Opinion

During the 2023 DDW Presidential Plenary Session held in May during the annual Digestive Disease Week^®, attendees heard about two major historical events that helped shape the field of gastroenterology.

University of Michigan

The first event took place in 1822 at Fort Mackinac, which today is known as Mackinac Island on northern Lake Huron in Michigan. Alexis St. Martin, a French-Canadian fur trapper, was standing outside of the general store when a shotgun blast accidentally struck him in the stomach. Ordinarily, this would have been a fatal wound, but St. Martin miraculously survived--but with a gastric fistula that permanently exposed the interior of his stomach.

William Beaumont, the post surgeon at Fort Mackinac, engaged in a series of experiments – purportedly 238 – to study human digestion. In one experiment, Dr. Beaumont would pull food in and out of the stomach to study digestion. In another, he would withdraw fluid from the stomach to observe digestion outside of the body. The experiments caused St. Martin considerable discomfort. He eventually returned to Canada, but returned later when the U.S. Army agreed to compensate him for some of his expenses. Today, the experiments would be called into question as having crossed ethical boundaries. Dr. Beaumont published the results from his experiments in a book that established the fundamental basics of our current beliefs about digestion. The experiments arguably mark the first example of gastrointestinal research in the United States.

The second historical event – the invention of the fiber-optic endoscope – also occurred in Michigan. At the University of Michigan, Basil Hirschowitz, MD, invented a flexible, fiber-optic instrument that could be used to look into the stomach, and perhaps even the duodenum. He first tried the invention on himself, and in 1957, he demonstrated it at the national meeting of the American Gastroscopic Society by reading a telephone directory through the new device.

The instrument was soon adopted for clinical use by physicians. Whether the fiber-optic machine was superior for visualizing the stomach was hotly debated, but what was very clear was that the fiber-optic tool was more comfortable for patients. By the mid-1960s, the fiber-optic invention had become the instrument of choice for gastrointestinal endoscopy. Many advances have since been made to the original instrument.

Dr. Howell is the Elizabeth Farrand Professor and a professor of internal medicine, history, and health management and policy at the University of Michigan, Ann Arbor. He has no financial disclosures.

During the 2023 DDW Presidential Plenary Session held in May during the annual Digestive Disease Week^®, attendees heard about two major historical events that helped shape the field of gastroenterology.

University of Michigan

The first event took place in 1822 at Fort Mackinac, which today is known as Mackinac Island on northern Lake Huron in Michigan. Alexis St. Martin, a French-Canadian fur trapper, was standing outside of the general store when a shotgun blast accidentally struck him in the stomach. Ordinarily, this would have been a fatal wound, but St. Martin miraculously survived--but with a gastric fistula that permanently exposed the interior of his stomach.

William Beaumont, the post surgeon at Fort Mackinac, engaged in a series of experiments – purportedly 238 – to study human digestion. In one experiment, Dr. Beaumont would pull food in and out of the stomach to study digestion. In another, he would withdraw fluid from the stomach to observe digestion outside of the body. The experiments caused St. Martin considerable discomfort. He eventually returned to Canada, but returned later when the U.S. Army agreed to compensate him for some of his expenses. Today, the experiments would be called into question as having crossed ethical boundaries. Dr. Beaumont published the results from his experiments in a book that established the fundamental basics of our current beliefs about digestion. The experiments arguably mark the first example of gastrointestinal research in the United States.

The second historical event – the invention of the fiber-optic endoscope – also occurred in Michigan. At the University of Michigan, Basil Hirschowitz, MD, invented a flexible, fiber-optic instrument that could be used to look into the stomach, and perhaps even the duodenum. He first tried the invention on himself, and in 1957, he demonstrated it at the national meeting of the American Gastroscopic Society by reading a telephone directory through the new device.

The instrument was soon adopted for clinical use by physicians. Whether the fiber-optic machine was superior for visualizing the stomach was hotly debated, but what was very clear was that the fiber-optic tool was more comfortable for patients. By the mid-1960s, the fiber-optic invention had become the instrument of choice for gastrointestinal endoscopy. Many advances have since been made to the original instrument.

Dr. Howell is the Elizabeth Farrand Professor and a professor of internal medicine, history, and health management and policy at the University of Michigan, Ann Arbor. He has no financial disclosures.

During the 2023 DDW Presidential Plenary Session held in May during the annual Digestive Disease Week^®, attendees heard about two major historical events that helped shape the field of gastroenterology.

University of Michigan

The first event took place in 1822 at Fort Mackinac, which today is known as Mackinac Island on northern Lake Huron in Michigan. Alexis St. Martin, a French-Canadian fur trapper, was standing outside of the general store when a shotgun blast accidentally struck him in the stomach. Ordinarily, this would have been a fatal wound, but St. Martin miraculously survived--but with a gastric fistula that permanently exposed the interior of his stomach.

William Beaumont, the post surgeon at Fort Mackinac, engaged in a series of experiments – purportedly 238 – to study human digestion. In one experiment, Dr. Beaumont would pull food in and out of the stomach to study digestion. In another, he would withdraw fluid from the stomach to observe digestion outside of the body. The experiments caused St. Martin considerable discomfort. He eventually returned to Canada, but returned later when the U.S. Army agreed to compensate him for some of his expenses. Today, the experiments would be called into question as having crossed ethical boundaries. Dr. Beaumont published the results from his experiments in a book that established the fundamental basics of our current beliefs about digestion. The experiments arguably mark the first example of gastrointestinal research in the United States.

The second historical event – the invention of the fiber-optic endoscope – also occurred in Michigan. At the University of Michigan, Basil Hirschowitz, MD, invented a flexible, fiber-optic instrument that could be used to look into the stomach, and perhaps even the duodenum. He first tried the invention on himself, and in 1957, he demonstrated it at the national meeting of the American Gastroscopic Society by reading a telephone directory through the new device.

The instrument was soon adopted for clinical use by physicians. Whether the fiber-optic machine was superior for visualizing the stomach was hotly debated, but what was very clear was that the fiber-optic tool was more comfortable for patients. By the mid-1960s, the fiber-optic invention had become the instrument of choice for gastrointestinal endoscopy. Many advances have since been made to the original instrument.

Dr. Howell is the Elizabeth Farrand Professor and a professor of internal medicine, history, and health management and policy at the University of Michigan, Ann Arbor. He has no financial disclosures.

Dermatomyositis is a rare autoimmune condition characterized by muscle inflammation and weakness, and skin findings. The classical presentation includes symmetric proximal muscle weakness and underlying malignancy and is very common in adult patients. The etiology is unknown, however.

Courtesy Lucas Shapiro and Dr. Natalie Y. Nasser

Some studies suggest people with certain HLA subtypes are at higher risk, and various infectious and pharmacological triggers are suspected to play a role in the pathogenesis of dermatomyositis. Infectious causes include Coxsackie B, enterovirus, and parvovirus. Drugs such as antineoplastic agents, antibiotics, and NSAIDs have been found to be triggers.

The pathogenesis of dermatomyositis involves immune-mediated damage to muscle capillaries and the endothelium of arterioles. In the typical humoral immune response, complement activation occurs. One mechanism of damage in dermatomyositis occurs when the membrane attack complex formed at the end of the complement process deposits in blood vessels, causing inflammation. B cells, autoantibodies, and interferon overexpression may also play a role in damaging the vasculature and muscle fibers. Hypoxia leads to muscular atrophy, resulting in degeneration and death of the fibers. On muscle biopsy, a perivascular and perimysial inflammatory infiltrate, perifascicular atrophy, and microangiopathy may be present. Skin histology reveals vacuolar changes in the basal layer, a lymphocytic infiltrate, and increased mucin production in the dermis.

On clinical examination, patients will have proximal muscle weakness and a skin rash that may include Gottron’s papules, heliotrope erythema, V-sign, shawl sign, holster sign, scalp erythema, midfacial erythema, and photosensitivity. Scalp erythema in dermatomyositis is highly linked to pruritus, alopecia, and telogen effluvium. Patients may experience small fiber neuropathy in dermatomyositis.

Serologies for this patient, who had previously been diagnosed and treated for dermatomyositis, were significant for a positive ANA 1:2560. Anti-Jo-1 antibody was negative. Her liver function tests, aldolase, creatinine kinase, sedimentation rate, C-reactive protein, and serum protein electrophoresis were normal. Imaging revealed mild chronic interstitial lung disease. A malignancy workup was negative.

Treatment of dermatomyositis involves lifestyle changes and pharmacologic therapy. Because of the intense photosensitivity, patients should be diligent with their sun protection. Methotrexate, azathioprine, and mycophenolate mofetil are considered first-line therapies for dermatomyositis. Therapies such as cyclophosphamide, rituximab, IVIg, and plasmapheresis may also be indicated in severe or refractory cases. Additionally, patients with pulmonary involvement should be given systemic steroids. The side effects of these drugs must be considered in the context of the patient’s demographics, comorbidities and lifestyle.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Natalie Y. Nasser, MD, of Kaiser Permanente Riverside Medical Center, Riverside, Calif. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Qudsiya Z and Waseem M. Dermatomyositis, in “StatPearls.” Treasure Island, Fla.: StatPearls Publishing, 2023 Jan.

2. Kamperman RG et al. Int J Mol Sci. 2022 Apr 13;23(8):4301.

3. Kassamali B et al. Int J WomensDermatol. 2021 Sep 24;7(5Part A):576-82.

4. Vázquez-Herrera NE et al. Skin Appendage Disord. 2018 Aug;4(3):187-99.

Dermatomyositis is a rare autoimmune condition characterized by muscle inflammation and weakness, and skin findings. The classical presentation includes symmetric proximal muscle weakness and underlying malignancy and is very common in adult patients. The etiology is unknown, however.

Courtesy Lucas Shapiro and Dr. Natalie Y. Nasser

Some studies suggest people with certain HLA subtypes are at higher risk, and various infectious and pharmacological triggers are suspected to play a role in the pathogenesis of dermatomyositis. Infectious causes include Coxsackie B, enterovirus, and parvovirus. Drugs such as antineoplastic agents, antibiotics, and NSAIDs have been found to be triggers.

The pathogenesis of dermatomyositis involves immune-mediated damage to muscle capillaries and the endothelium of arterioles. In the typical humoral immune response, complement activation occurs. One mechanism of damage in dermatomyositis occurs when the membrane attack complex formed at the end of the complement process deposits in blood vessels, causing inflammation. B cells, autoantibodies, and interferon overexpression may also play a role in damaging the vasculature and muscle fibers. Hypoxia leads to muscular atrophy, resulting in degeneration and death of the fibers. On muscle biopsy, a perivascular and perimysial inflammatory infiltrate, perifascicular atrophy, and microangiopathy may be present. Skin histology reveals vacuolar changes in the basal layer, a lymphocytic infiltrate, and increased mucin production in the dermis.

On clinical examination, patients will have proximal muscle weakness and a skin rash that may include Gottron’s papules, heliotrope erythema, V-sign, shawl sign, holster sign, scalp erythema, midfacial erythema, and photosensitivity. Scalp erythema in dermatomyositis is highly linked to pruritus, alopecia, and telogen effluvium. Patients may experience small fiber neuropathy in dermatomyositis.

Serologies for this patient, who had previously been diagnosed and treated for dermatomyositis, were significant for a positive ANA 1:2560. Anti-Jo-1 antibody was negative. Her liver function tests, aldolase, creatinine kinase, sedimentation rate, C-reactive protein, and serum protein electrophoresis were normal. Imaging revealed mild chronic interstitial lung disease. A malignancy workup was negative.

Treatment of dermatomyositis involves lifestyle changes and pharmacologic therapy. Because of the intense photosensitivity, patients should be diligent with their sun protection. Methotrexate, azathioprine, and mycophenolate mofetil are considered first-line therapies for dermatomyositis. Therapies such as cyclophosphamide, rituximab, IVIg, and plasmapheresis may also be indicated in severe or refractory cases. Additionally, patients with pulmonary involvement should be given systemic steroids. The side effects of these drugs must be considered in the context of the patient’s demographics, comorbidities and lifestyle.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Natalie Y. Nasser, MD, of Kaiser Permanente Riverside Medical Center, Riverside, Calif. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Qudsiya Z and Waseem M. Dermatomyositis, in “StatPearls.” Treasure Island, Fla.: StatPearls Publishing, 2023 Jan.

2. Kamperman RG et al. Int J Mol Sci. 2022 Apr 13;23(8):4301.

3. Kassamali B et al. Int J WomensDermatol. 2021 Sep 24;7(5Part A):576-82.

4. Vázquez-Herrera NE et al. Skin Appendage Disord. 2018 Aug;4(3):187-99.

Dermatomyositis is a rare autoimmune condition characterized by muscle inflammation and weakness, and skin findings. The classical presentation includes symmetric proximal muscle weakness and underlying malignancy and is very common in adult patients. The etiology is unknown, however.

Courtesy Lucas Shapiro and Dr. Natalie Y. Nasser

Some studies suggest people with certain HLA subtypes are at higher risk, and various infectious and pharmacological triggers are suspected to play a role in the pathogenesis of dermatomyositis. Infectious causes include Coxsackie B, enterovirus, and parvovirus. Drugs such as antineoplastic agents, antibiotics, and NSAIDs have been found to be triggers.

The pathogenesis of dermatomyositis involves immune-mediated damage to muscle capillaries and the endothelium of arterioles. In the typical humoral immune response, complement activation occurs. One mechanism of damage in dermatomyositis occurs when the membrane attack complex formed at the end of the complement process deposits in blood vessels, causing inflammation. B cells, autoantibodies, and interferon overexpression may also play a role in damaging the vasculature and muscle fibers. Hypoxia leads to muscular atrophy, resulting in degeneration and death of the fibers. On muscle biopsy, a perivascular and perimysial inflammatory infiltrate, perifascicular atrophy, and microangiopathy may be present. Skin histology reveals vacuolar changes in the basal layer, a lymphocytic infiltrate, and increased mucin production in the dermis.

On clinical examination, patients will have proximal muscle weakness and a skin rash that may include Gottron’s papules, heliotrope erythema, V-sign, shawl sign, holster sign, scalp erythema, midfacial erythema, and photosensitivity. Scalp erythema in dermatomyositis is highly linked to pruritus, alopecia, and telogen effluvium. Patients may experience small fiber neuropathy in dermatomyositis.

Serologies for this patient, who had previously been diagnosed and treated for dermatomyositis, were significant for a positive ANA 1:2560. Anti-Jo-1 antibody was negative. Her liver function tests, aldolase, creatinine kinase, sedimentation rate, C-reactive protein, and serum protein electrophoresis were normal. Imaging revealed mild chronic interstitial lung disease. A malignancy workup was negative.

Treatment of dermatomyositis involves lifestyle changes and pharmacologic therapy. Because of the intense photosensitivity, patients should be diligent with their sun protection. Methotrexate, azathioprine, and mycophenolate mofetil are considered first-line therapies for dermatomyositis. Therapies such as cyclophosphamide, rituximab, IVIg, and plasmapheresis may also be indicated in severe or refractory cases. Additionally, patients with pulmonary involvement should be given systemic steroids. The side effects of these drugs must be considered in the context of the patient’s demographics, comorbidities and lifestyle.

This case and the photos were submitted by Lucas Shapiro, BS, of Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Fla., and Natalie Y. Nasser, MD, of Kaiser Permanente Riverside Medical Center, Riverside, Calif. The column was edited by Dr. Bilu Martin.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, MD, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

References

1. Qudsiya Z and Waseem M. Dermatomyositis, in “StatPearls.” Treasure Island, Fla.: StatPearls Publishing, 2023 Jan.

2. Kamperman RG et al. Int J Mol Sci. 2022 Apr 13;23(8):4301.

3. Kassamali B et al. Int J WomensDermatol. 2021 Sep 24;7(5Part A):576-82.

4. Vázquez-Herrera NE et al. Skin Appendage Disord. 2018 Aug;4(3):187-99.

Case 1: A 48-year-old female with a 10-year history of left-sided Ulcerative Colitis (UC) has been well controlled on an injectable biologic for 5 years. Her last colonoscopy one year ago was normal without erythema or friability. She presents for an interim visit due to an increase in stool frequency from 2 to 4 bowel movements a day. She denies urgency, nocturnal bowel movements, or blood in her stool. She is concerned about a disease flare and wonders if she is on the right medication. She just saw a TV ad for a new oral UC medication and wants to switch because she prefers an oral medication to an injectable one. Physical exam was normal and in-office flexible sigmoidoscopy demonstrates no change in her colon appearance. You advise her to stay on the biologic because she is still considered well-controlled. She insists on being switched to the new oral medicine. When you probe her more, she says that the TV ad she saw shows people getting the medicine leading normal lives, which has enormous appeal to her.



Case 2: A 52-year-old healthy male is referred for colonoscopy evaluation. He reports no change in bowel habits with rare blood in his stool and thinks his uncle had colon cancer at age 48. He is anxious and not very receptive to having a procedure. He recently saw a TV advertisement promoting non-colonoscopy-based colon cancer screening. You recommend a colonoscopy based on his family history, but he insists on stool-based screening.

AGA

Massachusetts General Hospital

In bioethics terms, DTCA can be beneficial in facilitating patient autonomy and promoting justice. For example, DTCA can “even the playing field” by ensuring that patients have equitable access to information about available treatments regardless of their socioeconomic status. In doing so, it can empower patients and allow them to have more meaningful discussions with their health care providers and make more informed decisions. In addition, patients may be introduced to alternative testing modalities (i.e., stool-based CRC screening) that, while not necessarily the best screening modality given individual risk (as in Case 2), may offer benefit with greater acceptance compared to inaction (i.e., no screening). Last, the idea of direct-to-consumer “omics” profiling has empowered patients as “citizen scientists” and led to the advent of “biohacking” among the lay population. In doing so, it has challenged the previous bounds of patient autonomy in healthcare by broadening the types of personal health data available to individuals, even when the clinical utility of this data may not yet be clear.

On the flip side, it is undeniable that DTCA of medical products is driven by commercial interests. Branded drugs are primarily, if not exclusively, promoted in DTCA, but these drugs may not always align with standard of care treatment recommendations. A study published in February 2023 in JAMA found that drugs with lower added clinical benefit and higher total sales were associated with higher DTCA spending.

With patients entering medical encounters with preconceived notions of what drugs they want to be prescribed based on media exposure, the ability of health care providers to provide sound medical advice regarding treatment may be circumvented. A patient’s preferred therapy based on exposure to DTCA may sharply contrast with their provider’s recommendation based on their experience and expertise and knowledge of the patient’s unique clinical history.
 

Unreasonable expectations

An additional potential downside of DTCA is that it can instill unreasonable expectations on the part of patients that the advertised product will benefit them. While DTCA is required to be fair and balanced in reporting benefits and risks, it is difficult to meaningfully address nuanced clinical risks in a brief TV ad and patients may come away with a skewed view of the risk-benefit equation. Furthermore, social media advertising and associated formats may not provide the same level of digestible information as other forms of media and are targeted to individuals likely to identify with the product. Finally, as stated above, only branded products (vs. generics) are advertised. Branded products are generally more costly, and where less expensive and equally effective therapies exist societal costs need to be considered. This can lead to inequities in distributive justice which is the societal allocation of resources. The more the healthcare market is driven towards higher costs in one segment, the less resources are available in another. This may affect regions where healthcare resources are limited.
 

Shared decision-making

Returning to the 3 cases above, in case 1 the UC patient’s awareness of new treatment options has prompted a shared decision-making discussion. She has a renewed interest in exploring a different route of medication administration because of DTCA. In spite of the patient seemingly well-controlled on her current IBD therapy and minor fluctuations in symptoms that might otherwise be a reason to observe more closely, the patient sees this as a reason to change her treatment based on her impression from the DTCA.

Regarding case 2, disease awareness and CRC screening acceptance is itself a positive outcome. Although commercially driven, the outcome/benefit to society leads to a decrease in disease burden and is a ready alternative with established benefits compared to no screening.

Regarding the proactive “omics-curious” IBD patient in case 3, despite the patient’s disappointment with the DCTA-promoted test’s limited clinical utility at this time, the patient may be communicating a general openness to novel approaches to treating IBD and to advancing her understanding of her disease.

So where does that leave you as a clinician?

As of today, if you live in the U.S., DTCA is a reality. As you navigate day-to-day patient interactions, it is important to keep in mind that your first obligation is to your patients and their best medical interests. Having a well-informed and engaged patient is a positive effect of DTCA over the past 30 years despite the challenging discussions you sometimes are forced to have. In many cases, patients are more self-aware of and engaged in their health and are acting on it due to direct acquisition of information from DTCA platforms. As a clinician, you have an ethical obligation to educate your patients and manage expectations, even when those expectations may be formed on the basis of DTCA with inherent conflicts of interest for promoting a product. Moreover, though certain products may be trendy or promoted on a popular science basis, the underlying technology (i.e. stool-based screening or metagenomics) and/or resultant data are likely not well understood by the typical lay patient, such that it may be difficult for a patient to comprehend how the product may not be particularly informative or inappropriate with respect to their personal medical history without additional counseling. Despite the potentially awkward clinician-patient dynamic precipitated by DTCA, these moments do offer an opportunity for you to gain rapport with your patients by taking the time to fill in the gaps of their understanding of their treatment plans, alternatives, individual risk factors and/or disease while gaining a greater appreciation for what they may personally prioritize with respect to their own health. Ultimately, as we transition further toward precision medicine approaches in healthcare, shared interest in individualized health decisions, at least partially informed by DTCA, is a positive outcome.

Dr. Sloan is a chief medical officer at Abivax. He is a member of the AGA Ethics Committee for COI. David A. Drew, PhD is assistant professor of medicine, Harvard Medical School, Boston. He is director of the Massachusetts General Hospital Biobanking, Clinical & Translational Epidemiology Unit, Boston. He is a member of the AGA Ethics Committee.

Case 1: A 48-year-old female with a 10-year history of left-sided Ulcerative Colitis (UC) has been well controlled on an injectable biologic for 5 years. Her last colonoscopy one year ago was normal without erythema or friability. She presents for an interim visit due to an increase in stool frequency from 2 to 4 bowel movements a day. She denies urgency, nocturnal bowel movements, or blood in her stool. She is concerned about a disease flare and wonders if she is on the right medication. She just saw a TV ad for a new oral UC medication and wants to switch because she prefers an oral medication to an injectable one. Physical exam was normal and in-office flexible sigmoidoscopy demonstrates no change in her colon appearance. You advise her to stay on the biologic because she is still considered well-controlled. She insists on being switched to the new oral medicine. When you probe her more, she says that the TV ad she saw shows people getting the medicine leading normal lives, which has enormous appeal to her.



Case 2: A 52-year-old healthy male is referred for colonoscopy evaluation. He reports no change in bowel habits with rare blood in his stool and thinks his uncle had colon cancer at age 48. He is anxious and not very receptive to having a procedure. He recently saw a TV advertisement promoting non-colonoscopy-based colon cancer screening. You recommend a colonoscopy based on his family history, but he insists on stool-based screening.

AGA

Massachusetts General Hospital

In bioethics terms, DTCA can be beneficial in facilitating patient autonomy and promoting justice. For example, DTCA can “even the playing field” by ensuring that patients have equitable access to information about available treatments regardless of their socioeconomic status. In doing so, it can empower patients and allow them to have more meaningful discussions with their health care providers and make more informed decisions. In addition, patients may be introduced to alternative testing modalities (i.e., stool-based CRC screening) that, while not necessarily the best screening modality given individual risk (as in Case 2), may offer benefit with greater acceptance compared to inaction (i.e., no screening). Last, the idea of direct-to-consumer “omics” profiling has empowered patients as “citizen scientists” and led to the advent of “biohacking” among the lay population. In doing so, it has challenged the previous bounds of patient autonomy in healthcare by broadening the types of personal health data available to individuals, even when the clinical utility of this data may not yet be clear.

On the flip side, it is undeniable that DTCA of medical products is driven by commercial interests. Branded drugs are primarily, if not exclusively, promoted in DTCA, but these drugs may not always align with standard of care treatment recommendations. A study published in February 2023 in JAMA found that drugs with lower added clinical benefit and higher total sales were associated with higher DTCA spending.

With patients entering medical encounters with preconceived notions of what drugs they want to be prescribed based on media exposure, the ability of health care providers to provide sound medical advice regarding treatment may be circumvented. A patient’s preferred therapy based on exposure to DTCA may sharply contrast with their provider’s recommendation based on their experience and expertise and knowledge of the patient’s unique clinical history.
 

Unreasonable expectations

An additional potential downside of DTCA is that it can instill unreasonable expectations on the part of patients that the advertised product will benefit them. While DTCA is required to be fair and balanced in reporting benefits and risks, it is difficult to meaningfully address nuanced clinical risks in a brief TV ad and patients may come away with a skewed view of the risk-benefit equation. Furthermore, social media advertising and associated formats may not provide the same level of digestible information as other forms of media and are targeted to individuals likely to identify with the product. Finally, as stated above, only branded products (vs. generics) are advertised. Branded products are generally more costly, and where less expensive and equally effective therapies exist societal costs need to be considered. This can lead to inequities in distributive justice which is the societal allocation of resources. The more the healthcare market is driven towards higher costs in one segment, the less resources are available in another. This may affect regions where healthcare resources are limited.
 

Shared decision-making

Returning to the 3 cases above, in case 1 the UC patient’s awareness of new treatment options has prompted a shared decision-making discussion. She has a renewed interest in exploring a different route of medication administration because of DTCA. In spite of the patient seemingly well-controlled on her current IBD therapy and minor fluctuations in symptoms that might otherwise be a reason to observe more closely, the patient sees this as a reason to change her treatment based on her impression from the DTCA.

Regarding case 2, disease awareness and CRC screening acceptance is itself a positive outcome. Although commercially driven, the outcome/benefit to society leads to a decrease in disease burden and is a ready alternative with established benefits compared to no screening.

Regarding the proactive “omics-curious” IBD patient in case 3, despite the patient’s disappointment with the DCTA-promoted test’s limited clinical utility at this time, the patient may be communicating a general openness to novel approaches to treating IBD and to advancing her understanding of her disease.

So where does that leave you as a clinician?

As of today, if you live in the U.S., DTCA is a reality. As you navigate day-to-day patient interactions, it is important to keep in mind that your first obligation is to your patients and their best medical interests. Having a well-informed and engaged patient is a positive effect of DTCA over the past 30 years despite the challenging discussions you sometimes are forced to have. In many cases, patients are more self-aware of and engaged in their health and are acting on it due to direct acquisition of information from DTCA platforms. As a clinician, you have an ethical obligation to educate your patients and manage expectations, even when those expectations may be formed on the basis of DTCA with inherent conflicts of interest for promoting a product. Moreover, though certain products may be trendy or promoted on a popular science basis, the underlying technology (i.e. stool-based screening or metagenomics) and/or resultant data are likely not well understood by the typical lay patient, such that it may be difficult for a patient to comprehend how the product may not be particularly informative or inappropriate with respect to their personal medical history without additional counseling. Despite the potentially awkward clinician-patient dynamic precipitated by DTCA, these moments do offer an opportunity for you to gain rapport with your patients by taking the time to fill in the gaps of their understanding of their treatment plans, alternatives, individual risk factors and/or disease while gaining a greater appreciation for what they may personally prioritize with respect to their own health. Ultimately, as we transition further toward precision medicine approaches in healthcare, shared interest in individualized health decisions, at least partially informed by DTCA, is a positive outcome.

Dr. Sloan is a chief medical officer at Abivax. He is a member of the AGA Ethics Committee for COI. David A. Drew, PhD is assistant professor of medicine, Harvard Medical School, Boston. He is director of the Massachusetts General Hospital Biobanking, Clinical & Translational Epidemiology Unit, Boston. He is a member of the AGA Ethics Committee.

Case 1: A 48-year-old female with a 10-year history of left-sided Ulcerative Colitis (UC) has been well controlled on an injectable biologic for 5 years. Her last colonoscopy one year ago was normal without erythema or friability. She presents for an interim visit due to an increase in stool frequency from 2 to 4 bowel movements a day. She denies urgency, nocturnal bowel movements, or blood in her stool. She is concerned about a disease flare and wonders if she is on the right medication. She just saw a TV ad for a new oral UC medication and wants to switch because she prefers an oral medication to an injectable one. Physical exam was normal and in-office flexible sigmoidoscopy demonstrates no change in her colon appearance. You advise her to stay on the biologic because she is still considered well-controlled. She insists on being switched to the new oral medicine. When you probe her more, she says that the TV ad she saw shows people getting the medicine leading normal lives, which has enormous appeal to her.



Case 2: A 52-year-old healthy male is referred for colonoscopy evaluation. He reports no change in bowel habits with rare blood in his stool and thinks his uncle had colon cancer at age 48. He is anxious and not very receptive to having a procedure. He recently saw a TV advertisement promoting non-colonoscopy-based colon cancer screening. You recommend a colonoscopy based on his family history, but he insists on stool-based screening.

AGA

Massachusetts General Hospital

In bioethics terms, DTCA can be beneficial in facilitating patient autonomy and promoting justice. For example, DTCA can “even the playing field” by ensuring that patients have equitable access to information about available treatments regardless of their socioeconomic status. In doing so, it can empower patients and allow them to have more meaningful discussions with their health care providers and make more informed decisions. In addition, patients may be introduced to alternative testing modalities (i.e., stool-based CRC screening) that, while not necessarily the best screening modality given individual risk (as in Case 2), may offer benefit with greater acceptance compared to inaction (i.e., no screening). Last, the idea of direct-to-consumer “omics” profiling has empowered patients as “citizen scientists” and led to the advent of “biohacking” among the lay population. In doing so, it has challenged the previous bounds of patient autonomy in healthcare by broadening the types of personal health data available to individuals, even when the clinical utility of this data may not yet be clear.

On the flip side, it is undeniable that DTCA of medical products is driven by commercial interests. Branded drugs are primarily, if not exclusively, promoted in DTCA, but these drugs may not always align with standard of care treatment recommendations. A study published in February 2023 in JAMA found that drugs with lower added clinical benefit and higher total sales were associated with higher DTCA spending.

With patients entering medical encounters with preconceived notions of what drugs they want to be prescribed based on media exposure, the ability of health care providers to provide sound medical advice regarding treatment may be circumvented. A patient’s preferred therapy based on exposure to DTCA may sharply contrast with their provider’s recommendation based on their experience and expertise and knowledge of the patient’s unique clinical history.
 

Unreasonable expectations

An additional potential downside of DTCA is that it can instill unreasonable expectations on the part of patients that the advertised product will benefit them. While DTCA is required to be fair and balanced in reporting benefits and risks, it is difficult to meaningfully address nuanced clinical risks in a brief TV ad and patients may come away with a skewed view of the risk-benefit equation. Furthermore, social media advertising and associated formats may not provide the same level of digestible information as other forms of media and are targeted to individuals likely to identify with the product. Finally, as stated above, only branded products (vs. generics) are advertised. Branded products are generally more costly, and where less expensive and equally effective therapies exist societal costs need to be considered. This can lead to inequities in distributive justice which is the societal allocation of resources. The more the healthcare market is driven towards higher costs in one segment, the less resources are available in another. This may affect regions where healthcare resources are limited.
 

Shared decision-making

Returning to the 3 cases above, in case 1 the UC patient’s awareness of new treatment options has prompted a shared decision-making discussion. She has a renewed interest in exploring a different route of medication administration because of DTCA. In spite of the patient seemingly well-controlled on her current IBD therapy and minor fluctuations in symptoms that might otherwise be a reason to observe more closely, the patient sees this as a reason to change her treatment based on her impression from the DTCA.

Regarding case 2, disease awareness and CRC screening acceptance is itself a positive outcome. Although commercially driven, the outcome/benefit to society leads to a decrease in disease burden and is a ready alternative with established benefits compared to no screening.

Regarding the proactive “omics-curious” IBD patient in case 3, despite the patient’s disappointment with the DCTA-promoted test’s limited clinical utility at this time, the patient may be communicating a general openness to novel approaches to treating IBD and to advancing her understanding of her disease.

So where does that leave you as a clinician?

As of today, if you live in the U.S., DTCA is a reality. As you navigate day-to-day patient interactions, it is important to keep in mind that your first obligation is to your patients and their best medical interests. Having a well-informed and engaged patient is a positive effect of DTCA over the past 30 years despite the challenging discussions you sometimes are forced to have. In many cases, patients are more self-aware of and engaged in their health and are acting on it due to direct acquisition of information from DTCA platforms. As a clinician, you have an ethical obligation to educate your patients and manage expectations, even when those expectations may be formed on the basis of DTCA with inherent conflicts of interest for promoting a product. Moreover, though certain products may be trendy or promoted on a popular science basis, the underlying technology (i.e. stool-based screening or metagenomics) and/or resultant data are likely not well understood by the typical lay patient, such that it may be difficult for a patient to comprehend how the product may not be particularly informative or inappropriate with respect to their personal medical history without additional counseling. Despite the potentially awkward clinician-patient dynamic precipitated by DTCA, these moments do offer an opportunity for you to gain rapport with your patients by taking the time to fill in the gaps of their understanding of their treatment plans, alternatives, individual risk factors and/or disease while gaining a greater appreciation for what they may personally prioritize with respect to their own health. Ultimately, as we transition further toward precision medicine approaches in healthcare, shared interest in individualized health decisions, at least partially informed by DTCA, is a positive outcome.

Dr. Sloan is a chief medical officer at Abivax. He is a member of the AGA Ethics Committee for COI. David A. Drew, PhD is assistant professor of medicine, Harvard Medical School, Boston. He is director of the Massachusetts General Hospital Biobanking, Clinical & Translational Epidemiology Unit, Boston. He is a member of the AGA Ethics Committee.

Initially approved by the U.S. Food and Drug Administration (FDA) in 1994, metformin has been the preferred first-line glucose-lowering agent for patients with type 2 diabetes (T2D) owing to its effectiveness, low hypoglycemia risk, weight neutrality, long clinical track record of safety, and affordability. However, the advent of newer glucose-lowering agents with evidence-based cardiovascular (CV) and renal benefits calls into question whether metformin should continue to be the initial pharmacotherapy for all patients with T2D. To help determine whether metformin has been “dethroned” as first-line treatment for T2D, here is a brief review of recent evidence and current guideline recommendations.

Cardiovascular outcome trials transform standard of care

In 2008, the FDA issued guidance to industry to ensure that CV risk is more thoroughly addressed during development of T2D therapies. This guidance document required dedicated trials to establish CV safety of new glucose-lowering therapies. Findings from subsequent cardiovascular outcome trials (CVOTs) and subsequent large renal and heart failure (HF) outcome trials have since prompted frequent and substantial updates to major guidelines. On the basis of recent evidence from CVOT and renal trials, contemporary clinical practice guidelines have transitioned from a traditional glucocentric treatment approach to a holistic management approach that emphasizes organ protection through heart-kidney-metabolic risk reduction.

Per the 2008 FDA guidance, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors were evaluated in large dedicated CVOTs. Findings from several CVOTs established GLP-1 receptor agonist and SGLT2 inhibitor CV safety, and unexpectedly demonstrated reduced rates of major adverse cardiovascular events (MACE) relative to placebo. The LEADER and EMPA-REG OUTCOME trials were the first CVOTs to report cardioprotective benefits of the GLP-1 receptor agonist liraglutide and the SGLT2 inhibitor empagliflozin, respectively. The LEADER trial reported a 13% significant relative risk reduction for its primary composite MACE outcome, and the EMPA-REG OUTCOME trial similarly reported a 14% relative risk reduction for MACE. After CVOTs on other GLP-1 receptor agonists and SGLT2 inhibitors reported CV benefit, clinical practice guidelines began to recommend use of these agents in at-risk patients to mitigate CV risk.

During the period when most CVOTs were designed and conducted, a majority of trial participants were receiving metformin at baseline. Inclusion of a small subset of metformin-naive participants in these trials allowed for several post hoc and meta-analyses investigating the impact of background metformin use on the overall CV benefits reported. Depending on the trial, baseline metformin use in large GLP-1 receptor agonist CVOTs ranged from 66% to 81%. For instance, 76% of participants in the LEADER trial were receiving metformin at baseline, but a post hoc analysis found no heterogeneity for the observed CV benefit based on background metformin use. Similarly, a subgroup analysis of pooled data from the SUSTAIN-6 and PIONEER 6 trials of injectable and oral formulations of semaglutide, respectively, reported similar CV outcomes for participants, regardless of concomitant metformin use. When looking at the GLP-1 receptor agonist class overall, a meta-analysis of seven CVOTs, which included participants with established atherosclerotic cardiovascular disease (ASCVD) and those with multiple ASCVD risk factors, concluded that GLP-1 receptor agonist therapy reduced the overall incidence of MACE in participants not receiving concomitant metformin at baseline.

Similar analyses have examined the impact of background metformin use on CV outcomes with SGLT2 inhibitors. An analysis of EMPA-REG OUTCOME found that empagliflozin improved CV outcomes and reduced mortality irrespective of background metformin, sulfonylurea, or insulin use. Of note, this analysis suggested a greater risk reduction for incident or worsening nephropathy in patients not on concomitant metformin (hazard ratio, 0.47; 95% confidence interval, 0.37-0.59; P = .01), when compared with those taking metformin at baseline (HR, 0.68; 95% CI, 0.58-0.79; P = .01). In addition, a meta-analysis of six large outcome trials found consistent benefits of SGLT2 inhibition on CV, kidney, and mortality outcomes regardless of background metformin treatment. Therefore, although CVOTs on GLP-1 receptor agonists and SGLT2 inhibitors were not designed to assess the impact of background metformin use on CV outcomes, available evidence supports the CV benefits of these agents independent of metformin use.
 

Individualizing care to attain cardiorenal-metabolic goals

Three dedicated SGLT2 inhibitor renal outcome trials have been published to date: CREDENCE, DAPA-CKD, and EMPA-KIDNEY. All three studies confirmed the positive secondary renal outcomes observed in SGLT2 inhibitor CVOTs: reduced progression of kidney disease, HF-associated hospital admissions, and CV-related death. The observed renal and CV benefits from the CREDENCE trial were consistent across different levels of kidney function. Similarly, a meta-analysis of five SGLT2 inhibitor trials of patients with HF demonstrated a decreased risk for CV-related death and admission for HF, irrespective of baseline heart function. The ongoing FLOW is the first dedicated kidney-outcome trial to evaluate the effectiveness of a GLP-1 receptor agonist (semaglutide) in slowing the progression and worsening of chronic kidney disease (CKD) in patients with T2D.

As previously noted, findings from the LEADER and EMPA-REG OUTCOME trials demonstrated the beneficial effects of GLP-1 receptor agonists and SGLT2 inhibitors not only on MACE but also on secondary HF and kidney disease outcomes. These findings have supported a series of dedicated HF and kidney outcome trials further informing the standard of care for patients with these key comorbidities. Indeed, the American Diabetes Association’s 2023 Standards of Care in Diabetes updated its recommendations and algorithm for the use of glucose-lowering medications in the management of T2D. The current ADA recommendations stress cardiorenal risk reduction while concurrently achieving and maintaining glycemic and weight management goals. On the basis of evolving outcome trial data, GLP-1 receptor agonists and SGLT2 inhibitors with evidence of benefit are recommended for patients with established or at high risk for ASCVD. Further, the Standards preferentially recommend SGLT2 inhibitors for patients with HF and/or CKD. Because evidence suggests no heterogeneity of benefit based on hemoglobin A1c for MACE outcomes with GLP-1 receptor agonists and no heterogeneity of benefit for HF or CKD benefits with SGLT2 inhibitors, these agents are recommended for cardiorenal risk reduction regardless of the need to lower glucose.

The 2023 update to the American Association of Clinical Endocrinology Consensus Statement: Type 2 Diabetes Management Algorithm similarly recommends the use of GLP-1 receptor agonists and SGLT2 inhibitors to improve cardiorenal outcomes. To further emphasize the importance of prescribing agents with proven organ-protective benefits, the AACE consensus statement provides a complications-centric algorithm to guide therapeutic decisions for risk reduction in patients with key comorbidities (for instance, ASCVD, HF, CKD) and a separate glucocentric algorithm to guide selection and intensification of glucose-lowering agents in patients without key comorbidities to meet individualized glycemic targets. Within the complications-centric algorithm, AACE recommends GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment for cardiorenal risk reduction regardless of background metformin use or A1c level.

In addition to the emphasis on the use of GLP-1 receptor agonists and SGLT2 inhibitors for organ protection, guidelines now recommend SGLT2 inhibitors as the standard-of-care therapy in patients with T2D and CKD with an estimated glomerular filtration rate ≥ 20 mL/min per 1.73 m², and irrespective of ejection fraction or a diagnosis of diabetes in the setting of HF. Overall, a common thread within current guidelines is the importance of individualized therapy based on patient- and medication-specific factors.
 

Optimizing guideline-directed medical therapy

Results from the DISCOVER trial found that GLP-1 receptor agonist and SGLT2 inhibitor use was less likely in the key patient subgroups most likely to benefit from therapy, including patients with peripheral artery disease and CKD. Factors contributing to underutilization of newer cardiorenal protective glucose-lowering therapies range from cost and access barriers to clinician-level barriers (for example, lack of knowledge on CKD, lack of familiarity with CKD practice guidelines). Addressing these issues and helping patients work through financial and other access barriers is essential to optimize the utilization of these therapies and improve cardiorenal and metabolic outcomes.

So, has metformin been “dethroned” as a first-line therapy for T2D? As is often the case in medicine, the answer depends on the individual patient and clinical situation. Metformin remains an important first-line treatment in combination with lifestyle interventions to help patients with T2D without key cardiorenal comorbidities achieve individualized glycemic targets. However, based on evidence demonstrating cardiorenal protective benefits and improved glycemia and weight loss, GLP-1 agonists and SGLT2 inhibitors may be considered as first-line treatment for patients with T2D with or at high risk for ASCVD, HF, or CKD, regardless of the need for additional glucose-lowering agents and independent of background metformin. Ultimately, the choice of first-line therapy for patients with T2D should be informed by individualized treatment goals, preferences, and cost-related access. Continued efforts to increase patient access to GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment when indicated are essential to ensure optimal treatment and outcomes.

Dr. Neumiller is professor, department of pharmacotherapy, Washington State University, Spokane. He disclosed ties with Bayer, Boehringer Ingelheim, and Eli Lilly. Dr. Alicic is clinical professor, department of medicine, University of Washington; and associate director of research, Inland Northwest Washington, Providence St. Joseph Health, Spokane. She disclosed ties with Providence St. Joseph Health, Boehringer Ingelheim/Lilly, and Bayer.

A version of this article appeared on Medscape.com.

Initially approved by the U.S. Food and Drug Administration (FDA) in 1994, metformin has been the preferred first-line glucose-lowering agent for patients with type 2 diabetes (T2D) owing to its effectiveness, low hypoglycemia risk, weight neutrality, long clinical track record of safety, and affordability. However, the advent of newer glucose-lowering agents with evidence-based cardiovascular (CV) and renal benefits calls into question whether metformin should continue to be the initial pharmacotherapy for all patients with T2D. To help determine whether metformin has been “dethroned” as first-line treatment for T2D, here is a brief review of recent evidence and current guideline recommendations.

Cardiovascular outcome trials transform standard of care

In 2008, the FDA issued guidance to industry to ensure that CV risk is more thoroughly addressed during development of T2D therapies. This guidance document required dedicated trials to establish CV safety of new glucose-lowering therapies. Findings from subsequent cardiovascular outcome trials (CVOTs) and subsequent large renal and heart failure (HF) outcome trials have since prompted frequent and substantial updates to major guidelines. On the basis of recent evidence from CVOT and renal trials, contemporary clinical practice guidelines have transitioned from a traditional glucocentric treatment approach to a holistic management approach that emphasizes organ protection through heart-kidney-metabolic risk reduction.

Per the 2008 FDA guidance, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors were evaluated in large dedicated CVOTs. Findings from several CVOTs established GLP-1 receptor agonist and SGLT2 inhibitor CV safety, and unexpectedly demonstrated reduced rates of major adverse cardiovascular events (MACE) relative to placebo. The LEADER and EMPA-REG OUTCOME trials were the first CVOTs to report cardioprotective benefits of the GLP-1 receptor agonist liraglutide and the SGLT2 inhibitor empagliflozin, respectively. The LEADER trial reported a 13% significant relative risk reduction for its primary composite MACE outcome, and the EMPA-REG OUTCOME trial similarly reported a 14% relative risk reduction for MACE. After CVOTs on other GLP-1 receptor agonists and SGLT2 inhibitors reported CV benefit, clinical practice guidelines began to recommend use of these agents in at-risk patients to mitigate CV risk.

During the period when most CVOTs were designed and conducted, a majority of trial participants were receiving metformin at baseline. Inclusion of a small subset of metformin-naive participants in these trials allowed for several post hoc and meta-analyses investigating the impact of background metformin use on the overall CV benefits reported. Depending on the trial, baseline metformin use in large GLP-1 receptor agonist CVOTs ranged from 66% to 81%. For instance, 76% of participants in the LEADER trial were receiving metformin at baseline, but a post hoc analysis found no heterogeneity for the observed CV benefit based on background metformin use. Similarly, a subgroup analysis of pooled data from the SUSTAIN-6 and PIONEER 6 trials of injectable and oral formulations of semaglutide, respectively, reported similar CV outcomes for participants, regardless of concomitant metformin use. When looking at the GLP-1 receptor agonist class overall, a meta-analysis of seven CVOTs, which included participants with established atherosclerotic cardiovascular disease (ASCVD) and those with multiple ASCVD risk factors, concluded that GLP-1 receptor agonist therapy reduced the overall incidence of MACE in participants not receiving concomitant metformin at baseline.

Similar analyses have examined the impact of background metformin use on CV outcomes with SGLT2 inhibitors. An analysis of EMPA-REG OUTCOME found that empagliflozin improved CV outcomes and reduced mortality irrespective of background metformin, sulfonylurea, or insulin use. Of note, this analysis suggested a greater risk reduction for incident or worsening nephropathy in patients not on concomitant metformin (hazard ratio, 0.47; 95% confidence interval, 0.37-0.59; P = .01), when compared with those taking metformin at baseline (HR, 0.68; 95% CI, 0.58-0.79; P = .01). In addition, a meta-analysis of six large outcome trials found consistent benefits of SGLT2 inhibition on CV, kidney, and mortality outcomes regardless of background metformin treatment. Therefore, although CVOTs on GLP-1 receptor agonists and SGLT2 inhibitors were not designed to assess the impact of background metformin use on CV outcomes, available evidence supports the CV benefits of these agents independent of metformin use.
 

Individualizing care to attain cardiorenal-metabolic goals

Three dedicated SGLT2 inhibitor renal outcome trials have been published to date: CREDENCE, DAPA-CKD, and EMPA-KIDNEY. All three studies confirmed the positive secondary renal outcomes observed in SGLT2 inhibitor CVOTs: reduced progression of kidney disease, HF-associated hospital admissions, and CV-related death. The observed renal and CV benefits from the CREDENCE trial were consistent across different levels of kidney function. Similarly, a meta-analysis of five SGLT2 inhibitor trials of patients with HF demonstrated a decreased risk for CV-related death and admission for HF, irrespective of baseline heart function. The ongoing FLOW is the first dedicated kidney-outcome trial to evaluate the effectiveness of a GLP-1 receptor agonist (semaglutide) in slowing the progression and worsening of chronic kidney disease (CKD) in patients with T2D.

As previously noted, findings from the LEADER and EMPA-REG OUTCOME trials demonstrated the beneficial effects of GLP-1 receptor agonists and SGLT2 inhibitors not only on MACE but also on secondary HF and kidney disease outcomes. These findings have supported a series of dedicated HF and kidney outcome trials further informing the standard of care for patients with these key comorbidities. Indeed, the American Diabetes Association’s 2023 Standards of Care in Diabetes updated its recommendations and algorithm for the use of glucose-lowering medications in the management of T2D. The current ADA recommendations stress cardiorenal risk reduction while concurrently achieving and maintaining glycemic and weight management goals. On the basis of evolving outcome trial data, GLP-1 receptor agonists and SGLT2 inhibitors with evidence of benefit are recommended for patients with established or at high risk for ASCVD. Further, the Standards preferentially recommend SGLT2 inhibitors for patients with HF and/or CKD. Because evidence suggests no heterogeneity of benefit based on hemoglobin A1c for MACE outcomes with GLP-1 receptor agonists and no heterogeneity of benefit for HF or CKD benefits with SGLT2 inhibitors, these agents are recommended for cardiorenal risk reduction regardless of the need to lower glucose.

The 2023 update to the American Association of Clinical Endocrinology Consensus Statement: Type 2 Diabetes Management Algorithm similarly recommends the use of GLP-1 receptor agonists and SGLT2 inhibitors to improve cardiorenal outcomes. To further emphasize the importance of prescribing agents with proven organ-protective benefits, the AACE consensus statement provides a complications-centric algorithm to guide therapeutic decisions for risk reduction in patients with key comorbidities (for instance, ASCVD, HF, CKD) and a separate glucocentric algorithm to guide selection and intensification of glucose-lowering agents in patients without key comorbidities to meet individualized glycemic targets. Within the complications-centric algorithm, AACE recommends GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment for cardiorenal risk reduction regardless of background metformin use or A1c level.

In addition to the emphasis on the use of GLP-1 receptor agonists and SGLT2 inhibitors for organ protection, guidelines now recommend SGLT2 inhibitors as the standard-of-care therapy in patients with T2D and CKD with an estimated glomerular filtration rate ≥ 20 mL/min per 1.73 m², and irrespective of ejection fraction or a diagnosis of diabetes in the setting of HF. Overall, a common thread within current guidelines is the importance of individualized therapy based on patient- and medication-specific factors.
 

Optimizing guideline-directed medical therapy

Results from the DISCOVER trial found that GLP-1 receptor agonist and SGLT2 inhibitor use was less likely in the key patient subgroups most likely to benefit from therapy, including patients with peripheral artery disease and CKD. Factors contributing to underutilization of newer cardiorenal protective glucose-lowering therapies range from cost and access barriers to clinician-level barriers (for example, lack of knowledge on CKD, lack of familiarity with CKD practice guidelines). Addressing these issues and helping patients work through financial and other access barriers is essential to optimize the utilization of these therapies and improve cardiorenal and metabolic outcomes.

So, has metformin been “dethroned” as a first-line therapy for T2D? As is often the case in medicine, the answer depends on the individual patient and clinical situation. Metformin remains an important first-line treatment in combination with lifestyle interventions to help patients with T2D without key cardiorenal comorbidities achieve individualized glycemic targets. However, based on evidence demonstrating cardiorenal protective benefits and improved glycemia and weight loss, GLP-1 agonists and SGLT2 inhibitors may be considered as first-line treatment for patients with T2D with or at high risk for ASCVD, HF, or CKD, regardless of the need for additional glucose-lowering agents and independent of background metformin. Ultimately, the choice of first-line therapy for patients with T2D should be informed by individualized treatment goals, preferences, and cost-related access. Continued efforts to increase patient access to GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment when indicated are essential to ensure optimal treatment and outcomes.

Dr. Neumiller is professor, department of pharmacotherapy, Washington State University, Spokane. He disclosed ties with Bayer, Boehringer Ingelheim, and Eli Lilly. Dr. Alicic is clinical professor, department of medicine, University of Washington; and associate director of research, Inland Northwest Washington, Providence St. Joseph Health, Spokane. She disclosed ties with Providence St. Joseph Health, Boehringer Ingelheim/Lilly, and Bayer.

A version of this article appeared on Medscape.com.

Initially approved by the U.S. Food and Drug Administration (FDA) in 1994, metformin has been the preferred first-line glucose-lowering agent for patients with type 2 diabetes (T2D) owing to its effectiveness, low hypoglycemia risk, weight neutrality, long clinical track record of safety, and affordability. However, the advent of newer glucose-lowering agents with evidence-based cardiovascular (CV) and renal benefits calls into question whether metformin should continue to be the initial pharmacotherapy for all patients with T2D. To help determine whether metformin has been “dethroned” as first-line treatment for T2D, here is a brief review of recent evidence and current guideline recommendations.

Cardiovascular outcome trials transform standard of care

In 2008, the FDA issued guidance to industry to ensure that CV risk is more thoroughly addressed during development of T2D therapies. This guidance document required dedicated trials to establish CV safety of new glucose-lowering therapies. Findings from subsequent cardiovascular outcome trials (CVOTs) and subsequent large renal and heart failure (HF) outcome trials have since prompted frequent and substantial updates to major guidelines. On the basis of recent evidence from CVOT and renal trials, contemporary clinical practice guidelines have transitioned from a traditional glucocentric treatment approach to a holistic management approach that emphasizes organ protection through heart-kidney-metabolic risk reduction.

Per the 2008 FDA guidance, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagonlike peptide-1 (GLP-1) receptor agonists, and sodium-glucose cotransporter-2 (SGLT2) inhibitors were evaluated in large dedicated CVOTs. Findings from several CVOTs established GLP-1 receptor agonist and SGLT2 inhibitor CV safety, and unexpectedly demonstrated reduced rates of major adverse cardiovascular events (MACE) relative to placebo. The LEADER and EMPA-REG OUTCOME trials were the first CVOTs to report cardioprotective benefits of the GLP-1 receptor agonist liraglutide and the SGLT2 inhibitor empagliflozin, respectively. The LEADER trial reported a 13% significant relative risk reduction for its primary composite MACE outcome, and the EMPA-REG OUTCOME trial similarly reported a 14% relative risk reduction for MACE. After CVOTs on other GLP-1 receptor agonists and SGLT2 inhibitors reported CV benefit, clinical practice guidelines began to recommend use of these agents in at-risk patients to mitigate CV risk.

During the period when most CVOTs were designed and conducted, a majority of trial participants were receiving metformin at baseline. Inclusion of a small subset of metformin-naive participants in these trials allowed for several post hoc and meta-analyses investigating the impact of background metformin use on the overall CV benefits reported. Depending on the trial, baseline metformin use in large GLP-1 receptor agonist CVOTs ranged from 66% to 81%. For instance, 76% of participants in the LEADER trial were receiving metformin at baseline, but a post hoc analysis found no heterogeneity for the observed CV benefit based on background metformin use. Similarly, a subgroup analysis of pooled data from the SUSTAIN-6 and PIONEER 6 trials of injectable and oral formulations of semaglutide, respectively, reported similar CV outcomes for participants, regardless of concomitant metformin use. When looking at the GLP-1 receptor agonist class overall, a meta-analysis of seven CVOTs, which included participants with established atherosclerotic cardiovascular disease (ASCVD) and those with multiple ASCVD risk factors, concluded that GLP-1 receptor agonist therapy reduced the overall incidence of MACE in participants not receiving concomitant metformin at baseline.

Similar analyses have examined the impact of background metformin use on CV outcomes with SGLT2 inhibitors. An analysis of EMPA-REG OUTCOME found that empagliflozin improved CV outcomes and reduced mortality irrespective of background metformin, sulfonylurea, or insulin use. Of note, this analysis suggested a greater risk reduction for incident or worsening nephropathy in patients not on concomitant metformin (hazard ratio, 0.47; 95% confidence interval, 0.37-0.59; P = .01), when compared with those taking metformin at baseline (HR, 0.68; 95% CI, 0.58-0.79; P = .01). In addition, a meta-analysis of six large outcome trials found consistent benefits of SGLT2 inhibition on CV, kidney, and mortality outcomes regardless of background metformin treatment. Therefore, although CVOTs on GLP-1 receptor agonists and SGLT2 inhibitors were not designed to assess the impact of background metformin use on CV outcomes, available evidence supports the CV benefits of these agents independent of metformin use.
 

Individualizing care to attain cardiorenal-metabolic goals

Three dedicated SGLT2 inhibitor renal outcome trials have been published to date: CREDENCE, DAPA-CKD, and EMPA-KIDNEY. All three studies confirmed the positive secondary renal outcomes observed in SGLT2 inhibitor CVOTs: reduced progression of kidney disease, HF-associated hospital admissions, and CV-related death. The observed renal and CV benefits from the CREDENCE trial were consistent across different levels of kidney function. Similarly, a meta-analysis of five SGLT2 inhibitor trials of patients with HF demonstrated a decreased risk for CV-related death and admission for HF, irrespective of baseline heart function. The ongoing FLOW is the first dedicated kidney-outcome trial to evaluate the effectiveness of a GLP-1 receptor agonist (semaglutide) in slowing the progression and worsening of chronic kidney disease (CKD) in patients with T2D.

As previously noted, findings from the LEADER and EMPA-REG OUTCOME trials demonstrated the beneficial effects of GLP-1 receptor agonists and SGLT2 inhibitors not only on MACE but also on secondary HF and kidney disease outcomes. These findings have supported a series of dedicated HF and kidney outcome trials further informing the standard of care for patients with these key comorbidities. Indeed, the American Diabetes Association’s 2023 Standards of Care in Diabetes updated its recommendations and algorithm for the use of glucose-lowering medications in the management of T2D. The current ADA recommendations stress cardiorenal risk reduction while concurrently achieving and maintaining glycemic and weight management goals. On the basis of evolving outcome trial data, GLP-1 receptor agonists and SGLT2 inhibitors with evidence of benefit are recommended for patients with established or at high risk for ASCVD. Further, the Standards preferentially recommend SGLT2 inhibitors for patients with HF and/or CKD. Because evidence suggests no heterogeneity of benefit based on hemoglobin A1c for MACE outcomes with GLP-1 receptor agonists and no heterogeneity of benefit for HF or CKD benefits with SGLT2 inhibitors, these agents are recommended for cardiorenal risk reduction regardless of the need to lower glucose.

The 2023 update to the American Association of Clinical Endocrinology Consensus Statement: Type 2 Diabetes Management Algorithm similarly recommends the use of GLP-1 receptor agonists and SGLT2 inhibitors to improve cardiorenal outcomes. To further emphasize the importance of prescribing agents with proven organ-protective benefits, the AACE consensus statement provides a complications-centric algorithm to guide therapeutic decisions for risk reduction in patients with key comorbidities (for instance, ASCVD, HF, CKD) and a separate glucocentric algorithm to guide selection and intensification of glucose-lowering agents in patients without key comorbidities to meet individualized glycemic targets. Within the complications-centric algorithm, AACE recommends GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment for cardiorenal risk reduction regardless of background metformin use or A1c level.

In addition to the emphasis on the use of GLP-1 receptor agonists and SGLT2 inhibitors for organ protection, guidelines now recommend SGLT2 inhibitors as the standard-of-care therapy in patients with T2D and CKD with an estimated glomerular filtration rate ≥ 20 mL/min per 1.73 m², and irrespective of ejection fraction or a diagnosis of diabetes in the setting of HF. Overall, a common thread within current guidelines is the importance of individualized therapy based on patient- and medication-specific factors.
 

Optimizing guideline-directed medical therapy

Results from the DISCOVER trial found that GLP-1 receptor agonist and SGLT2 inhibitor use was less likely in the key patient subgroups most likely to benefit from therapy, including patients with peripheral artery disease and CKD. Factors contributing to underutilization of newer cardiorenal protective glucose-lowering therapies range from cost and access barriers to clinician-level barriers (for example, lack of knowledge on CKD, lack of familiarity with CKD practice guidelines). Addressing these issues and helping patients work through financial and other access barriers is essential to optimize the utilization of these therapies and improve cardiorenal and metabolic outcomes.

So, has metformin been “dethroned” as a first-line therapy for T2D? As is often the case in medicine, the answer depends on the individual patient and clinical situation. Metformin remains an important first-line treatment in combination with lifestyle interventions to help patients with T2D without key cardiorenal comorbidities achieve individualized glycemic targets. However, based on evidence demonstrating cardiorenal protective benefits and improved glycemia and weight loss, GLP-1 agonists and SGLT2 inhibitors may be considered as first-line treatment for patients with T2D with or at high risk for ASCVD, HF, or CKD, regardless of the need for additional glucose-lowering agents and independent of background metformin. Ultimately, the choice of first-line therapy for patients with T2D should be informed by individualized treatment goals, preferences, and cost-related access. Continued efforts to increase patient access to GLP-1 receptor agonists and SGLT2 inhibitors as first-line treatment when indicated are essential to ensure optimal treatment and outcomes.

Dr. Neumiller is professor, department of pharmacotherapy, Washington State University, Spokane. He disclosed ties with Bayer, Boehringer Ingelheim, and Eli Lilly. Dr. Alicic is clinical professor, department of medicine, University of Washington; and associate director of research, Inland Northwest Washington, Providence St. Joseph Health, Spokane. She disclosed ties with Providence St. Joseph Health, Boehringer Ingelheim/Lilly, and Bayer.

A version of this article appeared on Medscape.com.

In July, the Centers for Medicare and Medicaid Services released the 2024 Physician Fee Schedule (PFS) proposed rule on proposed policy changes for Medicare payments. The proposed rule contains 2,883 pages of proposals for physician, hospital outpatient department, and ambulatory surgery center (ASC) payments for calendar year 2024. For gastroenterologists, there was good news and bad news.

CMS proposed to decrease the RVU conversion factor from $33.8872 in 2023 to $32.7476 in 2024, which would result in a 3.36% cut to physician payment. Medicare physician payments have been cut each year for the better part of a decade, with additional cuts proposed for 2024.

According to the American Medical Assocition, Medicare physician payment has already declined 26% in the last 22 years when adjusting for inflation, and that’s before factoring in the proposed cuts for 2024. Physicians are one of the only health care providers without an automatic inflationary increase, the AMA reports.

AGA opposes additional cuts to physician payments and will continue to advocate to stop them. AGA and many other specialty societies support H.R. 2474, the Strengthening Medicare for Patients and Providers Act. This bill would provide a permanent, annual update equal to the increase in the Medicare Economic Index, which is how the government measures inflation in medical practice. We will continue to advocate for permanent positive annual inflation updates, which would allow physicians to invest in their practices and implement new strategies to provide high-value care.

But in some positive news from the 2024 Medicare PFS, the Hospital Outpatient Prospective Payment System (OPPS) and the ASC proposed rules include increased hospital outpatient departments and ASC payments, continued telemedicine reimbursement and coverage through 2024, and a second one-year delay in changes to rules governing split/shared visits. Specifically:

OPPS Conversion Factor: The proposed CY 2024 Medicare conversion factor for outpatient hospital departments is $87.488, an increase of 2.8%, for hospitals that meet applicable quality reporting requirements.

ASC Conversion Factor: The proposed CY 2024 Ambulatory Surgical Center conversion factor is $53.397, an increase of 2.8%, for ASCs that meet applicable quality reporting requirements. The AGA and our sister societies continue to urge CMS to reduce this gap in the ASC facility fees, when compared to the outpatient hospital facility rates, which are estimated to be a roughly 48% differential in CY 2024.

Telehealth: CMS proposes to continue reimbursing telehealth services at current levels through 2024. Payment for audio-only evaluation and management (E/M) codes will continue at parity with follow-up in-person visits as it has throughout the pandemic. Additionally, CMS is implementing telehealth flexibilities that were included in the Consolidated Appropriations Act 2023 by allowing telehealth visits to originate at any site in the United States. This will allow patients throughout the country to maintain access to needed telehealth services without facing the logistical and safety challenges that can surround in-person visits. CMS is proposing to pay telehealth services at the nonfacility payment rate, which is the same rate as in-person office visits, lift the frequency limits on telehealth visits for subsequent hospital and skilled nursing facility visits, and allow direct supervision to be provided virtually.

Split (or shared) visits: CMS has proposed a second one-year delay to its proposed split/shared visits policy. The original proposal required that the billing provider in split/shared visits be whoever spent more than half of the total time with the patient (making time the only way to define substantive portion). CMS plans to delay that through at least Dec. 31, 2024. In the interim, practices can continue to use one of the three key components (history, exam, or medical decision-making) or more than half of the total time spent to determine who can bill for the visit. The GI societies will continue to advocate for appropriate reimbursement to align with new team-based models of care delivery.

Notably, the split (or shared) visits policy was also delayed in 2023 because of widespread concerns and feedback that the policy would disrupt team-based care and care delivery in the hospital setting. The American Medical Association CPT editorial panel, the body responsible for creating and maintaining CPT codes, has approved revisions to E/M guidelines that may help address some of CMS’s concerns.

For more information on issues affecting gastroenterologists in the 2024 Medicare PFS and OPPS/ASC proposed rules, visit the AGA news website.

Dr. Garcia serves as an advisor to the AGA AMA Relative-value Update Committee. She is clinical associate professor of medicine at Stanford (Calif.) University, where she is director of the neurogastroenterology and motility laboratory in the division of gastroenterology and hepatology, and associate chief medical information officer in ambulatory care at Stanford Health Care.

Dr. Mehta serves as an alternate advisor to the AGA AMA Relative-value Update Committee. She is associate chief innovation officer, Penn Medicine, and associate professor of medicine and health policy, University of Pennsylvania, Philadelphia.

Neither author has relevant conflicts of interest.

In July, the Centers for Medicare and Medicaid Services released the 2024 Physician Fee Schedule (PFS) proposed rule on proposed policy changes for Medicare payments. The proposed rule contains 2,883 pages of proposals for physician, hospital outpatient department, and ambulatory surgery center (ASC) payments for calendar year 2024. For gastroenterologists, there was good news and bad news.

CMS proposed to decrease the RVU conversion factor from $33.8872 in 2023 to $32.7476 in 2024, which would result in a 3.36% cut to physician payment. Medicare physician payments have been cut each year for the better part of a decade, with additional cuts proposed for 2024.

According to the American Medical Assocition, Medicare physician payment has already declined 26% in the last 22 years when adjusting for inflation, and that’s before factoring in the proposed cuts for 2024. Physicians are one of the only health care providers without an automatic inflationary increase, the AMA reports.

AGA opposes additional cuts to physician payments and will continue to advocate to stop them. AGA and many other specialty societies support H.R. 2474, the Strengthening Medicare for Patients and Providers Act. This bill would provide a permanent, annual update equal to the increase in the Medicare Economic Index, which is how the government measures inflation in medical practice. We will continue to advocate for permanent positive annual inflation updates, which would allow physicians to invest in their practices and implement new strategies to provide high-value care.

But in some positive news from the 2024 Medicare PFS, the Hospital Outpatient Prospective Payment System (OPPS) and the ASC proposed rules include increased hospital outpatient departments and ASC payments, continued telemedicine reimbursement and coverage through 2024, and a second one-year delay in changes to rules governing split/shared visits. Specifically:

OPPS Conversion Factor: The proposed CY 2024 Medicare conversion factor for outpatient hospital departments is $87.488, an increase of 2.8%, for hospitals that meet applicable quality reporting requirements.

ASC Conversion Factor: The proposed CY 2024 Ambulatory Surgical Center conversion factor is $53.397, an increase of 2.8%, for ASCs that meet applicable quality reporting requirements. The AGA and our sister societies continue to urge CMS to reduce this gap in the ASC facility fees, when compared to the outpatient hospital facility rates, which are estimated to be a roughly 48% differential in CY 2024.

Telehealth: CMS proposes to continue reimbursing telehealth services at current levels through 2024. Payment for audio-only evaluation and management (E/M) codes will continue at parity with follow-up in-person visits as it has throughout the pandemic. Additionally, CMS is implementing telehealth flexibilities that were included in the Consolidated Appropriations Act 2023 by allowing telehealth visits to originate at any site in the United States. This will allow patients throughout the country to maintain access to needed telehealth services without facing the logistical and safety challenges that can surround in-person visits. CMS is proposing to pay telehealth services at the nonfacility payment rate, which is the same rate as in-person office visits, lift the frequency limits on telehealth visits for subsequent hospital and skilled nursing facility visits, and allow direct supervision to be provided virtually.

Split (or shared) visits: CMS has proposed a second one-year delay to its proposed split/shared visits policy. The original proposal required that the billing provider in split/shared visits be whoever spent more than half of the total time with the patient (making time the only way to define substantive portion). CMS plans to delay that through at least Dec. 31, 2024. In the interim, practices can continue to use one of the three key components (history, exam, or medical decision-making) or more than half of the total time spent to determine who can bill for the visit. The GI societies will continue to advocate for appropriate reimbursement to align with new team-based models of care delivery.

Notably, the split (or shared) visits policy was also delayed in 2023 because of widespread concerns and feedback that the policy would disrupt team-based care and care delivery in the hospital setting. The American Medical Association CPT editorial panel, the body responsible for creating and maintaining CPT codes, has approved revisions to E/M guidelines that may help address some of CMS’s concerns.

For more information on issues affecting gastroenterologists in the 2024 Medicare PFS and OPPS/ASC proposed rules, visit the AGA news website.

Dr. Garcia serves as an advisor to the AGA AMA Relative-value Update Committee. She is clinical associate professor of medicine at Stanford (Calif.) University, where she is director of the neurogastroenterology and motility laboratory in the division of gastroenterology and hepatology, and associate chief medical information officer in ambulatory care at Stanford Health Care.

Dr. Mehta serves as an alternate advisor to the AGA AMA Relative-value Update Committee. She is associate chief innovation officer, Penn Medicine, and associate professor of medicine and health policy, University of Pennsylvania, Philadelphia.

Neither author has relevant conflicts of interest.

In July, the Centers for Medicare and Medicaid Services released the 2024 Physician Fee Schedule (PFS) proposed rule on proposed policy changes for Medicare payments. The proposed rule contains 2,883 pages of proposals for physician, hospital outpatient department, and ambulatory surgery center (ASC) payments for calendar year 2024. For gastroenterologists, there was good news and bad news.

CMS proposed to decrease the RVU conversion factor from $33.8872 in 2023 to $32.7476 in 2024, which would result in a 3.36% cut to physician payment. Medicare physician payments have been cut each year for the better part of a decade, with additional cuts proposed for 2024.

According to the American Medical Assocition, Medicare physician payment has already declined 26% in the last 22 years when adjusting for inflation, and that’s before factoring in the proposed cuts for 2024. Physicians are one of the only health care providers without an automatic inflationary increase, the AMA reports.

AGA opposes additional cuts to physician payments and will continue to advocate to stop them. AGA and many other specialty societies support H.R. 2474, the Strengthening Medicare for Patients and Providers Act. This bill would provide a permanent, annual update equal to the increase in the Medicare Economic Index, which is how the government measures inflation in medical practice. We will continue to advocate for permanent positive annual inflation updates, which would allow physicians to invest in their practices and implement new strategies to provide high-value care.

But in some positive news from the 2024 Medicare PFS, the Hospital Outpatient Prospective Payment System (OPPS) and the ASC proposed rules include increased hospital outpatient departments and ASC payments, continued telemedicine reimbursement and coverage through 2024, and a second one-year delay in changes to rules governing split/shared visits. Specifically:

OPPS Conversion Factor: The proposed CY 2024 Medicare conversion factor for outpatient hospital departments is $87.488, an increase of 2.8%, for hospitals that meet applicable quality reporting requirements.

ASC Conversion Factor: The proposed CY 2024 Ambulatory Surgical Center conversion factor is $53.397, an increase of 2.8%, for ASCs that meet applicable quality reporting requirements. The AGA and our sister societies continue to urge CMS to reduce this gap in the ASC facility fees, when compared to the outpatient hospital facility rates, which are estimated to be a roughly 48% differential in CY 2024.

Telehealth: CMS proposes to continue reimbursing telehealth services at current levels through 2024. Payment for audio-only evaluation and management (E/M) codes will continue at parity with follow-up in-person visits as it has throughout the pandemic. Additionally, CMS is implementing telehealth flexibilities that were included in the Consolidated Appropriations Act 2023 by allowing telehealth visits to originate at any site in the United States. This will allow patients throughout the country to maintain access to needed telehealth services without facing the logistical and safety challenges that can surround in-person visits. CMS is proposing to pay telehealth services at the nonfacility payment rate, which is the same rate as in-person office visits, lift the frequency limits on telehealth visits for subsequent hospital and skilled nursing facility visits, and allow direct supervision to be provided virtually.

Split (or shared) visits: CMS has proposed a second one-year delay to its proposed split/shared visits policy. The original proposal required that the billing provider in split/shared visits be whoever spent more than half of the total time with the patient (making time the only way to define substantive portion). CMS plans to delay that through at least Dec. 31, 2024. In the interim, practices can continue to use one of the three key components (history, exam, or medical decision-making) or more than half of the total time spent to determine who can bill for the visit. The GI societies will continue to advocate for appropriate reimbursement to align with new team-based models of care delivery.

Notably, the split (or shared) visits policy was also delayed in 2023 because of widespread concerns and feedback that the policy would disrupt team-based care and care delivery in the hospital setting. The American Medical Association CPT editorial panel, the body responsible for creating and maintaining CPT codes, has approved revisions to E/M guidelines that may help address some of CMS’s concerns.

For more information on issues affecting gastroenterologists in the 2024 Medicare PFS and OPPS/ASC proposed rules, visit the AGA news website.

Dr. Garcia serves as an advisor to the AGA AMA Relative-value Update Committee. She is clinical associate professor of medicine at Stanford (Calif.) University, where she is director of the neurogastroenterology and motility laboratory in the division of gastroenterology and hepatology, and associate chief medical information officer in ambulatory care at Stanford Health Care.

Dr. Mehta serves as an alternate advisor to the AGA AMA Relative-value Update Committee. She is associate chief innovation officer, Penn Medicine, and associate professor of medicine and health policy, University of Pennsylvania, Philadelphia.

Neither author has relevant conflicts of interest.

Physicians tend to be compulsive multitaskers. We switch from one task to another all the time – even in front of patients. We think we are more efficient and productive, and that we are accomplishing more in less time. In fact, there is no credible evidence that this is true, and a mountain of evidence showing exactly the opposite.

According to this study and others, multitasking results in an average of 2 hours per day of lost productivity. It decreases the quality of work performed and increases cortisol levels, which impedes cognitive functioning, leading to a further decrease in productivity in a vicious cycle, making you increasingly ineffective and destroying your motivation and mood.

On the surface, the reasons for this are not intuitively obvious. After all, simple and routine tasks are easy to perform simultaneously; we can all walk and chew gum at the same time or eat a snack while watching TV. The problems arise when we try to multitask more complex tasks that require thought and decision-making.

It turns out that the pressures of our modern world have evolved faster than our brains. We are still hard-wired for monotasking. When we think we are completing two tasks simultaneously, we are actually performing individual actions in rapid succession. Each time you switch tasks, your brain must turn off the cognitive rules of the previous task and turn on new rules for the next one. When you switch back, the process repeats in reverse. Each of those mental gear shifts takes time and costs us productivity. According to one psychologist, even brief mental blocks created by shifting between tasks can cost as much as 40% of someone’s productive time. We are also far more likely to make mistakes while we are doing it.

Furthermore, you are stifling your creativity and innovation because you don’t focus on one task long enough to come up with original insights. Multitasking also slows down your general cognitive functions, in the same way that keeping many windows are open on your computer slows down the entire system. A study from my alma mater, the University of California, San Francisco, concluded that multitasking negativity affects memory in both younger and older adults (although the effects were greater in older adults) .

So, what to do? The fact remains that, all too often, there really are too many tasks and not enough hours in the day. How can you get through them without falling into the multitasking trap?

The first rule is to prioritize. In his book “The Seven Habits of Highly Effective People,” Stephen Covey makes an important distinction between tasks that are important and those that are merely urgent. Tasks that are important and urgent tend to make time for themselves, because they must be taken care of immediately.

Jobs that are important but not urgent are the ones we tend to try to multitask. Because there is no immediate deadline, we think we can do two or more of them simultaneously, or we fall into the other major productivity trap: procrastination. Neither of those strategies tends to end well. Identify those important but not urgent tasks and force yourself to go through them one by one.

Urgent but unimportant tasks are the productivity thieves. They demand your attention but are not worthy of it. Most tasks in this category can be delegated. I have written about physicians’ workaholic and perfectionist tendencies that drive our conviction that no one else can do anything as well as we can. Does that unimportant task, even if urgent, really demand your time, skills, education, and medical license? Is there someone in your office, or possibly an outside contractor, who could do it just as well, and maybe faster?

In fact, that is the question you should ask every time a project triggers your urge to multitask: “Who could be doing this job – or at least a major part of it – instead of me?”

If your multitasking urges are deeply ingrained – particularly those that involve phones, laptops, and the cloud – you might consider employing electronic aids. SelfControl, for example, is a free, open-sourced app that lets you block your own access to distracting websites, your email servers, social media, or anything else on the Internet. You list the sites you wish to block and set a period of time to block them. Until the set time expires, you will be unable to access those sites, even if you restart your computer or delete the application.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Physicians tend to be compulsive multitaskers. We switch from one task to another all the time – even in front of patients. We think we are more efficient and productive, and that we are accomplishing more in less time. In fact, there is no credible evidence that this is true, and a mountain of evidence showing exactly the opposite.

According to this study and others, multitasking results in an average of 2 hours per day of lost productivity. It decreases the quality of work performed and increases cortisol levels, which impedes cognitive functioning, leading to a further decrease in productivity in a vicious cycle, making you increasingly ineffective and destroying your motivation and mood.

On the surface, the reasons for this are not intuitively obvious. After all, simple and routine tasks are easy to perform simultaneously; we can all walk and chew gum at the same time or eat a snack while watching TV. The problems arise when we try to multitask more complex tasks that require thought and decision-making.

It turns out that the pressures of our modern world have evolved faster than our brains. We are still hard-wired for monotasking. When we think we are completing two tasks simultaneously, we are actually performing individual actions in rapid succession. Each time you switch tasks, your brain must turn off the cognitive rules of the previous task and turn on new rules for the next one. When you switch back, the process repeats in reverse. Each of those mental gear shifts takes time and costs us productivity. According to one psychologist, even brief mental blocks created by shifting between tasks can cost as much as 40% of someone’s productive time. We are also far more likely to make mistakes while we are doing it.

Furthermore, you are stifling your creativity and innovation because you don’t focus on one task long enough to come up with original insights. Multitasking also slows down your general cognitive functions, in the same way that keeping many windows are open on your computer slows down the entire system. A study from my alma mater, the University of California, San Francisco, concluded that multitasking negativity affects memory in both younger and older adults (although the effects were greater in older adults) .

So, what to do? The fact remains that, all too often, there really are too many tasks and not enough hours in the day. How can you get through them without falling into the multitasking trap?

The first rule is to prioritize. In his book “The Seven Habits of Highly Effective People,” Stephen Covey makes an important distinction between tasks that are important and those that are merely urgent. Tasks that are important and urgent tend to make time for themselves, because they must be taken care of immediately.

Jobs that are important but not urgent are the ones we tend to try to multitask. Because there is no immediate deadline, we think we can do two or more of them simultaneously, or we fall into the other major productivity trap: procrastination. Neither of those strategies tends to end well. Identify those important but not urgent tasks and force yourself to go through them one by one.

Urgent but unimportant tasks are the productivity thieves. They demand your attention but are not worthy of it. Most tasks in this category can be delegated. I have written about physicians’ workaholic and perfectionist tendencies that drive our conviction that no one else can do anything as well as we can. Does that unimportant task, even if urgent, really demand your time, skills, education, and medical license? Is there someone in your office, or possibly an outside contractor, who could do it just as well, and maybe faster?

In fact, that is the question you should ask every time a project triggers your urge to multitask: “Who could be doing this job – or at least a major part of it – instead of me?”

If your multitasking urges are deeply ingrained – particularly those that involve phones, laptops, and the cloud – you might consider employing electronic aids. SelfControl, for example, is a free, open-sourced app that lets you block your own access to distracting websites, your email servers, social media, or anything else on the Internet. You list the sites you wish to block and set a period of time to block them. Until the set time expires, you will be unable to access those sites, even if you restart your computer or delete the application.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Physicians tend to be compulsive multitaskers. We switch from one task to another all the time – even in front of patients. We think we are more efficient and productive, and that we are accomplishing more in less time. In fact, there is no credible evidence that this is true, and a mountain of evidence showing exactly the opposite.

According to this study and others, multitasking results in an average of 2 hours per day of lost productivity. It decreases the quality of work performed and increases cortisol levels, which impedes cognitive functioning, leading to a further decrease in productivity in a vicious cycle, making you increasingly ineffective and destroying your motivation and mood.

On the surface, the reasons for this are not intuitively obvious. After all, simple and routine tasks are easy to perform simultaneously; we can all walk and chew gum at the same time or eat a snack while watching TV. The problems arise when we try to multitask more complex tasks that require thought and decision-making.

It turns out that the pressures of our modern world have evolved faster than our brains. We are still hard-wired for monotasking. When we think we are completing two tasks simultaneously, we are actually performing individual actions in rapid succession. Each time you switch tasks, your brain must turn off the cognitive rules of the previous task and turn on new rules for the next one. When you switch back, the process repeats in reverse. Each of those mental gear shifts takes time and costs us productivity. According to one psychologist, even brief mental blocks created by shifting between tasks can cost as much as 40% of someone’s productive time. We are also far more likely to make mistakes while we are doing it.

Furthermore, you are stifling your creativity and innovation because you don’t focus on one task long enough to come up with original insights. Multitasking also slows down your general cognitive functions, in the same way that keeping many windows are open on your computer slows down the entire system. A study from my alma mater, the University of California, San Francisco, concluded that multitasking negativity affects memory in both younger and older adults (although the effects were greater in older adults) .

So, what to do? The fact remains that, all too often, there really are too many tasks and not enough hours in the day. How can you get through them without falling into the multitasking trap?

The first rule is to prioritize. In his book “The Seven Habits of Highly Effective People,” Stephen Covey makes an important distinction between tasks that are important and those that are merely urgent. Tasks that are important and urgent tend to make time for themselves, because they must be taken care of immediately.

Jobs that are important but not urgent are the ones we tend to try to multitask. Because there is no immediate deadline, we think we can do two or more of them simultaneously, or we fall into the other major productivity trap: procrastination. Neither of those strategies tends to end well. Identify those important but not urgent tasks and force yourself to go through them one by one.

Urgent but unimportant tasks are the productivity thieves. They demand your attention but are not worthy of it. Most tasks in this category can be delegated. I have written about physicians’ workaholic and perfectionist tendencies that drive our conviction that no one else can do anything as well as we can. Does that unimportant task, even if urgent, really demand your time, skills, education, and medical license? Is there someone in your office, or possibly an outside contractor, who could do it just as well, and maybe faster?

In fact, that is the question you should ask every time a project triggers your urge to multitask: “Who could be doing this job – or at least a major part of it – instead of me?”

If your multitasking urges are deeply ingrained – particularly those that involve phones, laptops, and the cloud – you might consider employing electronic aids. SelfControl, for example, is a free, open-sourced app that lets you block your own access to distracting websites, your email servers, social media, or anything else on the Internet. You list the sites you wish to block and set a period of time to block them. Until the set time expires, you will be unable to access those sites, even if you restart your computer or delete the application.

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

Postpartum depression (PPD) remains the most common complication in modern obstetrics, and a leading cause of postpartum mortality in the first year of life. The last 15 years have brought considerable progress with respect to adoption of systematic screening for PPD across America. Screening for PPD, most often using the Edinburgh Postnatal Depression Scale (EPDS), has become part of routine obstetrical care, and is also widely used in pediatric settings.

That is the good news. But the flip side of the identification of those women whose scores on the EPDS suggest significant depressive symptoms is that the number of these patients who, following identification, receive referrals for adequate treatment that gets them well is unfortunately low. This “perinatal treatment cascade” refers to the majority of women who, on the other side of identification of PPD, fail to receive adequate treatment and continue to have persistent depression (Cox E. et al. J Clin Psychiatry. 2016 Sep;77[9]:1189-1200). This is perhaps the greatest challenge to the field and to clinicians – how do we, on the other side of screening, see that these women get access to care and get well with the available treatments at hand?

Recently, a widely read and circulated article was published in The Wall Street Journal about the challenges associated with navigating care resources for women suffering from PPD. In that article, it was made clear, based on clinical vignette after clinical vignette from postpartum women across America, that neither obstetricians, mental health professionals, nor pediatricians are the “clinical home” for women suffering from postpartum mood and anxiety disorders. The article painfully highlights the system-wide failure to coordinate mental health care for women suffering from postpartum psychiatric illness.

Within a day of the publication of The Wall Street Journal article, the Food and Drug Administration approved zuranolone (Zurzuvae; Sage Therapeutics; Cambridge, Mass.) for the treatment of PPD following the review of two studies demonstrating the superiority of the new medicine over placebo. Women who were enrolled met criteria for major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders criteria beginning in no earlier than the third trimester of pregnancy or later than 4 weeks of delivery. The two studies included a combined sample size of approximately 350 patients suffering from severe PPD. In the studies, women received either 50 mg or 40 mg of zuranolone, or placebo for 14 days. Treatment was associated with a significant change in the Hamilton Depression Rating Scale at day 15, and treatment response was maintained at day 42, which was 4 weeks after the last dose of study medication.

Zuranolone is a neuroactive steroid, which is taken orally, unlike brexanolone (Zulresso; Sage Therapeutics; Cambridge, Mass.), which requires intravenous administration. Zuranolone will be commercially available based on estimates around the fourth quarter of 2023. The most common side effects are drowsiness, dizziness, and sedation, and the FDA label will have a boxed warning about zuranolone’s potential to impact a person’s driving ability, and performance of potentially hazardous activities.

It is noteworthy that while this new medication received FDA approval for the PPD indication, it did not receive FDA approval for the treatment of major depressive disorder (MDD), and the agency issued a Complete Response Letter to the manufacturers noting their application did not provide substantial evidence of effectiveness in MDD. The FDA said in the Complete Response Letter that an additional study or studies will be needed; the manufacturers are currently evaluating next steps.
 

Where zuranolone fits into the treatment algorithm for severe PPD

Many clinicians who support women with PPD will wonder, upon hearing this news, where zuranolone fits into the treatment algorithm for severe postpartum major depression. Some relevant issues that may determine the answer are the following:

Cost. The cost of brexanolone was substantial, at $34,000 per year, and was viewed by some as a limiting factor in terms of its very limited uptake. As of this column’s publication, zuranolone’s manufacturer has not stated how much the medication will cost.

Breastfeeding. Unlike selective serotonin reuptake inhibitors, which have been demonstrated to be effective for the treatment of PPD and safe during pregnancy and lactation, we have sparse data on the safety of zuranolone for women who wish to breastfeed. It is also unclear whether women eligible for zuranolone would, based on the limited data on safety in lactation, choose deferral of breastfeeding for 14 days in exchange for treatment.

Duration of treatment. While zuranolone was studied in the context of 14 days of acute treatment, then out to day 42, we have no published data on what happens on the other side of this brief interval. As a simple example, in a patient with a history of recurrent major depression previously treated with antidepressants, but where antidepressants were perhaps deferred during pregnancy, is PPD to be treated with zuranolone for 14 days? Or, hypothetically, should it be followed by empiric antidepressant treatment at day 14? Alternatively, are patient and clinician supposed to wait until recurrence occurs before pursuing adjunctive antidepressant therapy whether it is pharmacologic, nonpharmacologic, or both?

Treatment in patients with bipolar disorder. It is also unclear whether treatment with zuranolone applies to other populations of postpartum women. Certainly, for women with bipolar depression, which is common in postpartum women given the vulnerability of bipolar women to new onset of depression or postpartum depressive relapse of underlying disorder, we simply have no data regarding where zuranolone might fit in with respect to this group of patients.

The answers to these questions may help to determine whether zuranolone, a new antidepressant with efficacy, quick time to onset, and a novel mechanism of action is a “game changer.” The article in The Wall Street Journal provided me with some optimism, as it gave PPD and the issues surrounding PPD the attention it deserves in a major periodical. As a new treatment, it may help alleviate suffering at a critical time for patients and their families. We are inching closer to mitigation of stigma associated with this common illness.

Thinking back across the last 3 decades of my treating women suffering from PPD, I have reflected on what has gotten these patients well. I concluded that successful treatment of PPD is not a “one-stop shop,” but rather typically includes a combination of pharmacologic and nonpharmacologic interventions, along with family and community-based support groups, as well as a culture that reduces stigma and by so doing lessens the toll of this important and too frequently incompletely-treated illness.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. The Center for Women’s Mental Health at MGH was a non-enrolling site for the pivotal phase 3 SKYLARK trial evaluating zuranolone. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

Postpartum depression (PPD) remains the most common complication in modern obstetrics, and a leading cause of postpartum mortality in the first year of life. The last 15 years have brought considerable progress with respect to adoption of systematic screening for PPD across America. Screening for PPD, most often using the Edinburgh Postnatal Depression Scale (EPDS), has become part of routine obstetrical care, and is also widely used in pediatric settings.

That is the good news. But the flip side of the identification of those women whose scores on the EPDS suggest significant depressive symptoms is that the number of these patients who, following identification, receive referrals for adequate treatment that gets them well is unfortunately low. This “perinatal treatment cascade” refers to the majority of women who, on the other side of identification of PPD, fail to receive adequate treatment and continue to have persistent depression (Cox E. et al. J Clin Psychiatry. 2016 Sep;77[9]:1189-1200). This is perhaps the greatest challenge to the field and to clinicians – how do we, on the other side of screening, see that these women get access to care and get well with the available treatments at hand?

Recently, a widely read and circulated article was published in The Wall Street Journal about the challenges associated with navigating care resources for women suffering from PPD. In that article, it was made clear, based on clinical vignette after clinical vignette from postpartum women across America, that neither obstetricians, mental health professionals, nor pediatricians are the “clinical home” for women suffering from postpartum mood and anxiety disorders. The article painfully highlights the system-wide failure to coordinate mental health care for women suffering from postpartum psychiatric illness.

Within a day of the publication of The Wall Street Journal article, the Food and Drug Administration approved zuranolone (Zurzuvae; Sage Therapeutics; Cambridge, Mass.) for the treatment of PPD following the review of two studies demonstrating the superiority of the new medicine over placebo. Women who were enrolled met criteria for major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders criteria beginning in no earlier than the third trimester of pregnancy or later than 4 weeks of delivery. The two studies included a combined sample size of approximately 350 patients suffering from severe PPD. In the studies, women received either 50 mg or 40 mg of zuranolone, or placebo for 14 days. Treatment was associated with a significant change in the Hamilton Depression Rating Scale at day 15, and treatment response was maintained at day 42, which was 4 weeks after the last dose of study medication.

Zuranolone is a neuroactive steroid, which is taken orally, unlike brexanolone (Zulresso; Sage Therapeutics; Cambridge, Mass.), which requires intravenous administration. Zuranolone will be commercially available based on estimates around the fourth quarter of 2023. The most common side effects are drowsiness, dizziness, and sedation, and the FDA label will have a boxed warning about zuranolone’s potential to impact a person’s driving ability, and performance of potentially hazardous activities.

It is noteworthy that while this new medication received FDA approval for the PPD indication, it did not receive FDA approval for the treatment of major depressive disorder (MDD), and the agency issued a Complete Response Letter to the manufacturers noting their application did not provide substantial evidence of effectiveness in MDD. The FDA said in the Complete Response Letter that an additional study or studies will be needed; the manufacturers are currently evaluating next steps.
 

Where zuranolone fits into the treatment algorithm for severe PPD

Many clinicians who support women with PPD will wonder, upon hearing this news, where zuranolone fits into the treatment algorithm for severe postpartum major depression. Some relevant issues that may determine the answer are the following:

Cost. The cost of brexanolone was substantial, at $34,000 per year, and was viewed by some as a limiting factor in terms of its very limited uptake. As of this column’s publication, zuranolone’s manufacturer has not stated how much the medication will cost.

Breastfeeding. Unlike selective serotonin reuptake inhibitors, which have been demonstrated to be effective for the treatment of PPD and safe during pregnancy and lactation, we have sparse data on the safety of zuranolone for women who wish to breastfeed. It is also unclear whether women eligible for zuranolone would, based on the limited data on safety in lactation, choose deferral of breastfeeding for 14 days in exchange for treatment.

Duration of treatment. While zuranolone was studied in the context of 14 days of acute treatment, then out to day 42, we have no published data on what happens on the other side of this brief interval. As a simple example, in a patient with a history of recurrent major depression previously treated with antidepressants, but where antidepressants were perhaps deferred during pregnancy, is PPD to be treated with zuranolone for 14 days? Or, hypothetically, should it be followed by empiric antidepressant treatment at day 14? Alternatively, are patient and clinician supposed to wait until recurrence occurs before pursuing adjunctive antidepressant therapy whether it is pharmacologic, nonpharmacologic, or both?

Treatment in patients with bipolar disorder. It is also unclear whether treatment with zuranolone applies to other populations of postpartum women. Certainly, for women with bipolar depression, which is common in postpartum women given the vulnerability of bipolar women to new onset of depression or postpartum depressive relapse of underlying disorder, we simply have no data regarding where zuranolone might fit in with respect to this group of patients.

The answers to these questions may help to determine whether zuranolone, a new antidepressant with efficacy, quick time to onset, and a novel mechanism of action is a “game changer.” The article in The Wall Street Journal provided me with some optimism, as it gave PPD and the issues surrounding PPD the attention it deserves in a major periodical. As a new treatment, it may help alleviate suffering at a critical time for patients and their families. We are inching closer to mitigation of stigma associated with this common illness.

Thinking back across the last 3 decades of my treating women suffering from PPD, I have reflected on what has gotten these patients well. I concluded that successful treatment of PPD is not a “one-stop shop,” but rather typically includes a combination of pharmacologic and nonpharmacologic interventions, along with family and community-based support groups, as well as a culture that reduces stigma and by so doing lessens the toll of this important and too frequently incompletely-treated illness.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. The Center for Women’s Mental Health at MGH was a non-enrolling site for the pivotal phase 3 SKYLARK trial evaluating zuranolone. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

Postpartum depression (PPD) remains the most common complication in modern obstetrics, and a leading cause of postpartum mortality in the first year of life. The last 15 years have brought considerable progress with respect to adoption of systematic screening for PPD across America. Screening for PPD, most often using the Edinburgh Postnatal Depression Scale (EPDS), has become part of routine obstetrical care, and is also widely used in pediatric settings.

That is the good news. But the flip side of the identification of those women whose scores on the EPDS suggest significant depressive symptoms is that the number of these patients who, following identification, receive referrals for adequate treatment that gets them well is unfortunately low. This “perinatal treatment cascade” refers to the majority of women who, on the other side of identification of PPD, fail to receive adequate treatment and continue to have persistent depression (Cox E. et al. J Clin Psychiatry. 2016 Sep;77[9]:1189-1200). This is perhaps the greatest challenge to the field and to clinicians – how do we, on the other side of screening, see that these women get access to care and get well with the available treatments at hand?

Recently, a widely read and circulated article was published in The Wall Street Journal about the challenges associated with navigating care resources for women suffering from PPD. In that article, it was made clear, based on clinical vignette after clinical vignette from postpartum women across America, that neither obstetricians, mental health professionals, nor pediatricians are the “clinical home” for women suffering from postpartum mood and anxiety disorders. The article painfully highlights the system-wide failure to coordinate mental health care for women suffering from postpartum psychiatric illness.

Within a day of the publication of The Wall Street Journal article, the Food and Drug Administration approved zuranolone (Zurzuvae; Sage Therapeutics; Cambridge, Mass.) for the treatment of PPD following the review of two studies demonstrating the superiority of the new medicine over placebo. Women who were enrolled met criteria for major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders criteria beginning in no earlier than the third trimester of pregnancy or later than 4 weeks of delivery. The two studies included a combined sample size of approximately 350 patients suffering from severe PPD. In the studies, women received either 50 mg or 40 mg of zuranolone, or placebo for 14 days. Treatment was associated with a significant change in the Hamilton Depression Rating Scale at day 15, and treatment response was maintained at day 42, which was 4 weeks after the last dose of study medication.

Zuranolone is a neuroactive steroid, which is taken orally, unlike brexanolone (Zulresso; Sage Therapeutics; Cambridge, Mass.), which requires intravenous administration. Zuranolone will be commercially available based on estimates around the fourth quarter of 2023. The most common side effects are drowsiness, dizziness, and sedation, and the FDA label will have a boxed warning about zuranolone’s potential to impact a person’s driving ability, and performance of potentially hazardous activities.

It is noteworthy that while this new medication received FDA approval for the PPD indication, it did not receive FDA approval for the treatment of major depressive disorder (MDD), and the agency issued a Complete Response Letter to the manufacturers noting their application did not provide substantial evidence of effectiveness in MDD. The FDA said in the Complete Response Letter that an additional study or studies will be needed; the manufacturers are currently evaluating next steps.
 

Where zuranolone fits into the treatment algorithm for severe PPD

Many clinicians who support women with PPD will wonder, upon hearing this news, where zuranolone fits into the treatment algorithm for severe postpartum major depression. Some relevant issues that may determine the answer are the following:

Cost. The cost of brexanolone was substantial, at $34,000 per year, and was viewed by some as a limiting factor in terms of its very limited uptake. As of this column’s publication, zuranolone’s manufacturer has not stated how much the medication will cost.

Breastfeeding. Unlike selective serotonin reuptake inhibitors, which have been demonstrated to be effective for the treatment of PPD and safe during pregnancy and lactation, we have sparse data on the safety of zuranolone for women who wish to breastfeed. It is also unclear whether women eligible for zuranolone would, based on the limited data on safety in lactation, choose deferral of breastfeeding for 14 days in exchange for treatment.

Duration of treatment. While zuranolone was studied in the context of 14 days of acute treatment, then out to day 42, we have no published data on what happens on the other side of this brief interval. As a simple example, in a patient with a history of recurrent major depression previously treated with antidepressants, but where antidepressants were perhaps deferred during pregnancy, is PPD to be treated with zuranolone for 14 days? Or, hypothetically, should it be followed by empiric antidepressant treatment at day 14? Alternatively, are patient and clinician supposed to wait until recurrence occurs before pursuing adjunctive antidepressant therapy whether it is pharmacologic, nonpharmacologic, or both?

Treatment in patients with bipolar disorder. It is also unclear whether treatment with zuranolone applies to other populations of postpartum women. Certainly, for women with bipolar depression, which is common in postpartum women given the vulnerability of bipolar women to new onset of depression or postpartum depressive relapse of underlying disorder, we simply have no data regarding where zuranolone might fit in with respect to this group of patients.

The answers to these questions may help to determine whether zuranolone, a new antidepressant with efficacy, quick time to onset, and a novel mechanism of action is a “game changer.” The article in The Wall Street Journal provided me with some optimism, as it gave PPD and the issues surrounding PPD the attention it deserves in a major periodical. As a new treatment, it may help alleviate suffering at a critical time for patients and their families. We are inching closer to mitigation of stigma associated with this common illness.

Thinking back across the last 3 decades of my treating women suffering from PPD, I have reflected on what has gotten these patients well. I concluded that successful treatment of PPD is not a “one-stop shop,” but rather typically includes a combination of pharmacologic and nonpharmacologic interventions, along with family and community-based support groups, as well as a culture that reduces stigma and by so doing lessens the toll of this important and too frequently incompletely-treated illness.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. The Center for Women’s Mental Health at MGH was a non-enrolling site for the pivotal phase 3 SKYLARK trial evaluating zuranolone. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

In case you are looking for a place to park your discretionary funds, I have recently learned that nonalcoholic beer is the fastest-growing segment of the beer industry. It is just barely outperforming the strong beer market while the standard beer market is flat. The reasons behind this surge in popularity are unclear. While the general population doesn’t seem to grasp the importance of diet and exercise, there seem to be enough folks who are health conscious to support a demand.

Possibly more important has been the emergence of a couple of small breweries that have been able to produce a nonalcoholic product that actually tastes as good as regular beer, and in some cases even better than the real stuff. In Europe, nonalcoholic beer has become popular as a rehydration drink among athletes. We recently found it everywhere we looked while bicycling in France. The large breweries have taken notice and it is hard to find a restaurant here in Maine that doesn’t offer nonalcoholic beer on its menu.

My history with beer goes back to preadolescence, when my father offered me a sip of his beer. I was never sure of his motive but that taste did not immediately whet my appetite for more. However, when I was in high school, New York State’s drinking age was 18 and beer just became part of growing up.

When I went into practice, my routine of having a can or bottle of beer with dinner presented a problem. When I was on call the odds of having to leave the house and see a patient or two was substantial. Back at the beginning I was never much concerned about having alcohol circulating through my brain but I didn’t want to be exhaling its vapors as I interacted with the parents and nurses. As I got older I became more aware that when I was tired, which was always the case at the end of a long office day, even just a glass of beer might impair my decision making. As a result, I drank only nonalcoholic beer when I was on call. Were I still practicing today this wouldn’t have represented a sacrifice on my part. However, until 5 years ago the nonalcoholic beer was not even a close approximation of the alcohol-containing product.

So this brings me to my question. Do you share any of my concerns about practicing under the influence of alcohol (P.U.I.)? And, if you have any concerns, how do you deal with them?

Do you make a distinction between physical and mental impairment? Would you have a drink if you were only fielding phone calls? Would your decision change if you knew you might be called in to perform surgery or start an intravenous on a premie?

Does the prospect of meeting face to face with your patient/parents change your decision? Is practicing telemedicine under the influence any less concerning to you than seeing patients in your office or the emergency room?

Can you imagine any extenuating circumstances? For example, let’s say you are the only pediatric ENT in your county. While you have office hours 4½ days per week, in effect you are on call 24/7 for emergencies. If you made a decision to never practice under the influence, does that mean you will never drink alcohol?

Am I making too big of a thing out of a can of beer or a glass of wine? We have certainly read concerns about patient safety when cared for by house officers working on schedules that leave them practicing while sleep deprived (P.W.S.D.) You don’t hear anything about physicians’ P.U.I. Is it a real problem? Certainly, with marijuana becoming legal in more states alcohol may not be the only influencer to consider.

In the bigger picture I suspect that P.W.S.D. is the bigger problem both for house officers and practicing physicians but it is time we swept away the cloud of silence around P.U.I and had a frank discussion about both among ourselves.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In case you are looking for a place to park your discretionary funds, I have recently learned that nonalcoholic beer is the fastest-growing segment of the beer industry. It is just barely outperforming the strong beer market while the standard beer market is flat. The reasons behind this surge in popularity are unclear. While the general population doesn’t seem to grasp the importance of diet and exercise, there seem to be enough folks who are health conscious to support a demand.

Possibly more important has been the emergence of a couple of small breweries that have been able to produce a nonalcoholic product that actually tastes as good as regular beer, and in some cases even better than the real stuff. In Europe, nonalcoholic beer has become popular as a rehydration drink among athletes. We recently found it everywhere we looked while bicycling in France. The large breweries have taken notice and it is hard to find a restaurant here in Maine that doesn’t offer nonalcoholic beer on its menu.

My history with beer goes back to preadolescence, when my father offered me a sip of his beer. I was never sure of his motive but that taste did not immediately whet my appetite for more. However, when I was in high school, New York State’s drinking age was 18 and beer just became part of growing up.

When I went into practice, my routine of having a can or bottle of beer with dinner presented a problem. When I was on call the odds of having to leave the house and see a patient or two was substantial. Back at the beginning I was never much concerned about having alcohol circulating through my brain but I didn’t want to be exhaling its vapors as I interacted with the parents and nurses. As I got older I became more aware that when I was tired, which was always the case at the end of a long office day, even just a glass of beer might impair my decision making. As a result, I drank only nonalcoholic beer when I was on call. Were I still practicing today this wouldn’t have represented a sacrifice on my part. However, until 5 years ago the nonalcoholic beer was not even a close approximation of the alcohol-containing product.

So this brings me to my question. Do you share any of my concerns about practicing under the influence of alcohol (P.U.I.)? And, if you have any concerns, how do you deal with them?

Do you make a distinction between physical and mental impairment? Would you have a drink if you were only fielding phone calls? Would your decision change if you knew you might be called in to perform surgery or start an intravenous on a premie?

Does the prospect of meeting face to face with your patient/parents change your decision? Is practicing telemedicine under the influence any less concerning to you than seeing patients in your office or the emergency room?

Can you imagine any extenuating circumstances? For example, let’s say you are the only pediatric ENT in your county. While you have office hours 4½ days per week, in effect you are on call 24/7 for emergencies. If you made a decision to never practice under the influence, does that mean you will never drink alcohol?

Am I making too big of a thing out of a can of beer or a glass of wine? We have certainly read concerns about patient safety when cared for by house officers working on schedules that leave them practicing while sleep deprived (P.W.S.D.) You don’t hear anything about physicians’ P.U.I. Is it a real problem? Certainly, with marijuana becoming legal in more states alcohol may not be the only influencer to consider.

In the bigger picture I suspect that P.W.S.D. is the bigger problem both for house officers and practicing physicians but it is time we swept away the cloud of silence around P.U.I and had a frank discussion about both among ourselves.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

In case you are looking for a place to park your discretionary funds, I have recently learned that nonalcoholic beer is the fastest-growing segment of the beer industry. It is just barely outperforming the strong beer market while the standard beer market is flat. The reasons behind this surge in popularity are unclear. While the general population doesn’t seem to grasp the importance of diet and exercise, there seem to be enough folks who are health conscious to support a demand.

Possibly more important has been the emergence of a couple of small breweries that have been able to produce a nonalcoholic product that actually tastes as good as regular beer, and in some cases even better than the real stuff. In Europe, nonalcoholic beer has become popular as a rehydration drink among athletes. We recently found it everywhere we looked while bicycling in France. The large breweries have taken notice and it is hard to find a restaurant here in Maine that doesn’t offer nonalcoholic beer on its menu.

My history with beer goes back to preadolescence, when my father offered me a sip of his beer. I was never sure of his motive but that taste did not immediately whet my appetite for more. However, when I was in high school, New York State’s drinking age was 18 and beer just became part of growing up.

When I went into practice, my routine of having a can or bottle of beer with dinner presented a problem. When I was on call the odds of having to leave the house and see a patient or two was substantial. Back at the beginning I was never much concerned about having alcohol circulating through my brain but I didn’t want to be exhaling its vapors as I interacted with the parents and nurses. As I got older I became more aware that when I was tired, which was always the case at the end of a long office day, even just a glass of beer might impair my decision making. As a result, I drank only nonalcoholic beer when I was on call. Were I still practicing today this wouldn’t have represented a sacrifice on my part. However, until 5 years ago the nonalcoholic beer was not even a close approximation of the alcohol-containing product.

So this brings me to my question. Do you share any of my concerns about practicing under the influence of alcohol (P.U.I.)? And, if you have any concerns, how do you deal with them?

Do you make a distinction between physical and mental impairment? Would you have a drink if you were only fielding phone calls? Would your decision change if you knew you might be called in to perform surgery or start an intravenous on a premie?

Does the prospect of meeting face to face with your patient/parents change your decision? Is practicing telemedicine under the influence any less concerning to you than seeing patients in your office or the emergency room?

Can you imagine any extenuating circumstances? For example, let’s say you are the only pediatric ENT in your county. While you have office hours 4½ days per week, in effect you are on call 24/7 for emergencies. If you made a decision to never practice under the influence, does that mean you will never drink alcohol?

Am I making too big of a thing out of a can of beer or a glass of wine? We have certainly read concerns about patient safety when cared for by house officers working on schedules that leave them practicing while sleep deprived (P.W.S.D.) You don’t hear anything about physicians’ P.U.I. Is it a real problem? Certainly, with marijuana becoming legal in more states alcohol may not be the only influencer to consider.

In the bigger picture I suspect that P.W.S.D. is the bigger problem both for house officers and practicing physicians but it is time we swept away the cloud of silence around P.U.I and had a frank discussion about both among ourselves.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected].

CHICAGO – At this year’s AGA Postgraduate Course in May at the annual Digestive Disease Week^®(DDW), we reviewed the latest updates in inflammatory bowel disease (IBD).

Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).¹ The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.²

University of Miami

The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.³

Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.⁴ In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.⁵

Brigham and Women's Hospital

The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.^6,7

There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.⁸ Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.⁹ Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.¹⁰

Dr. Loftus

For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.¹¹ Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.¹²

A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.¹³

We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.¹⁴ Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.¹⁵ We will see more studies combining therapies with diverse mechanisms of action.

In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.

DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).

Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.

References

1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.

2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.

3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.

4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.

5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.

6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.

7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.

8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.

9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.

10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.

11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30

12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.

13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.

14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.

15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.

CHICAGO – At this year’s AGA Postgraduate Course in May at the annual Digestive Disease Week^®(DDW), we reviewed the latest updates in inflammatory bowel disease (IBD).

Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).¹ The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.²

University of Miami

The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.³

Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.⁴ In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.⁵

Brigham and Women's Hospital

The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.^6,7

There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.⁸ Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.⁹ Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.¹⁰

Dr. Loftus

For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.¹¹ Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.¹²

A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.¹³

We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.¹⁴ Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.¹⁵ We will see more studies combining therapies with diverse mechanisms of action.

In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.

DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).

Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.

References

1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.

2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.

3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.

4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.

5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.

6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.

7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.

8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.

9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.

10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.

11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30

12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.

13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.

14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.

15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.

CHICAGO – At this year’s AGA Postgraduate Course in May at the annual Digestive Disease Week^®(DDW), we reviewed the latest updates in inflammatory bowel disease (IBD).

Although it had been thought that incidence rates of IBD were plateauing in high-incidence areas, a Danish study found a steady increase in incidence of Crohn’s disease and ulcerative colitis (UC).¹ The highest increase in rates occurred in children and young adults, which will have repercussions as people get older and contribute to higher compounding prevalence. We need to get better at dealing with other health conditions as patients get older. A very large prospective Spanish study found that 42% of IBD patients scanned consecutively had MAFLD (metabolic-associated fatty liver disease) – even if they didn’t have high BMI and type 2 diabetes, suggesting that systemic inflammation in IBD contributes to the development of metabolic liver disease.²

University of Miami

The AGA has recently published guidelines for using biomarkers in the management of UC. Patients with very low fecal calprotectin (FCP) are unlikely to have active disease whereas FCP over 150 with significant symptoms may warrant empiric changes in treatment.³

Intestinal ultrasound is gaining wider acceptance as a noninvasive way to monitor IBD.⁴ In a UC study, improvement in bowel wall thickness following tofacitinib treatment correlated well with endoscopic activity.⁵

Brigham and Women's Hospital

The majority of the presentation focused on the explosion of Food and Drug Administration–-approved medications for IBD in recent years. S1P receptor agonists, such as ozanimod and etrasimod, may work by trapping specific T-cell subsets in peripheral lymph nodes, preventing migration to intestinal tissues. Ozanimod is approved for UC. Etrasimod showed efficacy in UC with clinical remission rates of about 27% at week 12 and 32% at week 52.^6,7

There has been a lot of excitement about JAK inhibitors for IBD. Upadacitinib has recently been approved for both UC and Crohn’s disease. Response rates of 73% and remission rates of 26% were seen in UC patients who had been largely biologic exposed.⁸ Similar results were seen in a biologic-exposed Crohn’s disease population treated with upadacitinib including in endoscopy.⁹ Upadacitinib was effective in maintaining remission at both 15-mg and 30-mg doses; but the higher dose had a greater effect on endoscopic endpoints.¹⁰

Dr. Loftus

For Crohn’s disease, we now have risankizumab, an anti-p19/IL-23 inhibitor. Risankizumab was efficacious at inducing and maintain remission in the pivotal phase 3 studies, even with 75% of patients being biologic exposed. These studies used combined endpoints of clinical remission as well as endoscopic response.¹¹ Guselkumab (anti-p19/IL-23) is also being studied for Crohn’s disease and early trials has appears to be efficacious.¹²

A head-to-head study of naive CD patients treated with ustekinumab or adalimumab (SEAVUE) showed comparable rates of clinical remission. At 52 weeks, the rates of clinical remission were quite high: >60% and endoscopic remission >30% with either therapy.¹³

We now have phase 3 data showing that a biologic is efficacious in patients with chronic pouchitis. The EARNEST trial demonstrated that vedolizumab has efficacy in treating pouchitis with improved clinical symptoms and endoscopy.¹⁴ Future treatment strategies may involve combinations of biologic therapies. The VEGA study showed that combining an anti-TNF, golimumab, with an anti-IL23, guselkumab, was superior than either alone with respect to clinical remission and endoscopic improvement in UC.¹⁵ We will see more studies combining therapies with diverse mechanisms of action.

In summary, there have been many noteworthy advances in treatment and management of IBD in the past year.

DDW is sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and The Society for Surgery of the Alimentary Tract (SSAT).

Dr. Abreu is director of the Crohn’s and Colitis Center and professor of medicine, microbiology, and immunology at the University of Miami. She is president-elect of AGA. Dr. Allegretti is director of the Crohn’s and Colitis Center and director of the fecal microbiota transplant program at Brigham and Women’s Hospital, Boston. She is associate professor of medicine at Harvard Medical School, Boston. Dr. Loftus is the Maxine and Jack Zarrow Family Professor of Gastroenterology, codirector of the advanced IBD fellowship in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn. Dr. Ungaro is associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York.

References

1. Agrawal M et al. Gastroenterology. 2022;163(6):1547-54.e5.

2. Rodriguez-Duque JC et al. Clin Gastroenterol Hepatol. 2023;21(2):406-14.e7.

3. Singh S, et al. Gastroenterology. 2023;164(3):344-72.

4. de Voogd F et al. Gastroenterology. 2022;163(6):1569-81.

5. Sandborn WJ et al. N Engl J Med. 2017;376(18):1723-36.

6. Sandborn WJ et al. N Engl J Med. 2021;385(14):1280-91.

7. Sandborn WJ et al. Lancet. 2023 Mar 25;401(10381):1000]. Lancet. 2023;401(10383):1159-71.

8. Danese S et al. Lancet. 2022 Sep 24;400(10357):996]. Lancet. 2022;399(10341):2113-28.

9. Loftus EV Jr et al. N Engl J Med. 2023 May 25;388(21):1966-80.

10. Panes J et al. Am J Gastroenterol 2022;117(S10). Abstract S37.

11. D’Haens G, et al. Lancet. 2022;399(10340):2015-30

12. Sandborn WJ et al. Gastroenterology. 2022;162(6):1650-64.e8.

13. Sands BE, et al. Lancet. 2022;399(10342):2200-11.

14. Travis S et al. N Engl J Med. 2023;388(13):1191-1200.

15. Feagan BG et al. Lancet Gastroenterol Hepatol. 2023;8(4):307-20.

This transcript has been edited for clarity.

Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.

Many people are talking about where this fits into our current armamentarium, and I think there probably is no better person to discuss this than Paul Ridker, who’s been at the forefront of research into anti-inflammatory therapeutics.
 

Lifestyle lipid-lowering paramount

Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?

Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.

I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.

Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.

The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
 

Inflammatory pathway

Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?

Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.

Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.

The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.

It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
 

When to start colchicine, and in whom?

Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.

At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?

Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.

In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.

I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.

There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.

Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.

In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.

Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.

In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?

Colchicine safety and contraindications

Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.

One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.

Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.

Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?

Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.

I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.

The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
 

Inpatient vs. outpatient initiation

Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?

Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.

Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.

Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.

I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.

Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.

Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.

Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.

This transcript has been edited for clarity.

Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.

Many people are talking about where this fits into our current armamentarium, and I think there probably is no better person to discuss this than Paul Ridker, who’s been at the forefront of research into anti-inflammatory therapeutics.
 

Lifestyle lipid-lowering paramount

Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?

Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.

I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.

Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.

The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
 

Inflammatory pathway

Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?

Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.

Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.

The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.

It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
 

When to start colchicine, and in whom?

Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.

At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?

Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.

In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.

I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.

There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.

Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.

In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.

Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.

In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?

Colchicine safety and contraindications

Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.

One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.

Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.

Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?

Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.

I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.

The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
 

Inpatient vs. outpatient initiation

Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?

Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.

Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.

Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.

I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.

Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.

Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.

Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.

This transcript has been edited for clarity.

Dr. O’Donoghue: We’re going to discuss a very important and emerging topic, which is the use of low-dose colchicine. I think there’s much interest in the use of this drug, which now has a Food and Drug Administration indication, which we’ll talk about further, and it’s also been written into both European and American guidelines that have been recently released.

Many people are talking about where this fits into our current armamentarium, and I think there probably is no better person to discuss this than Paul Ridker, who’s been at the forefront of research into anti-inflammatory therapeutics.
 

Lifestyle lipid-lowering paramount

Dr. O’Donoghue: As we think about the concept behind the use of colchicine, we’ve obviously done a large amount of research into lipid-lowering drugs, but where does colchicine now fit in?

Dr. Ridker: Let’s make sure we get the basics down. Anti-inflammatory therapy is going to be added on top of quality other care. This is not a replacement for lipids; it’s not a change in diet, exercise, and smoking cessation. The new data are really telling us that a patient who’s aggressively treated to guideline-recommended levels can still do much better in terms of preventing heart attack, stroke, cardiovascular death, and revascularization by adding low-dose colchicine as the first proven anti-inflammatory therapy for atherosclerotic disease.

I have to say, Michelle, for me, it’s been a wonderful end of a journey in many ways. This story starts almost 30 years ago for quite a few of us, thinking about inflammation and atherosclerosis. The whole C-reactive protein (CRP) story is still an ongoing one. We recently showed, for example, that residual inflammatory risk in some 30,000 patients, all taking a statin, was a far better predictor of the likelihood of more cardiovascular events, in particular cardiovascular death, than was residual cholesterol risk.

Think about that. We’re all aggressively giving second lipid-lowering drugs in our very sick patients, but that means inflammation is really the untapped piece of this.

The two clinical trials we have in front of us, the COLCOT trial and the LoDoCo2 trial – both New England Journal of Medicine papers, both with roughly 5,000 patients – provide very clear evidence that following a relatively recent myocardial infarction (that’s COLCOT) in chronic stable atherosclerosis (that’s LoDoCo2), we’re getting 25%-30% relative risk reductions in major adverse cardiovascular events (MACEs) on top of aggressive statin therapy. That’s a big deal. It’s safe, it works, and it’s fully consistent with all the information we have about inflammation being part and parcel of atherosclerosis. It’s a pretty exciting time.
 

Inflammatory pathway

Dr. O’Donoghue: It beautifully proves the inflammatory hypothesis in many ways. You led CANTOS, and that was a much more specific target. Here, in terms of the effects of colchicine, what do we know about how it may work on the inflammatory cascade?

Dr. Ridker: Our CANTOS trial was proof of principle that you could directly target, with a very specific monoclonal antibody, a specific piece of this innate immune cascade and lower cardiovascular event rates.

Colchicine is a more broad-spectrum drug. It does have a number of antineutrophil effects – that’s important, by the way. Neutrophils are really becoming very important in atherosclerotic disease progression. It’s an indirect inhibitor of the so-called NLRP3 inflammasome, which is where both interleukin-1 (that’s the target for canakinumab) and IL-6 are up-regulated. As you know, it’s been used to treat gout and pericarditis in high doses in short, little bursts.

The change here is this use of low-dose colchicine, that’s 0.5 mg once a day for years to treat chronic, stable atherosclerosis. It is very much like using a statin. The idea here is to prevent the progression of the disease by slowing down and maybe stabilizing the plaque so we have fewer heart attacks and strokes down the road.

It’s entering the armamentarium – at least my armamentarium – as chronic, stable secondary prevention. That’s where the new American College of Cardiology/American Heart Association guidelines also put it. It’s really in as a treatment for chronic, stable atherosclerosis. I think that’s where it belongs.
 

When to start colchicine, and in whom?

Dr. O’Donoghue: To that point, as we think about the efficacy, I think it’s nice, as you outlined, that we have two complementary trials that are both showing a consistent reduction in MACEs, one in the post–acute coronary syndrome (ACS) state and one for more chronic patients.

At what point do you think would be the appropriate time to start therapy, and who would you be starting it for?

Dr. Ridker: Michelle, that’s a great question. There’s a very interesting analysis that just came out from the LoDoCo2 investigators. It’s kind of a landmark analysis. What they show is that 1 year, 2 years, 3 years, and 4 years since the initiating myocardial infarction, the drug is very effective.

In fact, you could think about starting this drug at your clinic in patients with chronic, stable atherosclerotic disease. That’s just like we would start a statin in people who had a heart attack some time ago, and that’s absolutely fine.

I’m using it for what I call my frequent fliers, those patients who just keep coming back. They’re already on aggressive lipid-lowering therapy. I have them on beta-blockers, aspirin, and all the usual things. I say, look, I can get a large risk reduction by starting them on this drug.

There are a few caveats, Michelle. Like all drugs, colchicine comes with some adverse effects. Most of them are pretty rare, but there are some patients I would not give this drug to, just to be very clear. Colchicine is cleared by the kidney and by the liver. Patients who have severe chronic kidney disease and severe liver disease – this is a no-go for those patients. We should talk about where patients in that realm might want to go.

Then there are some unusual drugs. Colchicine is metabolized by the CYP3A4 and the P-glycoprotein pathway. There are a few drugs, such as ketoconazole, fluconazole, and cyclosporine, that if your primary care doctor or internist is going to start for a short term, you probably want to stop your colchicine for a week or two.

In people with familial Mediterranean fever, for whom colchicine is lifesaving and life-changing and who take it for 20, 30, or 40 years, there’s been no increase in risk for cancer. There have been very few adverse effects. I think it’s interesting that we, who practice in North America, basically never see familial Mediterranean fever. If we were practicing in Lebanon, Israel, or North Africa, this would be a very common therapy that we’d all be extremely familiar with.

Dr. O’Donoghue: To that point, it’s interesting to hear that colchicine was even used by the ancient Greeks and ancient Egyptians. It’s a drug that’s been around for a long time.

In terms of its safety, some people have been talking about the fact that an increase in noncardiovascular death was seen in LoDoCo2. What are your thoughts on that? Is that anything that we should be concerned about?

Colchicine safety and contraindications

Dr. Ridker: First, to set the record straight, a meta-analysis has been done of all-cause mortality in the various colchicine trials, and the hazard ratio is 1.04. I’ll remind you, and all of us know, that the hazard ratios for all-cause mortality in the PCSK9 trials, the bempedoic acid trials, and the ezetimibe trials are also essentially neutral. We’re in a state where we don’t let these trials roll long enough to see benefits necessarily on all-cause mortality. Some of us think we probably should, but that’s just the reality of trials.

One of most interesting things that was part of the FDA review, I suspect, was that there was no specific cause of any of this. It was not like there was a set of particular issues. I suspect that most people think this is probably the play of chance and with time, things will get better.

Again, I do want to emphasize this is not a drug for severe chronic kidney disease and severe liver disease, because those patients will get in trouble with this. The other thing that’s worth knowing is when you start a patient on low-dose colchicine – that’s 0.5 mg/d – there will be some patients who get some short-term gastrointestinal upset. That’s very common when you start colchicine at the much higher doses you might use to treat acute gout or pericarditis. In these trials, the vast majority of patients treated through that, and there were very few episodes long-term. I think it’s generally safe. That’s where we’re at.

Dr. O’Donoghue: Paul, you’ve been a leader, certainly, at looking at CRP as a marker of inflammation. Do you, in your practice, consider CRP levels when making a decision about who is appropriate for this therapy?

Dr. Ridker: That’s another terrific question. I do, because I’m trying to distinguish in my own mind patients who have residual inflammatory risk, in whom the high-sensitivity CRP (hsCRP) level remains high despite being on statins versus those with residual cholesterol risk, in whom I’m really predominantly worried about LDL cholesterol, that I haven’t brought it down far enough.

I do measure it, and if the CRP remains high and the LDL cholesterol is low, to me, that’s residual inflammatory risk and that’s the patient I would target this to. Conversely, if the LDL cholesterol was still, say, above some threshold of 75-100 and I’m worried about that, even if the CRP is low, I’ll probably add a second lipid-lowering drug.

The complexity of this, however, is that CRP was not measured in either LoDoCo2 or COLCOT. That’s mostly because they didn’t have much funding. These trials were done really on a shoestring. They were not sponsored by major pharma at all. We know that the median hsCRP in these trials was probably around 3.5-4 mg/L so I’m pretty comfortable doing that. Others have just advocated giving it to many patients. I must say I like to use biomarkers to think through the biology and who might have the best benefit-to-risk ratio. In my practice, I am doing it that way.
 

Inpatient vs. outpatient initiation

Dr. O’Donoghue: This is perhaps my last question for you before we wrap up. I know you talked about use of low-dose colchicine for patients with more chronic, stable coronary disease. Now obviously, COLCOT studied patients who were early post ACS, and there we certainly think about the anti-inflammatory effects as potentially having more benefit. What are your thoughts about early initiation of colchicine in that setting, the acute hospitalized setting? Do you think it’s more appropriate for an outpatient start?

Dr. Ridker: Today, I think this is all about chronic, stable atherosclerosis. Yes, COLCOT enrolled their patients within 30 days of a recent myocardial infarction, but as we all know, that’s a pretty stable phase. The vast majority were enrolled after 15 days. There were a small number enrolled within 3 days or something like that, but the benefit is about the same in all these patients.

Conversely, there’s been a small number of trials looking at colchicine in acute coronary ischemia and they’ve not been terribly promising. That makes some sense, though, right? We want to get an artery open. In acute ischemia, that’s about revascularization. It’s about oxygenation. It’s about reperfusion injury. My guess is that 3, 4, 5, or 6 days later, when it becomes a stable situation, is when the drug is probably effective.

Again, there will be some ongoing true intervention trials with large sample sizes for acute coronary ischemia. We don’t have those yet. Right now, I think it’s a therapy for chronic, stable angina. That’s many of our patients.

I would say that if you compare the relative benefit in these trials of adding ezetimibe to a statin, that’s a 5% or 6% benefit. For PCSK9 inhibitors – we all use them – it’s about a 15% benefit. These are 25%-30% risk reductions. If we’re going to think about what’s the next drug to give on top of the statin, serious consideration should be given to low-dose colchicine.

Let me also emphasize that this is not an either/or situation. This is about the fact that we now understand atherosclerosis to be a disorder both of lipid accumulation and a proinflammatory systemic response. We can give these drugs together. I suspect that the best patient care is going to be very aggressive lipid-lowering combined with pretty aggressive inflammation inhibition. I suspect that, down the road, that’s where all of us are going to be.

Dr. O’Donoghue: Thank you so much, Paul, for walking us through that today. I think it was a very nice, succinct review of the evidence, and then also just getting our minds more accustomed to the concept that we can now start to target more orthogonal axes that really get at the pathobiology of what’s going on in the atherosclerotic plaque. I think it’s an important topic.

Dr. O’Donoghue is an associate professor of medicine at Harvard Medical School and an associate physician at Brigham and Women’s Hospital, both in Boston. Dr. Ridker is director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital. Both Dr. O’Donoghue and Dr. Ridker reported numerous conflicts of interest.