke. Effective contraception need not be compromised since progestogen-only and non-hormonal methods—

several of which are more effective than CHC—are not associated with increased risk.

Despite there being little concern regarding use of CHCs in women with migraine without aura, clinical experience suggests that many women with migraine are denied CHCs. In some cases, this stems from misdiagnosing premonitory migraine symptoms as aura. In other cases, even a clear diagnosis of menstrual migraine without aura can result in CHCs being withheld due to the misconception of risk. To ensure that women receive optimum contraceptive options, contraceptive providers need a better understanding of the Medical Eligibility Criteria for Contraceptive Use as well as simple tools to aid migraine diagnosis.

Pregnancy and breastfeeding

Around 60-70% of pregnant women with migraine experience fewer attacks compared to pre-pregnancy, with improvement more likely in women with a history of menstrual migraine. In contrast, migraine with aura tends to continue to occur throughout pregnancy and postpartum and may start for the first time during this period. Women can be reassured that migraine, both with or without aura, does not have any adverse effect on the outcome of pregnancy. However, women with aura should be monitored during pregnancy since there is an increased risk of comorbid conditions, such as arterial and venous thrombosis, pre-eclampsia, and gestational hypertension.

Healthcare professionals need to be aware of their female patients with migraine who may be planning to conceive so that strategies for treating migraine can be discussed. Most drugs and other teratogens exert their greatest effects on the fetus in the first trimester, often before pregnancy is confirmed. Symptomatic treatment with acetaminophen and metoclopramide is safe. If this is ineffective, sumatriptan is an option. Ergot derivatives are contraindicated. If prophylaxis is considered necessary, propranolol is the safest and most effective option. Valproate is contraindicated for migraine prophylaxis in women of reproductive capacity who are not using adequate contraception due to the increased risk of neural tube defects, cardiac defects, and other developmental effects associated with use of this medication.

Fertility treatment is frequently associated with increased headache and migraine. It is also important to consider that headache can be symptomatic of emotional stress, which would benefit from supportive management.

Breastfeeding generally maintains the benefits of pregnancy on migraine and should be encouraged, where possible. Recent studies suggest that the number of women choosing to breastfeed is rising, but there is also evidence that women with migraine do not initiate breastfeeding or discontinue because of their concerns about taking medication.

Unfortunately, many women and healthcare professionals rely on information in the package inserts, which may not tell the full story. Milk supply can reduce within 48 hours without full and repeated emptying of the breast, so advising a woman to interrupt breastfeeding for even a few days while treating a migraine attack can destroy her milk production. Hence, maintaining breastfeeding during drug treatment is increasingly recommended. Healthcare professionals should be informed about which treatments can safely be used at this time. For acute treatment, acetaminophen and NSAIDS are first-line options and can be combined with metoclopramide. Sumatriptan is a second-line option that allows breastfeeding to continue without the need to ‘pump and dump’.

Menopause and hormone replacement therapy

Despite increased prevalence of menstrual migraine during perimenopause, headache and migraine are under-reported by women with perimenopausal migraine. Management should be directed to treating the menopausal symptoms, which may include hormone replacement therapy (HRT). Studies suggest a significant association between migraine and current use of HRT.

Understanding the effects of different types of HRT is important, as some studies suggest that a history of worsening migraine at menopause is a factor in predicting worsening migraine with HRT. However, the regimen of HRT, route of estrogen, and type of progestogen all have differing effects on migraine. Non-oral routes of continuous estrogen/progestogen are less likely to have a negative effect on migraine than oral formulations, and continuous estrogen/progestogen appears to be better tolerated than cyclical combined HRT. Oral micronized progesterone may directly benefit migraine due to GABAergic effects. Disturbed sleep is both a common migraine trigger and the action of progesterone to restore normal sleep will also benefit migraine.   

In contrast to CHCs, physiologic doses of transdermal estradiol and progesterone used in HRT are not associated with increased risk of ischemic stroke and can be used by women with migraine aura.

Conclusion

Many questions related to these topics don't have ready answers—questions like increased prevalence of hormone-related migraine, age of onset of menstrual migraines, and multispecialty treatment of these patients. Research is either limited or yet to be done, and we may not get the answers until healthcare professionals and women are more aware of the hormonal effects of migraine.

The effects of hormonal changes on migraine provide physicians with specific opportunities to identify and manage migraine in women. Under-treatment – in addition to causing unnecessary disability and suffering – is not economically cost-effective in terms of time lost from work and burden placed on the families of these patients. More effective health care would alleviate much of the suffering and therefore reduce both the personal and financial costs of migraine. Ineffective management of migraine in women has significant implications for women, their families, and their employers.

The 3 “Rs” of multiple sclerosis (MS)—repair, remyelinate, and restore—spell out the goals of patients and physicians alike. MS is an incurable, immune-mediated, neurodegenerative disease of the central nervous system (CNS), and is thought to develop from unexplained autoimmune attacks directed at myelin (the covering on neurons) and glial cells, or “oligodendrocytes.” Neurodegeneration is evident early in the disease process and is characterized by mitochondrial dysfunction, energy failure, and neuronal and glial death.

While most new and investigational therapies aim to address immune dysfunction, a new idea—

one not involving immune dysregulation—is being explored in various studies: Are there agents, outside of traditional MS therapies, able to help with remyelination?

Mitochondria, oxidative stress, and MS

Neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are particularly sensitive to oxidative stress. In MS, chronic inflammation and autoimmunity are key drivers of oxidative stress and secondary mitochondrial dysfunction. 

Mitochondrial dysfunction is particularly relevant for neurodegeneration in MS. The observed dysfunction includes mitochondrial DNA damage, deficiency in mitochondrial DNA repair, reduced levels of antioxidants, and increased free radicals. Furthermore, the structure and number of mitochondria temporarily increase to accommodate the increased energy needs. Despite the attempted adaptation, energy failure ultimately occurs, resulting in a mismatch between energy needs or consumption and energy production. Neuroinflammation and the imbalance between energy consumption and generation create a vicious, continuous cycle that is characteristic in progressive MS. The energy failure is then associated with neuronal death, Wallerian degeneration, and subsequent accumulation of neurologic disability. 

Current therapeutic landscape

While the therapeutic landscape for MS continues to evolve, the approved 20-plus therapies are primarily directed at the immune system. The overall goal is to modulate immune dysregulation  and decrease inflammation. Current therapies  may be able to control this macroscopic inflammatory activity. 

However, current treatments only show modest effects on disease progression, and do not help to repair neurons, remyelinate axons, or restore function that was impaired due to disease progression. Some US Food and Drug Administration (FDA)–approved therapies are thought to modulate mitochondrial functions. For example, the class of fumarates (eg, dimethyl fumarate, diroximel fumarate, monomethyl fumarate) activates the nuclear factor erythroid 2 -related factor 2 (Nrf2) pathway in treated MS patients. However, it is unclear whether activation of the Nrf2 pathway is involved in the therapeutic effects of fumarates. A recent study challenged the importance of the Nrf2 pathway as a therapeutic target for fumarates. It showed that in an MS animal model, the effects of fumarates on disease control were similar between Nrf2 knock-out mice and the wild type, suggesting that fumarates' therapeutic effects are independent of the Nrf2 pathway. Furthermore, fumarates failed to show benefits in progressive forms of MS both clinically and on a biomarker level. 

Metformin, the mitochondria, and neurodegeneration

Metformin (1,1-dimethylbiguanide) is an oral medication used primarily as first-line treatment for type 2 diabetes. However, due to its pharmacologic properties, mitochondrial effects, and the ability to cross the blood-brain barrier, scientists have shown recent interest in studying metformin in neurodegenerative diseases, including MS. Some of the potential benefits of metformin in neurodegenerative diseases include reduction of oxidative stress and countering mitochondrial dysfunction. It is known that metformin inhibits mitochondrial complex 1. Also, several studies have shown a positive effect of metformin on the reduction of oxidative stress and mitochondrial DNA regulation. Therefore, could metformin help combat mitochondrial dysfunction in MS or rejuvenate certain elements within the CNS in people with neurodegenerative diseases, including MS?

Oligodendrocytes and remyelination

Oligodendrocytes are cells responsible for myelinating axons within the CNS. Those cells originate from progenitors called OPCs. Interestingly, in humans, OPCs can mature into oligodendrocytes throughout their lifecycle, although to a much lesser extent in adults compared with children. However, therapeutic efforts to facilitate OPC maturation in vivo in MS lesions have failed thus far. Examples include high-dose biotin, the anti-LINGO-1 opicinumab, and the anticancer, retinoid-analog drug bexarotene.

So, what is behind these unfortunate failures? Some molecules (eg, biotin, opicinumab) failed to meet their clinical endpoints in randomized clinical trials, while others had severe toxicity that halted further clinical testing (eg, bexarotene). On the other hand, some molecules (eg,      clemastine fumarate), showed a modest yet promising effect on biomarkers in small clinical trials. 

A discussion on molecule failures

What could explain the failure of molecules with such promising preclinical findings? One could argue that clinical trial designs may have been insufficient to detect small remyelinating effects. One could also argue that the maturation of OPCs into oligodendrocytes is too complex to facilitate using 1 molecule that may be an inhibitor of maturation or to activate/augment a facilitator of the maturation process. There are too many natural inhibitors and facilitators of OPC maturation, and an approach with combination therapy might have a better chance at achieving a favorable therapeutic effect. 

Another piece of the complexity of OPC maturation is the recent discovery that, in humans, nonhuman primates, and other mammals, aged OPCs do not have the same capacity to mature into oligodendrocytes as young OPCs. There might be some clinical support here, as children with MS have more ability to recover from MS attacks than their adult counterparts. Also, the older the individual with MS is, the less likely they are to recover from MS attacks and the more likely they are to show signs of disease progression compared with their younger counterparts. 

Theoretically, age-related recovery from clinical attacks may be partially explained by complications due to OPC aging. To this point, can we rejuvenate OPCs and restore their ability to mature into oligodendrocytes? Can metformin be the medicine that does so? 

Interestingly, scientists could restore the ability of older OPCs to mature into oligodendrocytes, at least in the rodent model, through calorie restriction (eg, intermittent fasting) or by mimicking this state using metformin. 

Metformin and the 3 “Rs”

One idea is to use metformin to create a biochemical state that allows OPCs to regain their ability to mature into oligodendrocytes in adult or aging individuals with MS. If that is achieved, other molecules may augment OPC' maturation or inhibit OPC maturation-inhibitors and become successful in promoting remyelination. A phase 2 clinical trial in the United Kingdom that is currently recruiting participants intends to investigate a combination of metformin and clemastine fumarate in 50 patients with relapsing-remitting MS. The goal is to learn whether metformin plus clemastine allows for therapeutic remyelination. In addition, a Canadian study is investigating metformin in children with MS. Two other studies are currently recruiting to study metformin in relapsing MS (Egypt) and progressive MS (United States). 

Although testing metformin as a treatment for MS is still in the early stages, the scientific rationale is valid and supported by compelling preclinical evidence. Ongoing clinical trials will likely provide preliminary results on whether metformin will advance in clinical testing and provide clinically meaningful improvements for people living with MS.

If metformin is, in fact, a conditioning agent for use in remyelinating therapies, future clinical trials could be designed to administer metformin to rejuvenate OPCs before the administration of any molecule combination designed to facilitate OPC maturation. However, these trials will need to address an important issue: dosage. In type 2 diabetes, the typical daily dose is between 500 and 3000 mg per day. But in tests on rodents – which weigh about 10 grams – to rejuvenate OPCs, the doses of metformin were very high: 200 to 300 mg/kg. Given the body weight of humans and to avoid drug toxicity, the resulting smaller doses of metformin will take time to exert their potential therapeutic effect.
 

Should future research be successful in developing combination molecular therapies with diverse and synergistic therapeutic targets, then the 3 “Rs” in MS will allow for a fourth “R” to effectively succeed: repair, remyelinate, restore, and rehabilitate.

The 3 “Rs” of multiple sclerosis (MS)—repair, remyelinate, and restore—spell out the goals of patients and physicians alike. MS is an incurable, immune-mediated, neurodegenerative disease of the central nervous system (CNS), and is thought to develop from unexplained autoimmune attacks directed at myelin (the covering on neurons) and glial cells, or “oligodendrocytes.” Neurodegeneration is evident early in the disease process and is characterized by mitochondrial dysfunction, energy failure, and neuronal and glial death.

While most new and investigational therapies aim to address immune dysfunction, a new idea—

one not involving immune dysregulation—is being explored in various studies: Are there agents, outside of traditional MS therapies, able to help with remyelination?

Mitochondria, oxidative stress, and MS

Neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are particularly sensitive to oxidative stress. In MS, chronic inflammation and autoimmunity are key drivers of oxidative stress and secondary mitochondrial dysfunction. 

Mitochondrial dysfunction is particularly relevant for neurodegeneration in MS. The observed dysfunction includes mitochondrial DNA damage, deficiency in mitochondrial DNA repair, reduced levels of antioxidants, and increased free radicals. Furthermore, the structure and number of mitochondria temporarily increase to accommodate the increased energy needs. Despite the attempted adaptation, energy failure ultimately occurs, resulting in a mismatch between energy needs or consumption and energy production. Neuroinflammation and the imbalance between energy consumption and generation create a vicious, continuous cycle that is characteristic in progressive MS. The energy failure is then associated with neuronal death, Wallerian degeneration, and subsequent accumulation of neurologic disability. 

Current therapeutic landscape

While the therapeutic landscape for MS continues to evolve, the approved 20-plus therapies are primarily directed at the immune system. The overall goal is to modulate immune dysregulation  and decrease inflammation. Current therapies  may be able to control this macroscopic inflammatory activity. 

However, current treatments only show modest effects on disease progression, and do not help to repair neurons, remyelinate axons, or restore function that was impaired due to disease progression. Some US Food and Drug Administration (FDA)–approved therapies are thought to modulate mitochondrial functions. For example, the class of fumarates (eg, dimethyl fumarate, diroximel fumarate, monomethyl fumarate) activates the nuclear factor erythroid 2 -related factor 2 (Nrf2) pathway in treated MS patients. However, it is unclear whether activation of the Nrf2 pathway is involved in the therapeutic effects of fumarates. A recent study challenged the importance of the Nrf2 pathway as a therapeutic target for fumarates. It showed that in an MS animal model, the effects of fumarates on disease control were similar between Nrf2 knock-out mice and the wild type, suggesting that fumarates' therapeutic effects are independent of the Nrf2 pathway. Furthermore, fumarates failed to show benefits in progressive forms of MS both clinically and on a biomarker level. 

Metformin, the mitochondria, and neurodegeneration

Metformin (1,1-dimethylbiguanide) is an oral medication used primarily as first-line treatment for type 2 diabetes. However, due to its pharmacologic properties, mitochondrial effects, and the ability to cross the blood-brain barrier, scientists have shown recent interest in studying metformin in neurodegenerative diseases, including MS. Some of the potential benefits of metformin in neurodegenerative diseases include reduction of oxidative stress and countering mitochondrial dysfunction. It is known that metformin inhibits mitochondrial complex 1. Also, several studies have shown a positive effect of metformin on the reduction of oxidative stress and mitochondrial DNA regulation. Therefore, could metformin help combat mitochondrial dysfunction in MS or rejuvenate certain elements within the CNS in people with neurodegenerative diseases, including MS?

Oligodendrocytes and remyelination

Oligodendrocytes are cells responsible for myelinating axons within the CNS. Those cells originate from progenitors called OPCs. Interestingly, in humans, OPCs can mature into oligodendrocytes throughout their lifecycle, although to a much lesser extent in adults compared with children. However, therapeutic efforts to facilitate OPC maturation in vivo in MS lesions have failed thus far. Examples include high-dose biotin, the anti-LINGO-1 opicinumab, and the anticancer, retinoid-analog drug bexarotene.

So, what is behind these unfortunate failures? Some molecules (eg, biotin, opicinumab) failed to meet their clinical endpoints in randomized clinical trials, while others had severe toxicity that halted further clinical testing (eg, bexarotene). On the other hand, some molecules (eg,      clemastine fumarate), showed a modest yet promising effect on biomarkers in small clinical trials. 

A discussion on molecule failures

What could explain the failure of molecules with such promising preclinical findings? One could argue that clinical trial designs may have been insufficient to detect small remyelinating effects. One could also argue that the maturation of OPCs into oligodendrocytes is too complex to facilitate using 1 molecule that may be an inhibitor of maturation or to activate/augment a facilitator of the maturation process. There are too many natural inhibitors and facilitators of OPC maturation, and an approach with combination therapy might have a better chance at achieving a favorable therapeutic effect. 

Another piece of the complexity of OPC maturation is the recent discovery that, in humans, nonhuman primates, and other mammals, aged OPCs do not have the same capacity to mature into oligodendrocytes as young OPCs. There might be some clinical support here, as children with MS have more ability to recover from MS attacks than their adult counterparts. Also, the older the individual with MS is, the less likely they are to recover from MS attacks and the more likely they are to show signs of disease progression compared with their younger counterparts. 

Theoretically, age-related recovery from clinical attacks may be partially explained by complications due to OPC aging. To this point, can we rejuvenate OPCs and restore their ability to mature into oligodendrocytes? Can metformin be the medicine that does so? 

Interestingly, scientists could restore the ability of older OPCs to mature into oligodendrocytes, at least in the rodent model, through calorie restriction (eg, intermittent fasting) or by mimicking this state using metformin. 

Metformin and the 3 “Rs”

One idea is to use metformin to create a biochemical state that allows OPCs to regain their ability to mature into oligodendrocytes in adult or aging individuals with MS. If that is achieved, other molecules may augment OPC' maturation or inhibit OPC maturation-inhibitors and become successful in promoting remyelination. A phase 2 clinical trial in the United Kingdom that is currently recruiting participants intends to investigate a combination of metformin and clemastine fumarate in 50 patients with relapsing-remitting MS. The goal is to learn whether metformin plus clemastine allows for therapeutic remyelination. In addition, a Canadian study is investigating metformin in children with MS. Two other studies are currently recruiting to study metformin in relapsing MS (Egypt) and progressive MS (United States). 

Although testing metformin as a treatment for MS is still in the early stages, the scientific rationale is valid and supported by compelling preclinical evidence. Ongoing clinical trials will likely provide preliminary results on whether metformin will advance in clinical testing and provide clinically meaningful improvements for people living with MS.

If metformin is, in fact, a conditioning agent for use in remyelinating therapies, future clinical trials could be designed to administer metformin to rejuvenate OPCs before the administration of any molecule combination designed to facilitate OPC maturation. However, these trials will need to address an important issue: dosage. In type 2 diabetes, the typical daily dose is between 500 and 3000 mg per day. But in tests on rodents – which weigh about 10 grams – to rejuvenate OPCs, the doses of metformin were very high: 200 to 300 mg/kg. Given the body weight of humans and to avoid drug toxicity, the resulting smaller doses of metformin will take time to exert their potential therapeutic effect.
 

Should future research be successful in developing combination molecular therapies with diverse and synergistic therapeutic targets, then the 3 “Rs” in MS will allow for a fourth “R” to effectively succeed: repair, remyelinate, restore, and rehabilitate.

The 3 “Rs” of multiple sclerosis (MS)—repair, remyelinate, and restore—spell out the goals of patients and physicians alike. MS is an incurable, immune-mediated, neurodegenerative disease of the central nervous system (CNS), and is thought to develop from unexplained autoimmune attacks directed at myelin (the covering on neurons) and glial cells, or “oligodendrocytes.” Neurodegeneration is evident early in the disease process and is characterized by mitochondrial dysfunction, energy failure, and neuronal and glial death.

While most new and investigational therapies aim to address immune dysfunction, a new idea—

one not involving immune dysregulation—is being explored in various studies: Are there agents, outside of traditional MS therapies, able to help with remyelination?

Mitochondria, oxidative stress, and MS

Neurons, oligodendrocytes, and oligodendrocyte precursor cells (OPCs) are particularly sensitive to oxidative stress. In MS, chronic inflammation and autoimmunity are key drivers of oxidative stress and secondary mitochondrial dysfunction. 

Mitochondrial dysfunction is particularly relevant for neurodegeneration in MS. The observed dysfunction includes mitochondrial DNA damage, deficiency in mitochondrial DNA repair, reduced levels of antioxidants, and increased free radicals. Furthermore, the structure and number of mitochondria temporarily increase to accommodate the increased energy needs. Despite the attempted adaptation, energy failure ultimately occurs, resulting in a mismatch between energy needs or consumption and energy production. Neuroinflammation and the imbalance between energy consumption and generation create a vicious, continuous cycle that is characteristic in progressive MS. The energy failure is then associated with neuronal death, Wallerian degeneration, and subsequent accumulation of neurologic disability. 

Current therapeutic landscape

While the therapeutic landscape for MS continues to evolve, the approved 20-plus therapies are primarily directed at the immune system. The overall goal is to modulate immune dysregulation  and decrease inflammation. Current therapies  may be able to control this macroscopic inflammatory activity. 

However, current treatments only show modest effects on disease progression, and do not help to repair neurons, remyelinate axons, or restore function that was impaired due to disease progression. Some US Food and Drug Administration (FDA)–approved therapies are thought to modulate mitochondrial functions. For example, the class of fumarates (eg, dimethyl fumarate, diroximel fumarate, monomethyl fumarate) activates the nuclear factor erythroid 2 -related factor 2 (Nrf2) pathway in treated MS patients. However, it is unclear whether activation of the Nrf2 pathway is involved in the therapeutic effects of fumarates. A recent study challenged the importance of the Nrf2 pathway as a therapeutic target for fumarates. It showed that in an MS animal model, the effects of fumarates on disease control were similar between Nrf2 knock-out mice and the wild type, suggesting that fumarates' therapeutic effects are independent of the Nrf2 pathway. Furthermore, fumarates failed to show benefits in progressive forms of MS both clinically and on a biomarker level. 

Metformin, the mitochondria, and neurodegeneration

Metformin (1,1-dimethylbiguanide) is an oral medication used primarily as first-line treatment for type 2 diabetes. However, due to its pharmacologic properties, mitochondrial effects, and the ability to cross the blood-brain barrier, scientists have shown recent interest in studying metformin in neurodegenerative diseases, including MS. Some of the potential benefits of metformin in neurodegenerative diseases include reduction of oxidative stress and countering mitochondrial dysfunction. It is known that metformin inhibits mitochondrial complex 1. Also, several studies have shown a positive effect of metformin on the reduction of oxidative stress and mitochondrial DNA regulation. Therefore, could metformin help combat mitochondrial dysfunction in MS or rejuvenate certain elements within the CNS in people with neurodegenerative diseases, including MS?

Oligodendrocytes and remyelination

Oligodendrocytes are cells responsible for myelinating axons within the CNS. Those cells originate from progenitors called OPCs. Interestingly, in humans, OPCs can mature into oligodendrocytes throughout their lifecycle, although to a much lesser extent in adults compared with children. However, therapeutic efforts to facilitate OPC maturation in vivo in MS lesions have failed thus far. Examples include high-dose biotin, the anti-LINGO-1 opicinumab, and the anticancer, retinoid-analog drug bexarotene.

So, what is behind these unfortunate failures? Some molecules (eg, biotin, opicinumab) failed to meet their clinical endpoints in randomized clinical trials, while others had severe toxicity that halted further clinical testing (eg, bexarotene). On the other hand, some molecules (eg,      clemastine fumarate), showed a modest yet promising effect on biomarkers in small clinical trials. 

A discussion on molecule failures

What could explain the failure of molecules with such promising preclinical findings? One could argue that clinical trial designs may have been insufficient to detect small remyelinating effects. One could also argue that the maturation of OPCs into oligodendrocytes is too complex to facilitate using 1 molecule that may be an inhibitor of maturation or to activate/augment a facilitator of the maturation process. There are too many natural inhibitors and facilitators of OPC maturation, and an approach with combination therapy might have a better chance at achieving a favorable therapeutic effect. 

Another piece of the complexity of OPC maturation is the recent discovery that, in humans, nonhuman primates, and other mammals, aged OPCs do not have the same capacity to mature into oligodendrocytes as young OPCs. There might be some clinical support here, as children with MS have more ability to recover from MS attacks than their adult counterparts. Also, the older the individual with MS is, the less likely they are to recover from MS attacks and the more likely they are to show signs of disease progression compared with their younger counterparts. 

Theoretically, age-related recovery from clinical attacks may be partially explained by complications due to OPC aging. To this point, can we rejuvenate OPCs and restore their ability to mature into oligodendrocytes? Can metformin be the medicine that does so? 

Interestingly, scientists could restore the ability of older OPCs to mature into oligodendrocytes, at least in the rodent model, through calorie restriction (eg, intermittent fasting) or by mimicking this state using metformin. 

Metformin and the 3 “Rs”

One idea is to use metformin to create a biochemical state that allows OPCs to regain their ability to mature into oligodendrocytes in adult or aging individuals with MS. If that is achieved, other molecules may augment OPC' maturation or inhibit OPC maturation-inhibitors and become successful in promoting remyelination. A phase 2 clinical trial in the United Kingdom that is currently recruiting participants intends to investigate a combination of metformin and clemastine fumarate in 50 patients with relapsing-remitting MS. The goal is to learn whether metformin plus clemastine allows for therapeutic remyelination. In addition, a Canadian study is investigating metformin in children with MS. Two other studies are currently recruiting to study metformin in relapsing MS (Egypt) and progressive MS (United States). 

Although testing metformin as a treatment for MS is still in the early stages, the scientific rationale is valid and supported by compelling preclinical evidence. Ongoing clinical trials will likely provide preliminary results on whether metformin will advance in clinical testing and provide clinically meaningful improvements for people living with MS.

If metformin is, in fact, a conditioning agent for use in remyelinating therapies, future clinical trials could be designed to administer metformin to rejuvenate OPCs before the administration of any molecule combination designed to facilitate OPC maturation. However, these trials will need to address an important issue: dosage. In type 2 diabetes, the typical daily dose is between 500 and 3000 mg per day. But in tests on rodents – which weigh about 10 grams – to rejuvenate OPCs, the doses of metformin were very high: 200 to 300 mg/kg. Given the body weight of humans and to avoid drug toxicity, the resulting smaller doses of metformin will take time to exert their potential therapeutic effect.
 

Should future research be successful in developing combination molecular therapies with diverse and synergistic therapeutic targets, then the 3 “Rs” in MS will allow for a fourth “R” to effectively succeed: repair, remyelinate, restore, and rehabilitate.

It’s back to school time, and some may be wondering what the current availability of vaccines may mean and the effects of the ever-changing COVID-19 guidelines on their children’s education and day-to-day experiences as students this year.

Unlike last school year, there are now vaccines available for all over the age of 6 months, and home rapid antigen tests are more readily available. Additionally, many have now been exposed either by infection or vaccination to the virus.

The CDC has removed the recommendations for maintaining cohorts in the K-12 population. This changing landscape along with differing levels of personal risk make it challenging to counsel families about what to expect in terms of COVID this year.

The best defense that we currently have against COVID is the vaccine. Although it seems that many are susceptible to the virus despite the vaccine, those who have been vaccinated are less susceptible to serious disease, including young children.

As older children may be heading to college, it is important

to encourage them to isolate when they have symptoms, even when they test negative for COVID as we would all like to avoid being sick in general.

Additionally, they should pay attention to the COVID risk level in their area and wear masks, particularly when indoors, as the levels increase. College students should have a plan for where they can isolate when not feeling well. If anyone does test positive for COVID, they should follow the most recent quarantine guidelines, including wearing a well fitted mask when they do begin returning to activities.
 

Monkeypox

We now have a new health concern for this school year.

Monkeypox has come onto the scene with information changing as rapidly as information previously did for COVID. With this virus, we must particularly counsel those heading away to college to be careful to limit their exposure to this disease.

Dormitories and other congregate settings are high-risk locations for the spread of monkeypox. Particularly, students headed to stay in dormitories should be counseled about avoiding:

• sexual activity with those with lesions consistent with monkeypox;
• sharing eating and drinking utensils; and
• sleeping in the same bed as or sharing bedding or towels with anyone with a diagnosis of or lesions consistent with monkeypox.

Additionally, as with prevention of all infections, it is important to frequently wash hands or use alcohol-based sanitizer before eating, and avoid touching the face after using the restroom.

Guidance for those eligible for vaccines against monkeypox seems to be quickly changing as well.

At the time of this article, CDC guidance recommends the vaccine against monkeypox for:

• those considered to be at high risk for it, including those identified by public health officials as a contact of someone with monkeypox;
• those who are aware that a sexual partner had a diagnosis of monkeypox within the past 2 weeks;
• those with multiple sex partners in the past 2 weeks in an area with known monkeypox; and
• those whose jobs may expose them to monkeypox.

Currently, the CDC recommends the vaccine JYNNEOS, a two-dose vaccine that reaches maximum protection after fourteen days. Ultimately, guidance is likely to continue to quickly change for both COVID-19 and Monkeypox throughout the fall. It is possible that new vaccinations will become available, and families and physicians alike will have many questions.

Primary care offices should ensure that someone is keeping up to date with the latest guidance to share with the office so that physicians may share accurate information with their patients.

Families should be counseled that we anticipate information about monkeypox, particularly related to vaccinations, to continue to change, as it has during all stages of the COVID pandemic.

As always, patients should be reminded to continue regular routine vaccinations, including the annual influenza vaccine.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

It’s back to school time, and some may be wondering what the current availability of vaccines may mean and the effects of the ever-changing COVID-19 guidelines on their children’s education and day-to-day experiences as students this year.

Unlike last school year, there are now vaccines available for all over the age of 6 months, and home rapid antigen tests are more readily available. Additionally, many have now been exposed either by infection or vaccination to the virus.

The CDC has removed the recommendations for maintaining cohorts in the K-12 population. This changing landscape along with differing levels of personal risk make it challenging to counsel families about what to expect in terms of COVID this year.

The best defense that we currently have against COVID is the vaccine. Although it seems that many are susceptible to the virus despite the vaccine, those who have been vaccinated are less susceptible to serious disease, including young children.

As older children may be heading to college, it is important

to encourage them to isolate when they have symptoms, even when they test negative for COVID as we would all like to avoid being sick in general.

Additionally, they should pay attention to the COVID risk level in their area and wear masks, particularly when indoors, as the levels increase. College students should have a plan for where they can isolate when not feeling well. If anyone does test positive for COVID, they should follow the most recent quarantine guidelines, including wearing a well fitted mask when they do begin returning to activities.
 

Monkeypox

We now have a new health concern for this school year.

Monkeypox has come onto the scene with information changing as rapidly as information previously did for COVID. With this virus, we must particularly counsel those heading away to college to be careful to limit their exposure to this disease.

Dormitories and other congregate settings are high-risk locations for the spread of monkeypox. Particularly, students headed to stay in dormitories should be counseled about avoiding:

• sexual activity with those with lesions consistent with monkeypox;
• sharing eating and drinking utensils; and
• sleeping in the same bed as or sharing bedding or towels with anyone with a diagnosis of or lesions consistent with monkeypox.

Additionally, as with prevention of all infections, it is important to frequently wash hands or use alcohol-based sanitizer before eating, and avoid touching the face after using the restroom.

Guidance for those eligible for vaccines against monkeypox seems to be quickly changing as well.

At the time of this article, CDC guidance recommends the vaccine against monkeypox for:

• those considered to be at high risk for it, including those identified by public health officials as a contact of someone with monkeypox;
• those who are aware that a sexual partner had a diagnosis of monkeypox within the past 2 weeks;
• those with multiple sex partners in the past 2 weeks in an area with known monkeypox; and
• those whose jobs may expose them to monkeypox.

Currently, the CDC recommends the vaccine JYNNEOS, a two-dose vaccine that reaches maximum protection after fourteen days. Ultimately, guidance is likely to continue to quickly change for both COVID-19 and Monkeypox throughout the fall. It is possible that new vaccinations will become available, and families and physicians alike will have many questions.

Primary care offices should ensure that someone is keeping up to date with the latest guidance to share with the office so that physicians may share accurate information with their patients.

Families should be counseled that we anticipate information about monkeypox, particularly related to vaccinations, to continue to change, as it has during all stages of the COVID pandemic.

As always, patients should be reminded to continue regular routine vaccinations, including the annual influenza vaccine.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

It’s back to school time, and some may be wondering what the current availability of vaccines may mean and the effects of the ever-changing COVID-19 guidelines on their children’s education and day-to-day experiences as students this year.

Unlike last school year, there are now vaccines available for all over the age of 6 months, and home rapid antigen tests are more readily available. Additionally, many have now been exposed either by infection or vaccination to the virus.

The CDC has removed the recommendations for maintaining cohorts in the K-12 population. This changing landscape along with differing levels of personal risk make it challenging to counsel families about what to expect in terms of COVID this year.

The best defense that we currently have against COVID is the vaccine. Although it seems that many are susceptible to the virus despite the vaccine, those who have been vaccinated are less susceptible to serious disease, including young children.

As older children may be heading to college, it is important

to encourage them to isolate when they have symptoms, even when they test negative for COVID as we would all like to avoid being sick in general.

Additionally, they should pay attention to the COVID risk level in their area and wear masks, particularly when indoors, as the levels increase. College students should have a plan for where they can isolate when not feeling well. If anyone does test positive for COVID, they should follow the most recent quarantine guidelines, including wearing a well fitted mask when they do begin returning to activities.
 

Monkeypox

We now have a new health concern for this school year.

Monkeypox has come onto the scene with information changing as rapidly as information previously did for COVID. With this virus, we must particularly counsel those heading away to college to be careful to limit their exposure to this disease.

Dormitories and other congregate settings are high-risk locations for the spread of monkeypox. Particularly, students headed to stay in dormitories should be counseled about avoiding:

• sexual activity with those with lesions consistent with monkeypox;
• sharing eating and drinking utensils; and
• sleeping in the same bed as or sharing bedding or towels with anyone with a diagnosis of or lesions consistent with monkeypox.

Additionally, as with prevention of all infections, it is important to frequently wash hands or use alcohol-based sanitizer before eating, and avoid touching the face after using the restroom.

Guidance for those eligible for vaccines against monkeypox seems to be quickly changing as well.

At the time of this article, CDC guidance recommends the vaccine against monkeypox for:

• those considered to be at high risk for it, including those identified by public health officials as a contact of someone with monkeypox;
• those who are aware that a sexual partner had a diagnosis of monkeypox within the past 2 weeks;
• those with multiple sex partners in the past 2 weeks in an area with known monkeypox; and
• those whose jobs may expose them to monkeypox.

Currently, the CDC recommends the vaccine JYNNEOS, a two-dose vaccine that reaches maximum protection after fourteen days. Ultimately, guidance is likely to continue to quickly change for both COVID-19 and Monkeypox throughout the fall. It is possible that new vaccinations will become available, and families and physicians alike will have many questions.

Primary care offices should ensure that someone is keeping up to date with the latest guidance to share with the office so that physicians may share accurate information with their patients.

Families should be counseled that we anticipate information about monkeypox, particularly related to vaccinations, to continue to change, as it has during all stages of the COVID pandemic.

As always, patients should be reminded to continue regular routine vaccinations, including the annual influenza vaccine.

Dr. Wheat is a family physician at Erie Family Health Center and program director of Northwestern University’s McGaw Family Medicine residency program, both in Chicago. Dr. Wheat serves on the editorial advisory board of Family Practice News. You can contact her at [email protected].

Many changes in the evolution of the treatment of diabetes have occurred during this year and 2021. Randomized controlled trials have resulted in updated guidelines for the use of glucagonlike peptide-1 receptor agonists (GLP1RAs) and continuous glucose monitoring (CGM) technology. I am hoping my discussion about these major advances in this edition of Highlights will be helpful to those caring for patients with diabetes.

Tirzepatide

The first GLP1RA, exenatide, was released in April 2005. Since then, numerous daily and weekly drugs of this class have been developed. We’ve learned they are effective glucose lowering drugs, and the weekly agents dulaglutide and semaglutide have shown impressive weight reduction properties as well as cardiovascular benefits.

Secondary outcomes have also shown renal benefits to these agents, and studies for primary renal efficacy are pending. Due to all of these properties, the GLP1RAs are recommended as the first injectable for the treatment of type 2 diabetes, prior to insulin initiation.¹

The next generation of these agents are a combination of a GLP1RA and a glucose-dependent insulinotropic polypeptide (GIP). Glucagonlike peptide-1 (GLP-1) stimulates insulin secretion, inhibits glucagon secretion, delays gastric emptying, and has central effects inducing satiety.

We now understand that GIP is the main incretin hormone in those without diabetes, causative of most of the incretin effects. But the insulin response after GIP secretion in type 2 diabetes is strongly reduced. It is now appreciated that this poor effect of GIP can be reduced when used in combination with a GLP1RA. This combination incretin, called by some a “twincretin,” is the basis for the drug tirzepatide which was approved by the Food and Drug Administration in May of 2022.

The data supporting this agent for both diabetes and obesity are impressive. For example, in a 40-week study with a baseline HbA1c of 8.0%, those randomized to tirzepatide at 5 mg, 10 mg, and 15 mg had HbA1c reductions of 1.87%, 1.89%, and 2.07% respectively.² Over 81% at all doses had HbA1c levels less than 6.5% at 40 weeks.

For the 5-mg, 10-mg, and 15-mg doses, weight change from baseline was 7.9%, 9.3%, and 11.0% respectively. Like older GLP1RAs, gastrointestinal side effects were the main problem. For the three doses, 3%, 5%, and 7%, respectively, had to stop the drug, compared with the 3% who stopped taking the placebo. In another study, tirzepatide was noninferior or superior at all three doses compared with semaglutide 1 mg weekly.³

In a population without diabetes, with 40% of patients having prediabetes, weight loss percentages for the three doses were 15.0%, 19.5%, and 20.9% respectively.⁴ Discontinuation percentages due to side effects were 4%-7%. The exciting part is we now have a drug that approaches weight loss from bariatric surgery. The cardiovascular and renal outcome trials are now underway, but the enthusiasm for this drug is clear from the data.

Like other GLP1RAs, the key is to start low and go slowly. It is recommended to start tirzepatide at 2.5 mg four times a week, then increase to 5 mg. Due to gastrointestinal side effects, some patients will do better at the lower dose before increasing. For those switching from another GLP1RA, there are no data to guide us but, in my practice, I start those patients at 5 mg weekly.
 

Continuous glucose monitoring

Data continue to accumulate that this form of glycemic self-monitoring is effective to reduce HbA1c levels and minimize hypoglycemia in both type 1 and type 2 diabetes. The most important change to the 2022 American Diabetes Association (ADA) standards of care is recognizing CGM as level A evidence for those receiving basal insulin without mealtime insulin.⁵ There are four CGMs on the market, but most of the market uses the Dexcom G6 or the Libre 2. Both of these devices will be updated within the next few months to newer generation sensors.

While there are similarities and differences between the two devices, by late 2022 and early 2023 changes to both will reduce the dissimilarities.

The next generation Libre (Libre 3) will be continuous, and “scanning” will no longer be required.  For those unable to get insurance to cover CGM, the Libre will continue to be more affordable than the Dexcom. Alerts will be present on both, but the Dexcom G7 will be approved for both the arm and the abdomen. The Dexcom also can communicate with several automated insulin delivery systems and data can be shared real-time with family members.

For clinicians just starting patients on this technology, my suggestion is to focus on one system so both the provider and staff can become familiar with it. It is key to review downloaded glucose metrics, in addition to the “ambulatory glucose profile,” a graphic overview of daily glycemia where patterns can be identified. It is also helpful to ask for assistance from endocrinologists who have experience with CGMs, in addition to the representatives of the companies.

COVID-19 and new-onset diabetes

From the beginning of the COVID 19 pandemic in 2020, it was clear that stress hyperglycemia and glucose dysregulation was an important observation for those infected. What was not known at the time is that for some, the hyperglycemia continued, and permanent diabetes ensued.

In one study of over 2.7 million U.S. veterans, men infected with COVID-19, but not women, were at a higher risk of new incident diabetes at 120 days after infection compared to no infection (odds ratio for men = 2.56).⁶

Another literature review using meta-analyses and cross-sectional studies concluded new-onset diabetes following COVID-19 infection can have a varied phenotype, with no risk factors, presenting from diabetic ketoacidosis to milder forms of diabetes.⁷

The current thought is that COVID-19 binds to the ACE2 and TMPRSS2 receptors which appear to be located on the beta-cells in the islet, resulting in insulin deficiency, in addition to the insulin resistance that seems to persist after the acute infection. Much more needs to be learned about this, but clinicians need to appreciate this appears to be a new form of diabetes and optimal treatments are not yet clear.

Dr. Hirsch is an endocrinologist, professor of medicine, and diabetes treatment and teaching chair at the University of Washington, Seattle. He has received research grant support from Dexcom and Insulet and has provided consulting to Abbott, Roche, Lifescan, and GWave. You can contact him at [email protected].

References

1. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S143.

2. Rosenstock J et al. Efficacy and safety of a novel GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet. 2021;398:143-55.

3. Frias JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-15.

4. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205-16.

5. American Diabetes Association Professional Practice Committee. Diabetes technology: Standards of Medical Care in Diabetes–2022. Diabetes Care. 2022;45(Suppl 1):S97-S112.

6. Wander PL et al. The incidence of diabetes in 2,777,768 veterans with and without recent SARS-CoV-2 infection. Diabetes Care 2022;45:782-8.

7. Joshi SC and Pozzilli P. COVID-19 induced diabetes: A novel presentation. Diabetes Res Clin Pract. 2022 Aug 6;191:110034.

Many changes in the evolution of the treatment of diabetes have occurred during this year and 2021. Randomized controlled trials have resulted in updated guidelines for the use of glucagonlike peptide-1 receptor agonists (GLP1RAs) and continuous glucose monitoring (CGM) technology. I am hoping my discussion about these major advances in this edition of Highlights will be helpful to those caring for patients with diabetes.

Tirzepatide

The first GLP1RA, exenatide, was released in April 2005. Since then, numerous daily and weekly drugs of this class have been developed. We’ve learned they are effective glucose lowering drugs, and the weekly agents dulaglutide and semaglutide have shown impressive weight reduction properties as well as cardiovascular benefits.

Secondary outcomes have also shown renal benefits to these agents, and studies for primary renal efficacy are pending. Due to all of these properties, the GLP1RAs are recommended as the first injectable for the treatment of type 2 diabetes, prior to insulin initiation.¹

The next generation of these agents are a combination of a GLP1RA and a glucose-dependent insulinotropic polypeptide (GIP). Glucagonlike peptide-1 (GLP-1) stimulates insulin secretion, inhibits glucagon secretion, delays gastric emptying, and has central effects inducing satiety.

We now understand that GIP is the main incretin hormone in those without diabetes, causative of most of the incretin effects. But the insulin response after GIP secretion in type 2 diabetes is strongly reduced. It is now appreciated that this poor effect of GIP can be reduced when used in combination with a GLP1RA. This combination incretin, called by some a “twincretin,” is the basis for the drug tirzepatide which was approved by the Food and Drug Administration in May of 2022.

The data supporting this agent for both diabetes and obesity are impressive. For example, in a 40-week study with a baseline HbA1c of 8.0%, those randomized to tirzepatide at 5 mg, 10 mg, and 15 mg had HbA1c reductions of 1.87%, 1.89%, and 2.07% respectively.² Over 81% at all doses had HbA1c levels less than 6.5% at 40 weeks.

For the 5-mg, 10-mg, and 15-mg doses, weight change from baseline was 7.9%, 9.3%, and 11.0% respectively. Like older GLP1RAs, gastrointestinal side effects were the main problem. For the three doses, 3%, 5%, and 7%, respectively, had to stop the drug, compared with the 3% who stopped taking the placebo. In another study, tirzepatide was noninferior or superior at all three doses compared with semaglutide 1 mg weekly.³

In a population without diabetes, with 40% of patients having prediabetes, weight loss percentages for the three doses were 15.0%, 19.5%, and 20.9% respectively.⁴ Discontinuation percentages due to side effects were 4%-7%. The exciting part is we now have a drug that approaches weight loss from bariatric surgery. The cardiovascular and renal outcome trials are now underway, but the enthusiasm for this drug is clear from the data.

Like other GLP1RAs, the key is to start low and go slowly. It is recommended to start tirzepatide at 2.5 mg four times a week, then increase to 5 mg. Due to gastrointestinal side effects, some patients will do better at the lower dose before increasing. For those switching from another GLP1RA, there are no data to guide us but, in my practice, I start those patients at 5 mg weekly.
 

Continuous glucose monitoring

Data continue to accumulate that this form of glycemic self-monitoring is effective to reduce HbA1c levels and minimize hypoglycemia in both type 1 and type 2 diabetes. The most important change to the 2022 American Diabetes Association (ADA) standards of care is recognizing CGM as level A evidence for those receiving basal insulin without mealtime insulin.⁵ There are four CGMs on the market, but most of the market uses the Dexcom G6 or the Libre 2. Both of these devices will be updated within the next few months to newer generation sensors.

While there are similarities and differences between the two devices, by late 2022 and early 2023 changes to both will reduce the dissimilarities.

The next generation Libre (Libre 3) will be continuous, and “scanning” will no longer be required.  For those unable to get insurance to cover CGM, the Libre will continue to be more affordable than the Dexcom. Alerts will be present on both, but the Dexcom G7 will be approved for both the arm and the abdomen. The Dexcom also can communicate with several automated insulin delivery systems and data can be shared real-time with family members.

For clinicians just starting patients on this technology, my suggestion is to focus on one system so both the provider and staff can become familiar with it. It is key to review downloaded glucose metrics, in addition to the “ambulatory glucose profile,” a graphic overview of daily glycemia where patterns can be identified. It is also helpful to ask for assistance from endocrinologists who have experience with CGMs, in addition to the representatives of the companies.

COVID-19 and new-onset diabetes

From the beginning of the COVID 19 pandemic in 2020, it was clear that stress hyperglycemia and glucose dysregulation was an important observation for those infected. What was not known at the time is that for some, the hyperglycemia continued, and permanent diabetes ensued.

In one study of over 2.7 million U.S. veterans, men infected with COVID-19, but not women, were at a higher risk of new incident diabetes at 120 days after infection compared to no infection (odds ratio for men = 2.56).⁶

Another literature review using meta-analyses and cross-sectional studies concluded new-onset diabetes following COVID-19 infection can have a varied phenotype, with no risk factors, presenting from diabetic ketoacidosis to milder forms of diabetes.⁷

The current thought is that COVID-19 binds to the ACE2 and TMPRSS2 receptors which appear to be located on the beta-cells in the islet, resulting in insulin deficiency, in addition to the insulin resistance that seems to persist after the acute infection. Much more needs to be learned about this, but clinicians need to appreciate this appears to be a new form of diabetes and optimal treatments are not yet clear.

Dr. Hirsch is an endocrinologist, professor of medicine, and diabetes treatment and teaching chair at the University of Washington, Seattle. He has received research grant support from Dexcom and Insulet and has provided consulting to Abbott, Roche, Lifescan, and GWave. You can contact him at [email protected].

References

1. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S143.

2. Rosenstock J et al. Efficacy and safety of a novel GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet. 2021;398:143-55.

3. Frias JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-15.

4. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205-16.

5. American Diabetes Association Professional Practice Committee. Diabetes technology: Standards of Medical Care in Diabetes–2022. Diabetes Care. 2022;45(Suppl 1):S97-S112.

6. Wander PL et al. The incidence of diabetes in 2,777,768 veterans with and without recent SARS-CoV-2 infection. Diabetes Care 2022;45:782-8.

7. Joshi SC and Pozzilli P. COVID-19 induced diabetes: A novel presentation. Diabetes Res Clin Pract. 2022 Aug 6;191:110034.

Many changes in the evolution of the treatment of diabetes have occurred during this year and 2021. Randomized controlled trials have resulted in updated guidelines for the use of glucagonlike peptide-1 receptor agonists (GLP1RAs) and continuous glucose monitoring (CGM) technology. I am hoping my discussion about these major advances in this edition of Highlights will be helpful to those caring for patients with diabetes.

Tirzepatide

The first GLP1RA, exenatide, was released in April 2005. Since then, numerous daily and weekly drugs of this class have been developed. We’ve learned they are effective glucose lowering drugs, and the weekly agents dulaglutide and semaglutide have shown impressive weight reduction properties as well as cardiovascular benefits.

Secondary outcomes have also shown renal benefits to these agents, and studies for primary renal efficacy are pending. Due to all of these properties, the GLP1RAs are recommended as the first injectable for the treatment of type 2 diabetes, prior to insulin initiation.¹

The next generation of these agents are a combination of a GLP1RA and a glucose-dependent insulinotropic polypeptide (GIP). Glucagonlike peptide-1 (GLP-1) stimulates insulin secretion, inhibits glucagon secretion, delays gastric emptying, and has central effects inducing satiety.

We now understand that GIP is the main incretin hormone in those without diabetes, causative of most of the incretin effects. But the insulin response after GIP secretion in type 2 diabetes is strongly reduced. It is now appreciated that this poor effect of GIP can be reduced when used in combination with a GLP1RA. This combination incretin, called by some a “twincretin,” is the basis for the drug tirzepatide which was approved by the Food and Drug Administration in May of 2022.

The data supporting this agent for both diabetes and obesity are impressive. For example, in a 40-week study with a baseline HbA1c of 8.0%, those randomized to tirzepatide at 5 mg, 10 mg, and 15 mg had HbA1c reductions of 1.87%, 1.89%, and 2.07% respectively.² Over 81% at all doses had HbA1c levels less than 6.5% at 40 weeks.

For the 5-mg, 10-mg, and 15-mg doses, weight change from baseline was 7.9%, 9.3%, and 11.0% respectively. Like older GLP1RAs, gastrointestinal side effects were the main problem. For the three doses, 3%, 5%, and 7%, respectively, had to stop the drug, compared with the 3% who stopped taking the placebo. In another study, tirzepatide was noninferior or superior at all three doses compared with semaglutide 1 mg weekly.³

In a population without diabetes, with 40% of patients having prediabetes, weight loss percentages for the three doses were 15.0%, 19.5%, and 20.9% respectively.⁴ Discontinuation percentages due to side effects were 4%-7%. The exciting part is we now have a drug that approaches weight loss from bariatric surgery. The cardiovascular and renal outcome trials are now underway, but the enthusiasm for this drug is clear from the data.

Like other GLP1RAs, the key is to start low and go slowly. It is recommended to start tirzepatide at 2.5 mg four times a week, then increase to 5 mg. Due to gastrointestinal side effects, some patients will do better at the lower dose before increasing. For those switching from another GLP1RA, there are no data to guide us but, in my practice, I start those patients at 5 mg weekly.
 

Continuous glucose monitoring

Data continue to accumulate that this form of glycemic self-monitoring is effective to reduce HbA1c levels and minimize hypoglycemia in both type 1 and type 2 diabetes. The most important change to the 2022 American Diabetes Association (ADA) standards of care is recognizing CGM as level A evidence for those receiving basal insulin without mealtime insulin.⁵ There are four CGMs on the market, but most of the market uses the Dexcom G6 or the Libre 2. Both of these devices will be updated within the next few months to newer generation sensors.

While there are similarities and differences between the two devices, by late 2022 and early 2023 changes to both will reduce the dissimilarities.

The next generation Libre (Libre 3) will be continuous, and “scanning” will no longer be required.  For those unable to get insurance to cover CGM, the Libre will continue to be more affordable than the Dexcom. Alerts will be present on both, but the Dexcom G7 will be approved for both the arm and the abdomen. The Dexcom also can communicate with several automated insulin delivery systems and data can be shared real-time with family members.

For clinicians just starting patients on this technology, my suggestion is to focus on one system so both the provider and staff can become familiar with it. It is key to review downloaded glucose metrics, in addition to the “ambulatory glucose profile,” a graphic overview of daily glycemia where patterns can be identified. It is also helpful to ask for assistance from endocrinologists who have experience with CGMs, in addition to the representatives of the companies.

COVID-19 and new-onset diabetes

From the beginning of the COVID 19 pandemic in 2020, it was clear that stress hyperglycemia and glucose dysregulation was an important observation for those infected. What was not known at the time is that for some, the hyperglycemia continued, and permanent diabetes ensued.

In one study of over 2.7 million U.S. veterans, men infected with COVID-19, but not women, were at a higher risk of new incident diabetes at 120 days after infection compared to no infection (odds ratio for men = 2.56).⁶

Another literature review using meta-analyses and cross-sectional studies concluded new-onset diabetes following COVID-19 infection can have a varied phenotype, with no risk factors, presenting from diabetic ketoacidosis to milder forms of diabetes.⁷

The current thought is that COVID-19 binds to the ACE2 and TMPRSS2 receptors which appear to be located on the beta-cells in the islet, resulting in insulin deficiency, in addition to the insulin resistance that seems to persist after the acute infection. Much more needs to be learned about this, but clinicians need to appreciate this appears to be a new form of diabetes and optimal treatments are not yet clear.

Dr. Hirsch is an endocrinologist, professor of medicine, and diabetes treatment and teaching chair at the University of Washington, Seattle. He has received research grant support from Dexcom and Insulet and has provided consulting to Abbott, Roche, Lifescan, and GWave. You can contact him at [email protected].

References

1. American Diabetes Association Professional Practice Committee. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S143.

2. Rosenstock J et al. Efficacy and safety of a novel GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial. Lancet. 2021;398:143-55.

3. Frias JP et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021;385:503-15.

4. Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387:205-16.

5. American Diabetes Association Professional Practice Committee. Diabetes technology: Standards of Medical Care in Diabetes–2022. Diabetes Care. 2022;45(Suppl 1):S97-S112.

6. Wander PL et al. The incidence of diabetes in 2,777,768 veterans with and without recent SARS-CoV-2 infection. Diabetes Care 2022;45:782-8.

7. Joshi SC and Pozzilli P. COVID-19 induced diabetes: A novel presentation. Diabetes Res Clin Pract. 2022 Aug 6;191:110034.

Those of us who treat patients with type 2 diabetes (T2D) daily have long recognized a disturbing irony: diabetes is a disease whose management requires consistency in approach and constancy in delivery, but it is most prevalent among those whose lives often allow little to no time for either. 

In our clinic, many patients with diabetes are struggling, in some way, to incorporate diabetes management into their daily lives. They are juggling multiple jobs and family responsibilities; they are working jobs with inconsistent access to food or refrigeration (such as farming, service industry work, and others); and many—even those with insurance—are struggling to afford their insulin and non insulin medications, insulin administration supplies, and glucose testing equipment.

Studies show how stress deleteriously affects this disease. The body does not deal well with these frequent and persistent stressors; higher cortisol levels result in higher blood glucose levels, increased systemic inflammation, and other drivers of both diabetes and its complications; all have been extensively documented. 

What has been frustrating for our clinical community is knowing that since the early 2000s, new diabetes medications and technologies have been available that can make a difference in our patients’ lives, but for various reasons, they have not been well adopted, particularly among patients most likely to benefit from them. Consequently, we have not consistently seen meaningfully reduced glycated hemoglobin (A1c) levels or reduced rates of acute or chronic diabetes complications. Therapeutic inertia exists at the patient, systemic, and physician levels. 

Many of the new glucose-lowering medications can also improve cardiovascular and kidney disease outcomes with low risk for hypoglycemia and weight gain. Diabetes technologies like insulin pumps and continuous glucose monitors (CGM) have been demonstrated in clinical trials to improve A1c and reduce hypoglycemia risk. But the reality is that clinicians are seeing an increasing number of patients with high A1c, with hypoglycemia, with severe hyperglycemia, and with long-term diabetes complications. 

If these advancements are supposed to improve health outcomes, why are patient, community, and population health not improving? Why are some patients not receiving the care they need, while others get extra services that do not improve their health and may even harm them?

These advancements also create new questions for clinicians. At what point in the disease course should existing medications be ramped up, ramped down, or changed? Which patient characteristics or comorbidities allow or do not allow these changes?  When should we use technologies or when does their burden outweigh their potential benefits? What resources and support systems do our patients need to live well with their disease and how can these be procured?

Herein lies the problem: Diabetes is a dynamic disease that needs to be handled in a dynamic way, and that has not universally—or even frequently—occurred. Management must be a team endeavor, meaning that both patient and clinician must be proactive in diabetes management. It has been our experience, demonstrated in our work and in other studies, that success relies on a robust and comprehensive primary care system whose team members—physicians, advanced practice providers, nurses, pharmacists, certified diabetes care and education specialists, social workers, nurses, pharmacists, and dietitians—are all resilient and motivated to tackle one of the most complex, multifaceted, and multidimensional chronic health conditions in our practice.

Proactivity also includes consistent monitoring, learning from successes and failures, and public reporting. For the patient, proactive involvement generally means self-care multiple times a day.    

Let us now discuss the evidence that prompted our team’s proactive approach to caring for people living with diabetes.

Gauges and perspective

The prevalence of T2D in this country stands at 11.3% within the adult population. Between 2015 and 2020, death from diabetes increased by 27%.

For years, the research community has documented the wide range of socioeconomic factors that increase the risk for developing T2D and that, once developed, make it more difficult for patients to manage their disease and achieve optimal health outcomes that are possible with available medications and technologies. 

In 2019, Kazemian et al published work that examined the indicators of diabetes management progress (eg, A1c levels, cholesterol levels) of 1742 individuals, from 2005 to 2016. Just 23% to 25% of these patients achieved all goals, even though, during the study period, numerous medications were approved to manage disease better. Arguably, these should have improved the all-goal findings in the study. 

The first injectable glucagon-like peptide 1 receptor agonist (GLP-1 RA) was approved in 2005; between 2013 and 2016, the FDA also approved 4 sodium-glucose cotransporter 2 (SGLT2) inhibitors. Both medication classes can safely and effectively lower A1c with no weight gain and low risk for hypoglycemia. Over the past 4 years, a robust body of evidence has emerged to show that GLP-1 RAs and SGLT2 inhibitors not only lower A1c, but also reduce the likelihood of death from cardiovascular and kidney diseases. SGLT2 inhibitors are better at saving lives from hypertensive heart failure while the GLP-1 RAs are more protective from atherosclerotic cardiovascular events like myocardial infarction and stroke, as compared with placebo. Yet, these medications have not been, and continue not to be, regularly prescribed. In 1 study, the authors found that the rate of use for SGLT2 inhibitors was 3.8% in 2015 and 11.9% in 2019.

But there are several other reasons that patients do not receive these medicines.

Insurance

We conducted a retrospective cohort study of  382,574 adults between 58 and 66 years of age, insured by either a Medicare Advantage plan or commercial insurance, and compared treatment initiation of the 3 most common brand-name, second-line diabetes medications (as opposed to generic sulfonylureas), between 2016 and 2019. The rate of initiation was universally lower for Medicare Advantage members vs commercially insured individuals. 

While the rates of initiation of GLP-1 RAs, SGLT2 inhibitors, and dipeptidyl peptidase 4 (DPP-4) inhibitors increased between 2016 and 2019, rates were significantly higher among patients with commercial insurance. Specifically, GLP-1 RA initiation increased from 2.1% to 20.0% among commercial insurance beneficiaries and from 1.5% to 11.4% among Medicare Advantage beneficiaries. SGLT2 inhibitor initiation increased from 2.7% to 18.2% with commercial insurance and from 1.57% to 8.51% with Medicare Advantage. DPP-4 inhibitor initiation increased from 3.3% to 11.7% with commercial insurance and from 2.44% to 7.68% with Medicare Advantage. Within each calendar year, the odds of initiating one of these 3 medications with Medicare Advantage as compared with commercial insurance ranged from 0.28 to 0.70 for GLP-1 RAs; from 0.21 to 0.57 for SGLT2 inhibitors; and from 0.37 to 0.73 for DPP-4 inhibitors. 

We also looked at the initiation of these medications in individuals with cardiorenal comorbidities. In many cases, a drug was prescribed indiscriminately. A patient who would benefit from a GLP-1 RA because of cardiovascular, cerebrovascular, or kidney disease was less likely to be prescribed a GLP-1 RA than a medication like a DPP-4 inhibitor, which usually has the same formulary tier/class but does not have any of the cardiovascular or kidney benefits. Likewise, in those with heart failure or kidney disease, an SGLT2 inhibitor would have been the appropriate choice, but these patients were too often started on a DPP-4 inhibitor, which is not advised for those with heart failure and does provide kidney benefits. 

Last year, Tummalapalli et al, in their evaluation of 4135 US health plans, including commercial- or employer-based, Medicare, Medicaid, and other public health plans, identified multiple barriers to accessing SGLT2 inhibitor medications. While all plans included at least 1 SGLT2 inhibitor on their formularies, they restricted access in other ways. Prior authorizations were required by nearly half of Medicaid plans and nearly 40% of other public plans such as the Veterans Health Administration. Medicare and other public plans commonly imposed quantity limits on fills. Commercial plans frequently (up to 40%) required step therapy (use or failure of a generic diabetes medication) before approval. Copayments were also high in commercial plans, Medicare, and others. 

The need for prior authorizations dominates attempts to prescribe. Centene Corporation, for example, which manages plans for private and public payers, will not approve use of an SGLT2 inhibitor until the patient fails for 3 consecutive months on a prior treatment, has established cardiovascular disease or diabetic nephropathy, or has multiple cardiovascular risk factors. These comorbidities must be documented and verified, and the prior authorizations must be completed, often resulting in substantial administrative burden to clinicians. No wonder many, especially in primary care, may be wary of prescribing drugs that come with a paperwork trail and hours spent on documentation and insurance appeals, rather than on patient care.

The same can be said for prescribing a GLP-1 RA. United Healthcare’s Oxford Benefit Management requires that clinicians show a “history of suboptimal response, contraindication, or intolerance to metformin” before prescribing any of the 8 GLP-1 RAs. 

The average retail cost of 30 empagliflozin tablets, a once-daily medication, is $752. During the pandemic, 24% of the 5000 patients surveyed in an American Diabetes Association (ADA) poll used their stimulus check, relied on loans, or spent savings to pay for diabetes care. GLP-1 RA medications are even more expensive.  Depending on the patient’s pharmacy benefits, they may have to pay a substantial coinsurance out of pocket even after the annual deductible is met, creating financial barriers to starting and continuing recommended, evidence-based medications. Even if patients do get the recommended medications, they may be forced to ration other aspects of their lives, including other medications, food, and other necessities.

There are other important barriers to optimal utilization of evidence-based therapies, stemming from the fundamental social determinants of health: low income, low education level, and living in a socioeconomically deprived neighborhood.  

Social Determinants of Health

Diabetes prevalence is higher in patients experiencing socioeconomic and other structural barriers to health and health care. Fundamentally, 1 study showed that prevalence of diabetes was 1.4 times higher among people living on less than $15,000 a year, as opposed to those earning at least $50,000 a year. 

The risk of diabetes complications is also higher in individuals experiencing food or housing insecurity, those who have low income or education level, and residents in rural and socioeconomically deprived neighborhoods. Importantly, the same patient populations are also less likely to receive timely evidence-based care, contributing to and worsening health disparities. Despite their prevalence and importance, social determinants of health (SDoH) are not routinely recognized or discussed during clinical encounters, such that improving diabetes care and health outcomes is predicated on developing a system to screen for, recognize, and address the wide range of barriers faced by our patients. If a patient cannot afford a new medication or get to the clinic on a regular basis, lacks access to healthy food, or does not have time for diabetes self-management education or to focus on their health, then their well-being will suffer.

Many of these SDoH disproportionately affect racial and ethnic minority populations as the direct result of longstanding and deeply embedded systems, policies, and laws that underlie disparities in diabetes incidence, prevalence, management, and outcomes. As such, structural racism is increasingly recognized as a root cause of health disparities in diabetes and other chronic health conditions.

Proactive strategies

Since reactive care has not and cannot provide patients with the help they need and deserve, many in the diabetes care community have turned to proactive, team-based care. The Chronic Care Model, established in the 1990s, stresses decision-making support, strong team organization and delivery system design, and the wherewithal to monitor progress continually. Research has shown that the best results for patients stem from a multidisciplinary, data-driven, and proactive approach to identifying and meeting the totality of patient care needs. 

The ADA stresses the importance of comprehensive, team-based care for successful management of diabetes. This includes expanding the role of teams to implement evidence-based diabetes care, using electronic health record tools to support timely and guideline-recommended delivery of services, empowering and educating patients and caregivers, eliciting and addressing financial and psychosocial barriers to care, and identifying, developing, and engaging community resources to support better health and well-being.

Recognizing the centrality of team-based care to diabetes management, our team has developed and implemented an enhanced primary care diabetes (EPCD) model across the internal medicine and family medicine practices of Mayo Clinic, first in Rochester, Minnesota and then across multiple rural and small urban sites in southeast Minnesota. This model is centered around the primary care team nurse, who partners with clinicians to oversee, enforce, and coordinate the diabetes management of patients paneled to those clinicians. Nurses proactively identify patients, engage other members of the healthcare team (eg, pharmacists, social workers, certified diabetes care and education specialists) as needed, and maintain a continuous relationship with each patient to help them achieve and maintain their goals. This model was not only effective at improving glycemic control and other indicators of diabetes care quality, but also improved nursing and clinician satisfaction. 

It is important to recognize that comprehensive diabetes care comprises both medical and nonmedical interventions that address the totality of the patient’s care needs and the circumstances that hinder optimal health. Increasingly, robust data are emerging in support of nonmedical interventions that target SDoH, including structural racism as a root cause of racial and ethnic disparities in diabetes care and outcomes, with demonstrated evidence of improved health outcomes and narrowed health disparities.

It takes work, effort, and commitment to manage diabetes. But a team-based approach allows players on all sides to win. 

Those of us who treat patients with type 2 diabetes (T2D) daily have long recognized a disturbing irony: diabetes is a disease whose management requires consistency in approach and constancy in delivery, but it is most prevalent among those whose lives often allow little to no time for either. 

In our clinic, many patients with diabetes are struggling, in some way, to incorporate diabetes management into their daily lives. They are juggling multiple jobs and family responsibilities; they are working jobs with inconsistent access to food or refrigeration (such as farming, service industry work, and others); and many—even those with insurance—are struggling to afford their insulin and non insulin medications, insulin administration supplies, and glucose testing equipment.

Studies show how stress deleteriously affects this disease. The body does not deal well with these frequent and persistent stressors; higher cortisol levels result in higher blood glucose levels, increased systemic inflammation, and other drivers of both diabetes and its complications; all have been extensively documented. 

What has been frustrating for our clinical community is knowing that since the early 2000s, new diabetes medications and technologies have been available that can make a difference in our patients’ lives, but for various reasons, they have not been well adopted, particularly among patients most likely to benefit from them. Consequently, we have not consistently seen meaningfully reduced glycated hemoglobin (A1c) levels or reduced rates of acute or chronic diabetes complications. Therapeutic inertia exists at the patient, systemic, and physician levels. 

Many of the new glucose-lowering medications can also improve cardiovascular and kidney disease outcomes with low risk for hypoglycemia and weight gain. Diabetes technologies like insulin pumps and continuous glucose monitors (CGM) have been demonstrated in clinical trials to improve A1c and reduce hypoglycemia risk. But the reality is that clinicians are seeing an increasing number of patients with high A1c, with hypoglycemia, with severe hyperglycemia, and with long-term diabetes complications. 

If these advancements are supposed to improve health outcomes, why are patient, community, and population health not improving? Why are some patients not receiving the care they need, while others get extra services that do not improve their health and may even harm them?

These advancements also create new questions for clinicians. At what point in the disease course should existing medications be ramped up, ramped down, or changed? Which patient characteristics or comorbidities allow or do not allow these changes?  When should we use technologies or when does their burden outweigh their potential benefits? What resources and support systems do our patients need to live well with their disease and how can these be procured?

Herein lies the problem: Diabetes is a dynamic disease that needs to be handled in a dynamic way, and that has not universally—or even frequently—occurred. Management must be a team endeavor, meaning that both patient and clinician must be proactive in diabetes management. It has been our experience, demonstrated in our work and in other studies, that success relies on a robust and comprehensive primary care system whose team members—physicians, advanced practice providers, nurses, pharmacists, certified diabetes care and education specialists, social workers, nurses, pharmacists, and dietitians—are all resilient and motivated to tackle one of the most complex, multifaceted, and multidimensional chronic health conditions in our practice.

Proactivity also includes consistent monitoring, learning from successes and failures, and public reporting. For the patient, proactive involvement generally means self-care multiple times a day.    

Let us now discuss the evidence that prompted our team’s proactive approach to caring for people living with diabetes.

Gauges and perspective

The prevalence of T2D in this country stands at 11.3% within the adult population. Between 2015 and 2020, death from diabetes increased by 27%.

For years, the research community has documented the wide range of socioeconomic factors that increase the risk for developing T2D and that, once developed, make it more difficult for patients to manage their disease and achieve optimal health outcomes that are possible with available medications and technologies. 

In 2019, Kazemian et al published work that examined the indicators of diabetes management progress (eg, A1c levels, cholesterol levels) of 1742 individuals, from 2005 to 2016. Just 23% to 25% of these patients achieved all goals, even though, during the study period, numerous medications were approved to manage disease better. Arguably, these should have improved the all-goal findings in the study. 

The first injectable glucagon-like peptide 1 receptor agonist (GLP-1 RA) was approved in 2005; between 2013 and 2016, the FDA also approved 4 sodium-glucose cotransporter 2 (SGLT2) inhibitors. Both medication classes can safely and effectively lower A1c with no weight gain and low risk for hypoglycemia. Over the past 4 years, a robust body of evidence has emerged to show that GLP-1 RAs and SGLT2 inhibitors not only lower A1c, but also reduce the likelihood of death from cardiovascular and kidney diseases. SGLT2 inhibitors are better at saving lives from hypertensive heart failure while the GLP-1 RAs are more protective from atherosclerotic cardiovascular events like myocardial infarction and stroke, as compared with placebo. Yet, these medications have not been, and continue not to be, regularly prescribed. In 1 study, the authors found that the rate of use for SGLT2 inhibitors was 3.8% in 2015 and 11.9% in 2019.

But there are several other reasons that patients do not receive these medicines.

Insurance

We conducted a retrospective cohort study of  382,574 adults between 58 and 66 years of age, insured by either a Medicare Advantage plan or commercial insurance, and compared treatment initiation of the 3 most common brand-name, second-line diabetes medications (as opposed to generic sulfonylureas), between 2016 and 2019. The rate of initiation was universally lower for Medicare Advantage members vs commercially insured individuals. 

While the rates of initiation of GLP-1 RAs, SGLT2 inhibitors, and dipeptidyl peptidase 4 (DPP-4) inhibitors increased between 2016 and 2019, rates were significantly higher among patients with commercial insurance. Specifically, GLP-1 RA initiation increased from 2.1% to 20.0% among commercial insurance beneficiaries and from 1.5% to 11.4% among Medicare Advantage beneficiaries. SGLT2 inhibitor initiation increased from 2.7% to 18.2% with commercial insurance and from 1.57% to 8.51% with Medicare Advantage. DPP-4 inhibitor initiation increased from 3.3% to 11.7% with commercial insurance and from 2.44% to 7.68% with Medicare Advantage. Within each calendar year, the odds of initiating one of these 3 medications with Medicare Advantage as compared with commercial insurance ranged from 0.28 to 0.70 for GLP-1 RAs; from 0.21 to 0.57 for SGLT2 inhibitors; and from 0.37 to 0.73 for DPP-4 inhibitors. 

We also looked at the initiation of these medications in individuals with cardiorenal comorbidities. In many cases, a drug was prescribed indiscriminately. A patient who would benefit from a GLP-1 RA because of cardiovascular, cerebrovascular, or kidney disease was less likely to be prescribed a GLP-1 RA than a medication like a DPP-4 inhibitor, which usually has the same formulary tier/class but does not have any of the cardiovascular or kidney benefits. Likewise, in those with heart failure or kidney disease, an SGLT2 inhibitor would have been the appropriate choice, but these patients were too often started on a DPP-4 inhibitor, which is not advised for those with heart failure and does provide kidney benefits. 

Last year, Tummalapalli et al, in their evaluation of 4135 US health plans, including commercial- or employer-based, Medicare, Medicaid, and other public health plans, identified multiple barriers to accessing SGLT2 inhibitor medications. While all plans included at least 1 SGLT2 inhibitor on their formularies, they restricted access in other ways. Prior authorizations were required by nearly half of Medicaid plans and nearly 40% of other public plans such as the Veterans Health Administration. Medicare and other public plans commonly imposed quantity limits on fills. Commercial plans frequently (up to 40%) required step therapy (use or failure of a generic diabetes medication) before approval. Copayments were also high in commercial plans, Medicare, and others. 

The need for prior authorizations dominates attempts to prescribe. Centene Corporation, for example, which manages plans for private and public payers, will not approve use of an SGLT2 inhibitor until the patient fails for 3 consecutive months on a prior treatment, has established cardiovascular disease or diabetic nephropathy, or has multiple cardiovascular risk factors. These comorbidities must be documented and verified, and the prior authorizations must be completed, often resulting in substantial administrative burden to clinicians. No wonder many, especially in primary care, may be wary of prescribing drugs that come with a paperwork trail and hours spent on documentation and insurance appeals, rather than on patient care.

The same can be said for prescribing a GLP-1 RA. United Healthcare’s Oxford Benefit Management requires that clinicians show a “history of suboptimal response, contraindication, or intolerance to metformin” before prescribing any of the 8 GLP-1 RAs. 

The average retail cost of 30 empagliflozin tablets, a once-daily medication, is $752. During the pandemic, 24% of the 5000 patients surveyed in an American Diabetes Association (ADA) poll used their stimulus check, relied on loans, or spent savings to pay for diabetes care. GLP-1 RA medications are even more expensive.  Depending on the patient’s pharmacy benefits, they may have to pay a substantial coinsurance out of pocket even after the annual deductible is met, creating financial barriers to starting and continuing recommended, evidence-based medications. Even if patients do get the recommended medications, they may be forced to ration other aspects of their lives, including other medications, food, and other necessities.

There are other important barriers to optimal utilization of evidence-based therapies, stemming from the fundamental social determinants of health: low income, low education level, and living in a socioeconomically deprived neighborhood.  

Social Determinants of Health

Diabetes prevalence is higher in patients experiencing socioeconomic and other structural barriers to health and health care. Fundamentally, 1 study showed that prevalence of diabetes was 1.4 times higher among people living on less than $15,000 a year, as opposed to those earning at least $50,000 a year. 

The risk of diabetes complications is also higher in individuals experiencing food or housing insecurity, those who have low income or education level, and residents in rural and socioeconomically deprived neighborhoods. Importantly, the same patient populations are also less likely to receive timely evidence-based care, contributing to and worsening health disparities. Despite their prevalence and importance, social determinants of health (SDoH) are not routinely recognized or discussed during clinical encounters, such that improving diabetes care and health outcomes is predicated on developing a system to screen for, recognize, and address the wide range of barriers faced by our patients. If a patient cannot afford a new medication or get to the clinic on a regular basis, lacks access to healthy food, or does not have time for diabetes self-management education or to focus on their health, then their well-being will suffer.

Many of these SDoH disproportionately affect racial and ethnic minority populations as the direct result of longstanding and deeply embedded systems, policies, and laws that underlie disparities in diabetes incidence, prevalence, management, and outcomes. As such, structural racism is increasingly recognized as a root cause of health disparities in diabetes and other chronic health conditions.

Proactive strategies

Since reactive care has not and cannot provide patients with the help they need and deserve, many in the diabetes care community have turned to proactive, team-based care. The Chronic Care Model, established in the 1990s, stresses decision-making support, strong team organization and delivery system design, and the wherewithal to monitor progress continually. Research has shown that the best results for patients stem from a multidisciplinary, data-driven, and proactive approach to identifying and meeting the totality of patient care needs. 

The ADA stresses the importance of comprehensive, team-based care for successful management of diabetes. This includes expanding the role of teams to implement evidence-based diabetes care, using electronic health record tools to support timely and guideline-recommended delivery of services, empowering and educating patients and caregivers, eliciting and addressing financial and psychosocial barriers to care, and identifying, developing, and engaging community resources to support better health and well-being.

Recognizing the centrality of team-based care to diabetes management, our team has developed and implemented an enhanced primary care diabetes (EPCD) model across the internal medicine and family medicine practices of Mayo Clinic, first in Rochester, Minnesota and then across multiple rural and small urban sites in southeast Minnesota. This model is centered around the primary care team nurse, who partners with clinicians to oversee, enforce, and coordinate the diabetes management of patients paneled to those clinicians. Nurses proactively identify patients, engage other members of the healthcare team (eg, pharmacists, social workers, certified diabetes care and education specialists) as needed, and maintain a continuous relationship with each patient to help them achieve and maintain their goals. This model was not only effective at improving glycemic control and other indicators of diabetes care quality, but also improved nursing and clinician satisfaction. 

It is important to recognize that comprehensive diabetes care comprises both medical and nonmedical interventions that address the totality of the patient’s care needs and the circumstances that hinder optimal health. Increasingly, robust data are emerging in support of nonmedical interventions that target SDoH, including structural racism as a root cause of racial and ethnic disparities in diabetes care and outcomes, with demonstrated evidence of improved health outcomes and narrowed health disparities.

It takes work, effort, and commitment to manage diabetes. But a team-based approach allows players on all sides to win. 

Those of us who treat patients with type 2 diabetes (T2D) daily have long recognized a disturbing irony: diabetes is a disease whose management requires consistency in approach and constancy in delivery, but it is most prevalent among those whose lives often allow little to no time for either. 

In our clinic, many patients with diabetes are struggling, in some way, to incorporate diabetes management into their daily lives. They are juggling multiple jobs and family responsibilities; they are working jobs with inconsistent access to food or refrigeration (such as farming, service industry work, and others); and many—even those with insurance—are struggling to afford their insulin and non insulin medications, insulin administration supplies, and glucose testing equipment.

Studies show how stress deleteriously affects this disease. The body does not deal well with these frequent and persistent stressors; higher cortisol levels result in higher blood glucose levels, increased systemic inflammation, and other drivers of both diabetes and its complications; all have been extensively documented. 

What has been frustrating for our clinical community is knowing that since the early 2000s, new diabetes medications and technologies have been available that can make a difference in our patients’ lives, but for various reasons, they have not been well adopted, particularly among patients most likely to benefit from them. Consequently, we have not consistently seen meaningfully reduced glycated hemoglobin (A1c) levels or reduced rates of acute or chronic diabetes complications. Therapeutic inertia exists at the patient, systemic, and physician levels. 

Many of the new glucose-lowering medications can also improve cardiovascular and kidney disease outcomes with low risk for hypoglycemia and weight gain. Diabetes technologies like insulin pumps and continuous glucose monitors (CGM) have been demonstrated in clinical trials to improve A1c and reduce hypoglycemia risk. But the reality is that clinicians are seeing an increasing number of patients with high A1c, with hypoglycemia, with severe hyperglycemia, and with long-term diabetes complications. 

If these advancements are supposed to improve health outcomes, why are patient, community, and population health not improving? Why are some patients not receiving the care they need, while others get extra services that do not improve their health and may even harm them?

These advancements also create new questions for clinicians. At what point in the disease course should existing medications be ramped up, ramped down, or changed? Which patient characteristics or comorbidities allow or do not allow these changes?  When should we use technologies or when does their burden outweigh their potential benefits? What resources and support systems do our patients need to live well with their disease and how can these be procured?

Herein lies the problem: Diabetes is a dynamic disease that needs to be handled in a dynamic way, and that has not universally—or even frequently—occurred. Management must be a team endeavor, meaning that both patient and clinician must be proactive in diabetes management. It has been our experience, demonstrated in our work and in other studies, that success relies on a robust and comprehensive primary care system whose team members—physicians, advanced practice providers, nurses, pharmacists, certified diabetes care and education specialists, social workers, nurses, pharmacists, and dietitians—are all resilient and motivated to tackle one of the most complex, multifaceted, and multidimensional chronic health conditions in our practice.

Proactivity also includes consistent monitoring, learning from successes and failures, and public reporting. For the patient, proactive involvement generally means self-care multiple times a day.    

Let us now discuss the evidence that prompted our team’s proactive approach to caring for people living with diabetes.

Gauges and perspective

The prevalence of T2D in this country stands at 11.3% within the adult population. Between 2015 and 2020, death from diabetes increased by 27%.

For years, the research community has documented the wide range of socioeconomic factors that increase the risk for developing T2D and that, once developed, make it more difficult for patients to manage their disease and achieve optimal health outcomes that are possible with available medications and technologies. 

In 2019, Kazemian et al published work that examined the indicators of diabetes management progress (eg, A1c levels, cholesterol levels) of 1742 individuals, from 2005 to 2016. Just 23% to 25% of these patients achieved all goals, even though, during the study period, numerous medications were approved to manage disease better. Arguably, these should have improved the all-goal findings in the study. 

The first injectable glucagon-like peptide 1 receptor agonist (GLP-1 RA) was approved in 2005; between 2013 and 2016, the FDA also approved 4 sodium-glucose cotransporter 2 (SGLT2) inhibitors. Both medication classes can safely and effectively lower A1c with no weight gain and low risk for hypoglycemia. Over the past 4 years, a robust body of evidence has emerged to show that GLP-1 RAs and SGLT2 inhibitors not only lower A1c, but also reduce the likelihood of death from cardiovascular and kidney diseases. SGLT2 inhibitors are better at saving lives from hypertensive heart failure while the GLP-1 RAs are more protective from atherosclerotic cardiovascular events like myocardial infarction and stroke, as compared with placebo. Yet, these medications have not been, and continue not to be, regularly prescribed. In 1 study, the authors found that the rate of use for SGLT2 inhibitors was 3.8% in 2015 and 11.9% in 2019.

But there are several other reasons that patients do not receive these medicines.

Insurance

We conducted a retrospective cohort study of  382,574 adults between 58 and 66 years of age, insured by either a Medicare Advantage plan or commercial insurance, and compared treatment initiation of the 3 most common brand-name, second-line diabetes medications (as opposed to generic sulfonylureas), between 2016 and 2019. The rate of initiation was universally lower for Medicare Advantage members vs commercially insured individuals. 

While the rates of initiation of GLP-1 RAs, SGLT2 inhibitors, and dipeptidyl peptidase 4 (DPP-4) inhibitors increased between 2016 and 2019, rates were significantly higher among patients with commercial insurance. Specifically, GLP-1 RA initiation increased from 2.1% to 20.0% among commercial insurance beneficiaries and from 1.5% to 11.4% among Medicare Advantage beneficiaries. SGLT2 inhibitor initiation increased from 2.7% to 18.2% with commercial insurance and from 1.57% to 8.51% with Medicare Advantage. DPP-4 inhibitor initiation increased from 3.3% to 11.7% with commercial insurance and from 2.44% to 7.68% with Medicare Advantage. Within each calendar year, the odds of initiating one of these 3 medications with Medicare Advantage as compared with commercial insurance ranged from 0.28 to 0.70 for GLP-1 RAs; from 0.21 to 0.57 for SGLT2 inhibitors; and from 0.37 to 0.73 for DPP-4 inhibitors. 

We also looked at the initiation of these medications in individuals with cardiorenal comorbidities. In many cases, a drug was prescribed indiscriminately. A patient who would benefit from a GLP-1 RA because of cardiovascular, cerebrovascular, or kidney disease was less likely to be prescribed a GLP-1 RA than a medication like a DPP-4 inhibitor, which usually has the same formulary tier/class but does not have any of the cardiovascular or kidney benefits. Likewise, in those with heart failure or kidney disease, an SGLT2 inhibitor would have been the appropriate choice, but these patients were too often started on a DPP-4 inhibitor, which is not advised for those with heart failure and does provide kidney benefits. 

Last year, Tummalapalli et al, in their evaluation of 4135 US health plans, including commercial- or employer-based, Medicare, Medicaid, and other public health plans, identified multiple barriers to accessing SGLT2 inhibitor medications. While all plans included at least 1 SGLT2 inhibitor on their formularies, they restricted access in other ways. Prior authorizations were required by nearly half of Medicaid plans and nearly 40% of other public plans such as the Veterans Health Administration. Medicare and other public plans commonly imposed quantity limits on fills. Commercial plans frequently (up to 40%) required step therapy (use or failure of a generic diabetes medication) before approval. Copayments were also high in commercial plans, Medicare, and others. 

The need for prior authorizations dominates attempts to prescribe. Centene Corporation, for example, which manages plans for private and public payers, will not approve use of an SGLT2 inhibitor until the patient fails for 3 consecutive months on a prior treatment, has established cardiovascular disease or diabetic nephropathy, or has multiple cardiovascular risk factors. These comorbidities must be documented and verified, and the prior authorizations must be completed, often resulting in substantial administrative burden to clinicians. No wonder many, especially in primary care, may be wary of prescribing drugs that come with a paperwork trail and hours spent on documentation and insurance appeals, rather than on patient care.

The same can be said for prescribing a GLP-1 RA. United Healthcare’s Oxford Benefit Management requires that clinicians show a “history of suboptimal response, contraindication, or intolerance to metformin” before prescribing any of the 8 GLP-1 RAs. 

The average retail cost of 30 empagliflozin tablets, a once-daily medication, is $752. During the pandemic, 24% of the 5000 patients surveyed in an American Diabetes Association (ADA) poll used their stimulus check, relied on loans, or spent savings to pay for diabetes care. GLP-1 RA medications are even more expensive.  Depending on the patient’s pharmacy benefits, they may have to pay a substantial coinsurance out of pocket even after the annual deductible is met, creating financial barriers to starting and continuing recommended, evidence-based medications. Even if patients do get the recommended medications, they may be forced to ration other aspects of their lives, including other medications, food, and other necessities.

There are other important barriers to optimal utilization of evidence-based therapies, stemming from the fundamental social determinants of health: low income, low education level, and living in a socioeconomically deprived neighborhood.  

Social Determinants of Health

Diabetes prevalence is higher in patients experiencing socioeconomic and other structural barriers to health and health care. Fundamentally, 1 study showed that prevalence of diabetes was 1.4 times higher among people living on less than $15,000 a year, as opposed to those earning at least $50,000 a year. 

The risk of diabetes complications is also higher in individuals experiencing food or housing insecurity, those who have low income or education level, and residents in rural and socioeconomically deprived neighborhoods. Importantly, the same patient populations are also less likely to receive timely evidence-based care, contributing to and worsening health disparities. Despite their prevalence and importance, social determinants of health (SDoH) are not routinely recognized or discussed during clinical encounters, such that improving diabetes care and health outcomes is predicated on developing a system to screen for, recognize, and address the wide range of barriers faced by our patients. If a patient cannot afford a new medication or get to the clinic on a regular basis, lacks access to healthy food, or does not have time for diabetes self-management education or to focus on their health, then their well-being will suffer.

Many of these SDoH disproportionately affect racial and ethnic minority populations as the direct result of longstanding and deeply embedded systems, policies, and laws that underlie disparities in diabetes incidence, prevalence, management, and outcomes. As such, structural racism is increasingly recognized as a root cause of health disparities in diabetes and other chronic health conditions.

Proactive strategies

Since reactive care has not and cannot provide patients with the help they need and deserve, many in the diabetes care community have turned to proactive, team-based care. The Chronic Care Model, established in the 1990s, stresses decision-making support, strong team organization and delivery system design, and the wherewithal to monitor progress continually. Research has shown that the best results for patients stem from a multidisciplinary, data-driven, and proactive approach to identifying and meeting the totality of patient care needs. 

The ADA stresses the importance of comprehensive, team-based care for successful management of diabetes. This includes expanding the role of teams to implement evidence-based diabetes care, using electronic health record tools to support timely and guideline-recommended delivery of services, empowering and educating patients and caregivers, eliciting and addressing financial and psychosocial barriers to care, and identifying, developing, and engaging community resources to support better health and well-being.

Recognizing the centrality of team-based care to diabetes management, our team has developed and implemented an enhanced primary care diabetes (EPCD) model across the internal medicine and family medicine practices of Mayo Clinic, first in Rochester, Minnesota and then across multiple rural and small urban sites in southeast Minnesota. This model is centered around the primary care team nurse, who partners with clinicians to oversee, enforce, and coordinate the diabetes management of patients paneled to those clinicians. Nurses proactively identify patients, engage other members of the healthcare team (eg, pharmacists, social workers, certified diabetes care and education specialists) as needed, and maintain a continuous relationship with each patient to help them achieve and maintain their goals. This model was not only effective at improving glycemic control and other indicators of diabetes care quality, but also improved nursing and clinician satisfaction. 

It is important to recognize that comprehensive diabetes care comprises both medical and nonmedical interventions that address the totality of the patient’s care needs and the circumstances that hinder optimal health. Increasingly, robust data are emerging in support of nonmedical interventions that target SDoH, including structural racism as a root cause of racial and ethnic disparities in diabetes care and outcomes, with demonstrated evidence of improved health outcomes and narrowed health disparities.

It takes work, effort, and commitment to manage diabetes. But a team-based approach allows players on all sides to win. 

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.

The Health Terminology/Ontology Portal (HeTOP), on which the curious can discover information about off-label use, lists 645 medications prescribed for migraine worldwide. Treatments ranging from blood pressure medications to antidepressants, and anticonvulsants to antiepileptics, along with their doses and administrations, are all listed. The number of migraine-indicated medications is 114.  Dominated by triptans and topiramate, the list also includes erenumab, the calcitonin gene-related peptide CGRP agonist. The difference in figures between the predominately off label and migraine-approved lists is a good indicator of the struggle that health care providers have had through the years to help their patients.

 The idea now is to make that list even longer by finding biomarkers that lead to new therapies.

But first, a conversation about the trigeminal ganglia.

The trigeminal ganglia

The trigeminal ganglia sit on either side of the head, in front of the ears. Their primary role is to receive stimuli and convey it to the brain. The humantrigeminal ganglia contain 20,000 to 35,000 neurons and express an array of neuropeptides, including CGRP. Some neuropeptides, like CGRP and pituitary adenylate cyclase–activating peptide 38 (PACAP38) are vasodilators. Others, like substance P, are vasoconstrictors. Edvinsson and Goadsby discussed in 1994 how CGRP was released simultaneously in those with “spontaneous attacks of migraine.”

Over the past 30 years, researchers in our institution  and elsewhere have shown repeatedly that migraine develops in individuals who are exposed to certain signaling molecules, namely nitroglycerin, CGRP, cyclic guanosine monophosphate (cGMP), intracellular cyclic adenosine monophosphate (cAMP), potassium, and PACAP38, among others. Such exposure reinforces the notion that peripheral sensitization of trigeminal sensory neurons brings on headache. The attack could occur due to vasodilation, mast cell degranulation, involvement of the parasympathetic system, or activation of nerve fibers.

Some examples from the literature:

• In our research, results from a small study of patients under spontaneous migraine attack, who underwent a 3-Tesla MRI scan, showed that cortical thickness diminishes in the prefrontal and pericalcarine cortices. The analysis we performed involving individuals with migraine without aura revealed that these patients experience reduced cortical thickness and volume when migraine attacks come on, suggesting that cortical thickness and volume may serve as a potential biomarker.
• A comparison of 20 individuals with chronic migraine and 20 healthy controls by way of 3-Tesla magnetic resonance imaging scans revealed that those with headache appeared to have substantially increased neural connectivity between the hypothalamus and certain brain areas – yet there appeared to be no connectivity irregularities between the hypothalamus and brainstem, which as the authors noted, is the “migraine generator.”

In other words, vasodilation might be  a secondary symptom of migraine but likely isn’t its source.

Other migraine makers

Neurochemicals and nucleotides play a role in migraine formation, too:

• Nitric oxide. Can open blood vessels in the head and brain and has been shown to set migraine in motion. It leads to peak headache intensity 5.5 hours after infusion and causes migraine without aura.

• GRP. Gastrin-releasing peptide receptors cause delayed headache, including what qualifies as an induced migraine attack. Researchers also note that similar pathways trigger migraine with and without aura. 

• Intracellular cGMP and intracellular cAMP. These 2 cyclic nucleotides are found extensively in the trigeminovascular system and have a role in the pathogenesis of migraine.  Studies demonstrate that cGMP levels increase after nitroglycerin administration and cAMP increases after CGRP and PACAP38 exposure.

• Levcromakalim. This potassium channel opener is sensitive to ATP. In a trial published in 2019, researchers showed that modulating potassium channels could cause some headache pain, even in those without migraine. They infused 20 healthy volunteers with levcromakalim; over the next 5-plus hours, the middle meningeal artery of all 20 became and remained dilated. Later research showed that this dilation is linked to substance P. 

Identifying migraine types

Diagnosing migraine is 1 step; determining its type is another.

Consider that a person with a posttraumatic headache can have migraine-like symptoms. To find objective separate characteristics, researchers at Mayo Clinic designed a headache classification model using questionnaires, which were then paired with the patient’s MRI data. The questionnaires delved into headache characteristics, sensory hypersensitivities, cognitive functioning, and mood. The system worked well with primary migraine, with 97% accuracy. But with posttraumatic headache, the system was 65% accurate. What proved to differentiate persistent posttraumatic headache were questions regarding decision making and anxiety. These patients had severe symptoms of anxiety, depression, physical issues, and mild brain injury attributed to blasts.

All of which explains why we and others are actively looking for biomarkers.

The biomarkers

A look at clinicaltrials.gov shows that 15 trials are recruiting patients (including us) in the search for biomarkers. One wants to identify a computational algorithm using AI, based on 9 types of markers in hopes of identifying those predictive elements that will respond to CGRP-targeting monoclonal antibodies (mABs). The factors range from the clinical to epigenetic to structural and functional brain imaging. Another registered study is using ocular coherence tomography, among other technologies, to identify photophobia.

Our interests are in identifying CGRP as a definitive biomarker; finding structural and functional cerebral changes, using MRI, in study subjects before and after they are given erenumab. We also want to create a registry for migraine based on the structural and functional MRI findings.

Another significant reason for finding biomarkers is to identify the alteration that accompany progression from episodic to chronic migraine. Pozo-Rosich et al write that these imaging, neurophysiological, and biochemical changes that occur with this progression could be used “for developing chronic migraine biomarkers that might assist with diagnosis, prognosticating individual patient outcomes, and predicting responses to migraine therapies.” And, ultimately, in practicing precision medicine to improve care of patients.

Significant barriers still exist in declaring a molecule is a biomarker. For example, a meta-analysis points to the replication challenge observed in neuroimaging research. Additionally, several genetic variants produce small effect sizes, which also might be impacted by environmental factors. This makes it difficult to map genetic biomarkers. Large prospective studies are needed to bring this area of research out of infancy to a place where treatment response can be clinically assessed. Additionally, while research evaluating provocation biomarkers has already contributed to the treatment landscape, large-scale registry studies may help uncover a predictive biomarker of treatment response. Blood biomarker research still needs a standardized protocol. Imaging-based biomarkers show much potential, but standardized imaging protocols and improved characterization and data integration are necessary going forward.

The patients

The discovery of the CGRPs couldn’t have been more timely.

Those of us who have been treating patients with migraine for years have seen the prevalence of this disease slowly rise. In 2018, the age-adjusted prevalence was 15.9% for all adults in the United States; in 2010, it was 13.2%. Worldwide, in 2019, it was 14%. In 2015, it was 11.6%.

In the past few years, journal articles have appeared regarding the connection between obesity, diabetes, hypertension, and migraine severity. Numerous other comorbidities affect our patients – not just the well-known psychiatric disorders – but also the respiratory, digestive, and central nervous system illnesses.

In other words, many of our patients come to us sicker than in years past.

Some cannot take one or more medications designed for acute migraine attacks due to comorbidities, including cardiovascular disease or related risk factors, and gastrointestinal bleeding.

A large survey of 15,133 people with migraine confirmed the findings on these numerous comorbidities; they reported that they have more insomnia, depression, and anxiety. As the authors point out, identifying these comorbidities can help with accurate diagnosis, treatment and its adherence, and prognosis. The authors also noted that as migraine days increase per month, so do the rates of comorbidities.

But the CGRPs are showing how beneficial they can be. One study assessing medication overuse showed how 60% of the enrolled patients no longer fit that description 6 months after receiving erenumab or galcanezumab. Some patients who contend with episodic migraine showed a complete response after receiving eptinezumab and galcanezumab. They also have helped patients with menstrual migraine and refractory migraine.

But they are not complete responses to these medications, which is an excellent reason to continue viewing, recording, and assessing the migraine brain, for all it can tell us.

The picture around the BA.4 and BA.5 subvariants of Omicron has been really confusing in that the pair is driving up cases but global COVID-19 deaths remain at their lowest level since the beginning of the pandemic. I wanted to explain what is happening with these subvariants, in that the picture seems to be one of antibody evasion without the dodging of cellular immunity. Explaining the two components of the immune response – antibodies versus cellular immune responses – can help us understand where we are in the pandemic and future booster options.

These two subvariants of Omicron, as of July 5, make up more than half of the COVID-19 strains in the United States and are expected to keep increasing. One of two reasons can lead to a variant or subvariant becoming dominant strain: increased transmissibility or evasion of antibodies.

Although BA.4 and BA.5 could be more transmissible than other subvariants of Omicron (which is already very transmissible), this has not yet been established in experiments showing increased affinity for the human receptor or in animal models. What we do know is that BA.4 and BA.5 seem to evade neutralizing antibodies conferred by the vaccines or even prior BA.1 infection (an earlier subvariant of Omicron), which could be the reason we are seeing so many reinfections now. Of note, BA.1 infection conferred antibodies that protected against subsequent BA.2 infection, so we did not see the same spike in cases in the United States with BA.2 (after a large BA.1 spike over the winter) earlier this spring.

Okay, so isn’t evasion of antibodies a bad thing? Of course it is but, luckily, our immune system is “redundant” and doesn›t just rely on antibodies to protect us from infection. In fact, antibodies (such as IgA, which is the mucosal antibody most prevalent in the nose and mouth, and IgG, which is the most prevalent antibody in the bloodstream) are our first line of COVID-19 defense in the nasal mucosa. Therefore, mild upper respiratory infections will be common as BA.4/BA.5 evade our nasal antibodies. Luckily, the rate of severe disease is remaining low throughout the world, probably because of the high amounts of cellular immunity to the virus. B and T cells are our protectors from severe disease.

For instance, two-dose vaccines are still conferring high rates of protection from severe disease with the BA.4 and BA.5 variants, with 87% protection against hospitalization per South Africa data. This is probably attributable to the fact that T-cell immunity from the vaccines remains protective across variants “from Alpha to Omicron,” as described by a recent and elegant paper.

Data from Qatar show that natural infection (even occurring up to 14 months ago) remains very protective (97.3%) against severe disease with the current circulating subvariants, including BA.4 and BA.5. Again, this is probably attributable to T cells which specifically amplify in response to a piece of the virus and help recruit cells to attack the pathogen directly.

The original BA.1 subvariant of Omicron has 26-32 mutations along its spike protein that differ from the “ancestral strain,” and BA.4 and BA.5 variants have a few more. Our T-cell response, even across a mutated spike protein, is so robust that we have not seen Omicron yet able to evade the many T cells (which we produce from the vaccines or infection) that descend upon the mutated virus to fight severe disease. Antibody-producing memory B cells, generated by the vaccines (or prior infection), have been shown to actually adapt their immune response to the variant to which they are exposed.

Therefore, the story of the BA.4 and BA.5 subvariants seems to remain about antibodies vs. cellular immunity. Our immunity in the United States is growing and is from both vaccination and natural infection, with 78.3% of the population having had at least one dose of the vaccine and at least 60% of adults (and 75% of children 0-18) having been exposed to the virus by February 2022, per the Centers for Disease Control and Prevention (with exposure probably much higher now in July 2022 after subsequent Omicron subvariants waves).

So, what about Omicron-specific boosters? A booster shot will just raise antibodies temporarily, but their effectiveness wanes several months later. Moreover, a booster shot against the ancestral strain is not very effective in neutralizing BA.4 and BA.5 (with a prior BA.1 Omicron infection being more effective than a booster). Luckily, Pfizer has promised a BA.4/BA.5-specific mRNA vaccine by October, and Moderna has promised a bivalent vaccine containing BA.4/BA.5 mRNA sequences around the same time. A vaccine that specifically increases antibodies against the most prevalent circulating strain should be important as a booster for those who are predisposed to severe breakthrough infections (for example, those with immunocompromise or older individuals with multiple comorbidities). Moreover, BA.4/BA.5–specific booster vaccines may help prevent mild infections for many individuals. Finally, any booster (or exposure) should diversify and broaden T-cell responses to the virus, and a booster shot will also expand the potency of B cells, making them better able to respond to the newest subvariants as we continue to live with COVID-19.
 

Monica Gandhi, MD, MPH, is an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco.

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

The picture around the BA.4 and BA.5 subvariants of Omicron has been really confusing in that the pair is driving up cases but global COVID-19 deaths remain at their lowest level since the beginning of the pandemic. I wanted to explain what is happening with these subvariants, in that the picture seems to be one of antibody evasion without the dodging of cellular immunity. Explaining the two components of the immune response – antibodies versus cellular immune responses – can help us understand where we are in the pandemic and future booster options.

These two subvariants of Omicron, as of July 5, make up more than half of the COVID-19 strains in the United States and are expected to keep increasing. One of two reasons can lead to a variant or subvariant becoming dominant strain: increased transmissibility or evasion of antibodies.

Although BA.4 and BA.5 could be more transmissible than other subvariants of Omicron (which is already very transmissible), this has not yet been established in experiments showing increased affinity for the human receptor or in animal models. What we do know is that BA.4 and BA.5 seem to evade neutralizing antibodies conferred by the vaccines or even prior BA.1 infection (an earlier subvariant of Omicron), which could be the reason we are seeing so many reinfections now. Of note, BA.1 infection conferred antibodies that protected against subsequent BA.2 infection, so we did not see the same spike in cases in the United States with BA.2 (after a large BA.1 spike over the winter) earlier this spring.

Okay, so isn’t evasion of antibodies a bad thing? Of course it is but, luckily, our immune system is “redundant” and doesn›t just rely on antibodies to protect us from infection. In fact, antibodies (such as IgA, which is the mucosal antibody most prevalent in the nose and mouth, and IgG, which is the most prevalent antibody in the bloodstream) are our first line of COVID-19 defense in the nasal mucosa. Therefore, mild upper respiratory infections will be common as BA.4/BA.5 evade our nasal antibodies. Luckily, the rate of severe disease is remaining low throughout the world, probably because of the high amounts of cellular immunity to the virus. B and T cells are our protectors from severe disease.

For instance, two-dose vaccines are still conferring high rates of protection from severe disease with the BA.4 and BA.5 variants, with 87% protection against hospitalization per South Africa data. This is probably attributable to the fact that T-cell immunity from the vaccines remains protective across variants “from Alpha to Omicron,” as described by a recent and elegant paper.

Data from Qatar show that natural infection (even occurring up to 14 months ago) remains very protective (97.3%) against severe disease with the current circulating subvariants, including BA.4 and BA.5. Again, this is probably attributable to T cells which specifically amplify in response to a piece of the virus and help recruit cells to attack the pathogen directly.

The original BA.1 subvariant of Omicron has 26-32 mutations along its spike protein that differ from the “ancestral strain,” and BA.4 and BA.5 variants have a few more. Our T-cell response, even across a mutated spike protein, is so robust that we have not seen Omicron yet able to evade the many T cells (which we produce from the vaccines or infection) that descend upon the mutated virus to fight severe disease. Antibody-producing memory B cells, generated by the vaccines (or prior infection), have been shown to actually adapt their immune response to the variant to which they are exposed.

Therefore, the story of the BA.4 and BA.5 subvariants seems to remain about antibodies vs. cellular immunity. Our immunity in the United States is growing and is from both vaccination and natural infection, with 78.3% of the population having had at least one dose of the vaccine and at least 60% of adults (and 75% of children 0-18) having been exposed to the virus by February 2022, per the Centers for Disease Control and Prevention (with exposure probably much higher now in July 2022 after subsequent Omicron subvariants waves).

So, what about Omicron-specific boosters? A booster shot will just raise antibodies temporarily, but their effectiveness wanes several months later. Moreover, a booster shot against the ancestral strain is not very effective in neutralizing BA.4 and BA.5 (with a prior BA.1 Omicron infection being more effective than a booster). Luckily, Pfizer has promised a BA.4/BA.5-specific mRNA vaccine by October, and Moderna has promised a bivalent vaccine containing BA.4/BA.5 mRNA sequences around the same time. A vaccine that specifically increases antibodies against the most prevalent circulating strain should be important as a booster for those who are predisposed to severe breakthrough infections (for example, those with immunocompromise or older individuals with multiple comorbidities). Moreover, BA.4/BA.5–specific booster vaccines may help prevent mild infections for many individuals. Finally, any booster (or exposure) should diversify and broaden T-cell responses to the virus, and a booster shot will also expand the potency of B cells, making them better able to respond to the newest subvariants as we continue to live with COVID-19.
 

Monica Gandhi, MD, MPH, is an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco.

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

The picture around the BA.4 and BA.5 subvariants of Omicron has been really confusing in that the pair is driving up cases but global COVID-19 deaths remain at their lowest level since the beginning of the pandemic. I wanted to explain what is happening with these subvariants, in that the picture seems to be one of antibody evasion without the dodging of cellular immunity. Explaining the two components of the immune response – antibodies versus cellular immune responses – can help us understand where we are in the pandemic and future booster options.

These two subvariants of Omicron, as of July 5, make up more than half of the COVID-19 strains in the United States and are expected to keep increasing. One of two reasons can lead to a variant or subvariant becoming dominant strain: increased transmissibility or evasion of antibodies.

Although BA.4 and BA.5 could be more transmissible than other subvariants of Omicron (which is already very transmissible), this has not yet been established in experiments showing increased affinity for the human receptor or in animal models. What we do know is that BA.4 and BA.5 seem to evade neutralizing antibodies conferred by the vaccines or even prior BA.1 infection (an earlier subvariant of Omicron), which could be the reason we are seeing so many reinfections now. Of note, BA.1 infection conferred antibodies that protected against subsequent BA.2 infection, so we did not see the same spike in cases in the United States with BA.2 (after a large BA.1 spike over the winter) earlier this spring.

Okay, so isn’t evasion of antibodies a bad thing? Of course it is but, luckily, our immune system is “redundant” and doesn›t just rely on antibodies to protect us from infection. In fact, antibodies (such as IgA, which is the mucosal antibody most prevalent in the nose and mouth, and IgG, which is the most prevalent antibody in the bloodstream) are our first line of COVID-19 defense in the nasal mucosa. Therefore, mild upper respiratory infections will be common as BA.4/BA.5 evade our nasal antibodies. Luckily, the rate of severe disease is remaining low throughout the world, probably because of the high amounts of cellular immunity to the virus. B and T cells are our protectors from severe disease.

For instance, two-dose vaccines are still conferring high rates of protection from severe disease with the BA.4 and BA.5 variants, with 87% protection against hospitalization per South Africa data. This is probably attributable to the fact that T-cell immunity from the vaccines remains protective across variants “from Alpha to Omicron,” as described by a recent and elegant paper.

Data from Qatar show that natural infection (even occurring up to 14 months ago) remains very protective (97.3%) against severe disease with the current circulating subvariants, including BA.4 and BA.5. Again, this is probably attributable to T cells which specifically amplify in response to a piece of the virus and help recruit cells to attack the pathogen directly.

The original BA.1 subvariant of Omicron has 26-32 mutations along its spike protein that differ from the “ancestral strain,” and BA.4 and BA.5 variants have a few more. Our T-cell response, even across a mutated spike protein, is so robust that we have not seen Omicron yet able to evade the many T cells (which we produce from the vaccines or infection) that descend upon the mutated virus to fight severe disease. Antibody-producing memory B cells, generated by the vaccines (or prior infection), have been shown to actually adapt their immune response to the variant to which they are exposed.

Therefore, the story of the BA.4 and BA.5 subvariants seems to remain about antibodies vs. cellular immunity. Our immunity in the United States is growing and is from both vaccination and natural infection, with 78.3% of the population having had at least one dose of the vaccine and at least 60% of adults (and 75% of children 0-18) having been exposed to the virus by February 2022, per the Centers for Disease Control and Prevention (with exposure probably much higher now in July 2022 after subsequent Omicron subvariants waves).

So, what about Omicron-specific boosters? A booster shot will just raise antibodies temporarily, but their effectiveness wanes several months later. Moreover, a booster shot against the ancestral strain is not very effective in neutralizing BA.4 and BA.5 (with a prior BA.1 Omicron infection being more effective than a booster). Luckily, Pfizer has promised a BA.4/BA.5-specific mRNA vaccine by October, and Moderna has promised a bivalent vaccine containing BA.4/BA.5 mRNA sequences around the same time. A vaccine that specifically increases antibodies against the most prevalent circulating strain should be important as a booster for those who are predisposed to severe breakthrough infections (for example, those with immunocompromise or older individuals with multiple comorbidities). Moreover, BA.4/BA.5–specific booster vaccines may help prevent mild infections for many individuals. Finally, any booster (or exposure) should diversify and broaden T-cell responses to the virus, and a booster shot will also expand the potency of B cells, making them better able to respond to the newest subvariants as we continue to live with COVID-19.
 

Monica Gandhi, MD, MPH, is an infectious diseases doctor, professor of medicine, and associate chief in the division of HIV, infectious diseases, and global medicine at the University of California, San Francisco.

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

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults. 

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults. 

The X vs Y chromosome

The impact of sex on MS is not surprising. The normal human CNS and immune system show fundamental sex-based differences in regional gray matter volumes1 and brain aerobic glycolysis, which is higher in females.² Females across virtually all species are known to have stronger innate and adaptive immune system responses, both cellular and humoral.³ Genetically, the X chromosome contains immune regulatory genes, such as TLR7 and Foxp3, while sex hormones are known to have an immune modulatory impact.⁴ Environmental MS risk factors appear to be influenced by sex as well.³ 

MS is more common in women by a 3:1 ratio. About 80% of all autoimmune/immune-mediated diseases show such a female predominance4; exceptions include male predominance in ankylosing spondylitis and equal sex ratio in inflammatory bowel disease. The MS female-to-male sex ratio has increased over time, but only for the relapsing clinical phenotype. This is not true for primary progressive MS (PPMS), which is essentially 1:1.5 The explanation for this is unknown. 

Prognosis

Sex impacts MS outcomes, with males showing a worse prognosis. This is not simply due to their increased risk for PPMS. Men are less likely to recover from relapses, they have more cognitive deficits and greater disability development, they have higher rates of transitioning from relapsing to secondary progressive MS (SPMS), and they have higher rates of brain volume loss.^5-7 In a large global database study of 15,826 MS subjects, men with relapse-onset MS showed greater annual expanded disability status scale (EDSS) increase (0.133 vs 0.112, P <.01) than women, while women showed a decreased risk of SPMS (P =.001). In contrast, patients with PPMS did not show sex-based EDSS worsening8.

In a recent observational and retrospective study of a national Argentinean MS registry of 3099 patients with MS, 34.7% (n=1074) were men.⁹ Presentation with PPMS occurred in 11% of men vs 5% of women. Exclusively infratentorial lesions were found more frequently in men with relapse-onset than in women (P=.00006). Worse EDSS scores were confirmed only in men with relapse-onset MS (P=.02), but this study confirmed no difference based on sex for PPMS.⁹

Lesion volumes

Sex-based differences in brain magnetic resonance imaging (MRI) have been reported in those with MS. In an ongoing prospective study of 106 MS subjects, men and women showed similar average lesion volumes on MRI.¹⁰ However, men showed higher whole brain lesion numbers (P=.033) and volume (P=.043). While brain volumes were higher in men in this study (P<.001), age- and sex-appropriate normative whole brain volume percentiles were smaller in men (P=.05). The greatest percentile difference involved normative hippocampal volume percentiles (mean 62 ± 32 in women vs 40 ± 31 in men, (P<.001). Men showed more spinal cord lesions (P=.018), and it was observed that their age-associated cervical spine volume loss started a decade earlier. 

A review of data in a large, real-world MRI database (N=2199), a greater proportion of men were diagnosed with progressive MS. Compared with women with progressive MS, they had lower normalized whole brain volume (P<.001) and gray matter volume (P<.001) and greater lateral ventricular volume (P<.001).¹¹ Both sex and age affected lateral ventricular gray matter volumes. Men over the age of 60 years did not show significant sex-based differences.

MS and hormones

Hormonal states seem to have a strong impact on MS onset. MS is rare before puberty (<1%). It begins to present in young adulthood, with an average age at onset of about 30 years. Progressive MS is even more age related and presents closer to mid-life, around 40 to 45 years of age. This is approaching female menopause and well into andropause. 

Pregnancy is the best studied hormonal state. MS has no negative impact on fertility or pregnancy, at least for relapsing MS.⁵ However, pregnancy has a strong impact on MS. Disease activity decreases during pregnancy, particularly in the last trimester. In the immediate postpartum period, there is an approximately 3-month risk for increased disease activity.⁵ In a recent study, postpartum relapses occurred in about 14% of untreated individuals. The protective factors are believed to involve sex hormones, which peak in the last trimester and then rapidly fall postpartum. These observations have led to estriol treatment studies in women with relapsing MS and indirectly to testosterone studies in men with MS.⁵ Regarding the safe use of disease-modifying therapies (DMTs) while pregnant, only glatiramer acetate and the interferon betas have had thousands of human exposures. 

No teratogenicity is documented; our study12 showed that branded glatiramer acetate did not expose a pregnancy to a higher risk for congenital anomalies than a pregnancy13 in the general population. No pregnancy washout14 is needed, and it can be used during pregnancy and breastfeeding. 

It is increasingly accepted not to use a pregnancy washout with the fumarates (their half-life is ≤1 hour) and with natalizumab. Due to its rebound risk, natalizumab is often continued into the first and even second trimester. Both natalizumab and fingolimod (sphingosine-1-phosphate  receptor modulators) are recognized to carry risk of rebound relapses during pregnancy, which can be severe.^15,16  

Breastfeeding (particularly exclusive, <1 bottle daily) appears to decrease postpartum risk for breakthrough activity. It is considered safe with the needle injectables (interferon betas and glatiramer acetate). Monoclonal antibodies are also considered acceptable, based on poor excretion into milk and negligible infant absorption. For example, a recent study of natalizumab showed the relative infant dose was 0.04% of maternal exposure.¹⁷ The MS oral DMTs carry unknown risk and, in general, are not used while breastfeeding.¹⁸ 

Assisted reproductive technology has been associated with an increased annualized relapse rate in the 3 months after the procedure fails (P≤.01).¹⁹ A recent review found that continuing DMTs during the assisted reproductive technology procedure lowered this risk.²⁰

MS and menstruation

Formal MS studies on the menstrual cycle are limited.²¹ Occasional subjects note menstrual-related relapses or pseudo relapses.¹⁹ Some women report worsening of symptoms prior to their cycle. This could reflect increased body temperature or hormonal fluctuations. In 1 study, cognitive and physical performance worsened in the premenstrual vs ovulation phase.²² Another small study reported that the number and volume of contrast lesions correlated with the progesterone-to-estradiol ratio in the luteal phase.¹⁹ This is clearly an understudied area. 

Hormone therapy was examined in 333 women in the Danish MS registry. There was no association with hormone therapy and 6-month confirmed or sustained disability, particularly when it was used for <5 years.²³ In a small study of women with MS, 19 of whom had relapsing MS and were on continuous oral contraception and 27 who were taking cyclic contraception, no difference was noted in time to relapse.²⁴ However, continuous users had a longer time to contrast lesion activity (P =.05) and a trend toward a longer time to T2 lesion formation (P =.09). In those observed for at least 1 year, the longer time to T2 lesion (P=.03) and contrast lesion (P =.02) development was more significant for continuous users. The authors suggested that this finding associated with continuous contraception use indicated less inflammatory MRI activity. Clearly, further studies are needed. 

MS and menopause

Menopause is another hormonal state that has been studied in MS. MS does not affect age at menopause. Anti-Mullerian hormone (AMH) is a biomarker of ovarian aging (reflecting follicular reserve) that can be measured in blood. Levels peak around age 25, tapering to undetectable levels at menopause.²⁵ Studies have been inconsistent about whether AMH levels are lower in women with MS. Most studies suggest menopause is associated with a transient worsening of MS symptoms.²⁵ A recent review concluded that hormone replacement therapy for menopausal women did not show consistent benefits.²⁶ In another study that looked at the association between menopause and MS disease progression, 20 postmenopausal women were compared with 35 premenopausal women and 30 men with MS for 24 months.²⁷ The postmenopausal group had higher age and disease duration (P<.0001), with higher initial and final EDSS scores. Similar proportions progressed. There was a significant association between final EDSS score and age, number of comorbidities, and menopause. All 3 may be cofactors in progression. 

Studies suggest menopause is associated with greater disability but with a lower relapse rate. This is expected based on the time course of falling relapses and increasing disability progression with age. In women with clinically isolated syndrome enrolled in the Barcelona prospective cohort, menopause was not associated with increased disability risk for women with MS.²⁸ A Mayo Clinic population-based cohort study evaluated 1376 subjects and 396 female control subjects. Premature or early menopause or nulliparity was associated with earlier onset of progressive MS; pregnancies appeared to have a “dose effect” on delaying progressive disease.²⁹ The authors’ interpretation of this finding was that estrogen had a possible beneficial impact on delaying MS progression. 

In summary, sex-based differences in MS continue to be a hot topic, with ongoing studies providing new data that require verification and larger-scale studies. Studying women and men with MS should ultimately give us important new insights into this major neurologic disorder of young adults.