AGA is accepting applications for the third annual AGA-Aman Armaan Ahmed Family Summer Undergraduate Research Fellowship (SURF).

Eight undergraduate students from groups traditionally underrepresented in biomedical research will have the opportunity to perform 10 weeks of research related to digestive diseases alongside an established investigator. Recipients will also receive a $5,400 stipend and funding to offset travel and meal expenses.

Students may independently secure support from an AGA member mentor or choose from our list of participating mentors. Past recipients are eligible to apply!

Additional information about the award, including application requirements and a downloadable preview, are available in the request for applications. Please see important dates below.
 

• Dec. 14, 2022 - Online applications close at 11:59 p.m. ET.
• March 2023 - Applicants are notified of their status.
• May-August 2023 - Recipients perform summer research with mentors.

AGA gratefully acknowledges the Aman Armaan Ahmed Family for supporting this program.

AGA is accepting applications for the third annual AGA-Aman Armaan Ahmed Family Summer Undergraduate Research Fellowship (SURF).

Eight undergraduate students from groups traditionally underrepresented in biomedical research will have the opportunity to perform 10 weeks of research related to digestive diseases alongside an established investigator. Recipients will also receive a $5,400 stipend and funding to offset travel and meal expenses.

Students may independently secure support from an AGA member mentor or choose from our list of participating mentors. Past recipients are eligible to apply!

Additional information about the award, including application requirements and a downloadable preview, are available in the request for applications. Please see important dates below.
 

• Dec. 14, 2022 - Online applications close at 11:59 p.m. ET.
• March 2023 - Applicants are notified of their status.
• May-August 2023 - Recipients perform summer research with mentors.

AGA gratefully acknowledges the Aman Armaan Ahmed Family for supporting this program.

AGA is accepting applications for the third annual AGA-Aman Armaan Ahmed Family Summer Undergraduate Research Fellowship (SURF).

Eight undergraduate students from groups traditionally underrepresented in biomedical research will have the opportunity to perform 10 weeks of research related to digestive diseases alongside an established investigator. Recipients will also receive a $5,400 stipend and funding to offset travel and meal expenses.

Students may independently secure support from an AGA member mentor or choose from our list of participating mentors. Past recipients are eligible to apply!

Additional information about the award, including application requirements and a downloadable preview, are available in the request for applications. Please see important dates below.
 

• Dec. 14, 2022 - Online applications close at 11:59 p.m. ET.
• March 2023 - Applicants are notified of their status.
• May-August 2023 - Recipients perform summer research with mentors.

AGA gratefully acknowledges the Aman Armaan Ahmed Family for supporting this program.

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive type of non- Hodgkin lymphoma (NHL), comprising 30% of all NHL. Due to a decreased state of immunosurveillance resulting from the disease itself and its associated therapies, patients are at increased risk of developing a secondary malignancy. Multiple primary malignancies have been reported to occur in up to 15% of patients with DLBCL, retrospectively.

Herein, we review a case of a man with DLBCL who concomitantly developed ALK negative anaplastic large cell lymphoma (ALCL) distinctly of T-cell lineage who was successfully treated with palliative therapy for both diagnoses despite his advanced age and diagnosis associated with a poor prognosis with continued effect and sustained quality of life.

Case Report

An 88-year-old man presented with stage III DLBCL, diagnosed in 12/2018, was deemed not to be an aggressive therapy candidate. As such, he was treated with Rituximab monotherapy for 6 cycles, ending in 02/2019, with remarkably good effect. He remained in a PR with stable disease on serial PET/CTs until 09/2021, at which time he was noted to have Horner’s Syndrome in clinic. CT chest demonstrated a right apical lung mass, not previously seen on prior scans measuring 4.2 x 2.7 cm. Other sites of nodal disease remained stable on PET/CT.

Biopsy of the lesion revealed CD30+ ALK-negative ALCL with distinct T-cell marker positivity on immunohistochemistry and the absence of B-cell lineage markers. After discussion at our treatment planning conference, we decided to treat with brentuximab-vedotin (Bv) monotherapy for 6 cycles. End of treatment PET/CT demonstrated a PR with near resolution in background PET avidity at the lesion. His symptoms of Horner syndrome also improved.

Conclusion

A diagnosis of aggressive lymphoma increases the risk of developing a secondary malignancy and providers should remain vigilant of this. Elderly individuals in whom aggressive therapies may be precluded can still greatly benefit from palliative targeted therapy even in the setting of diseases historically associated with a poor prognosis.

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive type of non- Hodgkin lymphoma (NHL), comprising 30% of all NHL. Due to a decreased state of immunosurveillance resulting from the disease itself and its associated therapies, patients are at increased risk of developing a secondary malignancy. Multiple primary malignancies have been reported to occur in up to 15% of patients with DLBCL, retrospectively.

Herein, we review a case of a man with DLBCL who concomitantly developed ALK negative anaplastic large cell lymphoma (ALCL) distinctly of T-cell lineage who was successfully treated with palliative therapy for both diagnoses despite his advanced age and diagnosis associated with a poor prognosis with continued effect and sustained quality of life.

Case Report

An 88-year-old man presented with stage III DLBCL, diagnosed in 12/2018, was deemed not to be an aggressive therapy candidate. As such, he was treated with Rituximab monotherapy for 6 cycles, ending in 02/2019, with remarkably good effect. He remained in a PR with stable disease on serial PET/CTs until 09/2021, at which time he was noted to have Horner’s Syndrome in clinic. CT chest demonstrated a right apical lung mass, not previously seen on prior scans measuring 4.2 x 2.7 cm. Other sites of nodal disease remained stable on PET/CT.

Biopsy of the lesion revealed CD30+ ALK-negative ALCL with distinct T-cell marker positivity on immunohistochemistry and the absence of B-cell lineage markers. After discussion at our treatment planning conference, we decided to treat with brentuximab-vedotin (Bv) monotherapy for 6 cycles. End of treatment PET/CT demonstrated a PR with near resolution in background PET avidity at the lesion. His symptoms of Horner syndrome also improved.

Conclusion

A diagnosis of aggressive lymphoma increases the risk of developing a secondary malignancy and providers should remain vigilant of this. Elderly individuals in whom aggressive therapies may be precluded can still greatly benefit from palliative targeted therapy even in the setting of diseases historically associated with a poor prognosis.

Background

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive type of non- Hodgkin lymphoma (NHL), comprising 30% of all NHL. Due to a decreased state of immunosurveillance resulting from the disease itself and its associated therapies, patients are at increased risk of developing a secondary malignancy. Multiple primary malignancies have been reported to occur in up to 15% of patients with DLBCL, retrospectively.

Herein, we review a case of a man with DLBCL who concomitantly developed ALK negative anaplastic large cell lymphoma (ALCL) distinctly of T-cell lineage who was successfully treated with palliative therapy for both diagnoses despite his advanced age and diagnosis associated with a poor prognosis with continued effect and sustained quality of life.

Case Report

An 88-year-old man presented with stage III DLBCL, diagnosed in 12/2018, was deemed not to be an aggressive therapy candidate. As such, he was treated with Rituximab monotherapy for 6 cycles, ending in 02/2019, with remarkably good effect. He remained in a PR with stable disease on serial PET/CTs until 09/2021, at which time he was noted to have Horner’s Syndrome in clinic. CT chest demonstrated a right apical lung mass, not previously seen on prior scans measuring 4.2 x 2.7 cm. Other sites of nodal disease remained stable on PET/CT.

Biopsy of the lesion revealed CD30+ ALK-negative ALCL with distinct T-cell marker positivity on immunohistochemistry and the absence of B-cell lineage markers. After discussion at our treatment planning conference, we decided to treat with brentuximab-vedotin (Bv) monotherapy for 6 cycles. End of treatment PET/CT demonstrated a PR with near resolution in background PET avidity at the lesion. His symptoms of Horner syndrome also improved.

Conclusion

A diagnosis of aggressive lymphoma increases the risk of developing a secondary malignancy and providers should remain vigilant of this. Elderly individuals in whom aggressive therapies may be precluded can still greatly benefit from palliative targeted therapy even in the setting of diseases historically associated with a poor prognosis.

The AGA Women in GI Regional Workshops – four separate events across the U.S. beginning in October – will provide women physicians and scientists with effective and accessible career development and networking to support professional success and work-life balance.

Registration is now open for the Midwest and Northeast workshops.

Each workshop is an opportunity to gain new knowledge from a unique lineup of experts and various topics. Select attendees also have the opportunity to participate in the Women’s Leadership Collaboration Conference at AGA Headquarters (Dec. 2-3, 2022) to advance the work from the regional events nationally. To register and for more information on the regional workshops, please visit www.gastro.org/AGAWomensRegional.

The AGA Women in GI Regional Workshops – four separate events across the U.S. beginning in October – will provide women physicians and scientists with effective and accessible career development and networking to support professional success and work-life balance.

Registration is now open for the Midwest and Northeast workshops.

Each workshop is an opportunity to gain new knowledge from a unique lineup of experts and various topics. Select attendees also have the opportunity to participate in the Women’s Leadership Collaboration Conference at AGA Headquarters (Dec. 2-3, 2022) to advance the work from the regional events nationally. To register and for more information on the regional workshops, please visit www.gastro.org/AGAWomensRegional.

The AGA Women in GI Regional Workshops – four separate events across the U.S. beginning in October – will provide women physicians and scientists with effective and accessible career development and networking to support professional success and work-life balance.

Registration is now open for the Midwest and Northeast workshops.

Each workshop is an opportunity to gain new knowledge from a unique lineup of experts and various topics. Select attendees also have the opportunity to participate in the Women’s Leadership Collaboration Conference at AGA Headquarters (Dec. 2-3, 2022) to advance the work from the regional events nationally. To register and for more information on the regional workshops, please visit www.gastro.org/AGAWomensRegional.

The number of doctors of osteopathic medicine (DOs) is enjoying a significant growth pattern. This year alone, 7,300 osteopathic physicians are entering the workforce, and they make up more than 25% of the medical student population. The pipeline of future DOs is at an all-time high of 36,500 students, according to the American Osteopathic Association.

All 50 states plus Washington, D.C., have DO practices, and Florida ranks third in terms of states with the most practicing DOs, topped by California in the No. 1 spot and Pennsylvania in second. New York and Michigan round out the top 5.

The pipeline to the profession is in a growth mode, too. For the upcoming academic year, the AOA’s Commission on Osteopathic College Accreditation will accredit 38 colleges of osteopathic medicine in about 60 different locations.

Although DOs have existed for more than 100 years, historically they have sat somewhat in the shadow of their MD peers. That tide has turned, for a variety of reasons – one of which is recognition via several high-profile DOs. Look no further than the White House, for instance, where President Biden’s physician is Kevin O’Connor, DO – the second DO to hold the position.

“The misrepresentation of osteopathic physicians has been a recent issue outside the nation’s health care delivery system,” says the American Medical Association’s Robert Mills. “To combat this mischaracterization, the AMA and the AOA issued a joint statement [in 2020] highlighting the fact that DOs are licensed physicians who practice in every specialty area and have equivalent training and practice rights to their MD peers.”
 

Attraction to the DO philosophy

For many DOs, the path to osteopathic medicine was always a clear one. “I wanted to go into osteopathic medicine from the age of 17,” says Nehal Gheewala, DO, national director of growth at ChenMed, a national primary care medical center.

Dr. Gheewala, who graduated from medical school in 2014, says he first spent time learning about the DO’s holistic philosophy, which appealed to him. “I liked how they were invested in their patient’s care, and that they first tried to treat musculoskeletal pain with manipulation. The result were quick, sometimes on the spot.”

While in medical school, Dr. Gheewala was joined by 250 peers seeking a DO rather than an MD. “I never felt like I was in the minority,” he says, “and today, as a practicing physician in Florida, we have a good number of DOs.”

Like Dr. Gheewala, Samuel Werner, a New Jersey–based DO, was inspired by his father, a DO who has served as a small-town general practitioner. “Growing up, I saw how well-respected my dad was in the community and watched his connection with patients,” Dr. Werner says. “He had the ability to pick up on small details others didn’t.”

Today, Dr. Werner sees the recognition and respect of DOs growing beyond where it was several decades ago.

One factor that is helping raise the DO profile is that residencies fall under the same umbrella for matching. In most states, medical licensing is the same, as well. Choosing to pursue a DO career requires additional training in wellness and manipulation. “In every specialty of medicine, DO students train alongside MD students,” Dr. Werner says. “In practice, most patients are unaware if they’re treated by a DO or an MD.”

That has sometimes been Dr. Gheewala’s experience. “Plenty of patients don’t ask whether I’m an MD or a DO,” he says, “and it doesn’t matter. We’re all board-certified doctors and as long as we’re taking care of, and spending time with, our patients, that’s what they want.”

Joseph A. Giaimo, a DO in Florida who has practiced for more than 30 years and is a past president of the AOA, says that some patients will seek out a DO instead of an MD. “Many patients see me because they specifically want to work with a DO; many of them are snowbirds who come to Florida during the winter,” he explains.

In his long career as a DO, Dr. Giaimo has witnessed the profession’s growth alongside a fading stigma that it’s somehow less “authentic” than allopathic medicine. “There are still people who need to be educated on osteopathic medicine, but much of that has simply been a lack of understanding,” he says. “That’s changing, and it’s our role to continue to educate people on what we’re about.”

Dr. Giaimo says that osteopathic medicine is striking the right tone in the moment, which is helpful to recognition and growth. “Coming out of the pandemic, people are more focused on staying healthy, and osteopathy offers an appealing approach,” he says. “There’s no better time for the two houses of medicine to come together, and it’s a great time to be in osteopathy.”
 

Moving forward

One of the biggest places the physician shortage is problematic is in rural America. The federal government estimates that by 2025, there will be a physician shortage of 25,000 primary care doctors in these areas. This is another way in which the growing osteopathic field is having an impact.

“We have a number of schools in underserved areas, such as Oklahoma and on indigenous lands,” says Dr. Giaimo. “There is a concerted effort to reach these communities, and we’re getting some recognition for those efforts, too.”

Dr. Gheewala also sees a greater emphasis on primary care physicians today, something that he believes has led more people to explore becoming or seeing a DO instead of an MD.

A full 57% of DOs focus on primary care, such as family practice, pediatrics, and internal medicine, with the others in specialized care. If those focused on primary care can fill some of the physician shortages, Dr. Gheewala says, it can help keep patients out of hospitals for their first line of care, reducing health care costs.

The tides are turning in the medical profession, as well, when it comes to respecting the osteopathy field. Students who graduate from osteopathic programs also have a high acceptance rate into residencies, which Dr. Giaimo credits to several factors.

He also doesn’t discount the fact that DOs are talking more about their practice approaches these days. “It hits the right note for modern medicine, and it’s also what the consumer is looking for today,” he adds.
 

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

The number of doctors of osteopathic medicine (DOs) is enjoying a significant growth pattern. This year alone, 7,300 osteopathic physicians are entering the workforce, and they make up more than 25% of the medical student population. The pipeline of future DOs is at an all-time high of 36,500 students, according to the American Osteopathic Association.

All 50 states plus Washington, D.C., have DO practices, and Florida ranks third in terms of states with the most practicing DOs, topped by California in the No. 1 spot and Pennsylvania in second. New York and Michigan round out the top 5.

The pipeline to the profession is in a growth mode, too. For the upcoming academic year, the AOA’s Commission on Osteopathic College Accreditation will accredit 38 colleges of osteopathic medicine in about 60 different locations.

Although DOs have existed for more than 100 years, historically they have sat somewhat in the shadow of their MD peers. That tide has turned, for a variety of reasons – one of which is recognition via several high-profile DOs. Look no further than the White House, for instance, where President Biden’s physician is Kevin O’Connor, DO – the second DO to hold the position.

“The misrepresentation of osteopathic physicians has been a recent issue outside the nation’s health care delivery system,” says the American Medical Association’s Robert Mills. “To combat this mischaracterization, the AMA and the AOA issued a joint statement [in 2020] highlighting the fact that DOs are licensed physicians who practice in every specialty area and have equivalent training and practice rights to their MD peers.”
 

Attraction to the DO philosophy

For many DOs, the path to osteopathic medicine was always a clear one. “I wanted to go into osteopathic medicine from the age of 17,” says Nehal Gheewala, DO, national director of growth at ChenMed, a national primary care medical center.

Dr. Gheewala, who graduated from medical school in 2014, says he first spent time learning about the DO’s holistic philosophy, which appealed to him. “I liked how they were invested in their patient’s care, and that they first tried to treat musculoskeletal pain with manipulation. The result were quick, sometimes on the spot.”

While in medical school, Dr. Gheewala was joined by 250 peers seeking a DO rather than an MD. “I never felt like I was in the minority,” he says, “and today, as a practicing physician in Florida, we have a good number of DOs.”

Like Dr. Gheewala, Samuel Werner, a New Jersey–based DO, was inspired by his father, a DO who has served as a small-town general practitioner. “Growing up, I saw how well-respected my dad was in the community and watched his connection with patients,” Dr. Werner says. “He had the ability to pick up on small details others didn’t.”

Today, Dr. Werner sees the recognition and respect of DOs growing beyond where it was several decades ago.

One factor that is helping raise the DO profile is that residencies fall under the same umbrella for matching. In most states, medical licensing is the same, as well. Choosing to pursue a DO career requires additional training in wellness and manipulation. “In every specialty of medicine, DO students train alongside MD students,” Dr. Werner says. “In practice, most patients are unaware if they’re treated by a DO or an MD.”

That has sometimes been Dr. Gheewala’s experience. “Plenty of patients don’t ask whether I’m an MD or a DO,” he says, “and it doesn’t matter. We’re all board-certified doctors and as long as we’re taking care of, and spending time with, our patients, that’s what they want.”

Joseph A. Giaimo, a DO in Florida who has practiced for more than 30 years and is a past president of the AOA, says that some patients will seek out a DO instead of an MD. “Many patients see me because they specifically want to work with a DO; many of them are snowbirds who come to Florida during the winter,” he explains.

In his long career as a DO, Dr. Giaimo has witnessed the profession’s growth alongside a fading stigma that it’s somehow less “authentic” than allopathic medicine. “There are still people who need to be educated on osteopathic medicine, but much of that has simply been a lack of understanding,” he says. “That’s changing, and it’s our role to continue to educate people on what we’re about.”

Dr. Giaimo says that osteopathic medicine is striking the right tone in the moment, which is helpful to recognition and growth. “Coming out of the pandemic, people are more focused on staying healthy, and osteopathy offers an appealing approach,” he says. “There’s no better time for the two houses of medicine to come together, and it’s a great time to be in osteopathy.”
 

Moving forward

One of the biggest places the physician shortage is problematic is in rural America. The federal government estimates that by 2025, there will be a physician shortage of 25,000 primary care doctors in these areas. This is another way in which the growing osteopathic field is having an impact.

“We have a number of schools in underserved areas, such as Oklahoma and on indigenous lands,” says Dr. Giaimo. “There is a concerted effort to reach these communities, and we’re getting some recognition for those efforts, too.”

Dr. Gheewala also sees a greater emphasis on primary care physicians today, something that he believes has led more people to explore becoming or seeing a DO instead of an MD.

A full 57% of DOs focus on primary care, such as family practice, pediatrics, and internal medicine, with the others in specialized care. If those focused on primary care can fill some of the physician shortages, Dr. Gheewala says, it can help keep patients out of hospitals for their first line of care, reducing health care costs.

The tides are turning in the medical profession, as well, when it comes to respecting the osteopathy field. Students who graduate from osteopathic programs also have a high acceptance rate into residencies, which Dr. Giaimo credits to several factors.

He also doesn’t discount the fact that DOs are talking more about their practice approaches these days. “It hits the right note for modern medicine, and it’s also what the consumer is looking for today,” he adds.
 

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

The number of doctors of osteopathic medicine (DOs) is enjoying a significant growth pattern. This year alone, 7,300 osteopathic physicians are entering the workforce, and they make up more than 25% of the medical student population. The pipeline of future DOs is at an all-time high of 36,500 students, according to the American Osteopathic Association.

All 50 states plus Washington, D.C., have DO practices, and Florida ranks third in terms of states with the most practicing DOs, topped by California in the No. 1 spot and Pennsylvania in second. New York and Michigan round out the top 5.

The pipeline to the profession is in a growth mode, too. For the upcoming academic year, the AOA’s Commission on Osteopathic College Accreditation will accredit 38 colleges of osteopathic medicine in about 60 different locations.

Although DOs have existed for more than 100 years, historically they have sat somewhat in the shadow of their MD peers. That tide has turned, for a variety of reasons – one of which is recognition via several high-profile DOs. Look no further than the White House, for instance, where President Biden’s physician is Kevin O’Connor, DO – the second DO to hold the position.

“The misrepresentation of osteopathic physicians has been a recent issue outside the nation’s health care delivery system,” says the American Medical Association’s Robert Mills. “To combat this mischaracterization, the AMA and the AOA issued a joint statement [in 2020] highlighting the fact that DOs are licensed physicians who practice in every specialty area and have equivalent training and practice rights to their MD peers.”
 

Attraction to the DO philosophy

For many DOs, the path to osteopathic medicine was always a clear one. “I wanted to go into osteopathic medicine from the age of 17,” says Nehal Gheewala, DO, national director of growth at ChenMed, a national primary care medical center.

Dr. Gheewala, who graduated from medical school in 2014, says he first spent time learning about the DO’s holistic philosophy, which appealed to him. “I liked how they were invested in their patient’s care, and that they first tried to treat musculoskeletal pain with manipulation. The result were quick, sometimes on the spot.”

While in medical school, Dr. Gheewala was joined by 250 peers seeking a DO rather than an MD. “I never felt like I was in the minority,” he says, “and today, as a practicing physician in Florida, we have a good number of DOs.”

Like Dr. Gheewala, Samuel Werner, a New Jersey–based DO, was inspired by his father, a DO who has served as a small-town general practitioner. “Growing up, I saw how well-respected my dad was in the community and watched his connection with patients,” Dr. Werner says. “He had the ability to pick up on small details others didn’t.”

Today, Dr. Werner sees the recognition and respect of DOs growing beyond where it was several decades ago.

One factor that is helping raise the DO profile is that residencies fall under the same umbrella for matching. In most states, medical licensing is the same, as well. Choosing to pursue a DO career requires additional training in wellness and manipulation. “In every specialty of medicine, DO students train alongside MD students,” Dr. Werner says. “In practice, most patients are unaware if they’re treated by a DO or an MD.”

That has sometimes been Dr. Gheewala’s experience. “Plenty of patients don’t ask whether I’m an MD or a DO,” he says, “and it doesn’t matter. We’re all board-certified doctors and as long as we’re taking care of, and spending time with, our patients, that’s what they want.”

Joseph A. Giaimo, a DO in Florida who has practiced for more than 30 years and is a past president of the AOA, says that some patients will seek out a DO instead of an MD. “Many patients see me because they specifically want to work with a DO; many of them are snowbirds who come to Florida during the winter,” he explains.

In his long career as a DO, Dr. Giaimo has witnessed the profession’s growth alongside a fading stigma that it’s somehow less “authentic” than allopathic medicine. “There are still people who need to be educated on osteopathic medicine, but much of that has simply been a lack of understanding,” he says. “That’s changing, and it’s our role to continue to educate people on what we’re about.”

Dr. Giaimo says that osteopathic medicine is striking the right tone in the moment, which is helpful to recognition and growth. “Coming out of the pandemic, people are more focused on staying healthy, and osteopathy offers an appealing approach,” he says. “There’s no better time for the two houses of medicine to come together, and it’s a great time to be in osteopathy.”
 

Moving forward

One of the biggest places the physician shortage is problematic is in rural America. The federal government estimates that by 2025, there will be a physician shortage of 25,000 primary care doctors in these areas. This is another way in which the growing osteopathic field is having an impact.

“We have a number of schools in underserved areas, such as Oklahoma and on indigenous lands,” says Dr. Giaimo. “There is a concerted effort to reach these communities, and we’re getting some recognition for those efforts, too.”

Dr. Gheewala also sees a greater emphasis on primary care physicians today, something that he believes has led more people to explore becoming or seeing a DO instead of an MD.

A full 57% of DOs focus on primary care, such as family practice, pediatrics, and internal medicine, with the others in specialized care. If those focused on primary care can fill some of the physician shortages, Dr. Gheewala says, it can help keep patients out of hospitals for their first line of care, reducing health care costs.

The tides are turning in the medical profession, as well, when it comes to respecting the osteopathy field. Students who graduate from osteopathic programs also have a high acceptance rate into residencies, which Dr. Giaimo credits to several factors.

He also doesn’t discount the fact that DOs are talking more about their practice approaches these days. “It hits the right note for modern medicine, and it’s also what the consumer is looking for today,” he adds.
 

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

Research that could set the stage for future clinical trials explored the potential role of adenosine signaling in altering the immune microenvironment of colorectal cancer (CRC), according to a study appearing in Cellular and Molecular Gastroenterology and Hepatology.

The study in human-derived cells and CRC mouse models suggests that addition of a CD73 inhibitor to the CDK4/6 inhibitor palbociclib may hold promise in the treatment of CRC because CD73 can produce extracellular adenosine. The results hold promise for future research since anticancer therapies often prompt increased expression of PD-L1, and CDK4/6 inhibitor monotherapy can fail because of accumulation of PD-L1 after such treatment.

Previous research has suggested that extracellular adenosine-mediated signaling can lead to accumulation of tumor-associated macrophages (TAMs) and an immunosuppressive tumor microenvironment. TAMs play an important role in the intestinal mucosal immune system in CRC, which mediates tumor-promoting metabolites in the intestine and inflammatory pathways that can lead to and progress CRC. TAMs are also linked to increases in extracellular enzymes like CD39 and CD73 as well as resistance to chemotherapy and anti-PD-1/PD-L1 therapy in CRC. Furthermore, they express PD-L1 and they promote other immunosuppressive molecules.

In normal tissues, CD73 produces adenosine to tamp down excessive immune responses. Some tumors express CD73 or even induce expression in normal cells, leading to immunosuppression in the tumor microenvironment. Previous studies have shown that CD73 expression is a biomarker for poor outcomes in gastric, liver, pancreatic, and colorectal cancer, the authors of this study noted.

To better understand the impact of adenosine, the researchers exposed human macrophages derived from peripheral blood to adenosine, and then analyzed the results using flow cytometry and Western blot. They used RNA sequencing and proteomics to discern changes in the cells that resulted from the exposure.

Adenosine treatment led to changes in the expression levels of genes involved in the cell cycle, cell division, cell cycle phase transition, and DNA repair. The researchers emphasized that extracellular treatment with adenosine led to a reduction in expression of the cell cycle–related gene CCND1, which encodes cyclin D1. Among three genes in the cyclin D family tested, CCND1 was the only one affected by adenosine. Cyclin D1 protein levels also went down.

Cyclin D1 is a known actor in regulating the cell cycle and tumorigenesis, among other roles. Previous reports indicated that cyclin D1 participates in posttranslational regulation of PD-L1, and the current study suggests it plays a similar role in TAMs after exposure to adenosine in the tumor microenvironment. Myeloid cells high in cyclin D1 expression had low levels or even an absence of the immunosuppressive molecule CD39. “Taken together, cyclin D1 may be one of the major orchestrators that trigger the differentiation of pro-tumorigenic TAMs. Our findings suggest a novel immune checkpoint regulatory mechanism of extracellular adenosine signaling, which might be related to the cell cycle of macrophages,” the authors wrote.

The researchers then introduced a short hairpin RNA directed against CCND1. This led to increases in PD-L1 protein levels. Simultaneous treatment with adenosine led to a slight increase in levels of the PD-L1 protein, which suggests that reduction of CCND1 levels is the primary cause of increased PD-L1, according to the authors.

The CD73 inhibitor AB680, currently in phase 1 clinical trials for castration-resistant prostate cancer and advanced pancreatic cancer and developed by Arcus Biosciences, led to reduced PD-L1 levels in both human and mouse macrophages, and AB680 combined with the CDK4/6 inhibitor palbociclib led to greater inhibition of tumor growth than palbociclib alone in CRC mouse models.

“Thus, the promising effects of CD73 inhibitors might breathe new life for those old drugs and provide potent therapeutic strategies. Given that the therapeutic effects of PD-1/PD-L1 immunotherapy have not been conclusively demonstrated in patients with CRC, our observations should support clinical trials of new combinational therapies for CRC,” the authors wrote.

The authors disclose no conflicts.
 

Research that could set the stage for future clinical trials explored the potential role of adenosine signaling in altering the immune microenvironment of colorectal cancer (CRC), according to a study appearing in Cellular and Molecular Gastroenterology and Hepatology.

The study in human-derived cells and CRC mouse models suggests that addition of a CD73 inhibitor to the CDK4/6 inhibitor palbociclib may hold promise in the treatment of CRC because CD73 can produce extracellular adenosine. The results hold promise for future research since anticancer therapies often prompt increased expression of PD-L1, and CDK4/6 inhibitor monotherapy can fail because of accumulation of PD-L1 after such treatment.

Previous research has suggested that extracellular adenosine-mediated signaling can lead to accumulation of tumor-associated macrophages (TAMs) and an immunosuppressive tumor microenvironment. TAMs play an important role in the intestinal mucosal immune system in CRC, which mediates tumor-promoting metabolites in the intestine and inflammatory pathways that can lead to and progress CRC. TAMs are also linked to increases in extracellular enzymes like CD39 and CD73 as well as resistance to chemotherapy and anti-PD-1/PD-L1 therapy in CRC. Furthermore, they express PD-L1 and they promote other immunosuppressive molecules.

In normal tissues, CD73 produces adenosine to tamp down excessive immune responses. Some tumors express CD73 or even induce expression in normal cells, leading to immunosuppression in the tumor microenvironment. Previous studies have shown that CD73 expression is a biomarker for poor outcomes in gastric, liver, pancreatic, and colorectal cancer, the authors of this study noted.

To better understand the impact of adenosine, the researchers exposed human macrophages derived from peripheral blood to adenosine, and then analyzed the results using flow cytometry and Western blot. They used RNA sequencing and proteomics to discern changes in the cells that resulted from the exposure.

Adenosine treatment led to changes in the expression levels of genes involved in the cell cycle, cell division, cell cycle phase transition, and DNA repair. The researchers emphasized that extracellular treatment with adenosine led to a reduction in expression of the cell cycle–related gene CCND1, which encodes cyclin D1. Among three genes in the cyclin D family tested, CCND1 was the only one affected by adenosine. Cyclin D1 protein levels also went down.

Cyclin D1 is a known actor in regulating the cell cycle and tumorigenesis, among other roles. Previous reports indicated that cyclin D1 participates in posttranslational regulation of PD-L1, and the current study suggests it plays a similar role in TAMs after exposure to adenosine in the tumor microenvironment. Myeloid cells high in cyclin D1 expression had low levels or even an absence of the immunosuppressive molecule CD39. “Taken together, cyclin D1 may be one of the major orchestrators that trigger the differentiation of pro-tumorigenic TAMs. Our findings suggest a novel immune checkpoint regulatory mechanism of extracellular adenosine signaling, which might be related to the cell cycle of macrophages,” the authors wrote.

The researchers then introduced a short hairpin RNA directed against CCND1. This led to increases in PD-L1 protein levels. Simultaneous treatment with adenosine led to a slight increase in levels of the PD-L1 protein, which suggests that reduction of CCND1 levels is the primary cause of increased PD-L1, according to the authors.

The CD73 inhibitor AB680, currently in phase 1 clinical trials for castration-resistant prostate cancer and advanced pancreatic cancer and developed by Arcus Biosciences, led to reduced PD-L1 levels in both human and mouse macrophages, and AB680 combined with the CDK4/6 inhibitor palbociclib led to greater inhibition of tumor growth than palbociclib alone in CRC mouse models.

“Thus, the promising effects of CD73 inhibitors might breathe new life for those old drugs and provide potent therapeutic strategies. Given that the therapeutic effects of PD-1/PD-L1 immunotherapy have not been conclusively demonstrated in patients with CRC, our observations should support clinical trials of new combinational therapies for CRC,” the authors wrote.

The authors disclose no conflicts.
 

Research that could set the stage for future clinical trials explored the potential role of adenosine signaling in altering the immune microenvironment of colorectal cancer (CRC), according to a study appearing in Cellular and Molecular Gastroenterology and Hepatology.

The study in human-derived cells and CRC mouse models suggests that addition of a CD73 inhibitor to the CDK4/6 inhibitor palbociclib may hold promise in the treatment of CRC because CD73 can produce extracellular adenosine. The results hold promise for future research since anticancer therapies often prompt increased expression of PD-L1, and CDK4/6 inhibitor monotherapy can fail because of accumulation of PD-L1 after such treatment.

Previous research has suggested that extracellular adenosine-mediated signaling can lead to accumulation of tumor-associated macrophages (TAMs) and an immunosuppressive tumor microenvironment. TAMs play an important role in the intestinal mucosal immune system in CRC, which mediates tumor-promoting metabolites in the intestine and inflammatory pathways that can lead to and progress CRC. TAMs are also linked to increases in extracellular enzymes like CD39 and CD73 as well as resistance to chemotherapy and anti-PD-1/PD-L1 therapy in CRC. Furthermore, they express PD-L1 and they promote other immunosuppressive molecules.

In normal tissues, CD73 produces adenosine to tamp down excessive immune responses. Some tumors express CD73 or even induce expression in normal cells, leading to immunosuppression in the tumor microenvironment. Previous studies have shown that CD73 expression is a biomarker for poor outcomes in gastric, liver, pancreatic, and colorectal cancer, the authors of this study noted.

To better understand the impact of adenosine, the researchers exposed human macrophages derived from peripheral blood to adenosine, and then analyzed the results using flow cytometry and Western blot. They used RNA sequencing and proteomics to discern changes in the cells that resulted from the exposure.

Adenosine treatment led to changes in the expression levels of genes involved in the cell cycle, cell division, cell cycle phase transition, and DNA repair. The researchers emphasized that extracellular treatment with adenosine led to a reduction in expression of the cell cycle–related gene CCND1, which encodes cyclin D1. Among three genes in the cyclin D family tested, CCND1 was the only one affected by adenosine. Cyclin D1 protein levels also went down.

Cyclin D1 is a known actor in regulating the cell cycle and tumorigenesis, among other roles. Previous reports indicated that cyclin D1 participates in posttranslational regulation of PD-L1, and the current study suggests it plays a similar role in TAMs after exposure to adenosine in the tumor microenvironment. Myeloid cells high in cyclin D1 expression had low levels or even an absence of the immunosuppressive molecule CD39. “Taken together, cyclin D1 may be one of the major orchestrators that trigger the differentiation of pro-tumorigenic TAMs. Our findings suggest a novel immune checkpoint regulatory mechanism of extracellular adenosine signaling, which might be related to the cell cycle of macrophages,” the authors wrote.

The researchers then introduced a short hairpin RNA directed against CCND1. This led to increases in PD-L1 protein levels. Simultaneous treatment with adenosine led to a slight increase in levels of the PD-L1 protein, which suggests that reduction of CCND1 levels is the primary cause of increased PD-L1, according to the authors.

The CD73 inhibitor AB680, currently in phase 1 clinical trials for castration-resistant prostate cancer and advanced pancreatic cancer and developed by Arcus Biosciences, led to reduced PD-L1 levels in both human and mouse macrophages, and AB680 combined with the CDK4/6 inhibitor palbociclib led to greater inhibition of tumor growth than palbociclib alone in CRC mouse models.

“Thus, the promising effects of CD73 inhibitors might breathe new life for those old drugs and provide potent therapeutic strategies. Given that the therapeutic effects of PD-1/PD-L1 immunotherapy have not been conclusively demonstrated in patients with CRC, our observations should support clinical trials of new combinational therapies for CRC,” the authors wrote.

The authors disclose no conflicts.
 

The RNA interference (RNAi) therapeutic, patisiran (Onpattro, Alnylam), showed a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-minute walk test (6-MWT), compared with placebo, in the treatment of transthyretin-mediated amyloidosis with cardiomyopathy, in the APOLLO-B trial.

The study also met its first secondary endpoint, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life.

These positive results, their first formal presentation, were announced Sept. 8 at the 18th International Symposium on Amyloidosis. However, the company announced positive top-line results from the trial in early August.

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract.

There are two different types of ATTR amyloidosis: hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, whereas wtATTR amyloidosis is estimated to affect 200,000-300,000 people worldwide.

Patisiran is an intravenously administered RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. It is also approved in the European Union, Switzerland, Brazil, and Japan for a similar indication. It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues.

“The results of the APOLLO-B phase 3 study are impressive, as I believe they underscore the potential for patisiran to provide a benefit on functional capacity and quality of life in patients living with ATTR amyloidosis with cardiomyopathy. Furthermore, these results were seen after only 12 months of treatment,” Mathew Maurer, MD, Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, New York, said in an Alnylam press release.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited. With the rapidly progressive nature of the disease, there is a significant need for treatments like patisiran, which has the potential to be a new option for patients and physicians to treat the cardiomyopathy of ATTR amyloidosis,” Dr. Maurer added.

APOLLO-B is a phase 3, randomized, double-blind study evaluating the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy who were randomly assigned 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every 3 weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

Results at 12 months, reported by Alnylam, found that the primary endpoint, the 6-MWT, showed a median change from baseline of –8.15 m for the patisiran group and –21.34 m for the placebo group, a significant difference favoring patisiran.

The first secondary endpoint was health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score. This showed a mean change from baseline of +0.300 for the patisiran group and –3.408 for the placebo group, a significant difference favoring patisiran.

Secondary composite outcome endpoints did not achieve statistical significance.

A nonsignificant result (win ratio, 1.27; P = .0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months, compared with placebo.

The final two composite endpoints were not powered for statistical significance, given the sample size and short duration of the study – all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (hazard ratio, 0.997) and in the overall study population (HR, 0.883).

Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR reduction of 87% at month 12.

A beneficial effect on the exploratory endpoint, N-terminal of the prohormone brain natriuretic peptide, a measure of cardiac stress, was observed in the patisiran arm, with a 20% reduction in the adjusted geometric mean fold change from baseline, compared with placebo.

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, during the 12-month treatment period, Alnylam reported.

The majority of adverse events were mild or moderate in severity. Treatment emergent adverse events in the patisiran group included infusion-related reactions, arthralgia, and muscle spasms.

In the safety analysis, there were five deaths (2.8%) observed in patisiran-treated patients and eight deaths (4.5%) observed in the placebo group.

Pushkal Garg, MD, chief medical officer at Alnylam, said: “We believe these data validate the therapeutic hypothesis that TTR silencing by an RNAi therapeutic may be an effective approach to treating cardiomyopathy of both wild-type and hereditary ATTR amyloidosis.”

Alnylam plans to file a supplemental new drug application for patisiran as a potential treatment for ATTR amyloidosis with cardiomyopathy in the United States in late 2022.

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

The RNA interference (RNAi) therapeutic, patisiran (Onpattro, Alnylam), showed a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-minute walk test (6-MWT), compared with placebo, in the treatment of transthyretin-mediated amyloidosis with cardiomyopathy, in the APOLLO-B trial.

The study also met its first secondary endpoint, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life.

These positive results, their first formal presentation, were announced Sept. 8 at the 18th International Symposium on Amyloidosis. However, the company announced positive top-line results from the trial in early August.

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract.

There are two different types of ATTR amyloidosis: hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, whereas wtATTR amyloidosis is estimated to affect 200,000-300,000 people worldwide.

Patisiran is an intravenously administered RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. It is also approved in the European Union, Switzerland, Brazil, and Japan for a similar indication. It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues.

“The results of the APOLLO-B phase 3 study are impressive, as I believe they underscore the potential for patisiran to provide a benefit on functional capacity and quality of life in patients living with ATTR amyloidosis with cardiomyopathy. Furthermore, these results were seen after only 12 months of treatment,” Mathew Maurer, MD, Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, New York, said in an Alnylam press release.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited. With the rapidly progressive nature of the disease, there is a significant need for treatments like patisiran, which has the potential to be a new option for patients and physicians to treat the cardiomyopathy of ATTR amyloidosis,” Dr. Maurer added.

APOLLO-B is a phase 3, randomized, double-blind study evaluating the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy who were randomly assigned 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every 3 weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

Results at 12 months, reported by Alnylam, found that the primary endpoint, the 6-MWT, showed a median change from baseline of –8.15 m for the patisiran group and –21.34 m for the placebo group, a significant difference favoring patisiran.

The first secondary endpoint was health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score. This showed a mean change from baseline of +0.300 for the patisiran group and –3.408 for the placebo group, a significant difference favoring patisiran.

Secondary composite outcome endpoints did not achieve statistical significance.

A nonsignificant result (win ratio, 1.27; P = .0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months, compared with placebo.

The final two composite endpoints were not powered for statistical significance, given the sample size and short duration of the study – all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (hazard ratio, 0.997) and in the overall study population (HR, 0.883).

Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR reduction of 87% at month 12.

A beneficial effect on the exploratory endpoint, N-terminal of the prohormone brain natriuretic peptide, a measure of cardiac stress, was observed in the patisiran arm, with a 20% reduction in the adjusted geometric mean fold change from baseline, compared with placebo.

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, during the 12-month treatment period, Alnylam reported.

The majority of adverse events were mild or moderate in severity. Treatment emergent adverse events in the patisiran group included infusion-related reactions, arthralgia, and muscle spasms.

In the safety analysis, there were five deaths (2.8%) observed in patisiran-treated patients and eight deaths (4.5%) observed in the placebo group.

Pushkal Garg, MD, chief medical officer at Alnylam, said: “We believe these data validate the therapeutic hypothesis that TTR silencing by an RNAi therapeutic may be an effective approach to treating cardiomyopathy of both wild-type and hereditary ATTR amyloidosis.”

Alnylam plans to file a supplemental new drug application for patisiran as a potential treatment for ATTR amyloidosis with cardiomyopathy in the United States in late 2022.

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

The RNA interference (RNAi) therapeutic, patisiran (Onpattro, Alnylam), showed a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-minute walk test (6-MWT), compared with placebo, in the treatment of transthyretin-mediated amyloidosis with cardiomyopathy, in the APOLLO-B trial.

The study also met its first secondary endpoint, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life.

These positive results, their first formal presentation, were announced Sept. 8 at the 18th International Symposium on Amyloidosis. However, the company announced positive top-line results from the trial in early August.

Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal tract.

There are two different types of ATTR amyloidosis: hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, whereas wtATTR amyloidosis is estimated to affect 200,000-300,000 people worldwide.

Patisiran is an intravenously administered RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. It is also approved in the European Union, Switzerland, Brazil, and Japan for a similar indication. It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues.

“The results of the APOLLO-B phase 3 study are impressive, as I believe they underscore the potential for patisiran to provide a benefit on functional capacity and quality of life in patients living with ATTR amyloidosis with cardiomyopathy. Furthermore, these results were seen after only 12 months of treatment,” Mathew Maurer, MD, Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center, New York, said in an Alnylam press release.

“The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited. With the rapidly progressive nature of the disease, there is a significant need for treatments like patisiran, which has the potential to be a new option for patients and physicians to treat the cardiomyopathy of ATTR amyloidosis,” Dr. Maurer added.

APOLLO-B is a phase 3, randomized, double-blind study evaluating the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy who were randomly assigned 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every 3 weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

Results at 12 months, reported by Alnylam, found that the primary endpoint, the 6-MWT, showed a median change from baseline of –8.15 m for the patisiran group and –21.34 m for the placebo group, a significant difference favoring patisiran.

The first secondary endpoint was health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score. This showed a mean change from baseline of +0.300 for the patisiran group and –3.408 for the placebo group, a significant difference favoring patisiran.

Secondary composite outcome endpoints did not achieve statistical significance.

A nonsignificant result (win ratio, 1.27; P = .0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months, compared with placebo.

The final two composite endpoints were not powered for statistical significance, given the sample size and short duration of the study – all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (hazard ratio, 0.997) and in the overall study population (HR, 0.883).

Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR reduction of 87% at month 12.

A beneficial effect on the exploratory endpoint, N-terminal of the prohormone brain natriuretic peptide, a measure of cardiac stress, was observed in the patisiran arm, with a 20% reduction in the adjusted geometric mean fold change from baseline, compared with placebo.

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, during the 12-month treatment period, Alnylam reported.

The majority of adverse events were mild or moderate in severity. Treatment emergent adverse events in the patisiran group included infusion-related reactions, arthralgia, and muscle spasms.

In the safety analysis, there were five deaths (2.8%) observed in patisiran-treated patients and eight deaths (4.5%) observed in the placebo group.

Pushkal Garg, MD, chief medical officer at Alnylam, said: “We believe these data validate the therapeutic hypothesis that TTR silencing by an RNAi therapeutic may be an effective approach to treating cardiomyopathy of both wild-type and hereditary ATTR amyloidosis.”

Alnylam plans to file a supplemental new drug application for patisiran as a potential treatment for ATTR amyloidosis with cardiomyopathy in the United States in late 2022.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

The Food and Drug Administration is alerting health care providers about the potential for clip lock malfunctions with Abbott’s MitraClip’s delivery system.

“These events appear to occur in approximately 1.3% of MitraClip procedures and have been observed with all device models,” the FDA says in a letter posted on its website.

The MitraClip device was approved in 2013 for patients with symptomatic, degenerative mitral regurgitation (MR) deemed high risk for mitral-valve surgery.

In its own “urgent medical device correction letter” to providers, Abbott reports a recent increase in reports of the clips failing to “establish final arm angle (EFAA)” and of “clip opening while locked (COWL)” events.

During device preparation and prior to clip deployment, the operator intentionally attempts to open a locked clip to verify that the locking mechanism is engaged.

COWL describes when the clip arm angle increases postdeployment. “In these cases, users observe a slippage in the lock, resulting in an arm angle greater than 10 degrees from the angle observed at deployment,” which can be identified through fluoroscopy, Abbott says.

From February 2021 to January 2022, the EFAA failure rate was 0.51% and COWL rate 0.28%, increasing to 0.80% and 0.50%, respectively, from February 2022 to July 2022, according to the company.

Despite the increase in reports, the acute procedural success rate remains consistent with historical data, according to Abbott. “Further, EFAA failure or COWL most often results in no adverse patient outcomes. COWL may lead to less MR reduction, which is often treated with the use of one or more additional clips.”

Abbott says there is also a “low incidence” of required additional interventions. No immediate open surgical conversions have occurred as a result of EFAA/COWL events, whereas 0.53% of such events have resulted in nonurgent surgical conversions.

“In any case where significant residual MR is observed after clip deployment, a second clip should be considered and implanted in accordance with the IFU [instructions for use],” it advises.

Abbott says that a “change in the material properties of one of the clip locking components” has been identified as a contributing cause of EFAA/COWL events. It is working on producing new lots with updated manufacturing processing and raw material to mitigate the risk.

Certain use conditions can also contribute to EFAA/COWL events, and are referenced in the IFU, Appendix A, it notes.

The FDA is working with Abbott and recommends that health care providers do the following:

• Review the recall notice from Abbott for all MitraClip Clip Delivery Systems.
• Be aware of the potential for clip lock malfunctions before or after deployment with this device.
• Read and carefully follow the instructions for use and the recommendations provided in the recall notice to help minimize the chance of the clip failing to lock. These include recommendations about procedural steps for implant positioning, locking sequences, establishing clip arm angle, preparation for clip release, and avoiding excessive force and manipulation when unlocking the clip during device preparation and during the procedure.

Health care professionals can also report adverse reactions or quality problems they experience using these devices to the FDA’s MedWatch program.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Health concerns about the consumption of artificial sweeteners could be strengthened with the publication of a new study linking their intake to increased risk of heart disease and stroke events.

In this latest large-scale, prospective study of French adults, total artificial sweetener intake from all sources was associated with increased risk overall of cardiovascular and cerebrovascular disease.

The study was published online in the BMJ.

The current study differs from those done previously in that it includes artificial sweetener intake from both food and drinks, whereas previous studies have focused mainly on artificial sweetener content of beverages alone.

“Here we have quantified for the first time the global exposure to artificial sweeteners. This is not just beverages but includes the use of tabletop sweeteners, and other foods that include artificial sweeteners such as yogurts and desserts. This is the first time this information has been correlated to risk of heart disease,” senior author Mathilde Touvier, MD, Sorbonne Paris Nord University, told this news organization.

Just over half of the artificial sweetener intake in the study came from drinks, with the rest coming from tabletop sweeteners and foods.

“We included hard cardio- and cerebrovascular clinical endpoints such as a heart attack or stroke, and our results suggest that the amount of artificial sweetener in less than one can of soda could increase the risk of such events,” Dr. Touvier noted.

“This is an important and statistically significant association which shows robustness in all models after adjusting for many other possible confounding factors,” she said.

“There is now mounting evidence correlating artificial sweeteners to weight gain and heart disease,” she concluded. “My advice would be that we all need to try to limit sugar intake, but we should not consider artificial sweeteners as safe alternatives. Rather, we need to try to reduce our need for a sugary taste in our diet.”

But another leading researcher in the field urges caution in interpreting these results.

John Sievenpiper, MD, departments of nutritional sciences and medicine, University of Toronto, commented: “This paper shows the same relationship seen by many other large prospective cohorts which model the intake of artificial sweeteners as baseline or prevalent exposures.

“These observations are well recognized to be at high risk of residual confounding from behavior clustering and reverse causality in which being at risk for cardiovascular disease causes people to consume artificial sweeteners as a strategy to mitigate this risk as opposed to the other way around.”
 

Risk increased by 9%

The current study included 103,388 French adults from the NutriNet-Sante cohort, of whom 37.1% reported consumption of artificial sweeteners. The sweeteners assessed were mainly aspartame (58% of sweetener intake), acesulfame potassium (29%), and sucralose (10%), with the other 3% made up of various other sweeteners including cyclamates and saccharin.

Results showed that over an average 9 years of follow-up, artificial sweetener intake was associated with a 9% increased risk of cardiovascular or cerebrovascular events, including myocardial infarction, acute coronary syndrome, angioplasty, angina, stroke, or transient ischemic attack, with a hazard ratio of 1.09 (95% confidence interval, 1.01-1.18; P = .03).

The average intake of artificial sweeteners among those who reported consuming them was 42.46 mg/day, which corresponds to approximately one individual packet of tabletop sweetener or 100 mL of diet soda.

“We don’t have enough evidence to work out an amount of artificial sweetener that is harmful, but we did show a dose-effect association, with a higher risk of cardiovascular events with higher consumption,” Dr. Touvier said.

“Higher consumption in this study was a mean of 77 mg/day artificial sweetener, which is about 200 mL of soda – just a bit less than one standard can of soda,” she added.

The absolute incidence rate of cardiovascular or cerebrovascular events in higher consumers was 346 per 100,000 person-years vs. 314 per 100,000 person-years in nonconsumers.

Further analysis suggested that aspartame intake was particularly associated with increased risk of cerebrovascular events, while acesulfame potassium and sucralose were associated with increased coronary heart disease risk.
 

Study strengths

Dr. Touvier acknowledged that dietary studies, which generally rely on individuals self-reporting food and drink intake, are always hard to interpret. But she said this study used a more reliable method of dietary assessment, with repeated 24-hour dietary records, which were validated by interviews with a trained dietitian and against blood and urinary biomarkers.

And whereas residual confounding cannot be totally excluded, she pointed out that models were adjusted for a wide range of potential sociodemographic, anthropometric, dietary, and lifestyle confounders.

Dr. Touvier also noted that cases of cardiovascular disease in the first 2 years of follow-up were excluded to minimize the bias caused by individuals who maybe have switched to artificial sweeteners because of a cardiovascular issue.

“While this study has many strengths, it cannot on its own prove a causal relationship between artificial sweetener and increased cardiovascular risk,” she added. “We need health agencies to examine all the literature in the field. This is however another important piece of evidence.”

Dr. Touvier says that although observational studies have their issues, they will form the basis of the evidence on the effects of artificial sweeteners on health.

“Randomized studies in this area can only really look at short-term outcomes such as weight gain or biomarker changes. So, we will have to use observational studies together with experimental research to build the evidence. This is what happened with cigarette smoking and lung cancer. That link was not established by randomized trials, but by the accumulation of observational and experimental data.”
 

Different artificial sweeteners may be better?

Commenting on the study, Kim Williams Sr., MD, University of Louisville (Ky.), pointed out that this study included artificial sweeteners that increase insulin or decrease insulin sensitivity, and that insulin spikes increase obesity, insulin resistance, hypertension, and atherosclerosis.

“There are some safer artificial sweeteners that do not increase insulin much or at all, such as erythritol, yacon root/yacon syrup, stevia root, but they weren’t included in the analysis,” Dr. Williams added.

Dr. Sievenpiper explained that most studies on artificial sweeteners look at their consumption in isolation without considering how they compare to the intake of the sugars that they are intended to replace.

“The comparator matters as no food is consumed in a vacuum,” he said.

To address this, Dr. Sievenpiper and colleagues have recently published a systematic review and meta-analysis of the prospective cohort study evidence that shows if exposure to artificially sweetened beverages is modeled in substitution for sugar-sweetened beverages, then they are associated with less coronary heart disease, cardiovascular mortality, and all-cause mortality.

On the other hand, if exposure to artificially sweetened beverages is compared with water, then no difference in these outcomes was seen.

“These observations are more biologically plausible, robust, and reproducible and agree with the evidence for the effect of artificial sweeteners on intermediate risk factors in randomized trials,” Dr. Sievenpiper notes.

His group has also recently published a review of randomized studies showing that when compared with sugar-sweetened beverages, intake of artificially sweetened beverages was associated with small improvements in body weight and cardiometabolic risk factors without evidence of harm.

“I think the context provided by these studies is important, and taken together, the totality of the evidence suggests that artificial sweeteners are likely to be a useful tool in sugar reduction strategies,” Dr. Sievenpiper concludes.

The current study was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program, French National Cancer Institute, French Ministry of Health, IdEx Université de Paris Cité, Bettencourt-Schueller Foundation Research Prize 2021. The authors have disclosed no relevant financial relationships.

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

Imagine that instead of a patient visiting their doctor for blood tests, they could rely on a noninvasive at-home test to predict their risk of diabetes, a disease that affects nearly 15% of U.S. adults (23% of whom are undiagnosed), according to the U.S. Centers for Disease Control and Prevention.

This technology could become a reality thanks to a research team that developed a machine learning algorithm to predict whether people had type 2 diabetes, prediabetes, or no diabetes. In an article published in BMJ Innovations, the researchers describe how their algorithm sorted people into these three categories with 97% accuracy on the basis of measurements of the heart’s electrical activity, determined from an electrocardiogram.

To develop and train their machine learning model – a type of artificial intelligence (AI) that keeps getting smarter over time – researchers used ECG measurements from 1,262 people in Central India. The study participants were part of the Sindhi population, an ethnic group that has been shown in past studies to be at elevated risk for type 2 diabetes.

Why ECG data? Because “cardiovascular abnormalities and diabetes, they go hand in hand,” says study author Manju Mamtani, MD, general manager of M&H Research, San Antonio, and treasurer of the Lata Medical Research Foundation. Subtle cardiovascular changes can occur even early in the development of diabetes.

“ECG has the power to detect these fluctuations, at least in theory, but those fluctuations are so tiny that many times we as humans looking at that might miss it,” says study author Hemant Kulkarni, MD, chief executive officer of M&H Research and president of the Lata Medical Research Foundation. “But the AI, which is powered to detect such specific fluctuations or subtle features, we hypothesized for the study that the AI algorithm might be able to pick those things up. And it did.”

Although this isn’t the first AI algorithm developed to predict diabetes risk, it outperforms previous models, the researchers say.

The team hopes to test and validate the algorithm in a variety of populations so that it can eventually be developed into an accessible, user-friendly technology. They envision that someday their algorithm could be used in smartwatches or other smart devices and could be integrated into telehealth so that people could be screened for diabetes even if they weren’t able to travel to a health care facility for blood testing.

The team is also studying other noninvasive methods of early disease detection and predictive models for adverse outcomes using AI.

“The fact that these algorithms are able to pick up the things of interest and learn on their own and keep learning in the future also adds excitement to their use in these settings,” says Dr. Kulkarni.

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

Imagine that instead of a patient visiting their doctor for blood tests, they could rely on a noninvasive at-home test to predict their risk of diabetes, a disease that affects nearly 15% of U.S. adults (23% of whom are undiagnosed), according to the U.S. Centers for Disease Control and Prevention.

This technology could become a reality thanks to a research team that developed a machine learning algorithm to predict whether people had type 2 diabetes, prediabetes, or no diabetes. In an article published in BMJ Innovations, the researchers describe how their algorithm sorted people into these three categories with 97% accuracy on the basis of measurements of the heart’s electrical activity, determined from an electrocardiogram.

To develop and train their machine learning model – a type of artificial intelligence (AI) that keeps getting smarter over time – researchers used ECG measurements from 1,262 people in Central India. The study participants were part of the Sindhi population, an ethnic group that has been shown in past studies to be at elevated risk for type 2 diabetes.

Why ECG data? Because “cardiovascular abnormalities and diabetes, they go hand in hand,” says study author Manju Mamtani, MD, general manager of M&H Research, San Antonio, and treasurer of the Lata Medical Research Foundation. Subtle cardiovascular changes can occur even early in the development of diabetes.

“ECG has the power to detect these fluctuations, at least in theory, but those fluctuations are so tiny that many times we as humans looking at that might miss it,” says study author Hemant Kulkarni, MD, chief executive officer of M&H Research and president of the Lata Medical Research Foundation. “But the AI, which is powered to detect such specific fluctuations or subtle features, we hypothesized for the study that the AI algorithm might be able to pick those things up. And it did.”

Although this isn’t the first AI algorithm developed to predict diabetes risk, it outperforms previous models, the researchers say.

The team hopes to test and validate the algorithm in a variety of populations so that it can eventually be developed into an accessible, user-friendly technology. They envision that someday their algorithm could be used in smartwatches or other smart devices and could be integrated into telehealth so that people could be screened for diabetes even if they weren’t able to travel to a health care facility for blood testing.

The team is also studying other noninvasive methods of early disease detection and predictive models for adverse outcomes using AI.

“The fact that these algorithms are able to pick up the things of interest and learn on their own and keep learning in the future also adds excitement to their use in these settings,” says Dr. Kulkarni.

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

Imagine that instead of a patient visiting their doctor for blood tests, they could rely on a noninvasive at-home test to predict their risk of diabetes, a disease that affects nearly 15% of U.S. adults (23% of whom are undiagnosed), according to the U.S. Centers for Disease Control and Prevention.

This technology could become a reality thanks to a research team that developed a machine learning algorithm to predict whether people had type 2 diabetes, prediabetes, or no diabetes. In an article published in BMJ Innovations, the researchers describe how their algorithm sorted people into these three categories with 97% accuracy on the basis of measurements of the heart’s electrical activity, determined from an electrocardiogram.

To develop and train their machine learning model – a type of artificial intelligence (AI) that keeps getting smarter over time – researchers used ECG measurements from 1,262 people in Central India. The study participants were part of the Sindhi population, an ethnic group that has been shown in past studies to be at elevated risk for type 2 diabetes.

Why ECG data? Because “cardiovascular abnormalities and diabetes, they go hand in hand,” says study author Manju Mamtani, MD, general manager of M&H Research, San Antonio, and treasurer of the Lata Medical Research Foundation. Subtle cardiovascular changes can occur even early in the development of diabetes.

“ECG has the power to detect these fluctuations, at least in theory, but those fluctuations are so tiny that many times we as humans looking at that might miss it,” says study author Hemant Kulkarni, MD, chief executive officer of M&H Research and president of the Lata Medical Research Foundation. “But the AI, which is powered to detect such specific fluctuations or subtle features, we hypothesized for the study that the AI algorithm might be able to pick those things up. And it did.”

Although this isn’t the first AI algorithm developed to predict diabetes risk, it outperforms previous models, the researchers say.

The team hopes to test and validate the algorithm in a variety of populations so that it can eventually be developed into an accessible, user-friendly technology. They envision that someday their algorithm could be used in smartwatches or other smart devices and could be integrated into telehealth so that people could be screened for diabetes even if they weren’t able to travel to a health care facility for blood testing.

The team is also studying other noninvasive methods of early disease detection and predictive models for adverse outcomes using AI.

“The fact that these algorithms are able to pick up the things of interest and learn on their own and keep learning in the future also adds excitement to their use in these settings,” says Dr. Kulkarni.

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