Clinical Endocrinology News

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Pediatric nephrologist Bryan Carmody, MD, recalls working alongside an extremely experienced neonatologist during his residency. She had managed a neonatal intensive care unit in her home country of Lithuania, but because she wanted to practice in the United States, it took years of repeat training before she was eligible for a medical license.

“She was very accomplished, and she was wonderful to have as a coresident at the time,” Dr. Carmody said in an interview.

The neonatologist now practices at a U.S. academic medical center, but to obtain that position, she had to complete 3 years of pediatric residency and 3 years of fellowship in the United States, Dr. Carmody said.

Such training for international medical graduates (IMGs) is a routine part of obtaining a U.S. medical license, but a new Tennessee law bypasses these requirements and creates a quicker pathway for IMGs to secure medical licenses in the United States.

The American Medical Association took similar measures at its recent annual meeting, making it easier for IMGs to gain licensure. Because the pandemic and Russia’s invasion of Ukraine disrupted the process by which some IMGs had their licenses verified, the AMA is now encouraging state licensing boards and other credentialing institutions to accept certification from the Educational Commission for Foreign Medical Graduates as verification, rather than requiring documents directly from international medical schools.

When it comes to Tennessee’s new law, signed by Gov. Bill Lee in April, experienced IMGs who have received medical training abroad can skip U.S. residency requirements and obtain a temporary license to practice medicine in Tennessee if they meet certain qualifications.

The international doctors must demonstrate competency, as determined by the state medical board. In addition, they must have completed a 3-year postgraduate training program in the graduate’s licensing country or otherwise have practiced as a medical professional in which they performed the duties of a physician for at least 3 of the past 5 years outside the United States, according to the new law.

To be approved, IMGs must also have received an employment offer from a Tennessee health care provider that has a residency program accredited by the Accreditation Council for Graduate Medical Education.

If physicians remain in good standing for 2 years, the board will grant them a full and unrestricted license to practice in Tennessee.

“The new legislation opens up a lot of doors for international medical graduates and is also a lifeline for a lot of underserved areas in Tennessee,” said Asim Ansari, MD, a Canadian who attended medical school in the Caribbean and is an advocate for IMGs.

Dr. Ansari is participating in a child and adolescent psychiatry fellowship at the University of Kansas Medical Center, Kansas City, until he can apply for the sixth time to a residency program. “This could possibly be a model that other states may want to implement in a few years.”
 

What’s behind the law?

A predicted physician shortage in Tennessee drove the legislation, said Rep. Sabi “Doc” Kumar, MD, vice chair for the Tennessee House Health Committee and a cosponsor of the legislation. Legislators hope the law will mitigate that shortage and boost the number of physicians practicing in underserved areas of the state.

“Considering that one in four physicians in the U.S. are international medical gradates, it was important for us to be able to attract those physicians to Tennessee,” he said.

The Tennessee Board of Medical Examiners will develop administrative rules for the law, which may take up to a year, Rep. Kumar said. He expects the program to be available to IMGs beginning in mid-2024.

Upon completion of the program, IMGs will be able to practice general medicine in Tennessee, not a specialty. Requirements for specialty certification would have to be met through the specialties’ respective boards.

Dr. Carmody, who blogs about medical education, including the new legislation, said in an interview the law will greatly benefit experienced IMGs, who often are bypassed as residency candidates because they graduated years ago. Hospitals also win because they can fill positions that otherwise might sit vacant, he said.

Family physician Sahil Bawa, MD, an IMG from India who recently matched into his specialty, said the Tennessee legislation will help fellow IMGs find U.S. medical jobs.

“It’s very difficult for IMGs to get into residency in the U.S.,” he said. “I’ve seen people with medical degrees from other countries drive Uber or do odd jobs to sustain themselves here. I’ve known a few people who have left and gone back to their home country because they were not accepted into a residency.”
 

Who benefits most?

Dr. Bawa noted that the legislation would not have helped him, as he needed a visa to practice in the United States and the law does not include the sponsoring of visas. The legislation requires IMGs to show evidence of citizenship or evidence that they are legally entitled to live or work in the United States.

U.S. citizen IMGs who haven’t completed residency or who practiced in another country also are left out of the law, Dr. Carmody said.

“This law is designed to take the most accomplished cream of the crop international medical graduates with the most experience and the most sophisticated skill set and send them to Tennessee. I think that’s the intent,” he said. “But many international medical graduates are U.S. citizens who don’t have the opportunity to practice in countries other than United States or do residencies. A lot of these people are sitting on the sidelines, unable to secure residency positions. I’m sure they would be desperate for a program like this.”
 

Questions remain

“Just because the doctor can get a [temporary] license without the training doesn’t mean employers are going to be interested in sponsoring those doctors,” said Adam Cohen, an immigration attorney who practices in Memphis. “What is the inclination of these employers to hire these physicians who have undergone training outside the U.S.? And will there be skepticism on the part of employers about the competence of these doctors?”

“Hospital systems will be able to hire experienced practitioners for a very low cost,” Dr. Ansari said. “So now you have these additional bodies who can do the work of a physician, but you don’t have to pay them as much as a physician for 2 years. And because some are desperate to work, they will take lower pay as long as they have a pathway to full licensure in Tennessee. What are the protections for these physicians? Who will cover their insurance? Who will be responsible for them, the attendees? And will the attendees be willing to put their license on the line for them?”

In addition, Dr. Carmody questions what, if anything, will encourage IMGs to work in underserved areas in Tennessee after their 2 years are up and whether there will be any incentives to guide them. He wonders, too, whether the physicians will be stuck practicing in Tennessee following completion of the program.

“Will these physicians only be able to work in Tennessee?” he asked. “I think that’s probably going to be the case, because they’ll be licensed in Tennessee, but to go to another state, they would be missing the required residency training. So it might be these folks are stuck in Tennessee unless other states develop reciprocal arrangements.”

Other states would have to decide whether to recognize the Tennessee license acquired through this pathway, Rep. Kumar said.

He explained that the sponsoring sites would be responsible for providing work-hour restrictions and liability protections. There are currently no incentives in the legislation for IMGs to practice in rural, underserved areas, but the hospitals and communities there generally offer incentives when recruiting, Rep. Kumar said.

“The law definitely has the potential to be helpful,” Mr. Cohen said, “because there’s an ability to place providers in the state without having to go through the bottleneck of limited residency slots. If other states see a positive effect on Tennessee or are exploring ways to alleviate their own shortages, it’s possible [they] might follow suit.”

Rep. Kumar agreed that other states will be watching Tennessee to weigh the law’s success.

“I think the law will have to prove itself and show that Tennessee has benefited from it and that the results have been good,” he said. “We are providing a pioneering way for attracting medical graduates and making it easier for them to obtain a license. I would think other states would want to do that.”

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

Interventions that specifically address diabetes distress can not only improve patient mental health but can also cut costs, according to two new studies in patients with type 1 diabetes presented at the annual scientific sessions of the American Diabetes Association.

Danielle Hessler Jones, PhD, presented findings from Behavioral Approaches to Reducing Diabetes Distress and Improving Glycemic Control (EMBARK) in adults with type 1 diabetes during an oral session.

The three-arm randomized trial found that patients had the greatest improvements in feelings of powerlessness after a 3-month behavioral intervention that combined type 1 diabetes education plus specific attention to diabetes distress.

And in a late-breaking poster, “Do The Right Thing: Behavioral Intervention for At-Risk T1D Youth,” David V. Wagner, PhD, showed that a behavioral intervention not only improved glycemic management but also reduced cost of care in disadvantaged youth.

“Diabetes distress is the emotional response to living with diabetes, the burden of relentless daily self-management, and the prospect of its long-term complications,” said Dr. Hessler Jones, professor and vice chair for research in the department of family and community medicine at the University of California, San Francisco.  

It is common, experienced by 20%-58% of people with type 1 and type 2 diabetes, and is different from depression, as it is associated with glycemic control and disease management. It “is also chronic and does not disappear on its own without intervention,” she stressed.

“It is the expected worries, concerns, and fears that are associated with struggling with a demanding and progressive chronic disease and its management,” she added.

The findings from EMBARK “suggest that distress reductions are greatest when interventions integrate education alongside approaches to address the emotional side of diabetes,” she said.  

The group is also analyzing changes in A1c with the three different interventions in EMBARK, with results expected this fall.

Dr. Hessler Jones said they also just received funding for DDASSIST, which will answer the question: “How do I translate this into care in my clinic?” The aim of the clinic training program is to bring the intervention to the diabetes care team.

“Could this program be delivered by somebody else, other than a psychologist?” an audience member asked. They will be looking at this, she replied.
 

‘Do the right thing’

For the late-breaking poster by Dr. Wagner and colleagues, researchers evaluated direct cost data from three health care systems provided for youth with type 1 diabetes who received an intensive behavioral health intervention, Novel Interventions in Children’s Healthcare (NICH).

Youths were included in the analyses if they had type 1 diabetes and at least 1 year of cost data prior to and following NICH enrollment. Outpatient, emergency department, and inpatient costs were combined. The analysis included 53 youth with the following characteristics: mean age, 14.2 years; 87% Medicaid; 58% female; 32% Black, 29% Non-Hispanic White, 28% Hispanic/Latinx, 7% Pacific Islander, 2% Asian, and 2% other racial and ethnic groups.

Average yearly costs significantly decreased from $20,400 per youth prior to NICH to $9,500 per youth afterward, largely due to inpatient charges.

“These results highlight the benefits of providing access to intensive interventions to pediatric populations experiencing health disparities,” said Dr. Wagner. “Investing early in the lives of youth experiencing health disparities is not only the right thing to do to improve patients’ health but it could also have a positive economic impact down the road.”
 

Three interventions in 300 adults with type 1 diabetes

Meanwhile, EMBARK recruited 300 patients with type 1 diabetes in the United States from clinics and community organizations who were aged 21 and older and had an elevated type 1 diabetes distress score (> 2.0) and A1c greater than or equal to 7.5%.

Participants were a mean age of 46 years, 79% were female, and 89% were White. They had a type 1 diabetes distress score of 2.8, a mean A1c of 8.3%, and 71% used an insulin pump and 79% used a continuous glucose monitor.

Participants were randomized to one of three interventions:

• Streamline: A traditional diabetes educator-led education and management program.
• Tuned-in: A psychologist-led program focused exclusively on reducing diabetes distress.
• Fixit: An integration of the two programs.

Interventions were given virtually over 3 months to small groups of 8-12 individuals and included initial workshops, one-to-one phone calls, and follow-up group meetings. Participants were then followed for 8 months.  

Researchers found statistically significant and substantial reductions in overall diabetes distress in all three interventions, with the greatest reductions in the combined intervention group, which were greater than in the educational approach alone group (P = .005).

The percentage of participants who no longer reported elevated diabetes distress at follow-up was 25% in Streamline, 37% in Tuned-in, and 42% in Fixit.

The percentage of participants who reported a minimal clinically important difference – the smallest change in a treatment outcome that an individual would identify as important – was also greatest in those in the Fixit intervention group (82%) than in the Tuned-in (74%) or Streamline (65%) interventions.
 

‘Adding the psychologist is where the real magic happens’

“The certified diabetes care specialist intervention is really a very standard thing that most clinicians would have access to; they tend to focus on knowledge and problem solving and some of the psychosocial issues,” Robert Gabbay, MD, PhD, chief scientific and medical officer for the ADA, said in an interview.

The EMBARK trial found a “graded response: CDCS alone, psychologist really focused on diabetes distress, and the two together, which would be the ideal practice model,” he noted.

There are these validated ways of measuring diabetes distress using a diabetes distress survey tool, which is also underutilized.  

“Adding the psychologist is really where the real magic happens in terms of diabetes distress,” Dr. Gabbay said.

“As you can imagine, [if] somebody ... feels powerless, it is going to be tough to manage their diabetes and unlikely to be terribly successful,” he observed. Often, these individuals are just not doing well. This study highlighted the importance of identifying this.

“I’m encouraged by the findings from the studies presented during this year’s Scientific Sessions as we continue to seek out innovative, evidence-based solutions that support people living with diabetes when they need it the most,” Dr. Gabbay concluded.

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

Interventions that specifically address diabetes distress can not only improve patient mental health but can also cut costs, according to two new studies in patients with type 1 diabetes presented at the annual scientific sessions of the American Diabetes Association.

Danielle Hessler Jones, PhD, presented findings from Behavioral Approaches to Reducing Diabetes Distress and Improving Glycemic Control (EMBARK) in adults with type 1 diabetes during an oral session.

The three-arm randomized trial found that patients had the greatest improvements in feelings of powerlessness after a 3-month behavioral intervention that combined type 1 diabetes education plus specific attention to diabetes distress.

And in a late-breaking poster, “Do The Right Thing: Behavioral Intervention for At-Risk T1D Youth,” David V. Wagner, PhD, showed that a behavioral intervention not only improved glycemic management but also reduced cost of care in disadvantaged youth.

“Diabetes distress is the emotional response to living with diabetes, the burden of relentless daily self-management, and the prospect of its long-term complications,” said Dr. Hessler Jones, professor and vice chair for research in the department of family and community medicine at the University of California, San Francisco.  

It is common, experienced by 20%-58% of people with type 1 and type 2 diabetes, and is different from depression, as it is associated with glycemic control and disease management. It “is also chronic and does not disappear on its own without intervention,” she stressed.

“It is the expected worries, concerns, and fears that are associated with struggling with a demanding and progressive chronic disease and its management,” she added.

The findings from EMBARK “suggest that distress reductions are greatest when interventions integrate education alongside approaches to address the emotional side of diabetes,” she said.  

The group is also analyzing changes in A1c with the three different interventions in EMBARK, with results expected this fall.

Dr. Hessler Jones said they also just received funding for DDASSIST, which will answer the question: “How do I translate this into care in my clinic?” The aim of the clinic training program is to bring the intervention to the diabetes care team.

“Could this program be delivered by somebody else, other than a psychologist?” an audience member asked. They will be looking at this, she replied.
 

‘Do the right thing’

For the late-breaking poster by Dr. Wagner and colleagues, researchers evaluated direct cost data from three health care systems provided for youth with type 1 diabetes who received an intensive behavioral health intervention, Novel Interventions in Children’s Healthcare (NICH).

Youths were included in the analyses if they had type 1 diabetes and at least 1 year of cost data prior to and following NICH enrollment. Outpatient, emergency department, and inpatient costs were combined. The analysis included 53 youth with the following characteristics: mean age, 14.2 years; 87% Medicaid; 58% female; 32% Black, 29% Non-Hispanic White, 28% Hispanic/Latinx, 7% Pacific Islander, 2% Asian, and 2% other racial and ethnic groups.

Average yearly costs significantly decreased from $20,400 per youth prior to NICH to $9,500 per youth afterward, largely due to inpatient charges.

“These results highlight the benefits of providing access to intensive interventions to pediatric populations experiencing health disparities,” said Dr. Wagner. “Investing early in the lives of youth experiencing health disparities is not only the right thing to do to improve patients’ health but it could also have a positive economic impact down the road.”
 

Three interventions in 300 adults with type 1 diabetes

Meanwhile, EMBARK recruited 300 patients with type 1 diabetes in the United States from clinics and community organizations who were aged 21 and older and had an elevated type 1 diabetes distress score (> 2.0) and A1c greater than or equal to 7.5%.

Participants were a mean age of 46 years, 79% were female, and 89% were White. They had a type 1 diabetes distress score of 2.8, a mean A1c of 8.3%, and 71% used an insulin pump and 79% used a continuous glucose monitor.

Participants were randomized to one of three interventions:

• Streamline: A traditional diabetes educator-led education and management program.
• Tuned-in: A psychologist-led program focused exclusively on reducing diabetes distress.
• Fixit: An integration of the two programs.

Interventions were given virtually over 3 months to small groups of 8-12 individuals and included initial workshops, one-to-one phone calls, and follow-up group meetings. Participants were then followed for 8 months.  

Researchers found statistically significant and substantial reductions in overall diabetes distress in all three interventions, with the greatest reductions in the combined intervention group, which were greater than in the educational approach alone group (P = .005).

The percentage of participants who no longer reported elevated diabetes distress at follow-up was 25% in Streamline, 37% in Tuned-in, and 42% in Fixit.

The percentage of participants who reported a minimal clinically important difference – the smallest change in a treatment outcome that an individual would identify as important – was also greatest in those in the Fixit intervention group (82%) than in the Tuned-in (74%) or Streamline (65%) interventions.
 

‘Adding the psychologist is where the real magic happens’

“The certified diabetes care specialist intervention is really a very standard thing that most clinicians would have access to; they tend to focus on knowledge and problem solving and some of the psychosocial issues,” Robert Gabbay, MD, PhD, chief scientific and medical officer for the ADA, said in an interview.

The EMBARK trial found a “graded response: CDCS alone, psychologist really focused on diabetes distress, and the two together, which would be the ideal practice model,” he noted.

There are these validated ways of measuring diabetes distress using a diabetes distress survey tool, which is also underutilized.  

“Adding the psychologist is really where the real magic happens in terms of diabetes distress,” Dr. Gabbay said.

“As you can imagine, [if] somebody ... feels powerless, it is going to be tough to manage their diabetes and unlikely to be terribly successful,” he observed. Often, these individuals are just not doing well. This study highlighted the importance of identifying this.

“I’m encouraged by the findings from the studies presented during this year’s Scientific Sessions as we continue to seek out innovative, evidence-based solutions that support people living with diabetes when they need it the most,” Dr. Gabbay concluded.

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

Interventions that specifically address diabetes distress can not only improve patient mental health but can also cut costs, according to two new studies in patients with type 1 diabetes presented at the annual scientific sessions of the American Diabetes Association.

Danielle Hessler Jones, PhD, presented findings from Behavioral Approaches to Reducing Diabetes Distress and Improving Glycemic Control (EMBARK) in adults with type 1 diabetes during an oral session.

The three-arm randomized trial found that patients had the greatest improvements in feelings of powerlessness after a 3-month behavioral intervention that combined type 1 diabetes education plus specific attention to diabetes distress.

And in a late-breaking poster, “Do The Right Thing: Behavioral Intervention for At-Risk T1D Youth,” David V. Wagner, PhD, showed that a behavioral intervention not only improved glycemic management but also reduced cost of care in disadvantaged youth.

“Diabetes distress is the emotional response to living with diabetes, the burden of relentless daily self-management, and the prospect of its long-term complications,” said Dr. Hessler Jones, professor and vice chair for research in the department of family and community medicine at the University of California, San Francisco.  

It is common, experienced by 20%-58% of people with type 1 and type 2 diabetes, and is different from depression, as it is associated with glycemic control and disease management. It “is also chronic and does not disappear on its own without intervention,” she stressed.

“It is the expected worries, concerns, and fears that are associated with struggling with a demanding and progressive chronic disease and its management,” she added.

The findings from EMBARK “suggest that distress reductions are greatest when interventions integrate education alongside approaches to address the emotional side of diabetes,” she said.  

The group is also analyzing changes in A1c with the three different interventions in EMBARK, with results expected this fall.

Dr. Hessler Jones said they also just received funding for DDASSIST, which will answer the question: “How do I translate this into care in my clinic?” The aim of the clinic training program is to bring the intervention to the diabetes care team.

“Could this program be delivered by somebody else, other than a psychologist?” an audience member asked. They will be looking at this, she replied.
 

‘Do the right thing’

For the late-breaking poster by Dr. Wagner and colleagues, researchers evaluated direct cost data from three health care systems provided for youth with type 1 diabetes who received an intensive behavioral health intervention, Novel Interventions in Children’s Healthcare (NICH).

Youths were included in the analyses if they had type 1 diabetes and at least 1 year of cost data prior to and following NICH enrollment. Outpatient, emergency department, and inpatient costs were combined. The analysis included 53 youth with the following characteristics: mean age, 14.2 years; 87% Medicaid; 58% female; 32% Black, 29% Non-Hispanic White, 28% Hispanic/Latinx, 7% Pacific Islander, 2% Asian, and 2% other racial and ethnic groups.

Average yearly costs significantly decreased from $20,400 per youth prior to NICH to $9,500 per youth afterward, largely due to inpatient charges.

“These results highlight the benefits of providing access to intensive interventions to pediatric populations experiencing health disparities,” said Dr. Wagner. “Investing early in the lives of youth experiencing health disparities is not only the right thing to do to improve patients’ health but it could also have a positive economic impact down the road.”
 

Three interventions in 300 adults with type 1 diabetes

Meanwhile, EMBARK recruited 300 patients with type 1 diabetes in the United States from clinics and community organizations who were aged 21 and older and had an elevated type 1 diabetes distress score (> 2.0) and A1c greater than or equal to 7.5%.

Participants were a mean age of 46 years, 79% were female, and 89% were White. They had a type 1 diabetes distress score of 2.8, a mean A1c of 8.3%, and 71% used an insulin pump and 79% used a continuous glucose monitor.

Participants were randomized to one of three interventions:

• Streamline: A traditional diabetes educator-led education and management program.
• Tuned-in: A psychologist-led program focused exclusively on reducing diabetes distress.
• Fixit: An integration of the two programs.

Interventions were given virtually over 3 months to small groups of 8-12 individuals and included initial workshops, one-to-one phone calls, and follow-up group meetings. Participants were then followed for 8 months.  

Researchers found statistically significant and substantial reductions in overall diabetes distress in all three interventions, with the greatest reductions in the combined intervention group, which were greater than in the educational approach alone group (P = .005).

The percentage of participants who no longer reported elevated diabetes distress at follow-up was 25% in Streamline, 37% in Tuned-in, and 42% in Fixit.

The percentage of participants who reported a minimal clinically important difference – the smallest change in a treatment outcome that an individual would identify as important – was also greatest in those in the Fixit intervention group (82%) than in the Tuned-in (74%) or Streamline (65%) interventions.
 

‘Adding the psychologist is where the real magic happens’

“The certified diabetes care specialist intervention is really a very standard thing that most clinicians would have access to; they tend to focus on knowledge and problem solving and some of the psychosocial issues,” Robert Gabbay, MD, PhD, chief scientific and medical officer for the ADA, said in an interview.

The EMBARK trial found a “graded response: CDCS alone, psychologist really focused on diabetes distress, and the two together, which would be the ideal practice model,” he noted.

There are these validated ways of measuring diabetes distress using a diabetes distress survey tool, which is also underutilized.  

“Adding the psychologist is really where the real magic happens in terms of diabetes distress,” Dr. Gabbay said.

“As you can imagine, [if] somebody ... feels powerless, it is going to be tough to manage their diabetes and unlikely to be terribly successful,” he observed. Often, these individuals are just not doing well. This study highlighted the importance of identifying this.

“I’m encouraged by the findings from the studies presented during this year’s Scientific Sessions as we continue to seek out innovative, evidence-based solutions that support people living with diabetes when they need it the most,” Dr. Gabbay concluded.

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

SAN DIEGO – A new analysis of a large-scale trial of a novel lipid-lowering agent has shown a particularly large reduction in cardiovascular events in the primary prevention population enrolled in the study, two-thirds of whom also had type 2 diabetes, leading to calls for more attention to be paid to this group of patients.

The main results of the CLEAR Outcomes trial of bempedoic acid (Nexletol, Esperion) in a mixed secondary and primary prevention population intolerant to statins, presented in March at the 2023 joint scientific sessions of the American College of Cardiology and the World Heart Federation, showed a 13% relative risk reduction in the main primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, or coronary revascularization.

This new analysis of the 4,206 high-risk primary prevention patients in the study – 67% of whom also had type 2 diabetes – has shown a 30% relative risk reduction in the same endpoint.

Other key endpoints were reduced to a similar or even greater extent, with the composite of cardiovascular death/stroke/MI showing a 36% relative risk reduction, and a 39% relative risk reduction for cardiovascular death and MI individually.

“These results are frankly striking,” lead investigator Steve Nissen, MD, said in an interview. 

“These are really large reductions. These results are telling us that high-risk primary prevention patients, although their absolute event rate is lower than secondary prevention patients, can have very impressive relative risk reductions in major cardiovascular events with lipid-lowering therapy,” he said.

But Dr. Nissen, chief academic officer at the Heart Vascular & Thoracic Institute at the Cleveland Clinic, pointed out that this population of patients is not well treated. 

“This is the problem: Less than half of high-risk primary prevention patients in the U.S., and in virtually every other developed country, are receiving cholesterol-lowering medication. These patients tend to get ignored,” he stressed. 

Asked what advice he would give to clinicians based on the current findings, Dr. Nissen said: “If a patient is at high risk of developing cardiovascular disease, particularly those with [type 2] diabetes, they need to go on a lipid-lowering drug.” 

“If patients can tolerate a statin then that should be the first choice. We know statins work, and they are now inexpensive. They are likely to give the exact same benefit as we have shown in this study with bempedoic acid, as the two drug classes work by very similar mechanisms. But if patients can’t tolerate a statin, then treat them with bempedoic acid. The bottom line is that these patients just need to be treated,” he said.
 

‘Wake-up call’

He said these new results are a “wake-up call for the medical community that we need to pay far more attention to high-risk primary prevention patients.”

Dr. Nissen does not believe the effect is specific to bempedoic acid; rather, it is more likely an effect of lowering LDL cholesterol (LDL-C) levels. 

“This message is not about bempedoic acid, in particular. We have seen similar findings in historical studies with the statins, but that seems to have been forgotten. The message is about lowering LDL in patients who are at high risk of having a first cardiovascular event. We need to identify patients at high risk for a first cardiac event and get them on a cholesterol-lowering drug – and in most cases that will be a statin.”

Dr. Nissen presented the new analysis from the CLEAR OUTCOMES trial at the annual scientific sessions of the American Diabetes Association. It was simultaneously published online in JAMA.

He pointed out that large trials of lipid-lowering therapy in the primary prevention population have not been done for many years. 

“All the contemporary trials with lipid-lowering therapy have only included secondary prevention patients and they often enroll patients after an acute coronary syndrome event.

“But for the CLEAR OUTCOMES trial, we included a significant amount of primary prevention patients – those with risk factors such as [type 2] diabetes and hypertension who are considered to be at high risk of developing cardiovascular disease,” he explained.

CLEAR OUTCOMES was a masked, randomized, trial that enrolled 13,970 statin-intolerant patients. The new analysis included 4,206 of those patients with risk factors for heart disease but without a prior cardiovascular event – the primary prevention group. The mean age of these participants was 68 years, 67% had diabetes, and 59% were women.

Treatment with bempedoic acid showed a 22% reduction in LDL-C, compared with placebo, with a reduction of 30.2 mg/dL from a mean baseline of 142.5 mg/dL. High-sensitivity C-reactive protein (CRP) levels were also reduced by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L.

Dr. Nissen told a press briefing at the ADA meeting that he believes “it’s the combination of LDL lowering and reduction in CRP that might have been the driver [for the effects we saw in the trial]. Certainly, bempedoic acid lowers both.”

And he noted the recent U.S. approval of a new low dose of colchicine 0.5 mg (Lodoco, Agepha Pharma) with a broad indication for use in atherosclerotic cardiovascular disease (ASCVD), which represents a completely new approach to treatment, specifically targeting inflammation as a driver of atherosclerosis.

Bempedoic acid is a prodrug that works along the same pathways as statins but does not cause muscle pain, which makes many people intolerant to statins. Bempedoic acid was first approved by the Food and Drug Administration in 2020 for the treatment of adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.
 

Greater benefit in primary prevention?

In this primary prevention group, treatment with bempedoic acid for 40 months was associated with a significant risk reduction for the primary endpoint – a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or coronary revascularization – which occurred in 5.3% of the treatment group versus 7.6% in the placebo group (adjusted hazard ratio, 0.70; P = .002). This represents a 30% relative risk reduction in major cardiovascular events.

Other key secondary endpoints also showed impressive reductions.

The rate of the composite endpoint of cardiovascular death, MI, or stroke was 6.4% in the placebo group and 4.0% with bempedoic acid (HR, 0.64; P < .001); MI occurred in 2.2% versus 1.4% (HR, 0.61), cardiovascular death in 3.1% versus 1.8% (HR, 0.61), and all-cause mortality in 5.2% versus 3.6% (HR, 0.73), respectively.

Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs. 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Dr. Nissen believed these results suggest that there may be a greater benefit of lipid lowering in high-risk primary prevention patients than in the secondary prevention population.

“It may seem paradoxical, but there is actually some history that this may be the case,” he said.

He pointed out that the JUPITER trial of rosuvastatin in 2008 was the last major primary prevention trial of a lipid-lowering agent, which was stopped early with a 44% reduction of the primary endpoint.

He noted that one of the arguments against the use of statins in primary prevention is the belief that absolute risk reductions are quite modest.

“But in this analysis, we found an absolute risk reduction of 2.3% for the primary endpoint. That’s a number needed to treat to prevent 1 event of 43. That’s pretty good,” he said.

Trying to explain why there may be more benefit in the primary prevention population, Dr. Nissen suggested that these patients may have more vulnerable plaques.

“I think high-risk primary prevention patients probably have a lot of lipid-laden plaque – some people call it ‘vulnerable’ plaque. These are softer, cholesterol-laden plaque. We know that treatment with cholesterol-lowering medication causes these plaques to shrink. The lipid core is delipidated and the plaque stabilizes,” he explained. “It may be that in secondary prevention patients to some extent the horse is already out of the barn – they have advanced disease. But primary prevention patients may have plaques that are more amenable to modification by cholesterol lowering.”

He admitted that the idea is only speculation. “But that is a potential explanation for our observations.”
 

Editorial cautious

In an accompanying editorial, also published in JAMA, Dhruv S. Kazi, MD, Beth Israel Deaconess Medical Center, Boston, said the findings need to be interpreted with caution as they come from one of many subgroup analyses of a larger trial.

Dr. Kazi pointed out that the intervention and control survival curves separate right away, on the first day of follow-up, whereas the true effect of lipid-lowering therapy for primary prevention would be expected to have a somewhat delayed onset, an observation he says supports the argument that this is a chance finding.

Dr. Kazi also reminded clinicians that bempedoic acid should not be regarded as a substitute for statins, which should remain the first-line therapy for primary prevention.

“For now, available evidence suggests that, although bempedoic acid is not a perfect substitute for a statin, it is a reasonable therapeutic choice for primary prevention of ASCVD events in high-risk, statin-intolerant patients,” he concluded.

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

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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

SAN DIEGO – Weekly tirzepatide injections in adults with type 2 diabetes and overweight or obesity safely led to 12.8%-14.7% in-trial weight loss after 72 weeks in the SURMOUNT-2 pivotal trial, a finding that will likely lead to Food and Drug Administration approval of a new indication for weight loss for tirzepatide.

Tirzepatide received FDA approval as a treatment for type 2 diabetes in adults, marketed as Mounjaro, in 2022. The agent – a “twincretin” that acts as an agonist at both the glucagon-like peptide-1 (GLP-1) receptor and glucose-dependent insulinotropic polypeptide (GIP) receptor – had also previously scored a decisive win for weight loss in adults with overweight or obesity without diabetes in the SURMOUNT-1 pivotal trial.

Taken together, results from SURMOUNT-1 and SURMOUNT-2 appear to make a good case for a weight-loss indication that will not depend on whether a patient also has type 2 diabetes.

“We anticipate that tirzepatide will be [FDA] approved for weight loss later this year,” W. Timothy Garvey, MD, lead researcher for SURMOUNT-2, said during a press briefing at the annual scientific sessions of the American Diabetes Association.
 

Tirzepatide ‘fills the gap’

Tirzepatide “fills the gap to get [medication-driven] weight loss in the range of 15% of baseline weight or better,” Dr. Garvey noted, which puts it in a favorable position relative to a 2.4-mg weekly subcutaneous injection with the GLP-1 agonist semaglutide (Wegovy), which produced an average weight loss from baseline of about 9.6% in people with type 2 diabetes in the STEP-2 trial. 

Mitchel L. Zoler/MDedge News

Although tirzepatide has not been compared head-to-head for weight loss with any of the several available GLP-1 agonists, the reported weight-loss numbers seem to favor tirzepatide, said Dr. Garvey, director of the Diabetes Research Center of the University of Alabama at Birmingham.

“If you look at the degree of weight loss across trials, we see a clinically significant difference in weight loss” compared with semaglutide and other agents that only act on the GLP-1 receptor, he noted. (Although cross-trial comparisons of different medications often have uncertain reliability.)

“The data suggest an incremental effect from tirzepatide” compared with the GLP-1 agonists now approved for weight loss, said Marlon Pragnell, PhD, vice president, research and science, ADA, who was not involved in the tirzepatide studies.

This is a “step forward for treating people with obesity and type 2 diabetes; it’s a very promising treatment option,” Dr. Pragnell said in an interview.
 

Tirzepatide the ‘most effective agent’

Ildiko Lingvay, MD, the designated discussant for the SURMOUNT-2 presentation at the meeting, fully agreed. The new findings “confirm that tirzepatide is the most effective agent currently on the [U.S.] market to help achieve the two coprimary goals for patients with type 2 diabetes – weight loss and glycemic control – while also having favorable effects on cardiovascular risk factors,” said Dr. Lingvay, an endocrinologist at UT Southwestern Medical Center in Dallas, who was not involved with the SURMOUNT studies.

Dr. Lingvay offered as evidence the performance of tirzepatide’s main rival for weight loss semaglutide (Wegovy), delivered at the 2.4 mg/week subcutaneous injected dosage approved for weight loss. The semaglutide trial that SURMOUNT-2 most resembles is the STEP-2 trial, she said, which showed as its primary outcome a 9.6% average weight loss from baseline after 68 weeks of weekly semaglutide that compares, in a cross-trial way, with the 14.7% average drop from baseline weight with 15 mg tirzepatide weekly for 72 weeks and an average 12.8% weight loss with a weekly 10-mg tirzepatide dose.

“It’s fair to say that tirzepatide has an edge,” despite the limitations of cross-trial comparisons, Dr. Lingvay said in an interview.

But she acknowledged that superior weight loss efficacy takes a back seat in U.S. practice to access and affordability when making a prescribing decision for individual patients as these newer drugs are all expensive. 
 

Affordability and access will remain a ‘big problem’

Dr. Garvey, too, cautioned that access and affordability of tirzepatide as well as other GLP-1 agonists remains a major sticking point.

“These medications are very expensive – more than $1,000 a dose – and this cost limits access ... [which is] a big problem,” Dr. Garvey noted. U.S. health care payers “do not want to open the gates [to expensive treatments] for a disorder that’s as common as obesity.”

“Access and affordability are always an issue for these medications,” agreed Janet Brown-Friday, RN, president, health care and education, ADA, who had no role in the tirzepatide studies.

SURMOUNT-2 randomized 938 adults with type 2 diabetes and overweight or obesity at 77 centers in seven countries including the United States from March 2021 to April 2023. The study had two primary outcomes: Average percent change in body weight from baseline to week 72, and percentage of participants who achieved a weight reduction from baseline of at least 5% after 72 weeks.
 

In-trial weight loss of 12.8%-14.7%

The in-trial analysis showed that a 10-mg weekly subcutaneous dose of tirzepatide resulted in an average 12.8% weight loss from baseline, and a 15-mg weekly subcutaneous dose led to an average 14.7% drop from baseline weight. People randomized to receive a placebo injection averaged a 3.2% drop from their baseline weight after 72 weeks, a finding that documents significant improvements compared with placebo with both tirzepatide doses.

The percentage of patients who achieved at least a 5% reduction in weight from baseline was 79% with the 10-mg dose of tirzepatide, 83% with the 15-mg dose, and 32% with placebo; these improvements were significant for both tirzepatide doses compared with placebo.

A 15% or greater reduction in weight from baseline occurred in 40%-48% of people who received tirzepatide compared with 3% of those who received placebo. A reduction in weight of this magnitude from baseline “will prevent a broad array of complications,” Dr. Garvey noted.

The results were simulatenously published online in The Lancet.
 

Glucose control without severe hypoglycemia

The safety profile of tirzepatide in SURMOUNT-2 was consistent with prior studies of the agent, as well as with other medications in the GLP-1 agonist class, with gastrointestinal adverse effects such as nausea and vomiting predominating, especially during the dose-escalation phase at treatment onset.

Dr. Garvey especially highlighted the overall safety of tirzepatide, and particularly its ability to produce clinically important reductions in A1c that averaged more than two percentage points from baseline values without producing a single episode of severe hypoglycemia, and an incidence of milder hypoglycemia of less than a 5%.

The absence of any severe hypoglycemia was “amazing,” Dr. Garvey said, especially given that 46%-49% of people taking tirzepatide in SURMOUNT-2 achieved normalization of their A1c to less than 5.7% on treatment compared with 4% of participants taking placebo.

The results also showed the benefit of a “big reduction in fasting insulin levels,” which averaged a 41% cut from baseline in those who received the 15-mg subcutaneous weekly dose of tirzepatide, coupled with increased insulin sensitivity, Dr. Garvey said.

Dr. Garvey disclosed ties to Eli Lilly, which sponsored SURMOUNT-2 and markets tirzepatide (Mounjaro), as well Boehringer Ingelheim, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck. He has been an investigator for studies sponsored by Novo Nordisk, Epitomee, Neurovalens, and Pfizer. Dr. Pragnell and Dr. Brown-Friday have disclosed no relevant financial relationships.



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

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

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

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

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

CHICAGO – Clinical trials are so White. Only a small percentage of eligible patients participate in clinical trials in the first place, and very few come from racial and ethnic minority groups.

For example, according to the Food and Drug Administration, in trials that resulted in drug approvals from 2017 to 2020, only 2%-5% of participants were Black patients.

When clinical trials lack diverse patient populations, those who are left out have fewer opportunities to get new therapies. Moreover, the scope of the research is limited by smaller phenotypic and genotypic samples, and the trial results are applicable only to more homogeneous patient groups.

There has been a push to include more underrepresented patients in clinical trials. One group reported its success in doing so here at the annual meeting of the American Society of Clinical Oncology.

Researchers from the Alliance for Clinical Trials in Oncology explained how a multifaceted approach resulted in a 75% relative improvement in trial enrollment from 2014 to 2022, a period that included a pandemic-induced hiatus in clinical trials in general.

Alliance member Electra D. Paskett, PhD, from the College of Public Health at the Ohio State University in Columbus, presented accrual data from 117 trials led by the Alliance from 2014 to 2022.

During this period, accrual of racial and ethnic minority patients increased from 13.6% to 25.3% for cancer treatment trials and from 13% to 21.5% for cancer control trials.

Overall, the recruitment program resulted in an absolute increase from 13.5 % to 23.6% of underrepresented populations, which translated into a relative 74.8% improvement.

“We’re focusing now on monitoring accrual of women, rural populations, younger AYAs [adolescents and young adults] and older patients, and we’ll see what strategies we need to implement,” Dr. Packett told this news organization.

The Alliance has implemented a real-time accrual dashboard on its website that allows individual sites to review accrual by trial and overall for all of the identified underrepresented populations, she noted.
 

Program to increase underrepresented patient accrual

The impetus for the program to increase enrollment of underrepresented patients came from the goal set by Monica M. Bertagnolli, MD, group chair of the Alliance from 2011 to 2022 and currently the director of the U.S. National Cancer Institute.

“Our leader, Dr. Bertagnolli, set out a group-wide goal for accrual of underrepresented minorities to our trials of 20%, and that gave us permission to implement a whole host of new strategies,” Dr. Paskett said in an interview.

“These strategies follow the Accrual of Clinical Trials framework, which essentially says that the interaction between the patient and the provider for going on a clinical trial is not just an interaction between the patient and provider but recognizes, for example, that the provider has coworkers and they have norms and beliefs and attitudes, and the patient comes from a family with their own values. And then there are system-level barriers, and there are community barriers that all relate to this interaction about going on a trial,” Dr. Packett said.
 

What works?

The study was presented as a poster at the meeting. During the poster discussion session, comoderator Victoria S. Blinder, MD, from Memorial Sloan Kettering Cancer Center in New York, asked Dr. Paskett, “If you had a certain amount of money and you really wanted to use that resource to focus on one area, where would you put that resource?”

“I’m going to violate the rules of your question,” Dr. Paskett replied.

“You cannot change this problem by focusing on one thing, and that’s what we showed in our Alliance poster, and what I’ve said is based on over 30 years of work in this area,” she said.

She cited what she considered as the two most important components for improving accrual of underrepresented populations: a commitment by leadership to a recruitment goal, and the development of protocols with specific accrual goals for minority populations.

Still, those are only two components of a comprehensive program that includes the aforementioned accrual goal set by Dr. Bertagnolli, as well as the following:

• Funding of minority junior investigators and research that focuses on issues of concern to underrepresented populations.
• Establishment of work groups that focus on specific populations with the Alliance health disparities committee.
• Translation of informational materials for patients.
• Opening studies at National Cancer Institute Community. Oncology Research Program–designated minority underserved sites.
• Real-time monitoring of accrual demographics by the Alliance and at the trial site.
• Closing protocol enrollment to majority populations.
• Increasing the study sample sizes to enroll additional minority participants and to allow for subgroup analyses.

The study was funded by the National Institutes of Health. Dr. Packett and Dr. Blinder reported no relevant financial relationships.

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

Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
 

They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.

The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.

Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.

In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.

They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.

The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.

For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.

The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.

The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.

However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”

Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.

Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).

While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.

Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.

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

Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
 

They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.

The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.

Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.

In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.

They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.

The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.

For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.

The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.

The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.

However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”

Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.

Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).

While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.

Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.

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

Thach Tran, MD, and colleagues introduced the concept of “skeletal age” in a recently published paper that aims to incorporate the impact of fragility, or low trauma, fractures – which can occur in patients with osteoporosis – on mortality risk.
 

They defined “skeletal age” as the age of the skeleton following a fragility fracture. This is calculated as the chronological age of the individual plus the number of years of “life lost” as a consequence of the specific fracture.

The risk for premature death following fragility fractures is concerning, with 22%-58% of patients with hip fracture dying within a year (Brauer et al.; Rapp et al.). Thus, it’s important to treat osteoporosis in a timely fashion to reduce the risk for such fractures and the excess mortality risk associated with them.

Implementation and uptake of such treatment, however, either before or after a fragility fracture, is far from optimal (Solomon et al). This may be because patients don’t fully understand the consequence of such a fracture, and outcomes measures currently in use (such as relative risk or hazard of mortality) are difficult to communicate to patients.

In the recent paper by Dr. Tran and colleagues, the authors examined the association between fractures and mortality based on sex, age, associated comorbidities, and fracture site. They pooled this information to create a “skeletal age” for each fracture site, using data from the Danish National Hospital Discharge Registry, which documents fractures and related mortality for all Danish people.

They examined mortality over a period of at least 2 years following a fragility fracture in individuals aged 50 or older, and reported that occurrence of any fragility fracture is associated with a 30%-45% increased risk for death, with the highest risk noted for hip and femur fractures (twofold increase). Fractures of the pelvis, vertebrae, humerus, ribs, clavicle, and lower leg were also associated with increased mortality risk, but no increase was seen with fractures of the forearm, knee, ankle, hand, or foot.

The number of years of life lost at any age depending on the fracture site is represented as a linear graph of skeletal age for any chronological age, for specific fracture sites, separated by sex.

For example, the skeletal age of a 50-year-old man who has a hip fracture is 57 years (7 years of life lost as a consequence of the fracture), while that for a 70-year-old man with the same fracture is 75 years (5 years of life lost because of the fracture). Similarly, the skeletal age of a 50-year-old man with a fracture of the pelvis, femur, vertebrae, and humerus is 55 years (5 years of life lost). Fractures of the lower leg, humerus, and clavicle lead to fewer lost years of life.

The authors are to be commended for creating a simple strategy to quantify mortality risk following low-impact or fragility fractures in older individuals; this could enable providers to communicate the importance of osteoporosis treatment more effectively to patients on the basis of their skeletal age, and for patients to better understand this information.

The study design appears reasonably robust as the authors considered many factors that might affect mortality risk, such as sex, age, and comorbidities, and the results are based on information from a very large number of people – 1.6 million.

However, there’s a major issue with the concept of “skeletal age” as proposed by Dr. Tran and colleagues. The term is already in use and defines the maturity of bones in children and adolescents, also called “bone age” (Greulich and Pyle 1959; Skeletal Age, Radiology Key). This is a real oversight and could cause confusion in interpreting “skeletal age.”

Skeletal age as currently defined in children and adolescents is influenced by chronological age, exposure to certain hormones, nutritional deficiencies, and systemic diseases, and is a predictor of adult height based on the skeletal age and current height. This concept is completely different from that being proposed by the authors in this paper. Dr. Tran and colleagues (and the reviewers of this paper) are probably not familiar with the use of the terminology in youth, which is a major oversight; they should consider changing the terminology given this overlap.

Further, fragility fractures can occur from osteoporosis at any age, and this study doesn’t provide information regarding years of life lost from occurrence of fragility fractures at younger ages, or the age at which mortality risk starts to increase (as the study was performed only in those aged 50 or older).

While the study takes into account general comorbidities in developing the model to define years of life lost, it doesn’t account for other factors that can influence fracture risk, such as lifestyle factors, activity level, and genetic risk (family history of osteoporosis, for example). Of note, the impact of additional fractures isn’t considered either and should be factored into future investigations.

Overall, the study is robust and important and provides valuable information regarding mortality risk from a fragility fracture in older people. However, there are some flaws that need to be considered and addressed, the most serious of which is that the term “skeletal age” has been in existence for decades, applied to a much younger age group, and its implications are completely different from those being proposed by the authors here.

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

VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.

Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.

In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.

The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.

“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.

“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
 

FDA-chosen endpoints likely to predict clinical outcomes

The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect. 

Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.

Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.

Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.

Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively. 

The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.

“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”   

Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.

Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.

Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
 

Safety profile

“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.

Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related. 

Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.

“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”

Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.

Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”

EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”

Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.

Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.

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

VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.

Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.

In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.

The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.

“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.

“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
 

FDA-chosen endpoints likely to predict clinical outcomes

The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect. 

Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.

Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.

Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.

Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively. 

The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.

“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”   

Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.

Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.

Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
 

Safety profile

“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.

Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related. 

Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.

“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”

Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.

Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”

EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”

Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.

Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.

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

VIENNA – Resolution of nonalcoholic steatohepatitis (NASH), and reduction of fibrosis on liver biopsy were achieved with the oral, thyroid hormone receptor beta-selective agonist resmetirom (Madrigal Pharmaceuticals) in patients with NASH and associated cirrhosis in a pivotal phase 3 clinical trial. The primary results of the MAESTRO-NASH (NCT03900429) trial were reported at the European Association for the Study of the Liver Congress 2023.

Both doses of resmetirom – 80 mg and 100 mg – met the primary endpoints of NASH resolution and no worsening of fibrosis on liver biopsy. The key secondary endpoint of LDL cholesterol lowering was also achieved with statistical significance. Likewise, improvement was seen in liver enzymes, and liver and spleen volumes.

In the intent-to-treat population, NASH resolution was achieved in 26% (P < .0001) in the 80-mg resmetirom group, 30% (P < .0001) in the 100-mg group, and 10% in those taking placebo. And ≥ 1-stage improvement in fibrosis with no worsening of the nonalcoholic fatty liver disease activity score (NAS) was achieved by 24% (P < .0002), 26% (P < .0001), and 14% in these groups respectively.

The investigational, liver-directed agent, designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity, was well tolerated overall with a favorable safety profile.

“This is an exciting time for NASH because we are at the forefront of having a drug to treat these patients, and the benefit to patients promises to be huge,” asserted Stephen Harrison, MD, principal investigator of the MAESTRO studies, gastroenterologist and hepatologist, and founder of Pinnacle Clinical Research, San Antonio, in reporting 52-week results.

“This is the first treatment to achieve meaningful effects on both primary liver biopsy endpoints – disease activity and fibrosis – which is absolutely critical because fibrosis pertains to a worse prognosis. [These results] are reasonably likely to predict clinical benefit in a phase 3 trial in patients with NASH,” he added.
 

FDA-chosen endpoints likely to predict clinical outcomes

The ongoing 54-month, phase 3, registrational, double-blind, placebo-controlled trial involved taking liver biopsies from 966 patients at around 200 global sites. Biopsy readings were taken by two pathologists that were then combined into a single treatment effect. 

Patients had biopsy-proven NASH with fibrosis stages F1B, F2, or F3, the presence of three or more metabolic risk factors, a FibroScan vibration-controlled transient elastography (VCTE) score of 8.5 kPa or more, baseline MRI proton density fat fraction (MRI-PDFF) of 8% or more, and a NAS score of 4 or more with at least 1 in each NAS component. Around 65% of participants had type 2 diabetes, between 13% and 16% were taking glucagonlike peptide-1 (GLP-1) receptor agonists, and 46%-51% were taking statins.

Patients were randomized 1:1:1 to once-daily resmetirom 80 mg or 100 mg orally or to placebo and treated for 52 weeks.

Both liver histological improvement primary endpoints at week-52 were proposed by the U.S. Food and Drug Administration as reasonably likely to predict clinical benefit and as such support accelerated approval for the treatment of NASH with liver fibrosis. These primary endpoints were NASH resolution (ballooning 0, inflammation 0/1) with ≥ 2-point improvement in NAS with no worsening of fibrosis, and ≥ 1-stage reduction in fibrosis with no worsening of NAS.

Patients on resmetirom showed improvement in NAS components and fibrosis, and less worsening of NAS and fibrosis, compared with placebo. Percentage improvement was seen in 31%, 33%, and 15% of patients on 80 mg resmetirom, 100 mg resmetirom, and placebo respectively; no change was seen in 51%, 48%, and 51% respectively; and worsening was seen in 18%, 19%, and 34% respectively. 

The key secondary endpoint of LDL cholesterol lowering was also met. “There was a significant effect of resmetirom 80 and 100 mg on multiple atherogenic lipids/lipoproteins at both week 24 and 52,” reported Dr. Harrison. The 52-week percentage change from baseline in LDL cholesterol was –14%, –20%, and 0% for the 80-mg resmetirom group, the 100-mg group, and the placebo group respectively.

“We also saw a significant reduction in liver enzymes [alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase (GGT)] relative to placebo both in terms of percentage and absolute measures,” Dr. Harrison added. “[And] the change in liver enzymes was associated with the neutral biomarker that increases with resmetirom target engagement.”   

Resmetirom at both doses also resulted in a significant effect on MRI-PDFF and Fibroscan CAP. At week 52, 80 mg resmetirom, 100 mg, and placebo led to –42.1%, –51.4% and –10.4% change from baseline in MRI-PDFF, while Fibroscan CAP changed by –39.6%, –41.3%, and –14.5% respectively, reported Dr. Harrison. Liver volume dropped by –21.6% in the 80-mg group and –25.8% in the 100-mg group, compared with –1.0% in the placebo group. Spleen volume changed by –5.9%, –6.1%, and +3.2% respectively.

Liver stiffness, as measured by Fibroscan VCTE at week 52, changed from –3.7 KPa (F1B) to –2.0 KPa (F3) at 80 mg, and from –3.7 KPa (F1B) to –2.5 KPa (F2) and –3.3 KPa (F3) at the 100-mg dose.

Further analysis showed that improvements in fibrosis and NASH resolution were seen across all key subgroups, including baseline fibrosis stage (F2 or F3), NAS (< 6, ≥ 6), type 2 diabetes status, age (< 65 years, ≥ 65 years), and sex.
 

Safety profile

“The safety profile of resmetirom in the MAESTRO-NASH trial is consistent with previous phase 2/3 trials in which the most common adverse events were diarrhea and nausea at treatment initiation,” said Dr. Harrison.

Study discontinuations in the 100-mg group were increased relative to placebo during the first few weeks of treatment and were similar in all treatment groups up to 52 weeks. Discontinuations of patients on resmetirom 100 mg were mainly gastrointestinal related. 

Phase 2 results of the serial liver biopsy trial in adults with biopsy-confirmed NASH showed that resmetirom resolved NASH in a significantly greater percentage of patients and reduced liver enzymes, inflammatory biomarkers, and fibrosis, compared with placebo.

“We’ve been waiting for a long, long time for a therapy for these patients because until now, they have been challenged with lifestyle modifications to lose and maintain weight,” said Dr. Harrison. “There’s been a delay in identifying patients with this disease because we’ve had no treatment, but now that we are on the forefront of a treatment, it allows clinicians to open their minds to the possibility of identifying these patients.”

Dr. Harrison noted that a limitation of these data was the lack of clinical outcomes data to correlate with the biopsy data; however, the MAESTRO-NASH trial will continue to 54 months to accrue and evaluate clinical outcomes.

Milan Mishkovikj, MSc, board director of the European Liver Patients Association, Bitola, North Macedonia, commented on the potential benefit of this drug for patients. “Adhering to a healthy lifestyle is not always easy – not in all countries – so it’s encouraging to have a drug that hopefully is affordable and accessible to us. Now we need to manage the expectations of patients and caregivers.”

EASL’s vice secretary Aleksander Krag, MD, PhD, professor and head of hepatology at University of Southern Denmark, Odense, and Odense University Hospital remarked, “This is so exciting. This phase 3 trial is a real game-changer in the field of fatty liver disease because it has nearly 1,000 patients over 52 weeks of treatment.”

Madrigal Pharmaceuticals plans to submit an application to the FDA by end of the second quarter with a priority review.

Dr. Harrison is founder of Madrigal Pharmaceuticals. Dr. Krag has served as speaker for Norgine, Siemens, and Nordic Bioscience, and participated in advisory boards for Norgine and Siemens, all outside the submitted work. He receives royalties from Gyldendal and Echosens. Dr. Mishkovikj has declared no relevant financial relationships.

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

TOPLINE:

The less U.S. patients pay out of pocket for drugs that often have high copays, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) agonists, the more adherent they are.

METHODOLOGY:

• Review of 90,041 U.S. adults who started a GLP-1 agonist (n = 39,149) or SGLT2 inhibitor (n = 50,892) in 2014-2020.
• Participants had type 2 diabetes, heart failure, or both.
• Data are from Clinformatics Data Mart, including both commercial and Medicare health insurance plans.
• Primary outcome: 12-month adherence to prescribed GLP-1 agonist or SGLT2 inhibitor.

TAKEAWAYS:

• U.S. adults with a lower drug copay had significantly higher odds of 12-month adherence to GLP-1 agonists and SGLT2 inhibitors, compared with those with a higher copay.
• These differences persisted after controlling for patient demographic, clinical, and socioeconomic covariates.
• After full adjustment, patients with a high copay (≥ $50/month) were, after 12 months, 53% less likely to adhere to an SGLT2 inhibitor and 32% less likely to adhere to a GLP-1 agonist, compared with patients with a low copay (< $10/month) for these agents.

IN PRACTICE:

“Lowering high out-of-pocket prescription costs may be key to improving adherence to guideline-recommended therapies and advancing overall quality of care in patients with type 2 diabetes and heart failure,” say the authors.

STUDY DETAILS:

The study was led by Utibe R. Essien, MD, from the University of California, Los Angeles, and Balvindar Singh, MD, PhD, from the University of Pittsburgh, and included several authors from other U.S. centers.

LIMITATIONS:

Study could not exclude residual confounding.

Generalizability uncertain for those without health insurance or with public insurance.

Study did not have information on patient preferences associated with medication use, including specific reasons for poor adherence.

Possible misclassifications of type 2 diabetes and heart failure diagnoses or medical comorbidities.

Study could not assess how copayments influenced initial prescription receipt or abandonment at the pharmacy, nor other factors including possible price inflation.
 

DISCLOSURES:

The study received no commercial funding. One author (not a lead author) is an advisor to several drug companies, including ones that market SGLT2 inhibitors or GLP-1 agonists.

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

TOPLINE:

The less U.S. patients pay out of pocket for drugs that often have high copays, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) agonists, the more adherent they are.

METHODOLOGY:

• Review of 90,041 U.S. adults who started a GLP-1 agonist (n = 39,149) or SGLT2 inhibitor (n = 50,892) in 2014-2020.
• Participants had type 2 diabetes, heart failure, or both.
• Data are from Clinformatics Data Mart, including both commercial and Medicare health insurance plans.
• Primary outcome: 12-month adherence to prescribed GLP-1 agonist or SGLT2 inhibitor.

TAKEAWAYS:

• U.S. adults with a lower drug copay had significantly higher odds of 12-month adherence to GLP-1 agonists and SGLT2 inhibitors, compared with those with a higher copay.
• These differences persisted after controlling for patient demographic, clinical, and socioeconomic covariates.
• After full adjustment, patients with a high copay (≥ $50/month) were, after 12 months, 53% less likely to adhere to an SGLT2 inhibitor and 32% less likely to adhere to a GLP-1 agonist, compared with patients with a low copay (< $10/month) for these agents.

IN PRACTICE:

“Lowering high out-of-pocket prescription costs may be key to improving adherence to guideline-recommended therapies and advancing overall quality of care in patients with type 2 diabetes and heart failure,” say the authors.

STUDY DETAILS:

The study was led by Utibe R. Essien, MD, from the University of California, Los Angeles, and Balvindar Singh, MD, PhD, from the University of Pittsburgh, and included several authors from other U.S. centers.

LIMITATIONS:

Study could not exclude residual confounding.

Generalizability uncertain for those without health insurance or with public insurance.

Study did not have information on patient preferences associated with medication use, including specific reasons for poor adherence.

Possible misclassifications of type 2 diabetes and heart failure diagnoses or medical comorbidities.

Study could not assess how copayments influenced initial prescription receipt or abandonment at the pharmacy, nor other factors including possible price inflation.
 

DISCLOSURES:

The study received no commercial funding. One author (not a lead author) is an advisor to several drug companies, including ones that market SGLT2 inhibitors or GLP-1 agonists.

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

TOPLINE:

The less U.S. patients pay out of pocket for drugs that often have high copays, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide-1 (GLP-1) agonists, the more adherent they are.

METHODOLOGY:

• Review of 90,041 U.S. adults who started a GLP-1 agonist (n = 39,149) or SGLT2 inhibitor (n = 50,892) in 2014-2020.
• Participants had type 2 diabetes, heart failure, or both.
• Data are from Clinformatics Data Mart, including both commercial and Medicare health insurance plans.
• Primary outcome: 12-month adherence to prescribed GLP-1 agonist or SGLT2 inhibitor.

TAKEAWAYS:

• U.S. adults with a lower drug copay had significantly higher odds of 12-month adherence to GLP-1 agonists and SGLT2 inhibitors, compared with those with a higher copay.
• These differences persisted after controlling for patient demographic, clinical, and socioeconomic covariates.
• After full adjustment, patients with a high copay (≥ $50/month) were, after 12 months, 53% less likely to adhere to an SGLT2 inhibitor and 32% less likely to adhere to a GLP-1 agonist, compared with patients with a low copay (< $10/month) for these agents.

IN PRACTICE:

“Lowering high out-of-pocket prescription costs may be key to improving adherence to guideline-recommended therapies and advancing overall quality of care in patients with type 2 diabetes and heart failure,” say the authors.

STUDY DETAILS:

The study was led by Utibe R. Essien, MD, from the University of California, Los Angeles, and Balvindar Singh, MD, PhD, from the University of Pittsburgh, and included several authors from other U.S. centers.

LIMITATIONS:

Study could not exclude residual confounding.

Generalizability uncertain for those without health insurance or with public insurance.

Study did not have information on patient preferences associated with medication use, including specific reasons for poor adherence.

Possible misclassifications of type 2 diabetes and heart failure diagnoses or medical comorbidities.

Study could not assess how copayments influenced initial prescription receipt or abandonment at the pharmacy, nor other factors including possible price inflation.
 

DISCLOSURES:

The study received no commercial funding. One author (not a lead author) is an advisor to several drug companies, including ones that market SGLT2 inhibitors or GLP-1 agonists.

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

Some patients continually cancel their appointments, ignore your medical directions, treat your staff rudely, or send you harassing emails.

Do you have to tolerate their behavior?

No, these are all appropriate reasons to terminate patients, attorneys say. Patients also can be dismissed for misleading doctors about their past medical history, chronic drug-seeking, displaying threatening or seductive behavior toward staff members or physicians, or any criminal behavior in the office, experts say.

But even if a reason seems legitimate, that doesn’t make it legal. Doctors should consider whether the reason is legal, said Chicago-area attorney Ericka Adler, JD, a partner at Roetzel & Andress, who advises doctors about terminating patients.

“Although a physician may think a reason to terminate a patient is legitimate, they should always be mindful of whether there is a legal concern at issue and consult with counsel if they’re unsure,” Ms. Adler said.

Terminating patients for an “illegal” reason such as discrimination based on race or gender or sexual orientation – even if couched as a legitimate patient issue – could open the practice to a lawsuit, Ms. Adler said.

Doctors also want to avoid patient abandonment claims by talking to the patient about problems and documenting them as they arise. If they can’t be resolved, doctors should ensure that there’s continuity of care when patients change physicians, said Ms. Adler.

About 90% of physicians have dismissed at least one patient during their career, according to a study of nearly 800 primary care practices. The most common reasons were legitimate: a patient was “extremely disruptive and/or behaved inappropriately toward clinicians or staff”; a patient had “violated chronic pain and controlled substance policies”; and a patient had “repeatedly missed appointments.” 

Jacqui O’Kane, DO, a family physician at South Georgia Medical Center in rural Nashville, said she has dismissed about 15 of 3,000 patients she has seen in the past 3 years at the clinic. Before she dismisses a patient, she looks at whether there has been a pattern of behavior and tries to talk to them about the problem first to find out if there are other reasons for it.

She also gives patients a warning: If the unacceptable behavior continues, it will lead to their dismissal.
 

When patients cross a line

Dr. O’Kane warned an elderly man who used the N-word with her that she wouldn’t tolerate that language in her office. Then, when he later called her front office employee the N-word, she decided to dismiss him.

“I said, ‘That’s it, you can’t say that to someone in this office. I already told you once, and you did it again. I’m sorry, you have to find another doctor,’ ” said Dr. O’Kane.

Another patient crossed a line when she missed four appointments, refused to come in, and kept sending Dr. O’Kane long messages on MyChart demanding medications and advice. One message was fairly obtrusive: “If you don’t give me something stronger for my nerves TODAY, I am going to LOSE MY MIND!!!” Dr. O’Kane said the patient wrote.

“I then told her that’s not how I run my practice and that she needed to find someone else.”

Another common reason doctors dismiss patients is for nonpayment, says Ms. Adler.

Recently, however, some patients have also begun demanding their money back from doctors for services already received and billed because they were unhappy about something that occurred at the doctor’s office, said Ms. Adler.

“I advise doctors to respond: ‘We disagree that you didn’t get the service, but we will give you your money back, and we’re also terminating you from our practice.’  At that point, the doctor-patient relationship has become impossible,” said Ms. Adler.
 

How to dismiss difficult patients ethically and legally

According to the AMA’s Council on Ethical and Judicial Affairs, a physician may not discontinue treatment of a patient if further treatment is medically indicated without giving the patient reasonable notice and sufficient opportunity to make alternative arrangements for care.

Terminating a patient abruptly without transferring their care could lead to a claim of patient abandonment and the physician being called before a licensing board for potentially violating the state’s Medical Practice Act, said Ms. Adler.

Doctors can take these six steps to set the stage for dismissal and avoid a claim of patient abandonment.

1. Create written policies. Medical practices can describe the rules and behavior they expect from patients in these policies, which can cover, for example, payment, treating staff with courtesy, and medications. “When the rules are in writing and patients sign off on them, that gives doctors a certain comfort level in being able to refer to them and say that the patient hasn’t been compliant,” said Ms. Adler.

She also recommends that your practice create a policy that doctors should let the patient know about their concerns and meet with them to discuss the problem before receiving a termination letter.

2. Document any consistent problems you’re having with a patient. When you start having problems with a patient, you should document when the problem occurred, how often it occurred, any discussions with the patient about the problem, warnings you gave the patient, and if and when you decided to terminate the patient.

3. Meet with the patient to discuss the problem. “Talking and meeting with a patient also allows the physician to assess whether there’s another issue. For example, is there a mental health concern? Is there a financial reason for nonpayment or no-shows? There are multiple benefits to finding out what the problem is,” said Ms. Adler.

Once you’ve decided to terminate a patient, here’s what you should do:

4. Allow enough time for the patient to find alternative care. Ms. Adler recommends giving patients 30 days’ notice and that physicians offer to provide emergency care during that time. However, if the patient is undergoing treatment or has other challenges, more time may be needed to transfer care.

“It’s important to consider the patient’s context – if the patient is receiving cancer treatment, or is in a late stage of pregnancy, or lives in a rural area where few specialists are available, you may want to treat them longer – at least until they finish their treatment,” said Ms. Adler. Also, states may have their own requirements about minimum notice periods, she said.

5. Provide patients with written notice that you intend to terminate their care. Ms. Adler recommends that each letter be tailored to the patient’s specific circumstances. “You could spell out a patient’s history of noncompliance or nonpayment or inappropriate conduct because it’s been documented and the patient is already aware of it from a previous discussion,” she said.

Ms. Adler also recommends that doctors consult with legal counsel when in doubt or if contacted by the patient’s lawyer. Some lawyers will draft the termination letters, she said.

6. Include the following information in the written letter: The date that they will no longer receive care, how they can obtain copies of their medical records, and how they can find a new physician by providing contact information for a state medical association or similar organization, which often maintains a database of clinicians by specialty and location.

The letter should also state that the doctor will provide emergency care during the 30 days. Ms. Adler also recommends sending the notice by certified mail.

Dr. O’Kane said she may be more likely to give patients a second chance because she practices in a rural underserved area, and she understands that her patients don’t have many other options for health care. She also has developed a reputation for being willing to take on difficult patients that other physicians didn’t want to deal with, she said.

She encourages physicians to talk to patients to find out why, for example, they may not be compliant with medications.

“The patient may say, ‘I had to choose between paying for medications and putting food on the table,’ ” said Dr. O’Kane.

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

Some patients continually cancel their appointments, ignore your medical directions, treat your staff rudely, or send you harassing emails.

Do you have to tolerate their behavior?

No, these are all appropriate reasons to terminate patients, attorneys say. Patients also can be dismissed for misleading doctors about their past medical history, chronic drug-seeking, displaying threatening or seductive behavior toward staff members or physicians, or any criminal behavior in the office, experts say.

But even if a reason seems legitimate, that doesn’t make it legal. Doctors should consider whether the reason is legal, said Chicago-area attorney Ericka Adler, JD, a partner at Roetzel & Andress, who advises doctors about terminating patients.

“Although a physician may think a reason to terminate a patient is legitimate, they should always be mindful of whether there is a legal concern at issue and consult with counsel if they’re unsure,” Ms. Adler said.

Terminating patients for an “illegal” reason such as discrimination based on race or gender or sexual orientation – even if couched as a legitimate patient issue – could open the practice to a lawsuit, Ms. Adler said.

Doctors also want to avoid patient abandonment claims by talking to the patient about problems and documenting them as they arise. If they can’t be resolved, doctors should ensure that there’s continuity of care when patients change physicians, said Ms. Adler.

About 90% of physicians have dismissed at least one patient during their career, according to a study of nearly 800 primary care practices. The most common reasons were legitimate: a patient was “extremely disruptive and/or behaved inappropriately toward clinicians or staff”; a patient had “violated chronic pain and controlled substance policies”; and a patient had “repeatedly missed appointments.” 

Jacqui O’Kane, DO, a family physician at South Georgia Medical Center in rural Nashville, said she has dismissed about 15 of 3,000 patients she has seen in the past 3 years at the clinic. Before she dismisses a patient, she looks at whether there has been a pattern of behavior and tries to talk to them about the problem first to find out if there are other reasons for it.

She also gives patients a warning: If the unacceptable behavior continues, it will lead to their dismissal.
 

When patients cross a line

Dr. O’Kane warned an elderly man who used the N-word with her that she wouldn’t tolerate that language in her office. Then, when he later called her front office employee the N-word, she decided to dismiss him.

“I said, ‘That’s it, you can’t say that to someone in this office. I already told you once, and you did it again. I’m sorry, you have to find another doctor,’ ” said Dr. O’Kane.

Another patient crossed a line when she missed four appointments, refused to come in, and kept sending Dr. O’Kane long messages on MyChart demanding medications and advice. One message was fairly obtrusive: “If you don’t give me something stronger for my nerves TODAY, I am going to LOSE MY MIND!!!” Dr. O’Kane said the patient wrote.

“I then told her that’s not how I run my practice and that she needed to find someone else.”

Another common reason doctors dismiss patients is for nonpayment, says Ms. Adler.

Recently, however, some patients have also begun demanding their money back from doctors for services already received and billed because they were unhappy about something that occurred at the doctor’s office, said Ms. Adler.

“I advise doctors to respond: ‘We disagree that you didn’t get the service, but we will give you your money back, and we’re also terminating you from our practice.’  At that point, the doctor-patient relationship has become impossible,” said Ms. Adler.
 

How to dismiss difficult patients ethically and legally

According to the AMA’s Council on Ethical and Judicial Affairs, a physician may not discontinue treatment of a patient if further treatment is medically indicated without giving the patient reasonable notice and sufficient opportunity to make alternative arrangements for care.

Terminating a patient abruptly without transferring their care could lead to a claim of patient abandonment and the physician being called before a licensing board for potentially violating the state’s Medical Practice Act, said Ms. Adler.

Doctors can take these six steps to set the stage for dismissal and avoid a claim of patient abandonment.

1. Create written policies. Medical practices can describe the rules and behavior they expect from patients in these policies, which can cover, for example, payment, treating staff with courtesy, and medications. “When the rules are in writing and patients sign off on them, that gives doctors a certain comfort level in being able to refer to them and say that the patient hasn’t been compliant,” said Ms. Adler.

She also recommends that your practice create a policy that doctors should let the patient know about their concerns and meet with them to discuss the problem before receiving a termination letter.

2. Document any consistent problems you’re having with a patient. When you start having problems with a patient, you should document when the problem occurred, how often it occurred, any discussions with the patient about the problem, warnings you gave the patient, and if and when you decided to terminate the patient.

3. Meet with the patient to discuss the problem. “Talking and meeting with a patient also allows the physician to assess whether there’s another issue. For example, is there a mental health concern? Is there a financial reason for nonpayment or no-shows? There are multiple benefits to finding out what the problem is,” said Ms. Adler.

Once you’ve decided to terminate a patient, here’s what you should do:

4. Allow enough time for the patient to find alternative care. Ms. Adler recommends giving patients 30 days’ notice and that physicians offer to provide emergency care during that time. However, if the patient is undergoing treatment or has other challenges, more time may be needed to transfer care.

“It’s important to consider the patient’s context – if the patient is receiving cancer treatment, or is in a late stage of pregnancy, or lives in a rural area where few specialists are available, you may want to treat them longer – at least until they finish their treatment,” said Ms. Adler. Also, states may have their own requirements about minimum notice periods, she said.

5. Provide patients with written notice that you intend to terminate their care. Ms. Adler recommends that each letter be tailored to the patient’s specific circumstances. “You could spell out a patient’s history of noncompliance or nonpayment or inappropriate conduct because it’s been documented and the patient is already aware of it from a previous discussion,” she said.

Ms. Adler also recommends that doctors consult with legal counsel when in doubt or if contacted by the patient’s lawyer. Some lawyers will draft the termination letters, she said.

6. Include the following information in the written letter: The date that they will no longer receive care, how they can obtain copies of their medical records, and how they can find a new physician by providing contact information for a state medical association or similar organization, which often maintains a database of clinicians by specialty and location.

The letter should also state that the doctor will provide emergency care during the 30 days. Ms. Adler also recommends sending the notice by certified mail.

Dr. O’Kane said she may be more likely to give patients a second chance because she practices in a rural underserved area, and she understands that her patients don’t have many other options for health care. She also has developed a reputation for being willing to take on difficult patients that other physicians didn’t want to deal with, she said.

She encourages physicians to talk to patients to find out why, for example, they may not be compliant with medications.

“The patient may say, ‘I had to choose between paying for medications and putting food on the table,’ ” said Dr. O’Kane.

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

Some patients continually cancel their appointments, ignore your medical directions, treat your staff rudely, or send you harassing emails.

Do you have to tolerate their behavior?

No, these are all appropriate reasons to terminate patients, attorneys say. Patients also can be dismissed for misleading doctors about their past medical history, chronic drug-seeking, displaying threatening or seductive behavior toward staff members or physicians, or any criminal behavior in the office, experts say.

But even if a reason seems legitimate, that doesn’t make it legal. Doctors should consider whether the reason is legal, said Chicago-area attorney Ericka Adler, JD, a partner at Roetzel & Andress, who advises doctors about terminating patients.

“Although a physician may think a reason to terminate a patient is legitimate, they should always be mindful of whether there is a legal concern at issue and consult with counsel if they’re unsure,” Ms. Adler said.

Terminating patients for an “illegal” reason such as discrimination based on race or gender or sexual orientation – even if couched as a legitimate patient issue – could open the practice to a lawsuit, Ms. Adler said.

Doctors also want to avoid patient abandonment claims by talking to the patient about problems and documenting them as they arise. If they can’t be resolved, doctors should ensure that there’s continuity of care when patients change physicians, said Ms. Adler.

About 90% of physicians have dismissed at least one patient during their career, according to a study of nearly 800 primary care practices. The most common reasons were legitimate: a patient was “extremely disruptive and/or behaved inappropriately toward clinicians or staff”; a patient had “violated chronic pain and controlled substance policies”; and a patient had “repeatedly missed appointments.” 

Jacqui O’Kane, DO, a family physician at South Georgia Medical Center in rural Nashville, said she has dismissed about 15 of 3,000 patients she has seen in the past 3 years at the clinic. Before she dismisses a patient, she looks at whether there has been a pattern of behavior and tries to talk to them about the problem first to find out if there are other reasons for it.

She also gives patients a warning: If the unacceptable behavior continues, it will lead to their dismissal.
 

When patients cross a line

Dr. O’Kane warned an elderly man who used the N-word with her that she wouldn’t tolerate that language in her office. Then, when he later called her front office employee the N-word, she decided to dismiss him.

“I said, ‘That’s it, you can’t say that to someone in this office. I already told you once, and you did it again. I’m sorry, you have to find another doctor,’ ” said Dr. O’Kane.

Another patient crossed a line when she missed four appointments, refused to come in, and kept sending Dr. O’Kane long messages on MyChart demanding medications and advice. One message was fairly obtrusive: “If you don’t give me something stronger for my nerves TODAY, I am going to LOSE MY MIND!!!” Dr. O’Kane said the patient wrote.

“I then told her that’s not how I run my practice and that she needed to find someone else.”

Another common reason doctors dismiss patients is for nonpayment, says Ms. Adler.

Recently, however, some patients have also begun demanding their money back from doctors for services already received and billed because they were unhappy about something that occurred at the doctor’s office, said Ms. Adler.

“I advise doctors to respond: ‘We disagree that you didn’t get the service, but we will give you your money back, and we’re also terminating you from our practice.’  At that point, the doctor-patient relationship has become impossible,” said Ms. Adler.
 

How to dismiss difficult patients ethically and legally

According to the AMA’s Council on Ethical and Judicial Affairs, a physician may not discontinue treatment of a patient if further treatment is medically indicated without giving the patient reasonable notice and sufficient opportunity to make alternative arrangements for care.

Terminating a patient abruptly without transferring their care could lead to a claim of patient abandonment and the physician being called before a licensing board for potentially violating the state’s Medical Practice Act, said Ms. Adler.

Doctors can take these six steps to set the stage for dismissal and avoid a claim of patient abandonment.

1. Create written policies. Medical practices can describe the rules and behavior they expect from patients in these policies, which can cover, for example, payment, treating staff with courtesy, and medications. “When the rules are in writing and patients sign off on them, that gives doctors a certain comfort level in being able to refer to them and say that the patient hasn’t been compliant,” said Ms. Adler.

She also recommends that your practice create a policy that doctors should let the patient know about their concerns and meet with them to discuss the problem before receiving a termination letter.

2. Document any consistent problems you’re having with a patient. When you start having problems with a patient, you should document when the problem occurred, how often it occurred, any discussions with the patient about the problem, warnings you gave the patient, and if and when you decided to terminate the patient.

3. Meet with the patient to discuss the problem. “Talking and meeting with a patient also allows the physician to assess whether there’s another issue. For example, is there a mental health concern? Is there a financial reason for nonpayment or no-shows? There are multiple benefits to finding out what the problem is,” said Ms. Adler.

Once you’ve decided to terminate a patient, here’s what you should do:

4. Allow enough time for the patient to find alternative care. Ms. Adler recommends giving patients 30 days’ notice and that physicians offer to provide emergency care during that time. However, if the patient is undergoing treatment or has other challenges, more time may be needed to transfer care.

“It’s important to consider the patient’s context – if the patient is receiving cancer treatment, or is in a late stage of pregnancy, or lives in a rural area where few specialists are available, you may want to treat them longer – at least until they finish their treatment,” said Ms. Adler. Also, states may have their own requirements about minimum notice periods, she said.

5. Provide patients with written notice that you intend to terminate their care. Ms. Adler recommends that each letter be tailored to the patient’s specific circumstances. “You could spell out a patient’s history of noncompliance or nonpayment or inappropriate conduct because it’s been documented and the patient is already aware of it from a previous discussion,” she said.

Ms. Adler also recommends that doctors consult with legal counsel when in doubt or if contacted by the patient’s lawyer. Some lawyers will draft the termination letters, she said.

6. Include the following information in the written letter: The date that they will no longer receive care, how they can obtain copies of their medical records, and how they can find a new physician by providing contact information for a state medical association or similar organization, which often maintains a database of clinicians by specialty and location.

The letter should also state that the doctor will provide emergency care during the 30 days. Ms. Adler also recommends sending the notice by certified mail.

Dr. O’Kane said she may be more likely to give patients a second chance because she practices in a rural underserved area, and she understands that her patients don’t have many other options for health care. She also has developed a reputation for being willing to take on difficult patients that other physicians didn’t want to deal with, she said.

She encourages physicians to talk to patients to find out why, for example, they may not be compliant with medications.

“The patient may say, ‘I had to choose between paying for medications and putting food on the table,’ ” said Dr. O’Kane.

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

Low-calorie tastes sweeter with a little salt

Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.

That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.

Jason Tuinstra/Unsplash

Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.

The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.

The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.

Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch

Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.

LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.

P. aeruginosa: No problem. I think we can all guess what that little devil is up to.

Benoit-Joseph Laventie, Biozentrum, University of Basel

LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?

P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.

LOTME: Beans? What do beans have to do with it?

P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.

LOTME: Sure, we knew that. Please, continue your spilling.

P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.

LOTME: The Clash? Now we’re really confused.

P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.

LOTME: And they say you guys don’t have brains.

P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”

LOTME: Pretty clever stuff, for humans, anyway.

P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.

LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.

P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.

LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
 

What a pain in the Butt

Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.

Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.

Bildflut/Wikimedia Commons

The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.

Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.

So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.

And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.

Low-calorie tastes sweeter with a little salt

Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.

That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.

Jason Tuinstra/Unsplash

Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.

The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.

The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.

Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch

Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.

LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.

P. aeruginosa: No problem. I think we can all guess what that little devil is up to.

Benoit-Joseph Laventie, Biozentrum, University of Basel

LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?

P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.

LOTME: Beans? What do beans have to do with it?

P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.

LOTME: Sure, we knew that. Please, continue your spilling.

P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.

LOTME: The Clash? Now we’re really confused.

P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.

LOTME: And they say you guys don’t have brains.

P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”

LOTME: Pretty clever stuff, for humans, anyway.

P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.

LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.

P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.

LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
 

What a pain in the Butt

Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.

Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.

Bildflut/Wikimedia Commons

The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.

Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.

So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.

And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.

Low-calorie tastes sweeter with a little salt

Diet and sugar-free foods and drinks seem like a good idea, but it’s hard to get past that strange aftertaste, right? It’s the calling card for the noncaloric aspartame- and stevia-containing sweeteners that we consume to make us feel like we can have the best of both worlds.

That weird lingering taste can be a total turn-off for some (raises hand), but researchers have found an almost facepalm solution to the not-so-sweet problem, and it’s salt.

Jason Tuinstra/Unsplash

Now, the concept of sweet and salty is not a far-fetched partnership when it comes to snack consumption (try M&Ms in your popcorn). The researchers at Almendra, a manufacturer of stevia sweeteners, put that iconic flavor pair to the test by adding mineral salts that have some nutritional value to lessen the effect of a stevia compound, rebaudioside A, found in noncaloric sweeteners.

The researchers added in magnesium chloride, calcium chloride, and potassium chloride separately to lessen rebaudioside A’s intensity, but they needed so much salt that it killed the sweet taste completely. A blend of the three mineral salts, however, reduced the lingering taste by 79% and improved the real sugar-like taste. The researchers tried this blend in reduced-calorie orange juice and a citrus-flavored soft drink, improving the taste in both.

The salty and sweet match comes in for the win once again. This time helping against the fight of obesity instead of making it worse.

Pseudomonas’ Achilles’ heel is more of an Achilles’ genetic switch

Today, on the long-awaited return of “Bacteria vs. the World,” we meet one of the rock stars of infectious disease.

LOTME: Through the use of imaginary technology, we’re talking to Pseudomonas aeruginosa. Thanks for joining us on such short notice, after Neisseria gonorrhoeae canceled at the last minute.

P. aeruginosa: No problem. I think we can all guess what that little devil is up to.

Benoit-Joseph Laventie, Biozentrum, University of Basel

LOTME: Bacterial resistance to antibiotics is a huge problem for our species. What makes you so hard to fight?

P. aeruginosa: We’ve been trying to keep that a secret, actually, but now that researchers in Switzerland and Denmark seem to have figured it out, I guess it’s okay for me to spill the beans.

LOTME: Beans? What do beans have to do with it?

P. aeruginosa: Nothing, it’s just a colloquial expression that means I’m sharing previously private information.

LOTME: Sure, we knew that. Please, continue your spilling.

P. aeruginosa: The secret is … Well, let’s just say we were a little worried when the Clash released “Should I Stay or Should I Go” back in the 1980s.

LOTME: The Clash? Now we’re really confused.

P. aeruginosa: The answer to their question, “Should I stay or should I go? is yes. Successful invasion of a human is all about division of labor. “While one fraction of the bacterial population adheres to the mucosal surface and forms a biofilm, the other subpopulation spreads to distant tissue sites,” is how the investigators described it. We can increase surface colonization by using a “job-sharing” process, they said, and even resist antibiotics because most of us remain in the protective biofilm.

LOTME: And they say you guys don’t have brains.

P. aeruginosa: But wait, there’s more. We don’t just divide the labor randomly. After the initial colonization we form two functionally distinct subpopulations. One has high levels of the bacterial signaling molecule c-di-GMP and stays put to work on the biofilm. The other group, with low levels of c-di-GMP, heads out to the surrounding tissue to continue the colonization. As project leader Urs Jenal put it, “By identifying the genetic switch, we have tracked down the Achilles heel of the pathogen.”

LOTME: Pretty clever stuff, for humans, anyway.

P. aeruginosa: We agree, but now that you know our secret, we can’t let you share it.

LOTME: Wait! The journal article’s already been published. Your secret is out. You can’t stop that by infecting me.

P. aeruginosa: True enough, but are you familiar with the fable of the scorpion and the frog? It’s our nature.

LOTME: Nooooo! N. gonorrhoeae wouldn’t have done this!
 

What a pain in the Butt

Businesses rise and businesses fall. We all know that one cursed location, that spot in town where we see businesses move in and close up in a matter of months. At the same time, though, there are also businesses that have been around as long as anyone can remember, pillars of the community.

Corydon, IN., likely has a few such long-lived shops, but it is officially down one 70-year-old family business as of late April, with the unfortunate passing of beloved local pharmacy Butt Drugs. Prescription pick-up in rear.

Bildflut/Wikimedia Commons

The business dates back to 1952, when it was founded as William H. Butt Drugs. We’re sure William Butt was never teased about his last name. Nope. No one would ever do that. After he passed the store to his children, it underwent a stint as Butt Rexall Drugs. When the shop was passed down to its third-generation and ultimately final owner, Katie Butt Beckort, she decided to simplify the name. Get right down to the bottom of things, as it were.

Butt Drugs was a popular spot, featuring an old-school soda fountain and themed souvenirs. According to Ms. Butt Beckort, people would come from miles away to buy “I love Butt Drugs” T-shirts, magnets, and so on. Yes, they knew perfectly well what they were sitting on.

So, if was such a hit, why did it close? Butt Drugs may have a hilarious name and merchandise to match, but the pharmacy portion of the pharmacy had been losing money for years. You know, the actual point of the business. As with so many things, we can blame it on the insurance companies. More than half the drugs that passed through Butt Drugs’ doors were sold at a loss, because the insurance companies refused to reimburse the store more than the wholesale price of the drug. Not even a good butt drug could clear up that financial diarrhea.

And so, we’ve lost Butt Drugs forever. Spicy food enthusiasts, coffee drinkers, and all patrons of Taco Bell, take a moment to reflect and mourn on what you’ve lost. No more Butt Drugs to relieve your suffering. A true kick in the butt indeed.