Diabetes

Pericardial fat is associated with a heightened risk for heart failure, particularly in women, new research suggests.

In a prospective cohort study of nearly 7,000 individuals, excess pericardial fat was linked to a higher risk for heart failure, even after adjustment for established risk factors for heart failure.

Women with high pericardial fat volume (PFV), defined as more than 70 cm³ or 2.4 fluid ounces, had double the risk of developing heart failure. For men, high PFV, defined as more than 120 cm³ or 4.0 fluid ounces, was associated with a 50% increase in the risk for heart failure.

The findings were published in the Journal of the American College of Cardiology.

“People will ask why should they measure fat around the heart. Why can’t they just take the waist circumference or body mass index as a measure for increased risk?” lead author Satish Kenchaiah, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“Yet, when we adjusted for waist circumference, hip circumference, waist to hip ratio, and other known variables, pericardial fat was still associated with an increased risk of heart failure. This tells me that it is not just overall fat in the body but something about its location around the heart that is playing a role,” Dr. Kenchaiah said.

“Now that we have found an association between any amount of fat around the pericardium and heart failure, it gives us an impetus to build future research on identifying how exactly these fat deposits influence the development of cardiomyopathy,” he said.

Dr. Kenchaiah and colleagues investigated the association of pericardial fat with incident heart failure by examining chest CT scans from 6,785 participants (3,584 women and 3,201 men aged 45-84 years) in the Multi-Ethnic Study of Atherosclerosis.

The participants were from four different ethnic groups: 38% were White; 28% were Black, 22% were Hispanic, and 12% were Chinese American. They were recruited between July 17, 2000, and Aug. 31, 2002, from six communities in the United States: Baltimore and Baltimore County; Chicago; Forsyth County, N.C.; Los Angeles County northern Manhattan and the Bronx, New York; and St. Paul, Minn.

All participants were free of cardiovascular disease at baseline.

The researchers followed participants for more than 17 years. During this time, 385 (5.7%; 164 women and 221 men) developed newly diagnosed heart failure.

In women, the hazard ratio for every 42 cm³ increase in PFV was 1.44 (95% confidence interval, 1.21-1.71; P < .001). In men, the HR was 1.13 (95% CI, 1.01-1.27; P = .03).

High PVF conferred a twofold greater risk for heart failure in women (HR, 2.06; 95% CI, 1.48-2.87; P < .001) and a 53% higher risk in men (HR, 1.53; 95% CI, 1.13-2.07; P = .006).

These associations remained significant after further adjustment for circulating markers of systemic inflammation (that is, C-reactive protein and interleukin-6), and abdominal subcutaneous or visceral fat.

They also found that the heightened risk persisted, even after adjustment for established risk factors for heart failure, such as age, cigarette smoking, alcohol consumption, sedentary lifestyle, high blood pressure, high blood sugar, high cholesterol, and myocardial infarction.

Results were similar among all of the ethnic groups studied.
 

A surprise finding

“The most surprising part of this study was that the risk for heart failure with increased pericardial fat does not seem to be explained by obesity and systemic inflammation alone,” Andreas P. Kalogeropoulos, MD, MPH, PhD, Stony Brook (N.Y.) University, said in an interview.

“If pericardial fat was merely a proxy for increased visceral fat, one would expect the association of pericardial fat with heart failure risk to go away after factoring in abdominal CT findings, which was not the case here. Also, accounting for inflammatory markers did not change things dramatically. However, we need to be careful here, as abdominal CT scans have not been done simultaneously with the pericardial fat scans in the study,” said Dr. Kalogeropoulos, who coauthored an accompanying editorial with Michael E. Hall, MD, University of Mississippi Medical Center, Jackson.

The other striking finding, although not entirely surprising, was the stronger association of pericardial fat with heart failure risk in women, he noted.

“Although several clues have been reported pointing to women being more sensitive to the adverse cardiac effects of pericardial fat, this is the first large prospective study to connect the dots and show much higher risk in women in a convincing way. For the record, this is the first prospective study to show the connection between pericardial fat and heart failure risk altogether,” Dr. Kalogeropoulos said.

“Obviously, we need to do more work to see how we can use the important findings of Kenchaiah and colleagues to reduce risk for heart failure among patients with increased pericardial fat, especially women. For starters, we would need a way to identify these patients,” he said. “In this aspect, it is encouraging that pericardial fat can be measured in low-radiation CT scans, similar to those used for coronary calcium, and that automation technology to speed up pericardial fat measurements is already in the pipeline.

“The next step would be to see what kind of interventions would reduce risk for heart failure in these patients,” he added. “Weight loss would be an obvious thing, but novel agents with favorable cardiometabolic effects, like newer antidiabetic medications, are intriguing options, too.”

The study was supported by the National Heart, Lung, and Blood Institute and the National Institutes of Health. Dr. Kenchaiah and Dr. Kalogeropoulos reported no relevant financial relationships.

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

Pericardial fat is associated with a heightened risk for heart failure, particularly in women, new research suggests.

In a prospective cohort study of nearly 7,000 individuals, excess pericardial fat was linked to a higher risk for heart failure, even after adjustment for established risk factors for heart failure.

Women with high pericardial fat volume (PFV), defined as more than 70 cm³ or 2.4 fluid ounces, had double the risk of developing heart failure. For men, high PFV, defined as more than 120 cm³ or 4.0 fluid ounces, was associated with a 50% increase in the risk for heart failure.

The findings were published in the Journal of the American College of Cardiology.

“People will ask why should they measure fat around the heart. Why can’t they just take the waist circumference or body mass index as a measure for increased risk?” lead author Satish Kenchaiah, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“Yet, when we adjusted for waist circumference, hip circumference, waist to hip ratio, and other known variables, pericardial fat was still associated with an increased risk of heart failure. This tells me that it is not just overall fat in the body but something about its location around the heart that is playing a role,” Dr. Kenchaiah said.

“Now that we have found an association between any amount of fat around the pericardium and heart failure, it gives us an impetus to build future research on identifying how exactly these fat deposits influence the development of cardiomyopathy,” he said.

Dr. Kenchaiah and colleagues investigated the association of pericardial fat with incident heart failure by examining chest CT scans from 6,785 participants (3,584 women and 3,201 men aged 45-84 years) in the Multi-Ethnic Study of Atherosclerosis.

The participants were from four different ethnic groups: 38% were White; 28% were Black, 22% were Hispanic, and 12% were Chinese American. They were recruited between July 17, 2000, and Aug. 31, 2002, from six communities in the United States: Baltimore and Baltimore County; Chicago; Forsyth County, N.C.; Los Angeles County northern Manhattan and the Bronx, New York; and St. Paul, Minn.

All participants were free of cardiovascular disease at baseline.

The researchers followed participants for more than 17 years. During this time, 385 (5.7%; 164 women and 221 men) developed newly diagnosed heart failure.

In women, the hazard ratio for every 42 cm³ increase in PFV was 1.44 (95% confidence interval, 1.21-1.71; P < .001). In men, the HR was 1.13 (95% CI, 1.01-1.27; P = .03).

High PVF conferred a twofold greater risk for heart failure in women (HR, 2.06; 95% CI, 1.48-2.87; P < .001) and a 53% higher risk in men (HR, 1.53; 95% CI, 1.13-2.07; P = .006).

These associations remained significant after further adjustment for circulating markers of systemic inflammation (that is, C-reactive protein and interleukin-6), and abdominal subcutaneous or visceral fat.

They also found that the heightened risk persisted, even after adjustment for established risk factors for heart failure, such as age, cigarette smoking, alcohol consumption, sedentary lifestyle, high blood pressure, high blood sugar, high cholesterol, and myocardial infarction.

Results were similar among all of the ethnic groups studied.
 

A surprise finding

“The most surprising part of this study was that the risk for heart failure with increased pericardial fat does not seem to be explained by obesity and systemic inflammation alone,” Andreas P. Kalogeropoulos, MD, MPH, PhD, Stony Brook (N.Y.) University, said in an interview.

“If pericardial fat was merely a proxy for increased visceral fat, one would expect the association of pericardial fat with heart failure risk to go away after factoring in abdominal CT findings, which was not the case here. Also, accounting for inflammatory markers did not change things dramatically. However, we need to be careful here, as abdominal CT scans have not been done simultaneously with the pericardial fat scans in the study,” said Dr. Kalogeropoulos, who coauthored an accompanying editorial with Michael E. Hall, MD, University of Mississippi Medical Center, Jackson.

The other striking finding, although not entirely surprising, was the stronger association of pericardial fat with heart failure risk in women, he noted.

“Although several clues have been reported pointing to women being more sensitive to the adverse cardiac effects of pericardial fat, this is the first large prospective study to connect the dots and show much higher risk in women in a convincing way. For the record, this is the first prospective study to show the connection between pericardial fat and heart failure risk altogether,” Dr. Kalogeropoulos said.

“Obviously, we need to do more work to see how we can use the important findings of Kenchaiah and colleagues to reduce risk for heart failure among patients with increased pericardial fat, especially women. For starters, we would need a way to identify these patients,” he said. “In this aspect, it is encouraging that pericardial fat can be measured in low-radiation CT scans, similar to those used for coronary calcium, and that automation technology to speed up pericardial fat measurements is already in the pipeline.

“The next step would be to see what kind of interventions would reduce risk for heart failure in these patients,” he added. “Weight loss would be an obvious thing, but novel agents with favorable cardiometabolic effects, like newer antidiabetic medications, are intriguing options, too.”

The study was supported by the National Heart, Lung, and Blood Institute and the National Institutes of Health. Dr. Kenchaiah and Dr. Kalogeropoulos reported no relevant financial relationships.

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

Pericardial fat is associated with a heightened risk for heart failure, particularly in women, new research suggests.

In a prospective cohort study of nearly 7,000 individuals, excess pericardial fat was linked to a higher risk for heart failure, even after adjustment for established risk factors for heart failure.

Women with high pericardial fat volume (PFV), defined as more than 70 cm³ or 2.4 fluid ounces, had double the risk of developing heart failure. For men, high PFV, defined as more than 120 cm³ or 4.0 fluid ounces, was associated with a 50% increase in the risk for heart failure.

The findings were published in the Journal of the American College of Cardiology.

“People will ask why should they measure fat around the heart. Why can’t they just take the waist circumference or body mass index as a measure for increased risk?” lead author Satish Kenchaiah, MD, MPH, Icahn School of Medicine at Mount Sinai, New York, said in an interview.

“Yet, when we adjusted for waist circumference, hip circumference, waist to hip ratio, and other known variables, pericardial fat was still associated with an increased risk of heart failure. This tells me that it is not just overall fat in the body but something about its location around the heart that is playing a role,” Dr. Kenchaiah said.

“Now that we have found an association between any amount of fat around the pericardium and heart failure, it gives us an impetus to build future research on identifying how exactly these fat deposits influence the development of cardiomyopathy,” he said.

Dr. Kenchaiah and colleagues investigated the association of pericardial fat with incident heart failure by examining chest CT scans from 6,785 participants (3,584 women and 3,201 men aged 45-84 years) in the Multi-Ethnic Study of Atherosclerosis.

The participants were from four different ethnic groups: 38% were White; 28% were Black, 22% were Hispanic, and 12% were Chinese American. They were recruited between July 17, 2000, and Aug. 31, 2002, from six communities in the United States: Baltimore and Baltimore County; Chicago; Forsyth County, N.C.; Los Angeles County northern Manhattan and the Bronx, New York; and St. Paul, Minn.

All participants were free of cardiovascular disease at baseline.

The researchers followed participants for more than 17 years. During this time, 385 (5.7%; 164 women and 221 men) developed newly diagnosed heart failure.

In women, the hazard ratio for every 42 cm³ increase in PFV was 1.44 (95% confidence interval, 1.21-1.71; P < .001). In men, the HR was 1.13 (95% CI, 1.01-1.27; P = .03).

High PVF conferred a twofold greater risk for heart failure in women (HR, 2.06; 95% CI, 1.48-2.87; P < .001) and a 53% higher risk in men (HR, 1.53; 95% CI, 1.13-2.07; P = .006).

These associations remained significant after further adjustment for circulating markers of systemic inflammation (that is, C-reactive protein and interleukin-6), and abdominal subcutaneous or visceral fat.

They also found that the heightened risk persisted, even after adjustment for established risk factors for heart failure, such as age, cigarette smoking, alcohol consumption, sedentary lifestyle, high blood pressure, high blood sugar, high cholesterol, and myocardial infarction.

Results were similar among all of the ethnic groups studied.
 

A surprise finding

“The most surprising part of this study was that the risk for heart failure with increased pericardial fat does not seem to be explained by obesity and systemic inflammation alone,” Andreas P. Kalogeropoulos, MD, MPH, PhD, Stony Brook (N.Y.) University, said in an interview.

“If pericardial fat was merely a proxy for increased visceral fat, one would expect the association of pericardial fat with heart failure risk to go away after factoring in abdominal CT findings, which was not the case here. Also, accounting for inflammatory markers did not change things dramatically. However, we need to be careful here, as abdominal CT scans have not been done simultaneously with the pericardial fat scans in the study,” said Dr. Kalogeropoulos, who coauthored an accompanying editorial with Michael E. Hall, MD, University of Mississippi Medical Center, Jackson.

The other striking finding, although not entirely surprising, was the stronger association of pericardial fat with heart failure risk in women, he noted.

“Although several clues have been reported pointing to women being more sensitive to the adverse cardiac effects of pericardial fat, this is the first large prospective study to connect the dots and show much higher risk in women in a convincing way. For the record, this is the first prospective study to show the connection between pericardial fat and heart failure risk altogether,” Dr. Kalogeropoulos said.

“Obviously, we need to do more work to see how we can use the important findings of Kenchaiah and colleagues to reduce risk for heart failure among patients with increased pericardial fat, especially women. For starters, we would need a way to identify these patients,” he said. “In this aspect, it is encouraging that pericardial fat can be measured in low-radiation CT scans, similar to those used for coronary calcium, and that automation technology to speed up pericardial fat measurements is already in the pipeline.

“The next step would be to see what kind of interventions would reduce risk for heart failure in these patients,” he added. “Weight loss would be an obvious thing, but novel agents with favorable cardiometabolic effects, like newer antidiabetic medications, are intriguing options, too.”

The study was supported by the National Heart, Lung, and Blood Institute and the National Institutes of Health. Dr. Kenchaiah and Dr. Kalogeropoulos reported no relevant financial relationships.

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

The American Association of Clinical Endocrinology (AACE) has issued its first-ever official guidelines addressing the use of advanced technologies in the management of people with diabetes.

They were presented on May 28 at the annual scientific & clinical congress of the American Association of Clinical Endocrinologists and simultaneously published in Endocrine Practice.

Previous AACE guidance on the clinical use of insulin pumps and CGM over the past decade has been published in the form of consensus or position statements rather than official evidence-based guidelines, task force cochair George Grunberger, MD, of the Grunberger Diabetes Institute, Bloomfield Hills, Mich., explained.

“There’s never really been, until now, hardcore evidence, [with] peer-reviewed, quality trials published in the literature to go after the evidence that is required for guidelines. ... This is not an opinion piece or position statement.”

The problem with that strict approach to “guidelines” is how quickly the diabetes technology field is evolving, he acknowledged. “It’s frustrating because we know what’s [coming up], but we can’t put it in a guideline because it hasn’t been published yet.”

In an AACE podcast, Dr. Grunberger said the guidelines will likely become a “living” document, along the lines of the American Diabetes Association’s annual Standards of Care, as “any cutoff date is arbitrary. More and more papers will be published on these technologies. ... This is certainly not a static field.”

In the meantime, task force cochair and author Jennifer Sherr, MD, PhD, a pediatric endocrinologist, said she hopes the guidelines will help to reduce insurance company barriers to use of the currently available technologies.

“I am very hopeful that these guidelines will also encourage payers to change their stance. And I think that we as a community can continue to advocate and inform them of these guidelines so they can appropriately change their coverage practices,” added Dr. Sherr, of Yale University, New Haven, Conn.
 

Recommendations address CGM, pumps, and connected systems

In the guidelines, CGM is “strongly recommended for all persons with diabetes treated with intensive insulin therapy, defined as three or more injections of insulin per day or the use of an insulin pump.” For those with diabetes who use CGM, “priority metrics” include a “time in range” of greater than 70% from 14 days of active use. Targets for mean glucose should be individualized, with glycemic variability 36% or lower.

Further specific CGM target metrics are given for people with type 1 diabetes, older/high risk individuals, and for pregnant women. The recommendations align with those issued in a 2019 joint consensus statement on CGM time-in-range endorsed by several organizations, including AACE.    

In response to an audience question about whether AACE is advising that time-in-range replace A1c for glycemia assessment, Dr. Sherr responded: “I think currently we’re not in a position where we can completely replace A1c with time in range. However, I’m hopeful that in future years we’ll see further data gathered ... to allow for that recommendation to occur.”

For now, she said, “What we really want to hone in on in the guidelines is that time-in-range and use of CGM truly allow clinicians to better understand how to optimize care for their persons with diabetes. It gives us a better picture. It’s not just a number of whether we’re hitting target. It tells us whether we need to attack time above range or time below range. So we really think it’s critical for clinical care.”

The document also provides specifics about real-time versus intermittently scanned CGM and use of diagnostic/professional CGM.

The “insulin delivery technologies” section covers use of connected pens, insulin pumps without CGM, insulin pumps with separate CGM, and the more advanced combined insulin pump-CGM systems including those with low-glucose suspend, predictive low-glucose suspend, and hybrid closed-loops (sometimes called the artificial pancreas).

In general, these automated insulin delivery systems (artificial pancreas), “are strongly recommended for all persons with [type 1 diabetes], since their use has been shown to increase time in range, especially in the overnight period, without causing an increased risk of hypoglycemia,” Dr. Sherr observed.
 

Other tech topics: Apps, telemedicine, and safety

The new guidelines say that “clinically validated” smartphone apps should be recommended to help teach or reinforce diabetes self-management skills and provide support and encouragement for healthy behaviors around food and exercise.

Dr. Grunberger pointed out: “As we know, there are tons of apps out there, and patients are using them. The problem is that very few of them have actually been validated in clinical trials in published peer-reviewed [journals].”

He recommended a joint statement on diabetes apps from the American Diabetes Association and the European Association for the Study of Diabetes that was initially discussed at the 2019 EASD meeting, as reported by this news organization, and subsequently published in January 2020 in Diabetes Care and Diabetologia.

“Telemedicine, including periodic phone calls, smartphone-web interactions ... by health care professionals ... is strongly recommended to treat persons with diabetes, provide diabetes education, remotely monitor glucose and/or insulin data to indicate the need for therapy adjustments, and improve diabetes-related outcomes/control with better engagement,” the document says.

Safety concerns addressed include the issue of certain medications interfering with CGM [readings] ... including acetaminophen, high-dose vitamin C, and hydroxyurea, as well as cautions about what to do in the event of device malfunction and assessing that the patient is sufficiently trained in proper device use. Criteria for insulin pump discontinuation are also given.
 

Implementation: Who will be prescribing? ‘This is not for amateurs’

A final section on implementation recommends that “initiation and use of diabetes technology should be implemented by health care professionals who are trained, committed, and experienced to prescribe and direct the use of these tools. Clinicians should have the infrastructure to support the needs of persons with diabetes using the technology.”

Dr. Grunberger commented: “I think the key is going to be who should be doing this? What is the role of a clinical endocrinologist in the future? What is our responsibility, [since] we don’t have the manpower and womanpower to take care of all these people as these technologies advance? It’s our responsibility to provide these hopefully valued recommendations as a resource for those who want to know more about it.”

However, he noted, “This is not for amateurs. If you want to actually use this in your practice, you need the infrastructure, the expertise, the training, the dedication, and the energy to be there for the patients all the time ... This clinical practice guideline is a foundation.”

Dr. Sherr added: “To me, it’s really thinking about ... changing our mindset from who is an appropriate candidate to who can benefit and how vast a group that entails ... I’m hopeful that we will see more technology use through continued conversations with our patients with diabetes, and hopefully through more clinicians being excited to be part of this revolution.”

Dr. Grunberger has reported being on speakers bureaus for Eli Lilly, Novo Nordisk, and Abbott. Dr. Sherr has reported being a consultant and speaker for Lilly and Medtronic Diabetes, a consultant for Insulet and Sanofi, and on advisory boards for Bigfoot Biomedical, Cecelia Health, Insulet, JDRF T1D fund, and Medtronic.

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

The American Association of Clinical Endocrinology (AACE) has issued its first-ever official guidelines addressing the use of advanced technologies in the management of people with diabetes.

They were presented on May 28 at the annual scientific & clinical congress of the American Association of Clinical Endocrinologists and simultaneously published in Endocrine Practice.

Previous AACE guidance on the clinical use of insulin pumps and CGM over the past decade has been published in the form of consensus or position statements rather than official evidence-based guidelines, task force cochair George Grunberger, MD, of the Grunberger Diabetes Institute, Bloomfield Hills, Mich., explained.

“There’s never really been, until now, hardcore evidence, [with] peer-reviewed, quality trials published in the literature to go after the evidence that is required for guidelines. ... This is not an opinion piece or position statement.”

The problem with that strict approach to “guidelines” is how quickly the diabetes technology field is evolving, he acknowledged. “It’s frustrating because we know what’s [coming up], but we can’t put it in a guideline because it hasn’t been published yet.”

In an AACE podcast, Dr. Grunberger said the guidelines will likely become a “living” document, along the lines of the American Diabetes Association’s annual Standards of Care, as “any cutoff date is arbitrary. More and more papers will be published on these technologies. ... This is certainly not a static field.”

In the meantime, task force cochair and author Jennifer Sherr, MD, PhD, a pediatric endocrinologist, said she hopes the guidelines will help to reduce insurance company barriers to use of the currently available technologies.

“I am very hopeful that these guidelines will also encourage payers to change their stance. And I think that we as a community can continue to advocate and inform them of these guidelines so they can appropriately change their coverage practices,” added Dr. Sherr, of Yale University, New Haven, Conn.
 

Recommendations address CGM, pumps, and connected systems

In the guidelines, CGM is “strongly recommended for all persons with diabetes treated with intensive insulin therapy, defined as three or more injections of insulin per day or the use of an insulin pump.” For those with diabetes who use CGM, “priority metrics” include a “time in range” of greater than 70% from 14 days of active use. Targets for mean glucose should be individualized, with glycemic variability 36% or lower.

Further specific CGM target metrics are given for people with type 1 diabetes, older/high risk individuals, and for pregnant women. The recommendations align with those issued in a 2019 joint consensus statement on CGM time-in-range endorsed by several organizations, including AACE.    

In response to an audience question about whether AACE is advising that time-in-range replace A1c for glycemia assessment, Dr. Sherr responded: “I think currently we’re not in a position where we can completely replace A1c with time in range. However, I’m hopeful that in future years we’ll see further data gathered ... to allow for that recommendation to occur.”

For now, she said, “What we really want to hone in on in the guidelines is that time-in-range and use of CGM truly allow clinicians to better understand how to optimize care for their persons with diabetes. It gives us a better picture. It’s not just a number of whether we’re hitting target. It tells us whether we need to attack time above range or time below range. So we really think it’s critical for clinical care.”

The document also provides specifics about real-time versus intermittently scanned CGM and use of diagnostic/professional CGM.

The “insulin delivery technologies” section covers use of connected pens, insulin pumps without CGM, insulin pumps with separate CGM, and the more advanced combined insulin pump-CGM systems including those with low-glucose suspend, predictive low-glucose suspend, and hybrid closed-loops (sometimes called the artificial pancreas).

In general, these automated insulin delivery systems (artificial pancreas), “are strongly recommended for all persons with [type 1 diabetes], since their use has been shown to increase time in range, especially in the overnight period, without causing an increased risk of hypoglycemia,” Dr. Sherr observed.
 

Other tech topics: Apps, telemedicine, and safety

The new guidelines say that “clinically validated” smartphone apps should be recommended to help teach or reinforce diabetes self-management skills and provide support and encouragement for healthy behaviors around food and exercise.

Dr. Grunberger pointed out: “As we know, there are tons of apps out there, and patients are using them. The problem is that very few of them have actually been validated in clinical trials in published peer-reviewed [journals].”

He recommended a joint statement on diabetes apps from the American Diabetes Association and the European Association for the Study of Diabetes that was initially discussed at the 2019 EASD meeting, as reported by this news organization, and subsequently published in January 2020 in Diabetes Care and Diabetologia.

“Telemedicine, including periodic phone calls, smartphone-web interactions ... by health care professionals ... is strongly recommended to treat persons with diabetes, provide diabetes education, remotely monitor glucose and/or insulin data to indicate the need for therapy adjustments, and improve diabetes-related outcomes/control with better engagement,” the document says.

Safety concerns addressed include the issue of certain medications interfering with CGM [readings] ... including acetaminophen, high-dose vitamin C, and hydroxyurea, as well as cautions about what to do in the event of device malfunction and assessing that the patient is sufficiently trained in proper device use. Criteria for insulin pump discontinuation are also given.
 

Implementation: Who will be prescribing? ‘This is not for amateurs’

A final section on implementation recommends that “initiation and use of diabetes technology should be implemented by health care professionals who are trained, committed, and experienced to prescribe and direct the use of these tools. Clinicians should have the infrastructure to support the needs of persons with diabetes using the technology.”

Dr. Grunberger commented: “I think the key is going to be who should be doing this? What is the role of a clinical endocrinologist in the future? What is our responsibility, [since] we don’t have the manpower and womanpower to take care of all these people as these technologies advance? It’s our responsibility to provide these hopefully valued recommendations as a resource for those who want to know more about it.”

However, he noted, “This is not for amateurs. If you want to actually use this in your practice, you need the infrastructure, the expertise, the training, the dedication, and the energy to be there for the patients all the time ... This clinical practice guideline is a foundation.”

Dr. Sherr added: “To me, it’s really thinking about ... changing our mindset from who is an appropriate candidate to who can benefit and how vast a group that entails ... I’m hopeful that we will see more technology use through continued conversations with our patients with diabetes, and hopefully through more clinicians being excited to be part of this revolution.”

Dr. Grunberger has reported being on speakers bureaus for Eli Lilly, Novo Nordisk, and Abbott. Dr. Sherr has reported being a consultant and speaker for Lilly and Medtronic Diabetes, a consultant for Insulet and Sanofi, and on advisory boards for Bigfoot Biomedical, Cecelia Health, Insulet, JDRF T1D fund, and Medtronic.

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

The American Association of Clinical Endocrinology (AACE) has issued its first-ever official guidelines addressing the use of advanced technologies in the management of people with diabetes.

They were presented on May 28 at the annual scientific & clinical congress of the American Association of Clinical Endocrinologists and simultaneously published in Endocrine Practice.

Previous AACE guidance on the clinical use of insulin pumps and CGM over the past decade has been published in the form of consensus or position statements rather than official evidence-based guidelines, task force cochair George Grunberger, MD, of the Grunberger Diabetes Institute, Bloomfield Hills, Mich., explained.

“There’s never really been, until now, hardcore evidence, [with] peer-reviewed, quality trials published in the literature to go after the evidence that is required for guidelines. ... This is not an opinion piece or position statement.”

The problem with that strict approach to “guidelines” is how quickly the diabetes technology field is evolving, he acknowledged. “It’s frustrating because we know what’s [coming up], but we can’t put it in a guideline because it hasn’t been published yet.”

In an AACE podcast, Dr. Grunberger said the guidelines will likely become a “living” document, along the lines of the American Diabetes Association’s annual Standards of Care, as “any cutoff date is arbitrary. More and more papers will be published on these technologies. ... This is certainly not a static field.”

In the meantime, task force cochair and author Jennifer Sherr, MD, PhD, a pediatric endocrinologist, said she hopes the guidelines will help to reduce insurance company barriers to use of the currently available technologies.

“I am very hopeful that these guidelines will also encourage payers to change their stance. And I think that we as a community can continue to advocate and inform them of these guidelines so they can appropriately change their coverage practices,” added Dr. Sherr, of Yale University, New Haven, Conn.
 

Recommendations address CGM, pumps, and connected systems

In the guidelines, CGM is “strongly recommended for all persons with diabetes treated with intensive insulin therapy, defined as three or more injections of insulin per day or the use of an insulin pump.” For those with diabetes who use CGM, “priority metrics” include a “time in range” of greater than 70% from 14 days of active use. Targets for mean glucose should be individualized, with glycemic variability 36% or lower.

Further specific CGM target metrics are given for people with type 1 diabetes, older/high risk individuals, and for pregnant women. The recommendations align with those issued in a 2019 joint consensus statement on CGM time-in-range endorsed by several organizations, including AACE.    

In response to an audience question about whether AACE is advising that time-in-range replace A1c for glycemia assessment, Dr. Sherr responded: “I think currently we’re not in a position where we can completely replace A1c with time in range. However, I’m hopeful that in future years we’ll see further data gathered ... to allow for that recommendation to occur.”

For now, she said, “What we really want to hone in on in the guidelines is that time-in-range and use of CGM truly allow clinicians to better understand how to optimize care for their persons with diabetes. It gives us a better picture. It’s not just a number of whether we’re hitting target. It tells us whether we need to attack time above range or time below range. So we really think it’s critical for clinical care.”

The document also provides specifics about real-time versus intermittently scanned CGM and use of diagnostic/professional CGM.

The “insulin delivery technologies” section covers use of connected pens, insulin pumps without CGM, insulin pumps with separate CGM, and the more advanced combined insulin pump-CGM systems including those with low-glucose suspend, predictive low-glucose suspend, and hybrid closed-loops (sometimes called the artificial pancreas).

In general, these automated insulin delivery systems (artificial pancreas), “are strongly recommended for all persons with [type 1 diabetes], since their use has been shown to increase time in range, especially in the overnight period, without causing an increased risk of hypoglycemia,” Dr. Sherr observed.
 

Other tech topics: Apps, telemedicine, and safety

The new guidelines say that “clinically validated” smartphone apps should be recommended to help teach or reinforce diabetes self-management skills and provide support and encouragement for healthy behaviors around food and exercise.

Dr. Grunberger pointed out: “As we know, there are tons of apps out there, and patients are using them. The problem is that very few of them have actually been validated in clinical trials in published peer-reviewed [journals].”

He recommended a joint statement on diabetes apps from the American Diabetes Association and the European Association for the Study of Diabetes that was initially discussed at the 2019 EASD meeting, as reported by this news organization, and subsequently published in January 2020 in Diabetes Care and Diabetologia.

“Telemedicine, including periodic phone calls, smartphone-web interactions ... by health care professionals ... is strongly recommended to treat persons with diabetes, provide diabetes education, remotely monitor glucose and/or insulin data to indicate the need for therapy adjustments, and improve diabetes-related outcomes/control with better engagement,” the document says.

Safety concerns addressed include the issue of certain medications interfering with CGM [readings] ... including acetaminophen, high-dose vitamin C, and hydroxyurea, as well as cautions about what to do in the event of device malfunction and assessing that the patient is sufficiently trained in proper device use. Criteria for insulin pump discontinuation are also given.
 

Implementation: Who will be prescribing? ‘This is not for amateurs’

A final section on implementation recommends that “initiation and use of diabetes technology should be implemented by health care professionals who are trained, committed, and experienced to prescribe and direct the use of these tools. Clinicians should have the infrastructure to support the needs of persons with diabetes using the technology.”

Dr. Grunberger commented: “I think the key is going to be who should be doing this? What is the role of a clinical endocrinologist in the future? What is our responsibility, [since] we don’t have the manpower and womanpower to take care of all these people as these technologies advance? It’s our responsibility to provide these hopefully valued recommendations as a resource for those who want to know more about it.”

However, he noted, “This is not for amateurs. If you want to actually use this in your practice, you need the infrastructure, the expertise, the training, the dedication, and the energy to be there for the patients all the time ... This clinical practice guideline is a foundation.”

Dr. Sherr added: “To me, it’s really thinking about ... changing our mindset from who is an appropriate candidate to who can benefit and how vast a group that entails ... I’m hopeful that we will see more technology use through continued conversations with our patients with diabetes, and hopefully through more clinicians being excited to be part of this revolution.”

Dr. Grunberger has reported being on speakers bureaus for Eli Lilly, Novo Nordisk, and Abbott. Dr. Sherr has reported being a consultant and speaker for Lilly and Medtronic Diabetes, a consultant for Insulet and Sanofi, and on advisory boards for Bigfoot Biomedical, Cecelia Health, Insulet, JDRF T1D fund, and Medtronic.

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

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

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

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

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

Combining minimally invasive endoscopic sleeve gastroplasty with a weekly injection of the glucagonlike peptide–1 agonist semaglutide (Ozempic, Novo Nordisk) leads to significantly greater weight loss than ESG alone in patients with diabetes and excess weight who are not candidates for bariatric surgery, new research shows.

During minimally invasive ESG, a flexible endoscope equipped with an endoscopic suturing device is inserted down the esophagus and into the stomach. The endoscopist then applies the sutures to the upper portion of the stomach, minimizing its size to restrict the amount of food a patient can ingest.

“Our stomachs can stretch back a bit, but we can use the suturing device again,” explained the lead investigator of the research Anna Carolina Hoff, MD, founder and clinical director of Angioskope Brazil in São José dos Campos.

“It’s important that patients with diabetes lose as much weight as possible because, if they lose about 10% of their total body weight, they have a great improvement in their glycemic levels, and some patients can even stop taking their [antidiabetic] medications,” Dr. Hoff said in an interview.

“And we found that by adding the GLP-1 agonist [semaglutide], we could increase weight loss from, on average, about 16%-18% of total body weight with ESG alone to up to 27%, so it’s a great metabolic combination,” she noted.

Dr. Hoff presented the findings at the annual Digestive Disease Week® (DDW).

Asked to comment, Scott Kahan, MD, MPH, director, National Center for Weight and Wellness, George Washington University, Washington, cautioned that it’s still early days for minimally invasive ESG.

“It is reasonable to assume that the long-term outcomes [with ESG] won’t be as good or durable over time as with bariatric surgery, but ... we will have to see.”

However, “we know that, typically, combinations of therapeutic options work better than a one-off option, so I think the real benefit of this study – outside the specific procedure and this specific medication – is that it is a very valuable proof-of-principle study showing that combinations do work better,” Dr. Kahan said in an interview.
 

Minimally invasive endoscopic sleeve gastroplasty

ESG is a surrogate for laparoscopic sleeve gastrectomy that can offer the benefits of such a procedure to those who don’t qualify for, or don’t wish to pursue, bariatric surgery. It can be performed at an earlier stage of disease, in those with a body mass index of 30 mg/kg², whereas generally people are not offered bariatric procedures unless they have a BMI of at least 35 with comorbidities or a BMI of at least 40 if they do not have comorbidities.

Subcutaneous semaglutide is already approved for the treatment of type 2 diabetes in adults at doses of up to 1 mg/week; higher doses are needed for weight loss. Novo Nordisk has been investigating higher doses for weight loss in the STEP trial program, which is now complete, and the company has submitted the data to the Food and Drug Administration and European Medicines Agency for an additional indication of adults with obesity (BMI ≥30) or who are overweight (BMI ≥27) and who have at least one weight-related comorbidity, as an adjunct to a reduced-calorie diet and increased physical activity, with a decision expected soon.

Novo Nordisk has also developed an oral form of semaglutide, which has been approved as a once-daily agent for type 2 diabetes (Rybelsus) in doses of 7 mg and 14 mg to improve glycemic control along with diet and exercise. It is the first GLP-1 agonist available in tablet form.
 

Patients lost fat mass as well as excess weight

The Brazilian study involved 58 patients with obesity or overweight who also had diabetes and were undergoing minimally invasive ESG; they were further randomized to receive semaglutide or placebo.

The GLP-1 agonist (or sham placebo) was initiated 1 month after participants had undergone the procedure and patients were monitored each month for weight loss and type of fat loss achieved with the combination versus ESG alone. The initial dose of semaglutide used was 0.25 mg subcutaneous a week but could be titrated up to a maximum dose of 1.5 mg.

At the end of 11 months of active treatment versus placebo (12 months after ESG), patients who received additional semaglutide lost 86.3% of their excess body weight – the amount of weight patients needed to lose to reach normal BMI – compared with only 60.4% for ESG controls.

Specifically, the mean percentage total body weight loss at the end of 12 months was 25.2% for those in the combination group, compared with 18.6% for those treated with ESG alone (P < .001).

More importantly, patients in the combination group lost 12.6% of their body fat mass, compared with 9% for ESG controls, while mean A1c levels fell more in those treated with additional semaglutide compared with controls (P = .0394).

Indeed, five patients in the combination group reverted to a nondiabetic state and were able to discontinue antidiabetic medications altogether, Dr. Hoff noted.

“Our main goal is not just to lose weight but to lose body mass fat, which is very different from just losing weight,” she explained.

If patients lose weight but still maintain a high percentage of body fat mass, they have what she refers to as “sarcopenic obesity” because in this state patients have lost a lot of muscle mass but still have high levels of metabolically active visceral fat. Among many other inflammatory complexes, metabolically active visceral fat contains a large number of inflammasomes, and it is the latter that have been associated with obesity-related cancers. 

“Obesity is a progressive disease, so what we are trying to do here is buy time for patients so they do not progress to [bariatric] surgery, and this approach gives patients a chance to act earlier before obesity takes over and more metabolic consequences occur,” Dr. Hoff emphasized.

So, when combined with semaglutide, “we now have a minimally invasive procedure that can be just as successful [as surgery] and which can be made available to even more people looking to lose a significant amount of weight,” she concluded.

Dr. Hoff and Dr. Kahan have reported no relevant financial relationships.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

A Food and Drug Administration advisory panel has voted narrowly to recommend approval of the monoclonal antibody teplizumab (Tzield, Provention Bio) for the delay of type 1 diabetes in at-risk individuals.

The 10-7 vote of the FDA’s endocrinologic and metabolic drugs advisory committee on May 27 reflected a difficult decision-making process on the part of many members to weigh the benefits of a potential 2-year delay in the onset of type 1 diabetes against both observed and theoretical risks, as well as what most considered to be insufficient data.

Regardless of their vote, nearly all panel members advised the FDA that the company should be required to conduct at least one additional larger long-term efficacy and safety trial to satisfy what they felt were major gaps in the data. Some advised that use of the drug be restricted to a very narrow group of recipients until efficacy and safety can be better established.

If approved, teplizumab, which interferes with T cell–mediated autoimmune destruction of pancreatic beta cells, would be the first disease-modifying therapy for impeding progression of type 1 diabetes. The proposed indication is for individuals who have two or more type 1 diabetes-associated autoantibodies and subclinical dysglycemia.

That “stage 2” or “at-risk” condition is associated with a nearly 100% lifetime risk of progression to clinical (“stage 3”) type 1 diabetes and a 75% risk of developing the disease within 5 years. As of now, most such individuals are first-degree relatives of people with type 1 diabetes identified through TrialNet.
 

What’s the evidence to support approval so far?

In 2019, a pivotal phase 2 randomized, placebo-controlled TN-10 trial involving 76 at-risk children and adults ages 8 years and older showed that a single 14-day treatment of daily intravenous infusions of teplizumab in 44 patients resulted in a significant median 2-year delay to onset of clinical type 1 diabetes, compared with 32 who received placebo. Further follow-up data continue to show that fewer patients who received teplizumab have progressed to clinical type 1 diabetes.

While most advisory panelists agreed that the TN-10 study demonstrated efficacy, several also said that the sample size was insufficient and at least one additional randomized trial should be conducted to replicate the findings.

Although the FDA typically requires companies to demonstrate a drug’s effectiveness with at least two separate clinical trials, the agency allows companies to substitute other forms of data for a second randomized clinical trial, such as study results for the drug in a closely related condition, mechanistic data, or knowledge of other drugs from the same class.

In this case, Provention’s submission included as “confirmatory” evidence a meta-analysis of data from five earlier randomized trials (three placebo controlled, two open label) of a total 942 individuals with newly diagnosed type 1 diabetes (“stage 3”) who received either one or two 14-day teplizumab courses (n = 729) or placebo. These showed consistent preservation of C-peptide, a surrogate marker of beta-cell function, along with lower mean insulin use.

Several panel members expressed dissatisfaction with those confirmatory data, noting the patient population was different from those for which the company is currently seeking the indication, and that C-peptide is an inadequate endpoint for demonstrating efficacy.
 

Safety: Adverse events mostly transient, but unanswered questions

Adverse events reported in at least 10% of teplizumab recipients included lymphopenia (76.8% vs. 9.4% placebo; relative risk, 8.2), leukopenia (82.1% vs. 24.1%; RR, 3.4), and rash (44.5% vs. 9.0%; RR, 4.9).

“Most adverse events related to teplizumab were mechanism-based, predictable, transient, and manageable,” Chief Medical Officer of Provention Bio, Eleanor Ramos, MD, said.

Among other safety issues that concerned the panel, diabetic ketoacidosis (DKA) was seen in 2.3% of 773 teplizumab recipients with new-onset type 1 diabetes versus just 1% among the 245 controls, a significant, nearly sixfold increase. No DKA occurred in the TN-10 trial. No clear explanation was offered for the imbalance in the meta-analysis.

Cytokine release syndrome occurred in 0.6% of patients who received teplizumab versus no controls, and infections in 3.4% versus 2.0%, respectively.

Approximately 10% of patients were not able to complete the treatment course because of protocol-directed withdrawal criteria, which included elevations in bilirubin or liver enzymes, or drops in platelet count, neutrophils, or hemoglobin, FDA reviewer Lauren Wood Heickman, MD, noted.

There was only one malignancy, a melanoma in a patient with a preexisting lesion, but malignancy is a theoretical concern with long-term immunosuppression, Dr. Heickman said.

Despite the concerns about the data, panel members expressed unanimous appreciation for the 18 people who spoke during public comments attesting to the lifelong burdens involved in living with type 1 diabetes who urged the FDA to approve teplizumab.

Many of them noted that even a 2-year reprieve from the burden of constant attention to managing blood glucose can make a major difference in the life of a young person. The speakers included physicians, parents of children with type 1 diabetes, adults who have the condition themselves and who worry about their children getting it, and researchers in the field.
 

Panel members describe ‘struggle’ with vote decision

Panel member Michael Blaha, MD, of Johns Hopkins University, Baltimore, voted in favor of teplizumab approval. However, he said, “I was very conflicted on this one and my ‘yes’ is very qualified. In my opinion the risk-benefit is very narrow, and I would only approve this drug for the exact indication of the trial. ... Patients who don’t fit the criteria could hopefully be enrolled in a second confirmatory trial.”

He also advised an extensive Risk Evaluation and Mitigation Strategies program to look for both short- and long-term adverse effects.

“My overall take on this is that I do think it’s a promising paradigm-shifting therapy that really needs to move forward, at least scientifically. I’m excited about it, but I have a lot of skepticism about the entire body of data to make any more than the most narrow of approval,” Dr. Blaha said.  

Susan S. Ellenberg, PhD, professor of biostatistics, medical ethics, and health policy at the University of Pennsylvania, Philadelphia, voted yes but also with difficulty.

“I really struggled with it. ... I was pushed by the very encouraging results of what is admittedly a very small study and something I can’t feel is completely definitive. But I would not like to deny the kind of people that we heard from today the opportunity to weigh their own risks and benefits to try this. And I would certainly agree that a very, very rigorous postmarketing program, preferably including another controlled trial, should be carried out.”

But David M. Nathan, MD, director of the Diabetes Center and Clinical Research Center, Massachusetts General Hospital, Boston, voted no.

“I struggled with this vote, tremendously, having listened carefully to the patients with type 1 diabetes ... but that said, having done clinical research for 40 years in type 1 diabetes, I think we need more data, both in terms of efficacy and of safety. I would hate a number of years down the road to figure out that we actually caused more harm than good, especially keeping in mind that the treatment of type 1 diabetes is evolving rapidly.”

A different perspective came from Mara L. Becker, MD, vice chair of the department of pediatric rheumatology at Duke University, Durham, N.C. She voted yes, pointing out that she’s accustomed to prescribing biologics for chronic conditions in children.

“I was unconflicted in my vote, which was yes. I thought the data ... were convincing and the need is great. I would support a label for children [aged 8 years] and older with at least stage 2 disease ... and I would require postmarketing safety surveillance to understand what the long-term side effects could be, but I would still be in favor of it.”

FDA advisory panel committee members are vetted for conflicts of interest and waivers granted for participation if necessary; none were granted for this meeting.

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

From Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA (Drs. Chu and Ma and Mimi Lou), and Department of Family Medicine, Keck Medicine, University of Southern California, Los Angeles, CA (Dr. Suh).

Objective: The objective of this study is to describe HbA_1c changes in patients who maintained continuous pharmacist care vs patients who had a gap in pharmacist care of 3 months or longer. 

Methods: This retrospective study was conducted from October 1, 2018, to September 30, 2019. Electronic health record data from an academic-affiliated, safety-net resident physician primary care clinic were collected to observe HbA_1c changes between patients with continuous pharmacist care and patients who had a gap of 3 months or longer in pharmacist care. A total of 189 patients met the inclusion criteria and were divided into 2 groups: those with continuous care and those with gaps in care. Data were analyzed using the Mann-Whitney test for continuous variables and the χ² (or Fisher exact) test for categorical variables. The differences-in-differences model was used to compare the changes in HbA_1c between the 2 groups.

Results: There was no significant difference in changes in HbA_1c between the continuous care group and the gaps in care group, although the mean magnitude of HbA_1c changes was numerically greater in the continuous care group (-1.48% vs -0.97%). Overall, both groups showed improvement in their HbA_1c levels and had similar numbers of primary care physician visits and acute care utilizations, while the gaps in care group had longer duration with pharmacists and between the adjacent pharmacist visits.

Conclusion: Maintaining continuous, regular visits with a pharmacist at a safety-net resident physician primary care clinic did not show a significant difference in HbA_1c changes compared to having gaps in pharmacist care. Future studies on socioeconomic and behavioral burden on HbA_1c improvement and on pharmacist visits in these populations should be explored.

Keywords: clinical pharmacist; diabetes management; continuous visit; primary care clinic.

Pharmacists have unique skills in identifying and resolving problems related to the safety and efficacy of drug therapy while addressing medication adherence and access for patients. Their expertise is especially important to meet the care needs of a growing population with chronic conditions amidst a primary care physician shortage.¹ As health care systems move toward value-based care, emphasis on improvement in quality and health measures have become central in care delivery. Pharmacists have been integrated into team-based care in primary care settings, but the value-based shift has opened more opportunities for pharmacists to address unmet quality standards.^2-5

Many studies have reported that the integration of pharmacists into team-based care improves health outcomes and reduces overall health care costs.^6-9 Specifically, when pharmacists were added to primary care teams to provide diabetes management, hemoglobin HbA_1c levels were reduced compared to teams without pharmacists.^10-13 Offering pharmacist visits as often as every 2 weeks to 3 months, with each patient having an average of 4.7 visits, resulted in improved therapeutic outcomes.^3,7 During visits, pharmacists address the need for additional drug therapy, deprescribe unnecessary therapy, correct insufficient doses or durations, and switch patients to more cost-efficient drug therapy.⁹ Likewise, patients who visit pharmacists in addition to seeing their primary care physician can have medication-related concerns resolved and improve their therapeutic outcomes.^10,11

Not much is known about the magnitude of HbA_1c change based on the regularity of pharmacist visits. Although pharmacists offer follow-up appointments in reasonable time intervals, patients do not keep every appointment for a variety of reasons, including forgetfulness, personal issues, and a lack of transportation.¹⁴ Such missed appointments can negatively impact health outcomes.^14-16 The purpose of this study is to describe HbA_1c changes in patients who maintained continuous, regular pharmacist visits without a 3-month gap and in patients who had history of inconsistent pharmacist visits with a gap of 3 months or longer. Furthermore, this study describes the frequency of health care utilization for these 2 groups.

Methods

Setting

The Internal Medicine resident physician primary care clinic is 1 of 2 adult primary care clinics at an academic, urban, public medical center. It is in the heart of East Los Angeles, where predominantly Spanish-speaking and minority populations reside. The clinic has approximately 19000 empaneled patients and is the largest resident primary care clinic in the public health system. The clinical pharmacy service addresses unmet quality standards, specifically HbA_1c. The clinical pharmacists are co-located and collaborate with resident physicians, attending physicians, care managers, nurses, social workers, and community health workers at the clinic. They operate under collaborative practice agreements with prescriptive authority, except for controlled substances, specialty drugs, and antipsychotic medications.

Pharmacist visit

Patients are primarily referred by resident physicians to clinical pharmacists when their HbA_1c level is above 8% for an extended period, when poor adherence and low health literacy are evident regardless of HbA_1c level, or when a complex medication regimen requires comprehensive medication review and reconciliation. The referral occurs through warm handoff by resident physicians as well as clinic nurses, and it is embedded in the clinic flow. Patients continue their visits with resident physicians for issues other than their referral to clinical pharmacists. The visits with pharmacists are appointment-based, occur independently from resident physician visits, and continue until the patient’s HbA_1c level or adherence is optimized. Clinical pharmacists continue to follow up with patients who may have reached their target HbA_1c level but still are deemed unstable due to inconsistency in their self-management and medication adherence.

After the desirable HbA_1c target is achieved along with full adherence to medications and self-management, clinical pharmacists will hand off patients back to resident physicians. At each visit, pharmacists perform a comprehensive medication assessment and reconciliation that includes adjusting medication therapy, placing orders for necessary laboratory tests and prescriptions, and assessing medication adherence. They also evaluate patients’ signs and symptoms for hyperglycemic complications, hypoglycemia, and other potential treatment-related adverse events. These are all within the pharmacist’s scope of practice in comprehensive medication management. Patient education is provided with the teach-back method and includes lifestyle modifications and medication counseling (Table 1). Pharmacists offer face-to-face visits as frequently as every 1 to 2 weeks to every 4 to 6 weeks, depending on the level of complexity and the severity of a patient’s conditions and medications. For patients whose HbA_1c has reached the target range but have not been deemed stable, pharmacists continue to check in with them every 2 months. Phone visits are also utilized as an additional care delivery method for patients having difficulty showing up for face-to-face visits or needing quick assessment of medication adherence and responses to changes in drug treatment in between the face-to-face visits. The maximal interval between pharmacist visits is offered no longer than every 8 weeks. Patients are contacted via phone or mail by the nursing staff to reschedule if they miss their appointments with pharmacists. Every pharmacy visit is documented in the patient’s electronic medical record.

Study design

This is a retrospective study describing the HbA_1c changes in a patient group that maintained pharmacist visits, with each interval less than 3 months, and in another group, who had a history of a 3-month or longer gap between pharmacist visits. The data were obtained from patients’ electronic medical records during the study period of October 1, 2018, and September 30, 2019, and collected using a HIPAA-compliant, electronic data storage website, REDCap. The institutional review board approval was obtained under HS-19-00929. Patients 18 years and older who were referred by primary care resident physicians for diabetes management, and had 2 or more visits with a pharmacist within the study period, were included. Patients were excluded if they had only 1 HbA_1c drawn during the study period, were referred to a pharmacist for reasons other than diabetes management, were concurrently managed by an endocrinologist, had only 1 visit with a pharmacist, or had no visits with their primary care resident physician for over a year. The patients were then divided into 2 groups: continuous care cohort (CCC) and gap in care cohort (GCC). Both face-to-face and phone visits were counted as pharmacist visits for each group.

Outcomes

The primary outcome was the change in HbA_1c from baseline between the 2 groups. Baseline HbA_1c was considered as the HbA_1c value obtained within 3 months prior to, or within 1 month, of the first visit with the pharmacist during the study period. The final HbA_1c was considered the value measured within 1 month of, or 3 months after, the patient’s last visit with the pharmacist during the study period.

Several subgroup analyses were conducted to examine the relationship between HbA_1c and each group. Among patients whose baseline HbA_1c was ≥ 8%, we looked at the percentage of patients reaching HbA_1c < 8%, the percentage of patients showing any level of improvement in HbA_1c, and the change in HbA_1c for each group. We also looked at the percentage of patients with baseline HbA_1c < 8% maintaining the level throughout the study period and the change in HbA_1c for each group. Additionally, we looked at health care utilization, which included pharmacist visits, primary care physician visits, emergency room and urgent care visits, and hospitalizations for each group. The latter 3 types of utilization were grouped as acute care utilization and further analyzed for visit reasons, which were subsequently categorized as diabetes related and non-diabetes related. The diabetes related reasons linking to acute care utilization were defined as any episodes related to hypoglycemia, diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), foot ulcers, retinopathy, and osteomyelitis infection. All other reasons leading to acute care utilization were categorized as non-diabetes related.

Statistical analysis

Descriptive analyses were conducted using the Mann-Whitney test for continuous data and χ² (or Fisher exact) test for categorical data. A basic difference-in-differences (D-I-D) method was used to compare the changes of HbA_1c between the CCC and GCC over 2 time points: baseline and final measurements. The repeated measures ANOVA was used for analyzing D-I-D. P < .05 was considered significant. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

Results

Baseline data

A total of 1272 patients were identified within the study period, and 189 met the study inclusion criteria. The CCC included 132 patients, the GCC 57. The mean age of patients in both groups was similar at 57 years old (P = .39). Most patients had Medicaid as their primary insurance. About one-third of patients in each group experienced clinical atherosclerotic cardiovascular disease, and about 12% overall had chronic kidney disease stage 3 and higher. The average number of days that patients were under pharmacist care during the study period was longer in the GCC compared to the CCC, and it was statistically significant (P < .001) (Table 2). The mean ± SD baseline HbA_1c for the CCC and GCC was 10.0% ± 2.0% and 9.9% ± 1.7%, respectively, and the difference was not statistically significant (P = .93). About 86% of patients in the CCC and 90% in the GCC had a baseline HbA_1c of ≥ 8%.

The mean change in HbA_1c between the 2 groups was not statistically significant (-1.5% ± 2.0% in the CCC vs -1.0% ± 2.1% in the GCC, P = .36) (Table 3). However, an absolute mean HbA_1c reduction of 1.3% was observed in both groups combined at the end of the study. Figure 1 shows a D-I-D model of the 2 groups. Based on the output, the P value of .11 on the interaction term (time*group) indicates that the D-I-D in HbA_1c change from baseline to final between the CCC and GCC is not statistically different. However, the magnitude of the difference calculated from the LSMEANS results showed a trend. The HbA_1c from baseline to final measurement of patients in the GCC declined by 0.97 percentage points (from 9.94% to 8.97%), while those in the CCC saw their HbA_1c decline by 1.48 percentage points (from 9.96% to 8.48%), for a D-I-D of 0.51. In other words, those in the GCC had an HbA_1c that decreased by 0.51% less than that of patients in the CCC, suggesting that the CCC shows a steeper line declining from baseline to final HbA_1c compared to the GCC, whose line declines less sharply.

In the subgroup analysis of patients whose baseline HbA_1c was ≥ 8%, about 42% in the CCC and 37% in the GCC achieved an HbA_1c < 8% (P = .56) (Table 4). Approximately 83% of patients in the CCC had some degree of HbA_1c improvement—the final HbA_1c was lower than their baseline HbA_1c—whereas this was observed in about 75% of patients in the GCC (P = .19). Of patients whose baseline HbA_1c was < 8%, there was no significant difference in proportion of patients maintaining an HbA_1c < 8% between the groups (P = .57), although some increases in HbA_1c and HbA_1c changes were observed in the GCC (Table 5).

Health care utilization

Patients in the CCC visited pharmacists 5 times on average over 12 months, whereas patients in the GCC had an average of 6 visits (5 ± 2.6 in the CCC vs 6 ± 2.6 in the GCC, P = .01) (Table 6). The mean length between any 2 adjacent visits was significantly different, averaging about 33 days in the CCC compared to 64 days in the GCC (33.2 ± 10 in the CCC vs 63.7 ± 39.4 in the GCC, P < .001). As shown in Figure 2, the GCC shows wider ranges between any adjacent pharmacy visits throughout until the 10th visit. Both groups had a similar number of visits with primary care physicians during the same time period (4.6 ± 1.86 in the CCC vs 4.3 ± 2.51 in the GCC, P = .44). About 30% of patients in the CCC and 47% in the GCC had at least 1 visit to the emergency room or urgent care or had at least 1 hospital admission, for a total of 124 acute care utilizations between the 2 groups combined. Only a small fraction of acute care visits with or without hospitalizations were related to diabetes and its complications (23.1% in the CCC vs 22.0% in the GCC).

Discussion

This is a real-world study that describes HbA_1c changes in patients who maintained pharmacy visits regularly and in those who had a history of a 3-month or longer gap in pharmacy visits. Although the study did not show statistically significant differences in HbA_1c reduction between the 2 groups, pharmacists’ care, overall, provided mean HbA_1c reductions of 1.3%. This result is consistent with those from multiple previous studies.^10-13 It is worth noting that the final HbA_1c was numerically lower in patients who followed up with pharmacists regularly than in patients with gaps in visits, with a difference of about 0.5 percentage points. This difference is considered clinically significant,¹⁷ and potentially could be even greater if the study duration was longer, as depicted by the slope of HbA_1c reductions in the D-I-D model (Figure 1).

Previous studies have shown that pharmacist visits are conducted in shorter intervals than primary care physician visits to provide closer follow-up and to resolve any medication-related problems that may hinder therapeutic outcome improvements.^3-4,7-9 Increasing access via pharmacists is particularly important in this clinic, where resident physician continuity and access is challenging. The pharmacist-driven program described in this study does not deviate from the norm, and this study confirms that pharmacist care, regardless of gaps in pharmacist visits, may still be beneficial.

Another notable finding from this study was that although the average number of pharmacist visits per patient was significantly different, this difference of 1 visit did not result in a statistically significant improvement in HbA_1c. In fact, the average number of pharmacist visits per patient seemed to be within the reported range by Choe et al in a similar setting.⁷ Conversely, patients with a history of a gap in pharmacist visits spent longer durations under pharmacist care compared to those who had continuous follow-up. This could mean that it may take longer times or 1 additional visit to achieve similar HbA_1c results with continuous pharmacist care. Higher number of visits with pharmacists in the group with the history of gaps between pharmacist visits could have been facilitated by resident physicians, as both groups had a similar number of visits with them. Although this is not conclusive, identifying the optimal number of visits with pharmacists in this underserved population could be beneficial in strategizing pharmacist visits. Acute care utilization was not different between the 2 groups, and most cases that led to acute care utilization were not directly related to diabetes or its complications.

The average HbA_1c at the end of the study did not measure < 8%, a target that was reached by less than half of patients from each group; however, this study is a snapshot of a series of ongoing clinical pharmacy services. About 25% of our patients started their first visit with a pharmacist less than 6 months from the study end date, and these patients may not have had enough time with pharmacists for their HbA_1c to reach below the target goal. In addition, most patients in this clinic were enrolled in public health plans and may carry a significant burden of social and behavioral factors that can affect diabetes management.^18,19 These patients may need longer care by pharmacists along with other integrated services, such as behavioral health and social work, to achieve optimal HbA_1c levels.²⁰

There are several limitations to this study, including the lack of a propensity matched control group of patients who only had resident physician visits; thus, it is hard to test the true impact of continuous or intermittent pharmacist visits on the therapeutic outcomes. The study also does not address potential social, economic, and physical environment factors that might have contributed to pharmacist visits and to overall diabetes care. These factors can negatively impact diabetes control and addressing them could help with an individualized diabetes management approach.^17,18 Additionally, by nature of being a descriptive study, the results may be subject to undetermined confounding factors.

Conclusion

Patients maintaining continuous pharmacist visits do not have statistically significant differences in change in HbA_1c compared to patients who had a history of 3-month or longer gaps in pharmacist visits at a resident physician primary care safety-net clinic. However, patients with diabetes will likely derive a benefit in HbA_1c reduction regardless of regularity of pharmacist care. This finding still holds true in collaboration with resident physicians who also regularly meet with patients.

The study highlights that it is important to integrate clinical pharmacists into primary care teams for improved therapeutic outcomes. It is our hope that regular visits to pharmacists can be a gateway for behavioral health and social work referrals, thereby addressing pharmacist-identified social barriers. Furthermore, exploration of socioeconomic and behavioral barriers to pharmacist visits is necessary to address and improve the patient experience, health care delivery, and health outcomes.

Acknowledgments: The authors thank Roxanna Perez, PharmD, Amy Li, and Julie Dopheide, PharmD, BCPP, FASHP for their contributions to this project.

Corresponding author: Michelle Koun Lee Chu, PharmD, BCACP, APh, Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90089-9121; [email protected].

Financial disclosures: None.

From Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA (Drs. Chu and Ma and Mimi Lou), and Department of Family Medicine, Keck Medicine, University of Southern California, Los Angeles, CA (Dr. Suh).

Objective: The objective of this study is to describe HbA_1c changes in patients who maintained continuous pharmacist care vs patients who had a gap in pharmacist care of 3 months or longer. 

Methods: This retrospective study was conducted from October 1, 2018, to September 30, 2019. Electronic health record data from an academic-affiliated, safety-net resident physician primary care clinic were collected to observe HbA_1c changes between patients with continuous pharmacist care and patients who had a gap of 3 months or longer in pharmacist care. A total of 189 patients met the inclusion criteria and were divided into 2 groups: those with continuous care and those with gaps in care. Data were analyzed using the Mann-Whitney test for continuous variables and the χ² (or Fisher exact) test for categorical variables. The differences-in-differences model was used to compare the changes in HbA_1c between the 2 groups.

Results: There was no significant difference in changes in HbA_1c between the continuous care group and the gaps in care group, although the mean magnitude of HbA_1c changes was numerically greater in the continuous care group (-1.48% vs -0.97%). Overall, both groups showed improvement in their HbA_1c levels and had similar numbers of primary care physician visits and acute care utilizations, while the gaps in care group had longer duration with pharmacists and between the adjacent pharmacist visits.

Conclusion: Maintaining continuous, regular visits with a pharmacist at a safety-net resident physician primary care clinic did not show a significant difference in HbA_1c changes compared to having gaps in pharmacist care. Future studies on socioeconomic and behavioral burden on HbA_1c improvement and on pharmacist visits in these populations should be explored.

Keywords: clinical pharmacist; diabetes management; continuous visit; primary care clinic.

Pharmacists have unique skills in identifying and resolving problems related to the safety and efficacy of drug therapy while addressing medication adherence and access for patients. Their expertise is especially important to meet the care needs of a growing population with chronic conditions amidst a primary care physician shortage.¹ As health care systems move toward value-based care, emphasis on improvement in quality and health measures have become central in care delivery. Pharmacists have been integrated into team-based care in primary care settings, but the value-based shift has opened more opportunities for pharmacists to address unmet quality standards.^2-5

Many studies have reported that the integration of pharmacists into team-based care improves health outcomes and reduces overall health care costs.^6-9 Specifically, when pharmacists were added to primary care teams to provide diabetes management, hemoglobin HbA_1c levels were reduced compared to teams without pharmacists.^10-13 Offering pharmacist visits as often as every 2 weeks to 3 months, with each patient having an average of 4.7 visits, resulted in improved therapeutic outcomes.^3,7 During visits, pharmacists address the need for additional drug therapy, deprescribe unnecessary therapy, correct insufficient doses or durations, and switch patients to more cost-efficient drug therapy.⁹ Likewise, patients who visit pharmacists in addition to seeing their primary care physician can have medication-related concerns resolved and improve their therapeutic outcomes.^10,11

Not much is known about the magnitude of HbA_1c change based on the regularity of pharmacist visits. Although pharmacists offer follow-up appointments in reasonable time intervals, patients do not keep every appointment for a variety of reasons, including forgetfulness, personal issues, and a lack of transportation.¹⁴ Such missed appointments can negatively impact health outcomes.^14-16 The purpose of this study is to describe HbA_1c changes in patients who maintained continuous, regular pharmacist visits without a 3-month gap and in patients who had history of inconsistent pharmacist visits with a gap of 3 months or longer. Furthermore, this study describes the frequency of health care utilization for these 2 groups.

Methods

Setting

The Internal Medicine resident physician primary care clinic is 1 of 2 adult primary care clinics at an academic, urban, public medical center. It is in the heart of East Los Angeles, where predominantly Spanish-speaking and minority populations reside. The clinic has approximately 19000 empaneled patients and is the largest resident primary care clinic in the public health system. The clinical pharmacy service addresses unmet quality standards, specifically HbA_1c. The clinical pharmacists are co-located and collaborate with resident physicians, attending physicians, care managers, nurses, social workers, and community health workers at the clinic. They operate under collaborative practice agreements with prescriptive authority, except for controlled substances, specialty drugs, and antipsychotic medications.

Pharmacist visit

Patients are primarily referred by resident physicians to clinical pharmacists when their HbA_1c level is above 8% for an extended period, when poor adherence and low health literacy are evident regardless of HbA_1c level, or when a complex medication regimen requires comprehensive medication review and reconciliation. The referral occurs through warm handoff by resident physicians as well as clinic nurses, and it is embedded in the clinic flow. Patients continue their visits with resident physicians for issues other than their referral to clinical pharmacists. The visits with pharmacists are appointment-based, occur independently from resident physician visits, and continue until the patient’s HbA_1c level or adherence is optimized. Clinical pharmacists continue to follow up with patients who may have reached their target HbA_1c level but still are deemed unstable due to inconsistency in their self-management and medication adherence.

After the desirable HbA_1c target is achieved along with full adherence to medications and self-management, clinical pharmacists will hand off patients back to resident physicians. At each visit, pharmacists perform a comprehensive medication assessment and reconciliation that includes adjusting medication therapy, placing orders for necessary laboratory tests and prescriptions, and assessing medication adherence. They also evaluate patients’ signs and symptoms for hyperglycemic complications, hypoglycemia, and other potential treatment-related adverse events. These are all within the pharmacist’s scope of practice in comprehensive medication management. Patient education is provided with the teach-back method and includes lifestyle modifications and medication counseling (Table 1). Pharmacists offer face-to-face visits as frequently as every 1 to 2 weeks to every 4 to 6 weeks, depending on the level of complexity and the severity of a patient’s conditions and medications. For patients whose HbA_1c has reached the target range but have not been deemed stable, pharmacists continue to check in with them every 2 months. Phone visits are also utilized as an additional care delivery method for patients having difficulty showing up for face-to-face visits or needing quick assessment of medication adherence and responses to changes in drug treatment in between the face-to-face visits. The maximal interval between pharmacist visits is offered no longer than every 8 weeks. Patients are contacted via phone or mail by the nursing staff to reschedule if they miss their appointments with pharmacists. Every pharmacy visit is documented in the patient’s electronic medical record.

Study design

This is a retrospective study describing the HbA_1c changes in a patient group that maintained pharmacist visits, with each interval less than 3 months, and in another group, who had a history of a 3-month or longer gap between pharmacist visits. The data were obtained from patients’ electronic medical records during the study period of October 1, 2018, and September 30, 2019, and collected using a HIPAA-compliant, electronic data storage website, REDCap. The institutional review board approval was obtained under HS-19-00929. Patients 18 years and older who were referred by primary care resident physicians for diabetes management, and had 2 or more visits with a pharmacist within the study period, were included. Patients were excluded if they had only 1 HbA_1c drawn during the study period, were referred to a pharmacist for reasons other than diabetes management, were concurrently managed by an endocrinologist, had only 1 visit with a pharmacist, or had no visits with their primary care resident physician for over a year. The patients were then divided into 2 groups: continuous care cohort (CCC) and gap in care cohort (GCC). Both face-to-face and phone visits were counted as pharmacist visits for each group.

Outcomes

The primary outcome was the change in HbA_1c from baseline between the 2 groups. Baseline HbA_1c was considered as the HbA_1c value obtained within 3 months prior to, or within 1 month, of the first visit with the pharmacist during the study period. The final HbA_1c was considered the value measured within 1 month of, or 3 months after, the patient’s last visit with the pharmacist during the study period.

Several subgroup analyses were conducted to examine the relationship between HbA_1c and each group. Among patients whose baseline HbA_1c was ≥ 8%, we looked at the percentage of patients reaching HbA_1c < 8%, the percentage of patients showing any level of improvement in HbA_1c, and the change in HbA_1c for each group. We also looked at the percentage of patients with baseline HbA_1c < 8% maintaining the level throughout the study period and the change in HbA_1c for each group. Additionally, we looked at health care utilization, which included pharmacist visits, primary care physician visits, emergency room and urgent care visits, and hospitalizations for each group. The latter 3 types of utilization were grouped as acute care utilization and further analyzed for visit reasons, which were subsequently categorized as diabetes related and non-diabetes related. The diabetes related reasons linking to acute care utilization were defined as any episodes related to hypoglycemia, diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), foot ulcers, retinopathy, and osteomyelitis infection. All other reasons leading to acute care utilization were categorized as non-diabetes related.

Statistical analysis

Descriptive analyses were conducted using the Mann-Whitney test for continuous data and χ² (or Fisher exact) test for categorical data. A basic difference-in-differences (D-I-D) method was used to compare the changes of HbA_1c between the CCC and GCC over 2 time points: baseline and final measurements. The repeated measures ANOVA was used for analyzing D-I-D. P < .05 was considered significant. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

Results

Baseline data

A total of 1272 patients were identified within the study period, and 189 met the study inclusion criteria. The CCC included 132 patients, the GCC 57. The mean age of patients in both groups was similar at 57 years old (P = .39). Most patients had Medicaid as their primary insurance. About one-third of patients in each group experienced clinical atherosclerotic cardiovascular disease, and about 12% overall had chronic kidney disease stage 3 and higher. The average number of days that patients were under pharmacist care during the study period was longer in the GCC compared to the CCC, and it was statistically significant (P < .001) (Table 2). The mean ± SD baseline HbA_1c for the CCC and GCC was 10.0% ± 2.0% and 9.9% ± 1.7%, respectively, and the difference was not statistically significant (P = .93). About 86% of patients in the CCC and 90% in the GCC had a baseline HbA_1c of ≥ 8%.

The mean change in HbA_1c between the 2 groups was not statistically significant (-1.5% ± 2.0% in the CCC vs -1.0% ± 2.1% in the GCC, P = .36) (Table 3). However, an absolute mean HbA_1c reduction of 1.3% was observed in both groups combined at the end of the study. Figure 1 shows a D-I-D model of the 2 groups. Based on the output, the P value of .11 on the interaction term (time*group) indicates that the D-I-D in HbA_1c change from baseline to final between the CCC and GCC is not statistically different. However, the magnitude of the difference calculated from the LSMEANS results showed a trend. The HbA_1c from baseline to final measurement of patients in the GCC declined by 0.97 percentage points (from 9.94% to 8.97%), while those in the CCC saw their HbA_1c decline by 1.48 percentage points (from 9.96% to 8.48%), for a D-I-D of 0.51. In other words, those in the GCC had an HbA_1c that decreased by 0.51% less than that of patients in the CCC, suggesting that the CCC shows a steeper line declining from baseline to final HbA_1c compared to the GCC, whose line declines less sharply.

In the subgroup analysis of patients whose baseline HbA_1c was ≥ 8%, about 42% in the CCC and 37% in the GCC achieved an HbA_1c < 8% (P = .56) (Table 4). Approximately 83% of patients in the CCC had some degree of HbA_1c improvement—the final HbA_1c was lower than their baseline HbA_1c—whereas this was observed in about 75% of patients in the GCC (P = .19). Of patients whose baseline HbA_1c was < 8%, there was no significant difference in proportion of patients maintaining an HbA_1c < 8% between the groups (P = .57), although some increases in HbA_1c and HbA_1c changes were observed in the GCC (Table 5).

Health care utilization

Patients in the CCC visited pharmacists 5 times on average over 12 months, whereas patients in the GCC had an average of 6 visits (5 ± 2.6 in the CCC vs 6 ± 2.6 in the GCC, P = .01) (Table 6). The mean length between any 2 adjacent visits was significantly different, averaging about 33 days in the CCC compared to 64 days in the GCC (33.2 ± 10 in the CCC vs 63.7 ± 39.4 in the GCC, P < .001). As shown in Figure 2, the GCC shows wider ranges between any adjacent pharmacy visits throughout until the 10th visit. Both groups had a similar number of visits with primary care physicians during the same time period (4.6 ± 1.86 in the CCC vs 4.3 ± 2.51 in the GCC, P = .44). About 30% of patients in the CCC and 47% in the GCC had at least 1 visit to the emergency room or urgent care or had at least 1 hospital admission, for a total of 124 acute care utilizations between the 2 groups combined. Only a small fraction of acute care visits with or without hospitalizations were related to diabetes and its complications (23.1% in the CCC vs 22.0% in the GCC).

Discussion

This is a real-world study that describes HbA_1c changes in patients who maintained pharmacy visits regularly and in those who had a history of a 3-month or longer gap in pharmacy visits. Although the study did not show statistically significant differences in HbA_1c reduction between the 2 groups, pharmacists’ care, overall, provided mean HbA_1c reductions of 1.3%. This result is consistent with those from multiple previous studies.^10-13 It is worth noting that the final HbA_1c was numerically lower in patients who followed up with pharmacists regularly than in patients with gaps in visits, with a difference of about 0.5 percentage points. This difference is considered clinically significant,¹⁷ and potentially could be even greater if the study duration was longer, as depicted by the slope of HbA_1c reductions in the D-I-D model (Figure 1).

Previous studies have shown that pharmacist visits are conducted in shorter intervals than primary care physician visits to provide closer follow-up and to resolve any medication-related problems that may hinder therapeutic outcome improvements.^3-4,7-9 Increasing access via pharmacists is particularly important in this clinic, where resident physician continuity and access is challenging. The pharmacist-driven program described in this study does not deviate from the norm, and this study confirms that pharmacist care, regardless of gaps in pharmacist visits, may still be beneficial.

Another notable finding from this study was that although the average number of pharmacist visits per patient was significantly different, this difference of 1 visit did not result in a statistically significant improvement in HbA_1c. In fact, the average number of pharmacist visits per patient seemed to be within the reported range by Choe et al in a similar setting.⁷ Conversely, patients with a history of a gap in pharmacist visits spent longer durations under pharmacist care compared to those who had continuous follow-up. This could mean that it may take longer times or 1 additional visit to achieve similar HbA_1c results with continuous pharmacist care. Higher number of visits with pharmacists in the group with the history of gaps between pharmacist visits could have been facilitated by resident physicians, as both groups had a similar number of visits with them. Although this is not conclusive, identifying the optimal number of visits with pharmacists in this underserved population could be beneficial in strategizing pharmacist visits. Acute care utilization was not different between the 2 groups, and most cases that led to acute care utilization were not directly related to diabetes or its complications.

The average HbA_1c at the end of the study did not measure < 8%, a target that was reached by less than half of patients from each group; however, this study is a snapshot of a series of ongoing clinical pharmacy services. About 25% of our patients started their first visit with a pharmacist less than 6 months from the study end date, and these patients may not have had enough time with pharmacists for their HbA_1c to reach below the target goal. In addition, most patients in this clinic were enrolled in public health plans and may carry a significant burden of social and behavioral factors that can affect diabetes management.^18,19 These patients may need longer care by pharmacists along with other integrated services, such as behavioral health and social work, to achieve optimal HbA_1c levels.²⁰

There are several limitations to this study, including the lack of a propensity matched control group of patients who only had resident physician visits; thus, it is hard to test the true impact of continuous or intermittent pharmacist visits on the therapeutic outcomes. The study also does not address potential social, economic, and physical environment factors that might have contributed to pharmacist visits and to overall diabetes care. These factors can negatively impact diabetes control and addressing them could help with an individualized diabetes management approach.^17,18 Additionally, by nature of being a descriptive study, the results may be subject to undetermined confounding factors.

Conclusion

Patients maintaining continuous pharmacist visits do not have statistically significant differences in change in HbA_1c compared to patients who had a history of 3-month or longer gaps in pharmacist visits at a resident physician primary care safety-net clinic. However, patients with diabetes will likely derive a benefit in HbA_1c reduction regardless of regularity of pharmacist care. This finding still holds true in collaboration with resident physicians who also regularly meet with patients.

The study highlights that it is important to integrate clinical pharmacists into primary care teams for improved therapeutic outcomes. It is our hope that regular visits to pharmacists can be a gateway for behavioral health and social work referrals, thereby addressing pharmacist-identified social barriers. Furthermore, exploration of socioeconomic and behavioral barriers to pharmacist visits is necessary to address and improve the patient experience, health care delivery, and health outcomes.

Acknowledgments: The authors thank Roxanna Perez, PharmD, Amy Li, and Julie Dopheide, PharmD, BCPP, FASHP for their contributions to this project.

Corresponding author: Michelle Koun Lee Chu, PharmD, BCACP, APh, Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90089-9121; [email protected].

Financial disclosures: None.

From Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA (Drs. Chu and Ma and Mimi Lou), and Department of Family Medicine, Keck Medicine, University of Southern California, Los Angeles, CA (Dr. Suh).

Objective: The objective of this study is to describe HbA_1c changes in patients who maintained continuous pharmacist care vs patients who had a gap in pharmacist care of 3 months or longer. 

Methods: This retrospective study was conducted from October 1, 2018, to September 30, 2019. Electronic health record data from an academic-affiliated, safety-net resident physician primary care clinic were collected to observe HbA_1c changes between patients with continuous pharmacist care and patients who had a gap of 3 months or longer in pharmacist care. A total of 189 patients met the inclusion criteria and were divided into 2 groups: those with continuous care and those with gaps in care. Data were analyzed using the Mann-Whitney test for continuous variables and the χ² (or Fisher exact) test for categorical variables. The differences-in-differences model was used to compare the changes in HbA_1c between the 2 groups.

Results: There was no significant difference in changes in HbA_1c between the continuous care group and the gaps in care group, although the mean magnitude of HbA_1c changes was numerically greater in the continuous care group (-1.48% vs -0.97%). Overall, both groups showed improvement in their HbA_1c levels and had similar numbers of primary care physician visits and acute care utilizations, while the gaps in care group had longer duration with pharmacists and between the adjacent pharmacist visits.

Conclusion: Maintaining continuous, regular visits with a pharmacist at a safety-net resident physician primary care clinic did not show a significant difference in HbA_1c changes compared to having gaps in pharmacist care. Future studies on socioeconomic and behavioral burden on HbA_1c improvement and on pharmacist visits in these populations should be explored.

Keywords: clinical pharmacist; diabetes management; continuous visit; primary care clinic.

Pharmacists have unique skills in identifying and resolving problems related to the safety and efficacy of drug therapy while addressing medication adherence and access for patients. Their expertise is especially important to meet the care needs of a growing population with chronic conditions amidst a primary care physician shortage.¹ As health care systems move toward value-based care, emphasis on improvement in quality and health measures have become central in care delivery. Pharmacists have been integrated into team-based care in primary care settings, but the value-based shift has opened more opportunities for pharmacists to address unmet quality standards.^2-5

Many studies have reported that the integration of pharmacists into team-based care improves health outcomes and reduces overall health care costs.^6-9 Specifically, when pharmacists were added to primary care teams to provide diabetes management, hemoglobin HbA_1c levels were reduced compared to teams without pharmacists.^10-13 Offering pharmacist visits as often as every 2 weeks to 3 months, with each patient having an average of 4.7 visits, resulted in improved therapeutic outcomes.^3,7 During visits, pharmacists address the need for additional drug therapy, deprescribe unnecessary therapy, correct insufficient doses or durations, and switch patients to more cost-efficient drug therapy.⁹ Likewise, patients who visit pharmacists in addition to seeing their primary care physician can have medication-related concerns resolved and improve their therapeutic outcomes.^10,11

Not much is known about the magnitude of HbA_1c change based on the regularity of pharmacist visits. Although pharmacists offer follow-up appointments in reasonable time intervals, patients do not keep every appointment for a variety of reasons, including forgetfulness, personal issues, and a lack of transportation.¹⁴ Such missed appointments can negatively impact health outcomes.^14-16 The purpose of this study is to describe HbA_1c changes in patients who maintained continuous, regular pharmacist visits without a 3-month gap and in patients who had history of inconsistent pharmacist visits with a gap of 3 months or longer. Furthermore, this study describes the frequency of health care utilization for these 2 groups.

Methods

Setting

The Internal Medicine resident physician primary care clinic is 1 of 2 adult primary care clinics at an academic, urban, public medical center. It is in the heart of East Los Angeles, where predominantly Spanish-speaking and minority populations reside. The clinic has approximately 19000 empaneled patients and is the largest resident primary care clinic in the public health system. The clinical pharmacy service addresses unmet quality standards, specifically HbA_1c. The clinical pharmacists are co-located and collaborate with resident physicians, attending physicians, care managers, nurses, social workers, and community health workers at the clinic. They operate under collaborative practice agreements with prescriptive authority, except for controlled substances, specialty drugs, and antipsychotic medications.

Pharmacist visit

Patients are primarily referred by resident physicians to clinical pharmacists when their HbA_1c level is above 8% for an extended period, when poor adherence and low health literacy are evident regardless of HbA_1c level, or when a complex medication regimen requires comprehensive medication review and reconciliation. The referral occurs through warm handoff by resident physicians as well as clinic nurses, and it is embedded in the clinic flow. Patients continue their visits with resident physicians for issues other than their referral to clinical pharmacists. The visits with pharmacists are appointment-based, occur independently from resident physician visits, and continue until the patient’s HbA_1c level or adherence is optimized. Clinical pharmacists continue to follow up with patients who may have reached their target HbA_1c level but still are deemed unstable due to inconsistency in their self-management and medication adherence.

After the desirable HbA_1c target is achieved along with full adherence to medications and self-management, clinical pharmacists will hand off patients back to resident physicians. At each visit, pharmacists perform a comprehensive medication assessment and reconciliation that includes adjusting medication therapy, placing orders for necessary laboratory tests and prescriptions, and assessing medication adherence. They also evaluate patients’ signs and symptoms for hyperglycemic complications, hypoglycemia, and other potential treatment-related adverse events. These are all within the pharmacist’s scope of practice in comprehensive medication management. Patient education is provided with the teach-back method and includes lifestyle modifications and medication counseling (Table 1). Pharmacists offer face-to-face visits as frequently as every 1 to 2 weeks to every 4 to 6 weeks, depending on the level of complexity and the severity of a patient’s conditions and medications. For patients whose HbA_1c has reached the target range but have not been deemed stable, pharmacists continue to check in with them every 2 months. Phone visits are also utilized as an additional care delivery method for patients having difficulty showing up for face-to-face visits or needing quick assessment of medication adherence and responses to changes in drug treatment in between the face-to-face visits. The maximal interval between pharmacist visits is offered no longer than every 8 weeks. Patients are contacted via phone or mail by the nursing staff to reschedule if they miss their appointments with pharmacists. Every pharmacy visit is documented in the patient’s electronic medical record.

Study design

This is a retrospective study describing the HbA_1c changes in a patient group that maintained pharmacist visits, with each interval less than 3 months, and in another group, who had a history of a 3-month or longer gap between pharmacist visits. The data were obtained from patients’ electronic medical records during the study period of October 1, 2018, and September 30, 2019, and collected using a HIPAA-compliant, electronic data storage website, REDCap. The institutional review board approval was obtained under HS-19-00929. Patients 18 years and older who were referred by primary care resident physicians for diabetes management, and had 2 or more visits with a pharmacist within the study period, were included. Patients were excluded if they had only 1 HbA_1c drawn during the study period, were referred to a pharmacist for reasons other than diabetes management, were concurrently managed by an endocrinologist, had only 1 visit with a pharmacist, or had no visits with their primary care resident physician for over a year. The patients were then divided into 2 groups: continuous care cohort (CCC) and gap in care cohort (GCC). Both face-to-face and phone visits were counted as pharmacist visits for each group.

Outcomes

The primary outcome was the change in HbA_1c from baseline between the 2 groups. Baseline HbA_1c was considered as the HbA_1c value obtained within 3 months prior to, or within 1 month, of the first visit with the pharmacist during the study period. The final HbA_1c was considered the value measured within 1 month of, or 3 months after, the patient’s last visit with the pharmacist during the study period.

Several subgroup analyses were conducted to examine the relationship between HbA_1c and each group. Among patients whose baseline HbA_1c was ≥ 8%, we looked at the percentage of patients reaching HbA_1c < 8%, the percentage of patients showing any level of improvement in HbA_1c, and the change in HbA_1c for each group. We also looked at the percentage of patients with baseline HbA_1c < 8% maintaining the level throughout the study period and the change in HbA_1c for each group. Additionally, we looked at health care utilization, which included pharmacist visits, primary care physician visits, emergency room and urgent care visits, and hospitalizations for each group. The latter 3 types of utilization were grouped as acute care utilization and further analyzed for visit reasons, which were subsequently categorized as diabetes related and non-diabetes related. The diabetes related reasons linking to acute care utilization were defined as any episodes related to hypoglycemia, diabetic ketoacidosis (DKA), hyperosmolar hyperglycemic state (HHS), foot ulcers, retinopathy, and osteomyelitis infection. All other reasons leading to acute care utilization were categorized as non-diabetes related.

Statistical analysis

Descriptive analyses were conducted using the Mann-Whitney test for continuous data and χ² (or Fisher exact) test for categorical data. A basic difference-in-differences (D-I-D) method was used to compare the changes of HbA_1c between the CCC and GCC over 2 time points: baseline and final measurements. The repeated measures ANOVA was used for analyzing D-I-D. P < .05 was considered significant. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC).

Results

Baseline data

A total of 1272 patients were identified within the study period, and 189 met the study inclusion criteria. The CCC included 132 patients, the GCC 57. The mean age of patients in both groups was similar at 57 years old (P = .39). Most patients had Medicaid as their primary insurance. About one-third of patients in each group experienced clinical atherosclerotic cardiovascular disease, and about 12% overall had chronic kidney disease stage 3 and higher. The average number of days that patients were under pharmacist care during the study period was longer in the GCC compared to the CCC, and it was statistically significant (P < .001) (Table 2). The mean ± SD baseline HbA_1c for the CCC and GCC was 10.0% ± 2.0% and 9.9% ± 1.7%, respectively, and the difference was not statistically significant (P = .93). About 86% of patients in the CCC and 90% in the GCC had a baseline HbA_1c of ≥ 8%.

The mean change in HbA_1c between the 2 groups was not statistically significant (-1.5% ± 2.0% in the CCC vs -1.0% ± 2.1% in the GCC, P = .36) (Table 3). However, an absolute mean HbA_1c reduction of 1.3% was observed in both groups combined at the end of the study. Figure 1 shows a D-I-D model of the 2 groups. Based on the output, the P value of .11 on the interaction term (time*group) indicates that the D-I-D in HbA_1c change from baseline to final between the CCC and GCC is not statistically different. However, the magnitude of the difference calculated from the LSMEANS results showed a trend. The HbA_1c from baseline to final measurement of patients in the GCC declined by 0.97 percentage points (from 9.94% to 8.97%), while those in the CCC saw their HbA_1c decline by 1.48 percentage points (from 9.96% to 8.48%), for a D-I-D of 0.51. In other words, those in the GCC had an HbA_1c that decreased by 0.51% less than that of patients in the CCC, suggesting that the CCC shows a steeper line declining from baseline to final HbA_1c compared to the GCC, whose line declines less sharply.

In the subgroup analysis of patients whose baseline HbA_1c was ≥ 8%, about 42% in the CCC and 37% in the GCC achieved an HbA_1c < 8% (P = .56) (Table 4). Approximately 83% of patients in the CCC had some degree of HbA_1c improvement—the final HbA_1c was lower than their baseline HbA_1c—whereas this was observed in about 75% of patients in the GCC (P = .19). Of patients whose baseline HbA_1c was < 8%, there was no significant difference in proportion of patients maintaining an HbA_1c < 8% between the groups (P = .57), although some increases in HbA_1c and HbA_1c changes were observed in the GCC (Table 5).

Health care utilization

Patients in the CCC visited pharmacists 5 times on average over 12 months, whereas patients in the GCC had an average of 6 visits (5 ± 2.6 in the CCC vs 6 ± 2.6 in the GCC, P = .01) (Table 6). The mean length between any 2 adjacent visits was significantly different, averaging about 33 days in the CCC compared to 64 days in the GCC (33.2 ± 10 in the CCC vs 63.7 ± 39.4 in the GCC, P < .001). As shown in Figure 2, the GCC shows wider ranges between any adjacent pharmacy visits throughout until the 10th visit. Both groups had a similar number of visits with primary care physicians during the same time period (4.6 ± 1.86 in the CCC vs 4.3 ± 2.51 in the GCC, P = .44). About 30% of patients in the CCC and 47% in the GCC had at least 1 visit to the emergency room or urgent care or had at least 1 hospital admission, for a total of 124 acute care utilizations between the 2 groups combined. Only a small fraction of acute care visits with or without hospitalizations were related to diabetes and its complications (23.1% in the CCC vs 22.0% in the GCC).

Discussion

This is a real-world study that describes HbA_1c changes in patients who maintained pharmacy visits regularly and in those who had a history of a 3-month or longer gap in pharmacy visits. Although the study did not show statistically significant differences in HbA_1c reduction between the 2 groups, pharmacists’ care, overall, provided mean HbA_1c reductions of 1.3%. This result is consistent with those from multiple previous studies.^10-13 It is worth noting that the final HbA_1c was numerically lower in patients who followed up with pharmacists regularly than in patients with gaps in visits, with a difference of about 0.5 percentage points. This difference is considered clinically significant,¹⁷ and potentially could be even greater if the study duration was longer, as depicted by the slope of HbA_1c reductions in the D-I-D model (Figure 1).

Previous studies have shown that pharmacist visits are conducted in shorter intervals than primary care physician visits to provide closer follow-up and to resolve any medication-related problems that may hinder therapeutic outcome improvements.^3-4,7-9 Increasing access via pharmacists is particularly important in this clinic, where resident physician continuity and access is challenging. The pharmacist-driven program described in this study does not deviate from the norm, and this study confirms that pharmacist care, regardless of gaps in pharmacist visits, may still be beneficial.

Another notable finding from this study was that although the average number of pharmacist visits per patient was significantly different, this difference of 1 visit did not result in a statistically significant improvement in HbA_1c. In fact, the average number of pharmacist visits per patient seemed to be within the reported range by Choe et al in a similar setting.⁷ Conversely, patients with a history of a gap in pharmacist visits spent longer durations under pharmacist care compared to those who had continuous follow-up. This could mean that it may take longer times or 1 additional visit to achieve similar HbA_1c results with continuous pharmacist care. Higher number of visits with pharmacists in the group with the history of gaps between pharmacist visits could have been facilitated by resident physicians, as both groups had a similar number of visits with them. Although this is not conclusive, identifying the optimal number of visits with pharmacists in this underserved population could be beneficial in strategizing pharmacist visits. Acute care utilization was not different between the 2 groups, and most cases that led to acute care utilization were not directly related to diabetes or its complications.

The average HbA_1c at the end of the study did not measure < 8%, a target that was reached by less than half of patients from each group; however, this study is a snapshot of a series of ongoing clinical pharmacy services. About 25% of our patients started their first visit with a pharmacist less than 6 months from the study end date, and these patients may not have had enough time with pharmacists for their HbA_1c to reach below the target goal. In addition, most patients in this clinic were enrolled in public health plans and may carry a significant burden of social and behavioral factors that can affect diabetes management.^18,19 These patients may need longer care by pharmacists along with other integrated services, such as behavioral health and social work, to achieve optimal HbA_1c levels.²⁰

There are several limitations to this study, including the lack of a propensity matched control group of patients who only had resident physician visits; thus, it is hard to test the true impact of continuous or intermittent pharmacist visits on the therapeutic outcomes. The study also does not address potential social, economic, and physical environment factors that might have contributed to pharmacist visits and to overall diabetes care. These factors can negatively impact diabetes control and addressing them could help with an individualized diabetes management approach.^17,18 Additionally, by nature of being a descriptive study, the results may be subject to undetermined confounding factors.

Conclusion

Patients maintaining continuous pharmacist visits do not have statistically significant differences in change in HbA_1c compared to patients who had a history of 3-month or longer gaps in pharmacist visits at a resident physician primary care safety-net clinic. However, patients with diabetes will likely derive a benefit in HbA_1c reduction regardless of regularity of pharmacist care. This finding still holds true in collaboration with resident physicians who also regularly meet with patients.

The study highlights that it is important to integrate clinical pharmacists into primary care teams for improved therapeutic outcomes. It is our hope that regular visits to pharmacists can be a gateway for behavioral health and social work referrals, thereby addressing pharmacist-identified social barriers. Furthermore, exploration of socioeconomic and behavioral barriers to pharmacist visits is necessary to address and improve the patient experience, health care delivery, and health outcomes.

Acknowledgments: The authors thank Roxanna Perez, PharmD, Amy Li, and Julie Dopheide, PharmD, BCPP, FASHP for their contributions to this project.

Corresponding author: Michelle Koun Lee Chu, PharmD, BCACP, APh, Titus Family Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90089-9121; [email protected].

Financial disclosures: None.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Overuse of basal insulin rather than adding therapies that target mealtime glucose levels is a common problem in primary care management of type 2 diabetes that impedes achievement of optimal glycemic control, new research suggests.

Such ‘overbasalization,’ defined as a hemoglobin A1c of greater than 8% despite use of more than 0.5 units/kg per day of basal insulin, was identified in about 40% of patients seen in a Florida primary care clinic during 2015-2018. The findings were published in the April 2021 issue of Clinical Diabetes by Kevin Cowart, PharmD, a diabetes care and education specialist at the University of South Florida, Tampa, and colleagues.

The literature suggests that once people with type 2 diabetes start basal insulin, the chance that they’ll achieve a given hemoglobin A1c target, i.e., less than 7%, diminishes significantly if that goal isn’t achieved within the first year of starting insulin, Dr. Cowart said in an interview.

“Our analysis suggests that overbasalization plays a role in patients with type 2 diabetes on basal insulin not achieving optimal glycemic control. Basal insulin is not designed to address postprandial hyperglycemia. I think there’s a clear need to address hesitancy in therapeutic progression beyond basal insulin. A lot of factors underlie the delays, with therapeutic inertia being one of them. It’s complex,” he said.
 

Overbasalization seen in large proportion of patients

The study comprised 655 adults diagnosed with type 2 diabetes for at least a year who received a prescription for a basal insulin (glargine U-100, glargine U-300, detemir, degludec U-100, degludec U-200, regular U-500, or NPH insulin).

The patients had a mean hemoglobin A1c of 8.4% and a mean basal insulin dose 0.4 units/kg per day. The prevalence of overbasalization was 38.1% for those with hemoglobin A1c above 8%, 42.7% for those with A1c of 9% or above, and 42% with A1c of 10% or greater.

Patient characteristics independently associated with overbasalization were age 35-54 years (odds ratio 1.89), age 65-80 years (0.44), A1c 9% or greater (13.97), and A1c 10% or greater (6.04). Having a prescription for insulin glargine U-100 was associated with a lower overbasalization risk (0.62). In multivariate analysis, only an A1c of 9% or greater remained significant.

Rozalina G. McCoy, MD, an endocrinologist and primary care clinician at the Mayo Clinic, Rochester, Minn., said in an interview that she sees [overbasalization] frequently in patients who are referred to her. “It’s kind of that wall that patients with type 2 diabetes hit because their A1c is high but their fasting blood sugars are normal. Sometimes it’s assumed that there’s a discrepancy, because people don’t always think about postprandial hyperglycemia.”

She also noted that there has been a push in recent years to simplify regimens, particularly in older patients.

“We really want to avoid rapid-acting insulin in older patients because we’re afraid of hypoglycemia, so we start them on basal and keep the noninsulins like metformin and sulfonylureas around. Initially those control the postprandial blood sugar but over time they’re no longer enough.”
 

Options exist for addressing postmeal blood sugar highs while minimizing lows

While in the past adding premeal insulin was the only option, today there are alternatives for addressing postmeal hyperglycemia, at least in the short term.

Dr. Cowart advised that the first step is to have patients self-monitor their blood glucose and titrate their basal insulin to address fasting hyperglycemia first. Once that appropriate dose is reached, if the patient’s hemoglobin A1c is still above target, the next step is to evaluate the need for postmeal control.

For patients who are at high cardiovascular risk, the next step might involve adding a sodium-glucose cotransporter 2 inhibitor (SGLT2i) or a glucagon-like peptide 1 receptor agonist (GLP-1RA) instead of premeal insulin. But for patients in whom overbasalization is the main concern, a GLP-1RA might be the better choice since it will have a greater impact on postprandial glucose levels, while an SGLT2i will have more effect on fasting blood sugar, he said.

Another option is to use a fixed-dose combination of basal insulin and a glucagon-like peptide 1 receptor agonist (GLP-1RA), provided there aren’t cost or formulary barriers. “We want to use the right combination of drugs and not use too much of one to lead to hypoglycemia,” Dr. Cowart said.

Dr. McCoy doesn’t use fixed-dose combinations because they don’t allow as much flexibility in dosing. To correct overbasalization, she also recommends adding either a GLP-1RA or SGLT2i instead of premeal insulin. However, she cautions, “you still have to monitor those patients because after a few years it still won’t be enough and you’ll have to add mealtime insulin.”

If cost or lack of coverage prevents a patient’s use of SLGT2i/GLP-1RAs, Dr. McCoy said that adding just one premeal injection of rapid-acting insulin before the largest meal of the day is one option. Another is to use twice-daily NPH insulin instead of analog basal insulin, since that does offer some postprandial coverage.

Dr. Cowart said his approach in cost barrier situations is to try to use patient assistance programs and to look into the patient’s formulary to see if there is step therapy or tier considerations, and maybe have a discussion with the insurance company. “We often have to navigate that, and it does take a significant amount of time and could potentially delay patients getting the right therapy when it’s warranted. That is an area where there is a particular role for pharmacists in helping to overcome that and get patients on the right drugs,” he explained.
 

Problem may be even more common; testing is key

Dr. McCoy said that the A1c cutoff of 8% used to define overbasalization in the study probably resulted in an underestimation of the problem, since many patients are experiencing nighttime hypoglycemia from the basal insulin. The lows bring down their A1c level, but they’re still experiencing postmeal highs.

“I think they’re missing a lot of people, to be honest. I see a lot of patients with A1cs that aren’t that bad, say 7.5%, and their fasting blood sugars are okay, but if you were to put a [continuous glucose monitor] on those patients, invariably there’s hypoglycemia at night that no one knew about.”

Of course, for insurance reasons, most people with type 2 diabetes don’t currently have access to continuous glucose monitors. And often those who are not taking multiple daily injections are limited to one fingerstick test strip a day.

Dr. McCoy says that if hypoglycemia is a concern she will write a prior authorization justifying more test strips.

“I state explicitly in my notes why I recommend frequent monitoring. If they’re on a sulfonylurea, they should be able to check more frequently because they can have hypoglycemia. Same thing with basal insulin.”

Dr. McCoy advises that patients test their blood sugar 2 hours after the largest meal on one day, and at other times on different days. “Blood glucose after a meal shouldn’t be more than 200 [mg/dL]. If it is, that’s not a failure of basal insulin. It’s doing its job. You just need a different agent.”

Dr. Cowart has no disclosures. Dr. McCoy receives funding from the National Institutes of Health.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Drinking one cup of coffee each day lowered individual risk for developing type 2 diabetes 4%-6%, according to data from a pair of large, population-based cohorts.

Coffee had previously been associated with a lower risk of type 2 diabetes, said Carolina Ochoa-Rosales, PhD, of Erasmus University Medical Center, Rotterdam, the Netherlands. However, the potential impact of coffee consumption on the subclinical inflammation associated with type 2 diabetes has not been well studied, she said.

amenic181/Getty Images

Large cohort adds credibility

Although the associations between coffee and type 2 diabetes have been previously reported, “this study offers important findings due to the carefully standardized analyses on these two major data sources,” Linda Van Horn, PhD, RD, said in an interview.

But what makes this study different is that “these investigators hypothesized that this association could be due to an anti-inflammatory benefit,” she said. 

The take-home message for clinicians is that drinking moderate amounts of filtered coffee offers a potentially reduced risk of developing type 2 diabetes, said Dr. Van Horn, of Northwestern University, Chicago. However, additional research is needed to account for the total amount of coffee per day, and whether additions such as cream or sugar or other additives make a difference in outcomes, she added.

“Also, the risk vs. benefit of drinking coffee over the life course, including childhood, pregnancy, and older age, with possible adverse drug-nutrient interactions, remain unexplored,” she noted.

Dr. Ochoa-Rosales disclosed study funding from the Institute for Scientific Information on Coffee but had no other financial conflicts to disclose. Dr. Van Horn had no financial conflicts to disclose.

Mortality is two to three times higher in patients with adrenal incidentalomas who have autonomous cortisol secretion levels of 83 nmol/L (3 µg/dL) or more after a 1 mg dexamethasone suppression test (DST), compared with those with levels below this, new research finds.

Autonomous cortisol secretion (ACS) has been linked to hypertension, cardiovascular disease, type 2 diabetes, and early mortality, and risks vary by cortisol level.

“To adequately decide whether treatment should be surgery or medical management of possible complications, it is essential to know the risk associated with the actual level of ACS,” write Albin Kjellbom, MD, of Skåne University Hospital, Lund, Sweden, and colleagues, in their article published May 25 in Annals of Internal Medicine.

Asked to comment, Salila Kurra, MD, of the Columbia adrenal center, Columbia University, New York, told this news organization that “this idea that mild cortisol excess that doesn’t meet the threshold for overt Cushing’s can, in and of itself, cause increased morbidity and mortality is something people have been thinking about for many years now.”

“But there isn’t very clear guidance on exactly what to do in that situation, whether the incidentaloma should be removed, medically managed, or the patient should just be watched ... It may be clinically significant, but the way to sort that out is to do other testing.”   
 

Most deaths were from cardiovascular disease or cancer

Adrenal lesions are found incidentally in approximately 2% to 7% of the adult population who undergo abdominal imaging, and up to a third of those have ACS in the absence of clinical signs of Cushing syndrome.

European guidelines state that a plasma cortisol level of 138 nmol/L (5 µg/dL) or greater following DST defines ACS, and a level less than 50 nmol/L (1.8 µg/dL) rules it out, while values 50-137 (1.8-5 µg/dL) are deemed “possible” ACS.

For their study, the authors retrospectively analyzed 1,048 consecutive patients with adrenal incidentalomas seen at two Swedish hospitals between 2005 and September 2015 who were followed for up to 14 years.

The patients were a median age of 64.9 years, and 58.5% were women.

At baseline, 45.1% had a cortisol level of 50 nmol/L (1.8 µg/dL) or higher following DST, 52.9% had hypertension, 18.7% had diabetes, and 20.6% had a medical history of one or more cardiovascular events. A total of 54 patients underwent adrenalectomy, eight of them more than 2 years after the DST.

Researchers found a linear increase in mortality risk with increasing cortisol values up to 200 nmol/L (7.25 µg/dL) following DST.

Over 14 years, 16.2% (170 patients) died. Compared with cortisol less than 50 nmol/L (1.8 µg/dL) following DST, adjusted hazard ratios for mortality were 2.30 and 3.04 for cortisol levels 83 to 137 nmol/L (3-5 µg/dL) and 138 nmol/L (5 µg/dL) or greater, respectively, and both were significant.

Among the patients who died, causes of death were cardiovascular disease in 38%, cancer in 30%, infection in 4%, and other diseases in 28%.

Patients with post-DST cortisol levels of 83 nmol/L (3 µg/dL) or higher had increased cardiovascular mortality, while those with levels of 50-82 nmol/L (1.8-3.0 µg/dL) did not. In contrast, mortality rates from cancer, infection, and other diseases didn’t vary across groups.
 

Implications: Further testing, prospective studies needed

“The increase in mortality associated with cortisol DST values of 83 nmol/L or higher has implications,” the authors say.

“We suggest [medical] treatment of known cardiovascular risk factors in these patients and incorporation of our results in the decision about which patients to recommend for adrenalectomy.”

In contrast, ACS with lower cortisol (<83 nmol/L or 3 µg/dL) following DST “is not associated with clinically relevant increased mortality within 5 to 10 years,” they observe.

Dr. Kurra said she would perform further testing for any patient with an adrenal incidentaloma and a cortisol level 50-137 nmol/L (1.8-5 µg/dL) following DST: Specifically, a dehydroepiandrosterone sulfate (DHEAS) test.

“If DHEAS is low and the patient has metabolic complications, then I will work them up more, with adrenocorticotropin (ACTH) and 24-hour urine and go down that path of looking for the extent of overproduction of cortisol.”

She recommended an algorithm published in 2017 of an age- and sex-adjusted DHEAS ratio that provides a sensitive and specific screening test for subclinical hypercortisolism in patients with adrenal incidentalomas.

In further analyses by Dr. Kjellbom and colleagues into incidentaloma size, bilateralism, basal ACTH less than 2.0 pmol/L, or DHEAS less than 1.04 mmol/L, only DHEAS significantly predicted mortality.

“This should be studied further, specific to sex, age, and [post-DST]-cortisol strata,” Dr. Kjellbom and colleagues say.

In conclusion, Dr. Kurra said the new data “confirm something that people have postulated. But because it’s a retrospective review, we need prospective studies. It is an interesting finding that needs further study before we can change clinical practice.”

The study was funded by unrestricted grants from the Lisa and Johan Grönberg Foundation and the Gyllenstiernska Krapperup Foundation. Dr. Kjellbom and Dr. Kurra have reported no relevant financial relationships.

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

Mortality is two to three times higher in patients with adrenal incidentalomas who have autonomous cortisol secretion levels of 83 nmol/L (3 µg/dL) or more after a 1 mg dexamethasone suppression test (DST), compared with those with levels below this, new research finds.

Autonomous cortisol secretion (ACS) has been linked to hypertension, cardiovascular disease, type 2 diabetes, and early mortality, and risks vary by cortisol level.

“To adequately decide whether treatment should be surgery or medical management of possible complications, it is essential to know the risk associated with the actual level of ACS,” write Albin Kjellbom, MD, of Skåne University Hospital, Lund, Sweden, and colleagues, in their article published May 25 in Annals of Internal Medicine.

Asked to comment, Salila Kurra, MD, of the Columbia adrenal center, Columbia University, New York, told this news organization that “this idea that mild cortisol excess that doesn’t meet the threshold for overt Cushing’s can, in and of itself, cause increased morbidity and mortality is something people have been thinking about for many years now.”

“But there isn’t very clear guidance on exactly what to do in that situation, whether the incidentaloma should be removed, medically managed, or the patient should just be watched ... It may be clinically significant, but the way to sort that out is to do other testing.”   
 

Most deaths were from cardiovascular disease or cancer

Adrenal lesions are found incidentally in approximately 2% to 7% of the adult population who undergo abdominal imaging, and up to a third of those have ACS in the absence of clinical signs of Cushing syndrome.

European guidelines state that a plasma cortisol level of 138 nmol/L (5 µg/dL) or greater following DST defines ACS, and a level less than 50 nmol/L (1.8 µg/dL) rules it out, while values 50-137 (1.8-5 µg/dL) are deemed “possible” ACS.

For their study, the authors retrospectively analyzed 1,048 consecutive patients with adrenal incidentalomas seen at two Swedish hospitals between 2005 and September 2015 who were followed for up to 14 years.

The patients were a median age of 64.9 years, and 58.5% were women.

At baseline, 45.1% had a cortisol level of 50 nmol/L (1.8 µg/dL) or higher following DST, 52.9% had hypertension, 18.7% had diabetes, and 20.6% had a medical history of one or more cardiovascular events. A total of 54 patients underwent adrenalectomy, eight of them more than 2 years after the DST.

Researchers found a linear increase in mortality risk with increasing cortisol values up to 200 nmol/L (7.25 µg/dL) following DST.

Over 14 years, 16.2% (170 patients) died. Compared with cortisol less than 50 nmol/L (1.8 µg/dL) following DST, adjusted hazard ratios for mortality were 2.30 and 3.04 for cortisol levels 83 to 137 nmol/L (3-5 µg/dL) and 138 nmol/L (5 µg/dL) or greater, respectively, and both were significant.

Among the patients who died, causes of death were cardiovascular disease in 38%, cancer in 30%, infection in 4%, and other diseases in 28%.

Patients with post-DST cortisol levels of 83 nmol/L (3 µg/dL) or higher had increased cardiovascular mortality, while those with levels of 50-82 nmol/L (1.8-3.0 µg/dL) did not. In contrast, mortality rates from cancer, infection, and other diseases didn’t vary across groups.
 

Implications: Further testing, prospective studies needed

“The increase in mortality associated with cortisol DST values of 83 nmol/L or higher has implications,” the authors say.

“We suggest [medical] treatment of known cardiovascular risk factors in these patients and incorporation of our results in the decision about which patients to recommend for adrenalectomy.”

In contrast, ACS with lower cortisol (<83 nmol/L or 3 µg/dL) following DST “is not associated with clinically relevant increased mortality within 5 to 10 years,” they observe.

Dr. Kurra said she would perform further testing for any patient with an adrenal incidentaloma and a cortisol level 50-137 nmol/L (1.8-5 µg/dL) following DST: Specifically, a dehydroepiandrosterone sulfate (DHEAS) test.

“If DHEAS is low and the patient has metabolic complications, then I will work them up more, with adrenocorticotropin (ACTH) and 24-hour urine and go down that path of looking for the extent of overproduction of cortisol.”

She recommended an algorithm published in 2017 of an age- and sex-adjusted DHEAS ratio that provides a sensitive and specific screening test for subclinical hypercortisolism in patients with adrenal incidentalomas.

In further analyses by Dr. Kjellbom and colleagues into incidentaloma size, bilateralism, basal ACTH less than 2.0 pmol/L, or DHEAS less than 1.04 mmol/L, only DHEAS significantly predicted mortality.

“This should be studied further, specific to sex, age, and [post-DST]-cortisol strata,” Dr. Kjellbom and colleagues say.

In conclusion, Dr. Kurra said the new data “confirm something that people have postulated. But because it’s a retrospective review, we need prospective studies. It is an interesting finding that needs further study before we can change clinical practice.”

The study was funded by unrestricted grants from the Lisa and Johan Grönberg Foundation and the Gyllenstiernska Krapperup Foundation. Dr. Kjellbom and Dr. Kurra have reported no relevant financial relationships.

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

Mortality is two to three times higher in patients with adrenal incidentalomas who have autonomous cortisol secretion levels of 83 nmol/L (3 µg/dL) or more after a 1 mg dexamethasone suppression test (DST), compared with those with levels below this, new research finds.

Autonomous cortisol secretion (ACS) has been linked to hypertension, cardiovascular disease, type 2 diabetes, and early mortality, and risks vary by cortisol level.

“To adequately decide whether treatment should be surgery or medical management of possible complications, it is essential to know the risk associated with the actual level of ACS,” write Albin Kjellbom, MD, of Skåne University Hospital, Lund, Sweden, and colleagues, in their article published May 25 in Annals of Internal Medicine.

Asked to comment, Salila Kurra, MD, of the Columbia adrenal center, Columbia University, New York, told this news organization that “this idea that mild cortisol excess that doesn’t meet the threshold for overt Cushing’s can, in and of itself, cause increased morbidity and mortality is something people have been thinking about for many years now.”

“But there isn’t very clear guidance on exactly what to do in that situation, whether the incidentaloma should be removed, medically managed, or the patient should just be watched ... It may be clinically significant, but the way to sort that out is to do other testing.”   
 

Most deaths were from cardiovascular disease or cancer

Adrenal lesions are found incidentally in approximately 2% to 7% of the adult population who undergo abdominal imaging, and up to a third of those have ACS in the absence of clinical signs of Cushing syndrome.

European guidelines state that a plasma cortisol level of 138 nmol/L (5 µg/dL) or greater following DST defines ACS, and a level less than 50 nmol/L (1.8 µg/dL) rules it out, while values 50-137 (1.8-5 µg/dL) are deemed “possible” ACS.

For their study, the authors retrospectively analyzed 1,048 consecutive patients with adrenal incidentalomas seen at two Swedish hospitals between 2005 and September 2015 who were followed for up to 14 years.

The patients were a median age of 64.9 years, and 58.5% were women.

At baseline, 45.1% had a cortisol level of 50 nmol/L (1.8 µg/dL) or higher following DST, 52.9% had hypertension, 18.7% had diabetes, and 20.6% had a medical history of one or more cardiovascular events. A total of 54 patients underwent adrenalectomy, eight of them more than 2 years after the DST.

Researchers found a linear increase in mortality risk with increasing cortisol values up to 200 nmol/L (7.25 µg/dL) following DST.

Over 14 years, 16.2% (170 patients) died. Compared with cortisol less than 50 nmol/L (1.8 µg/dL) following DST, adjusted hazard ratios for mortality were 2.30 and 3.04 for cortisol levels 83 to 137 nmol/L (3-5 µg/dL) and 138 nmol/L (5 µg/dL) or greater, respectively, and both were significant.

Among the patients who died, causes of death were cardiovascular disease in 38%, cancer in 30%, infection in 4%, and other diseases in 28%.

Patients with post-DST cortisol levels of 83 nmol/L (3 µg/dL) or higher had increased cardiovascular mortality, while those with levels of 50-82 nmol/L (1.8-3.0 µg/dL) did not. In contrast, mortality rates from cancer, infection, and other diseases didn’t vary across groups.
 

Implications: Further testing, prospective studies needed

“The increase in mortality associated with cortisol DST values of 83 nmol/L or higher has implications,” the authors say.

“We suggest [medical] treatment of known cardiovascular risk factors in these patients and incorporation of our results in the decision about which patients to recommend for adrenalectomy.”

In contrast, ACS with lower cortisol (<83 nmol/L or 3 µg/dL) following DST “is not associated with clinically relevant increased mortality within 5 to 10 years,” they observe.

Dr. Kurra said she would perform further testing for any patient with an adrenal incidentaloma and a cortisol level 50-137 nmol/L (1.8-5 µg/dL) following DST: Specifically, a dehydroepiandrosterone sulfate (DHEAS) test.

“If DHEAS is low and the patient has metabolic complications, then I will work them up more, with adrenocorticotropin (ACTH) and 24-hour urine and go down that path of looking for the extent of overproduction of cortisol.”

She recommended an algorithm published in 2017 of an age- and sex-adjusted DHEAS ratio that provides a sensitive and specific screening test for subclinical hypercortisolism in patients with adrenal incidentalomas.

In further analyses by Dr. Kjellbom and colleagues into incidentaloma size, bilateralism, basal ACTH less than 2.0 pmol/L, or DHEAS less than 1.04 mmol/L, only DHEAS significantly predicted mortality.

“This should be studied further, specific to sex, age, and [post-DST]-cortisol strata,” Dr. Kjellbom and colleagues say.

In conclusion, Dr. Kurra said the new data “confirm something that people have postulated. But because it’s a retrospective review, we need prospective studies. It is an interesting finding that needs further study before we can change clinical practice.”

The study was funded by unrestricted grants from the Lisa and Johan Grönberg Foundation and the Gyllenstiernska Krapperup Foundation. Dr. Kjellbom and Dr. Kurra have reported no relevant financial relationships.

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

For the first readers of Family Practice News, it started with this: “How safe is the pill? An extensive epidemiologic study being carried out in the United Kingdom by the Royal College of General Practitioners is expected to provide definitive answers to this question within the next few years.”

MDedge News

That was the first paragraph of the lead article on the front page of our very first issue, published in October 1971. The report on oral contraceptives, coming from the annual meeting of the British Medical Association in Leicester, largely focused on recruiting – noting that “all women in the study are married” – and data-gathering methods.

That first issue also covered such topics as the effect of “early and frequent coitus” on cervical dysplasia incidence (p. 4), breast cancer in men (p. 13), and treatment of prostate inflammation in patients with impotence (p. 34).

Our April 2021 issue included five articles related to the COVID-19 pandemic, starting on the front page and featuring a photo – a physician sitting at a computer, wearing a mask – and a topic – vaccine-hesitant patients.


 

Business of medicine today vs. in 1971

At the time of publication of our first issue the United States was in the midst of a 90-day freeze on wages and prices ordered by President Richard Nixon. Two articles in that first issue discussed the subject: “Freeze clouds future of health insurance plans” and “Freeze lets physicians ‘stabilize’ office fees.”

Besides COVID-19, here are some other topics covered in April 2021 but not in 1971: lessons learned from an electronic health records conversion, competition for physicians in the form of a “virtual primary care service” offered by United Healthcare, and the sleep effects of smartphone “addiction.”

Technology, clearly, plays a much larger role in physicians’ lives these days.
 

Similarities between issues

Not everything has changed, of course. We were informing physicians about heart disease in 1971 with “Primary MD can treat most vascular cases” and “Job satisfaction can help prevent heart disease.”

A look at the latest issue uncovered “Link clinched between high-glycemic index diets and cardiovascular disease events” and “Ultraprocessed ‘healthy’ foods raise cardiovascular disease events risk.” Diabetes is another topic that we have began covering since day one and continue to consider to be relevant to practicing family medicine. “Family attitude key to diabetic’s state” was published in our first issue and “Type 1 diabetes prevention moves toward reality as studies published” ran in our April 2021 issue.

The photos in that first issue, however, present a somewhat jarring counterpoint to our latest issue. The faces that look back from 50 years ago are men’s faces: 29 men, to be exact. There were no photos of women physicians in that issue.

That was not the case in April of 2021. Of the 26 physicians or research scientists who appeared in photos in that issue, 8 were women. Plus, three of those women appeared on the cover.

Among the photos from 1971 were 6 of the 14 founding members of our editorial advisory board, who were, again, all men. Our current board consists of 13 men and 8 women.

Times have changed.

[email protected]

This article was updated 5/27/21.

For the first readers of Family Practice News, it started with this: “How safe is the pill? An extensive epidemiologic study being carried out in the United Kingdom by the Royal College of General Practitioners is expected to provide definitive answers to this question within the next few years.”

MDedge News

That was the first paragraph of the lead article on the front page of our very first issue, published in October 1971. The report on oral contraceptives, coming from the annual meeting of the British Medical Association in Leicester, largely focused on recruiting – noting that “all women in the study are married” – and data-gathering methods.

That first issue also covered such topics as the effect of “early and frequent coitus” on cervical dysplasia incidence (p. 4), breast cancer in men (p. 13), and treatment of prostate inflammation in patients with impotence (p. 34).

Our April 2021 issue included five articles related to the COVID-19 pandemic, starting on the front page and featuring a photo – a physician sitting at a computer, wearing a mask – and a topic – vaccine-hesitant patients.


 

Business of medicine today vs. in 1971

At the time of publication of our first issue the United States was in the midst of a 90-day freeze on wages and prices ordered by President Richard Nixon. Two articles in that first issue discussed the subject: “Freeze clouds future of health insurance plans” and “Freeze lets physicians ‘stabilize’ office fees.”

Besides COVID-19, here are some other topics covered in April 2021 but not in 1971: lessons learned from an electronic health records conversion, competition for physicians in the form of a “virtual primary care service” offered by United Healthcare, and the sleep effects of smartphone “addiction.”

Technology, clearly, plays a much larger role in physicians’ lives these days.
 

Similarities between issues

Not everything has changed, of course. We were informing physicians about heart disease in 1971 with “Primary MD can treat most vascular cases” and “Job satisfaction can help prevent heart disease.”

A look at the latest issue uncovered “Link clinched between high-glycemic index diets and cardiovascular disease events” and “Ultraprocessed ‘healthy’ foods raise cardiovascular disease events risk.” Diabetes is another topic that we have began covering since day one and continue to consider to be relevant to practicing family medicine. “Family attitude key to diabetic’s state” was published in our first issue and “Type 1 diabetes prevention moves toward reality as studies published” ran in our April 2021 issue.

The photos in that first issue, however, present a somewhat jarring counterpoint to our latest issue. The faces that look back from 50 years ago are men’s faces: 29 men, to be exact. There were no photos of women physicians in that issue.

That was not the case in April of 2021. Of the 26 physicians or research scientists who appeared in photos in that issue, 8 were women. Plus, three of those women appeared on the cover.

Among the photos from 1971 were 6 of the 14 founding members of our editorial advisory board, who were, again, all men. Our current board consists of 13 men and 8 women.

Times have changed.

[email protected]

This article was updated 5/27/21.

For the first readers of Family Practice News, it started with this: “How safe is the pill? An extensive epidemiologic study being carried out in the United Kingdom by the Royal College of General Practitioners is expected to provide definitive answers to this question within the next few years.”

MDedge News

That was the first paragraph of the lead article on the front page of our very first issue, published in October 1971. The report on oral contraceptives, coming from the annual meeting of the British Medical Association in Leicester, largely focused on recruiting – noting that “all women in the study are married” – and data-gathering methods.

That first issue also covered such topics as the effect of “early and frequent coitus” on cervical dysplasia incidence (p. 4), breast cancer in men (p. 13), and treatment of prostate inflammation in patients with impotence (p. 34).

Our April 2021 issue included five articles related to the COVID-19 pandemic, starting on the front page and featuring a photo – a physician sitting at a computer, wearing a mask – and a topic – vaccine-hesitant patients.


 

Business of medicine today vs. in 1971

At the time of publication of our first issue the United States was in the midst of a 90-day freeze on wages and prices ordered by President Richard Nixon. Two articles in that first issue discussed the subject: “Freeze clouds future of health insurance plans” and “Freeze lets physicians ‘stabilize’ office fees.”

Besides COVID-19, here are some other topics covered in April 2021 but not in 1971: lessons learned from an electronic health records conversion, competition for physicians in the form of a “virtual primary care service” offered by United Healthcare, and the sleep effects of smartphone “addiction.”

Technology, clearly, plays a much larger role in physicians’ lives these days.
 

Similarities between issues

Not everything has changed, of course. We were informing physicians about heart disease in 1971 with “Primary MD can treat most vascular cases” and “Job satisfaction can help prevent heart disease.”

A look at the latest issue uncovered “Link clinched between high-glycemic index diets and cardiovascular disease events” and “Ultraprocessed ‘healthy’ foods raise cardiovascular disease events risk.” Diabetes is another topic that we have began covering since day one and continue to consider to be relevant to practicing family medicine. “Family attitude key to diabetic’s state” was published in our first issue and “Type 1 diabetes prevention moves toward reality as studies published” ran in our April 2021 issue.

The photos in that first issue, however, present a somewhat jarring counterpoint to our latest issue. The faces that look back from 50 years ago are men’s faces: 29 men, to be exact. There were no photos of women physicians in that issue.

That was not the case in April of 2021. Of the 26 physicians or research scientists who appeared in photos in that issue, 8 were women. Plus, three of those women appeared on the cover.

Among the photos from 1971 were 6 of the 14 founding members of our editorial advisory board, who were, again, all men. Our current board consists of 13 men and 8 women.

Times have changed.

[email protected]

This article was updated 5/27/21.

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]

It’s now official: The investigational sodium-glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin is the first agent clearly shown in a prespecified analysis of randomized trials to improve clinical outcomes in patients with heart failure with reduced ejection fraction (HFpEF).

Researchers who ran the SCORED and SOLOIST-WHF pivotal trials for sotagliflozin first made that claim in November 2020 when reporting top-line results from a prespecified meta-analysis of the two trials during the American Heart Association annual scientific sessions. A follow-up report during the annual scientific sessions of the American College of Cardiology fleshed out the evidence and firmed up their landmark conclusion.

The meta-analysis (Abstract 410-08) included 4,500 patients with type 2 diabetes and diagnosed heart failure at entry; its primary endpoint, which was the same in both trials, was the combined incidence of cardiovascular death and the total number of either hospitalization for heart failure or urgent outpatient visits for heart failure.

Compared with placebo, treatment with sotagliflozin for a median of about 15 months dropped this composite endpoint by a relative 33% among the 1,931 who began the study with a left ventricular ejection fraction (LVEF) of at least 50% (HFpEF), by a relative 22% in the 1,758 patients who entered with an LVEF of less than 40% (patients with heart failure with reduced ejection fraction), and by a relative 43% among the 811 patients who began with an LVEF of 40%-49% (patients with heart failure with mid-range ejection fraction). The relative risk reductions were significant for all three subgroups, Deepak L. Bhatt, MD, reported at the meeting.
 

Equally effective ‘across the full range of LVEFs.’

Perhaps as notable and unprecedented was the further finding that the clinical benefits seen with treatment of patients with type 2 diabetes with sotagliflozin was consistent regardless of the ejection fraction they had at entry. Enrolled patients with baseline LVEFs in the range of 25% received a relative benefit from sotagliflozin treatment that was statistically no different from the benefit seen in patients who entered with an LVEF in the neighborhood of 45%, 65%, or at any other level across the LVEF spectrum, a finding that Dr. Bhatt called “remarkable” during a press briefing. “The results show the benefit of sotagliflozin across the full range of LVEFs.”

“We are very excited in the heart failure world by the SGLT2 inhibitors; we’ve been impressed by their reduction in heart failure hospitalizations, but we wonder about the patients with HFpEF, where we haven’t had a blockbuster drug to give,” said Ileana L. Piña, MD, a heart failure specialist and medical officer with the Food and Drug Administration.

The new findings “look like they could pose a regulatory indication [for sotagliflozin] for patients with type 2 diabetes and heart failure across the entire spectrum of heart failure,” said Christopher M. O’Connor, MD, a heart failure specialist and president of the Inova Heart & Vascular institute in Falls Church, Va., and designated discussant for Dr. Bhatt’s report.

A significant on-treatment reduction in CV death

Other new, notable findings from the meta-analysis included the observation that while treatment with sotagliflozin failed to produce a significant reduction in cardiovascular death, compared with placebo, in the intent-to-treat analysis of all patients and of those with heart failure at baseline (it produced nonsignificant point-estimate reductions of 11% compared with placebo for all patients, and of 23% for patients who began the study with heart failure), it did result in a significant 23% relative risk reduction when the researchers focused on patients while they remained adherent to their sotagliflozin regimen (the on-treatment analysis). This 23% relative reduction appeared among all enrolled patients, as well as in the subgroup that started with diagnosed heart failure.

“Given the totality of data from the SGLT2 inhibitors, I think this is a real finding,” Dr. Bhatt said.

Additional analyses also showed that, among women, treatment with sotagliflozin was linked with significant relative reductions in the primary endpoint of roughly 30% compared with placebo among all patients, and also among those with heart failure at baseline. “HFpEF is a problem particularly in older women, and we showed that the benefit was consistent in men and women,” Dr. Bhatt said.

He acknowledged that results are expected soon from two pivotal trials that are examining two different SGLT2 inhibitors, dapagliflozin and empagliflozin, in patients with HFpEF. “I think there will be a class effect for both SGLT2 inhibitors and sotagliflozin for reducing heart failure events in patients with HFpEF, and I predict that the dapagliflozin and empagliflozin trials will have positive results,” Dr. Bhatt said.

Sotagliflozin differs from the SGLT2 inhibitors by also inhibiting SGLT1, an enzyme found in the gastrointestinal system that, when inhibited, results in increased glucose excretion from the gut and a cut in bloodstream levels of postprandial glucose levels. The Food and Drug Administration accepted data from SCORED and SOLOIST-WHF as part of the evidence the agency is now considering for granting a new drug approval to sotagliflozin.

SCORED and SOLOIST-WHF were initially sponsored by Sanofi, and later by Lexicon Pharmaceuticals. Dr. Bhatt’s institution, Brigham and Women’s Hospital, has received funding from Sanofi and Lexicon Pharmaceuticals. He has been a consultant to and received honoraria from K₂P, Level Ex, and MJH Life Sciences; he has been an adviser to Cardax, Cereno Scientific, Myokardia, Novo Nordisk, Phase Bio, and PLx Pharma; and he has received research funding from numerous companies. Dr. Piña has no relevant disclosures. Dr. O’Connor has been a consultant to Arena, Bayer, Bristol-Myers Squibb, Merck, and Windtree, and he has an ownership interest in Biscardia.

[email protected]