Sharon Worcester

LOS ANGELES – Serum neurofilament light chain shows promise as a biomarker for disease severity and response to treatment with autologous bone marrow transplant in patients with multiple sclerosis, according to findings from an analysis of paired samples.

solitude72/iStockphoto

Serum neurofilament light chain (Nf-L) levels were found to be significantly elevated in both the serum and cerebrospinal fluid (CSF) of 23 patients with aggressive multiple sclerosis (MS), compared with samples from 5 controls with noninflammatory neurologic conditions such as chronic fatigue syndrome or migraine. The levels in the patients with MS were significantly reduced following autologous bone marrow transplant (BMT), Simon Thebault, MD, reported in a poster at the annual meeting of the American Academy of Neurology.

Nf-L has been shown to be a biomarker for neuronal damage and to have potential for denoting disease severity and treatment response in MS; for this analysis, samples from patients were collected at baseline and annually for 3 years after transplant. Samples from controls were obtained for comparison.

“Our objective, really, was [to determine if we could] detect a treatment response in neurofilament light chain, and secondly, did the degree of neurofilament light chain being high at baseline predict anything about subsequent disease outcome?” Dr. Thebault, a third-year resident at the University of Ottawa, reported in the poster.

Indeed, a treatment response was detected; baseline levels were high, and levels in both serum and CSF were down significantly (P = .05) at both 1 and 3 years following bone marrow transplant, and they stayed down. “In fact, they were so low, they were not significantly different from [the levels] in noninflammatory controls,” he said, noting that serum and CSF NfL levels were highly correlated (r = .833; P less than .001).

Study subjects were patients with aggressive MS, characterized by early disease onset, rapid progression, frequent relapses, and poor treatment responses. Such patients who have received autologous BMT represent an interesting group for examining treatment responses, he said.

At baseline, these patients presumably have a high burden of tissue injury, which would be representative of high levels of Nf-L; good, prospective data show these patients have no evidence of ongoing inflammatory disease following an intensive regimen that includes chemoablation and reinfusion of autologous stem cells, which is representative of a significant reduction of neurofilament levels, he explained.

Importantly, serum and CSF levels were correlated in this study, he said, noting that most prior work has involved CSF, but “the real clinical utility in neurofilament light chain is probably in the serum, because patients don’t like having lumbar punctures too often.”

With respect to the second question pertaining to disease outcomes, the study did show that patients with baseline Nf-L levels above the median for the group had worse T1 lesion volumes at baseline and after transplant (P = .0021 at 36 months), and also had worsening brain atrophy even after transplant (P = .0389 at 60 months).

The curves appeared to be diverging, suggesting that, in the absence of inflammatory disease activity, patients with high Nf-L levels at baseline continue to have ongoing atrophy at a differential rate, compared with those with low baseline levels, Dr. Thebault said.

Other findings included better Expanded Disability Status Scale outcomes after transplant in patients with lower baseline Nf-L, and a trend toward worsening outcomes among those with higher baseline Nf-L levels, although the study may have been underpowered for this. Additionally, lower baseline Nf-L predicted significantly lower T1 and T2 lesion volume, number of gadolinium-enhancing lesions, and a reduction in brain atrophy, whereas higher baseline Nf-L predicted the opposite, he noted, adding that N-acetylaspartate-to-creatinine ratios also tended to vary inversely with Nf-L levels.

The most important findings of the study are “the sustained reduction in Nf-L levels after BMT, and that higher baseline levels predicted worse MRI outcomes,” Dr. Thebault noted. “Together these data add to a growing body of evidence that suggests that serum Nf-L has a role in monitoring treatment responses and even a predictive value in determining disease severity.”

This study was supported by Quanterix, which provided Nf-L assay kits. Dr. Thebault reported having no disclosures.

[email protected]

SOURCE: Thebault S et al. Neurology. 2018 Apr;90(15 Suppl.):P5.036.

LOS ANGELES – Serum neurofilament light chain shows promise as a biomarker for disease severity and response to treatment with autologous bone marrow transplant in patients with multiple sclerosis, according to findings from an analysis of paired samples.

solitude72/iStockphoto

Serum neurofilament light chain (Nf-L) levels were found to be significantly elevated in both the serum and cerebrospinal fluid (CSF) of 23 patients with aggressive multiple sclerosis (MS), compared with samples from 5 controls with noninflammatory neurologic conditions such as chronic fatigue syndrome or migraine. The levels in the patients with MS were significantly reduced following autologous bone marrow transplant (BMT), Simon Thebault, MD, reported in a poster at the annual meeting of the American Academy of Neurology.

Nf-L has been shown to be a biomarker for neuronal damage and to have potential for denoting disease severity and treatment response in MS; for this analysis, samples from patients were collected at baseline and annually for 3 years after transplant. Samples from controls were obtained for comparison.

“Our objective, really, was [to determine if we could] detect a treatment response in neurofilament light chain, and secondly, did the degree of neurofilament light chain being high at baseline predict anything about subsequent disease outcome?” Dr. Thebault, a third-year resident at the University of Ottawa, reported in the poster.

Indeed, a treatment response was detected; baseline levels were high, and levels in both serum and CSF were down significantly (P = .05) at both 1 and 3 years following bone marrow transplant, and they stayed down. “In fact, they were so low, they were not significantly different from [the levels] in noninflammatory controls,” he said, noting that serum and CSF NfL levels were highly correlated (r = .833; P less than .001).

Study subjects were patients with aggressive MS, characterized by early disease onset, rapid progression, frequent relapses, and poor treatment responses. Such patients who have received autologous BMT represent an interesting group for examining treatment responses, he said.

At baseline, these patients presumably have a high burden of tissue injury, which would be representative of high levels of Nf-L; good, prospective data show these patients have no evidence of ongoing inflammatory disease following an intensive regimen that includes chemoablation and reinfusion of autologous stem cells, which is representative of a significant reduction of neurofilament levels, he explained.

Importantly, serum and CSF levels were correlated in this study, he said, noting that most prior work has involved CSF, but “the real clinical utility in neurofilament light chain is probably in the serum, because patients don’t like having lumbar punctures too often.”

With respect to the second question pertaining to disease outcomes, the study did show that patients with baseline Nf-L levels above the median for the group had worse T1 lesion volumes at baseline and after transplant (P = .0021 at 36 months), and also had worsening brain atrophy even after transplant (P = .0389 at 60 months).

The curves appeared to be diverging, suggesting that, in the absence of inflammatory disease activity, patients with high Nf-L levels at baseline continue to have ongoing atrophy at a differential rate, compared with those with low baseline levels, Dr. Thebault said.

Other findings included better Expanded Disability Status Scale outcomes after transplant in patients with lower baseline Nf-L, and a trend toward worsening outcomes among those with higher baseline Nf-L levels, although the study may have been underpowered for this. Additionally, lower baseline Nf-L predicted significantly lower T1 and T2 lesion volume, number of gadolinium-enhancing lesions, and a reduction in brain atrophy, whereas higher baseline Nf-L predicted the opposite, he noted, adding that N-acetylaspartate-to-creatinine ratios also tended to vary inversely with Nf-L levels.

The most important findings of the study are “the sustained reduction in Nf-L levels after BMT, and that higher baseline levels predicted worse MRI outcomes,” Dr. Thebault noted. “Together these data add to a growing body of evidence that suggests that serum Nf-L has a role in monitoring treatment responses and even a predictive value in determining disease severity.”

This study was supported by Quanterix, which provided Nf-L assay kits. Dr. Thebault reported having no disclosures.

[email protected]

SOURCE: Thebault S et al. Neurology. 2018 Apr;90(15 Suppl.):P5.036.

LOS ANGELES – Serum neurofilament light chain shows promise as a biomarker for disease severity and response to treatment with autologous bone marrow transplant in patients with multiple sclerosis, according to findings from an analysis of paired samples.

solitude72/iStockphoto

Serum neurofilament light chain (Nf-L) levels were found to be significantly elevated in both the serum and cerebrospinal fluid (CSF) of 23 patients with aggressive multiple sclerosis (MS), compared with samples from 5 controls with noninflammatory neurologic conditions such as chronic fatigue syndrome or migraine. The levels in the patients with MS were significantly reduced following autologous bone marrow transplant (BMT), Simon Thebault, MD, reported in a poster at the annual meeting of the American Academy of Neurology.

Nf-L has been shown to be a biomarker for neuronal damage and to have potential for denoting disease severity and treatment response in MS; for this analysis, samples from patients were collected at baseline and annually for 3 years after transplant. Samples from controls were obtained for comparison.

“Our objective, really, was [to determine if we could] detect a treatment response in neurofilament light chain, and secondly, did the degree of neurofilament light chain being high at baseline predict anything about subsequent disease outcome?” Dr. Thebault, a third-year resident at the University of Ottawa, reported in the poster.

Indeed, a treatment response was detected; baseline levels were high, and levels in both serum and CSF were down significantly (P = .05) at both 1 and 3 years following bone marrow transplant, and they stayed down. “In fact, they were so low, they were not significantly different from [the levels] in noninflammatory controls,” he said, noting that serum and CSF NfL levels were highly correlated (r = .833; P less than .001).

Study subjects were patients with aggressive MS, characterized by early disease onset, rapid progression, frequent relapses, and poor treatment responses. Such patients who have received autologous BMT represent an interesting group for examining treatment responses, he said.

At baseline, these patients presumably have a high burden of tissue injury, which would be representative of high levels of Nf-L; good, prospective data show these patients have no evidence of ongoing inflammatory disease following an intensive regimen that includes chemoablation and reinfusion of autologous stem cells, which is representative of a significant reduction of neurofilament levels, he explained.

Importantly, serum and CSF levels were correlated in this study, he said, noting that most prior work has involved CSF, but “the real clinical utility in neurofilament light chain is probably in the serum, because patients don’t like having lumbar punctures too often.”

With respect to the second question pertaining to disease outcomes, the study did show that patients with baseline Nf-L levels above the median for the group had worse T1 lesion volumes at baseline and after transplant (P = .0021 at 36 months), and also had worsening brain atrophy even after transplant (P = .0389 at 60 months).

The curves appeared to be diverging, suggesting that, in the absence of inflammatory disease activity, patients with high Nf-L levels at baseline continue to have ongoing atrophy at a differential rate, compared with those with low baseline levels, Dr. Thebault said.

Other findings included better Expanded Disability Status Scale outcomes after transplant in patients with lower baseline Nf-L, and a trend toward worsening outcomes among those with higher baseline Nf-L levels, although the study may have been underpowered for this. Additionally, lower baseline Nf-L predicted significantly lower T1 and T2 lesion volume, number of gadolinium-enhancing lesions, and a reduction in brain atrophy, whereas higher baseline Nf-L predicted the opposite, he noted, adding that N-acetylaspartate-to-creatinine ratios also tended to vary inversely with Nf-L levels.

The most important findings of the study are “the sustained reduction in Nf-L levels after BMT, and that higher baseline levels predicted worse MRI outcomes,” Dr. Thebault noted. “Together these data add to a growing body of evidence that suggests that serum Nf-L has a role in monitoring treatment responses and even a predictive value in determining disease severity.”

This study was supported by Quanterix, which provided Nf-L assay kits. Dr. Thebault reported having no disclosures.

[email protected]

SOURCE: Thebault S et al. Neurology. 2018 Apr;90(15 Suppl.):P5.036.

NEW YORK – The overrepresentation of people with serious mental illness (SMI) in the criminal justice system has led to creation of a resource from the Judges’ and Psychiatrists’ Leadership Initiative (JPLI) aimed at helping psychiatry and law enforcement address the problem.

belchonock/Thinkstock

The resource, “Supporting People with Serious Mental Illnesses and Reducing Their Risk of Contact with the Criminal Justice System: A Primer for Psychiatrists,” released last year, was designed to provide psychiatrists with specific knowledge and tools, according to Michael Champion, MD, forensic chief at the Hawaii State Department of Health, Adult Mental Health Division, Honolulu, and a member of the JPLI executive leadership team.

In developing the primer, the JPLI, which was created about 10 years ago by the American Psychiatric Association Foundation in partnership with the Council of State Governments Justice Center in response to the growing problem of such overrepresentation, sought to teach psychiatrists about what the criminal justice literature has dubbed “criminogenic risk” and to explore strategies to address those risks in community treatment settings, Dr. Champion said at the annual meeting of the American Psychiatric Association.

“The fact is that one in three Americans has a criminal record, and people with serious mental illness and criminal justice involvement are frequently part of our patient population – particularly in the public mental health sector,” Dr. Champion said. “Part of the challenge is that psychiatrists ... aren’t typically trained in these principles ... so the JPLI saw that this as an area that we could try to make some traction in and try to make a difference.”

The JPLI’s goals in publishing this resource are to reduce the risk of patient involvement in the criminal justice system, and to improve clinical and recovery outcomes by educating community psychiatrists about Risk-Need-Responsivity (RNR) principles. The JPLI also seeks to provide strategies for collaborating with criminal justice partners, incorporating criminal justice history into screening and assessment, and integrating criminogenic risk needs of patients into comprehensive treatment plans, Dr. Champion said.

Criminogenic risk and RNR

Many factors contribute to the involvement of people with serious mental illnesses in the criminal justice system, including higher rates of arrest, longer stays, recidivism, and limited access to health care, said Fred C. Osher, MD, former director of health systems and services policy for the Council of State Governments Justice Center.

“We used to think that ... if we could just get folks the health care that they need, they wouldn’t get involved with the criminal justice system. It turns out that that’s a gross oversimplification, in that their needs are terribly complex, and while treatment is a necessary component, it isn’t often sufficient for a large number of individuals,” said Dr. Osher, now a member of the JPLI executive leadership team.

Criminogenic risk – the likelihood that a person who has been arrested and jailed will commit a new crime after release or return to custody – helps explain why that is the case, he said, adding: “We have ways in which we can understand those risks.”

The risks are measured via static factors (unchanging conditions such as criminal history, age at first arrest, current age, and gender) and dynamic factors, he explained.

“It’s the dynamic factors that we really want to focus on; [they are] dynamic in that they’re changeable,” he said, noting that the research has shown there are eight specific criminogenic risk factors: substance abuse, history of antisocial behavior, antisocial personality pattern, antisocial cognition, antisocial associates, family and/or marital discord, poor school and/or work output, and having few leisure/recreation outlets.

Notably, mental illness is not a part of that list, he said.

“The reason for that is it’s not explanatory in and of itself,” he added.

However, research shows that people with mental illness have more of these dynamic risk factors, and research by Jennifer L. Skeem, PhD, and others shows that those with mental illness were coming back to jail not for new criminal activity, but for failing to comply with their conditions of release.

“These risks, then, have been brought into a paradigm that is central to our criminal justice operations, and it’s called the Risk-Need-Responsivity model,” Dr. Osher said. “This paradigm is what allows a criminal justice system to think about how to prioritize the resources – to think about who really needs to be wrapped tight, who needs to have close supervision, frequent reporting, lots of contact.”

The risk principle in the RNR model says that resources should be focused on high-risk cases, with limited supervision in lower-risk cases. This is based on experience demonstrating that recidivism is lower in high-risk individuals with close supervision but higher in low-risk individuals with close supervision.

The needs principle suggests that dynamic needs are “the issues that get folks in trouble,” he said.

“So, if we’re going to intervene, if we’re going to provide programming, if we’re going to try and help that individual stay out of jail or prison, we need to address these criminogenic needs,” he said, adding that the “big four” are related to their antisocial thinking and personality and friends.

Targeted interventions can help those individuals make better choices going forward, he noted.

The responsivity principle is an acknowledgment that individuals have different ways of learning, different cultural factors and backgrounds that influence them, and social determinants that are important to understand if they predict the ability to stay out of trouble.

“This is where mental illness fits in,” Dr. Osher said. “It’s absolutely important that we understand that.”

Examples would be patients with severe major depressive disorder who need their depression treated before they can participate in a group treatment setting designed to address criminogenic risks.

Dynamic risk factors are best treated with cognitive-behavioral interventions, Dr. Osher said, noting that the most effective interventions provide opportunities for participants to practice new behavior patterns and skills with feedback from program staff.

In many states, those interventions are being provided by criminal justice personnel, including probation officers, partly because of “an absence of [psychiatrists’] understanding, willingness, or ability to step forward.” The JPLI primer is designed to “really amp up our own excitement about, and willingness to learn how to develop interventions to help that individual stay out of trouble,” and it includes detailed descriptions of numerous well-researched, standardized, manualized interventions that people can access that make it less likely for them to have criminal justice access going forward, he said.

Those include programs such as “Thinking for a Change,” “Reasoning and Rehabilitation,” “Moral Reconation Therapy,” and “Interactive Journaling.”

A focus on the Sequential Intercept Model, which describes how individuals move through the criminal justice system, illustrates multiple points where psychiatrists can “do things better and differently to intervene,” he said, noting that the primer includes a framework for prioritizing the target population, and validated screening and assessment tools, including tools to help corrections officers identify mental health/substance abuse/criminogenic issues at the time individuals are booked into jail so they can be referred for appropriate interventions.

Achieving positive public health and safety outcomes requires changes to policy and practice, Dr. Osher said.

The JPLI primer is a step toward making such changes, and with it comes a set of four principles:

1. Conduct universal risk, substance use, and mental health screening at booking, and full assessments as appropriate, he said, noting that “13 million times this year (9 million unduplicated count), 2 million folks with serious mental illness are going to be arrested and brought to jail. Let’s make sure they get assessed, identified, and then a plan can be made.”

2. Get relevant information into the hands of decision makers in time to inform pretrial release decisions. For example, knowing if someone is eligible for a mental health court could lead to that person’s receiving necessary support and supervision, he said.

3. Use assessment information to connect people to appropriate jail-based services and post-release services and supervision, and ensure that there is communication between the two.

4. Ensure services and supervision are evidence based and hold systems accountable by measuring outcomes.

In addition, the goal is to partner with the criminal justice system through information-sharing agreements and integrating dynamic criminogenic risk factors into treatment plans, he said.
 

The intercepts

To demonstrate ways in which psychiatrists can intervene over the course of a patients’ journey toward involvement in the criminal justice system, Stephanie Le Melle, MD, provided a case example involving a 30-year-old African American man diagnosed with schizophrenia at age 18 years.

Courtesy Dr. Stephanie Le Melle

As a child, “Joe” was neglected and abused; both parents had a history of mental illness and substance use. He experienced homelessness, never finished high school, and was hospitalized or visited the emergency department more than 15 times after going off medications or because of intoxication.

His history with the legal system involved a first arrest at age 14 years for gang-related fighting and assault (after being bullied as a child and seeking safety in a gang), followed by 3 years in juvenile detention. He was released with supervision at age 17 years, was arrested several times after that for public intoxication and loitering, and was held for several days or weeks each time – then released with time served or summons paid. His first hospitalization occurred at age 18, when he was diagnosed with psychosis.

Subsequent experiences included treatment in a community mental health program at age 25 for heroin use and drinking. However, he was denied admission to a substance abuse program because of his history of psychosis and violence. After stopping his medications because of side effects, he tried to buy heroin, got into a fight, and was arrested for assault with a pocket knife. He resisted arrest and was tasered, handcuffed, and taken to prison, where he was held because he could not afford bail. Involvement in gang activity while in prison led to sanctions, including time in solitary confinement.

During all of his time in the criminal justice system, Joe refused treatment, because he was afraid he’d be considered “crazy” and would be preyed upon even more by other inmates. After about 3 years, he was released to a Forensic Assertive Community Treatment team for 2 years and completed that program, and is now receiving treatment in the community. He lives alone in supported housing and has Supplemental Security Income. He does not engage in clinic-related activities and has a lack of trust in the clinical team. He often is agitated and disruptive in the clinic. Staff members have concerns about his history of violence and drug use, and were reluctant to bring him into the program.

“Going back to ... the sequential intercept model, we can think about things, as psychiatrists, that we could have done for Joe all along the way to help him not get into the criminal justice system in the first place,” said Dr. Le Melle, director of public psychiatry education at Columbia University/New York State Psychiatric Institute, New York.

This is a framework for thinking through treatment for a patient like Joe:

Intercept 0 (community services). At this early stage, Joe would have been screened for adverse childhood experiences, and that could have led to trauma treatment, substance abuse treatment, and educational and vocational services. Awareness of his family illness, discord, and poverty would have led to parenting interventions, early school involvement, and promotion of meaningful activities, she said.

“These are things, again, that we can address as clinicians ... to intervene with families and with schools and communities to try to give young people an opportunity to not get into the criminal justice system,” she said, adding that providing early co-occurring treatment for mental health and substance use is particularly important.

Intercept 1 (law enforcement) also is a stage during which a psychiatrist can intervene by giving pertinent information when 911 is called by providing police or corrections with contact information for follow-up. For Joe, psychiatrist involvement at this intercept could have allowed for treatment recommendations or assessment for diversion programs, and in fact, at some point during his care, did allow for communication about his treatment needs, Dr. Le Melle said.

In general, psychiatrists also can participate at this stage through provision of crisis intervention team training for first responders or by being part of a co-response team, she said.

Intercept 2 (initial detention/initial court hearings). Attending court on behalf of a patient can make a real difference in outcomes, she noted.

“Judges want to know that someone is out there who can help, and they want to know that there’s a team of people who can intervene and try to get someone out of the criminal justice system,” she said.

At this stage, psychiatrists can help by recommending a treatment plan for a diversion program, and – within HIPAA guidelines – can share pertinent information about treatment needs and preferences.

Intercept 3 (jails/courts). At this in-the-system stage, information shared between corrections and community behavioral health would have led to Joe’s transfer to a mental health/observation unit; he would have been offered mental health treatment and been started on substance use treatment; and he would have participated in motivational treatment and cognitive-behavioral therapy targeting his criminogenic needs, she said.

Meeting with individuals while they are incarcerated can be helpful for “keeping them grounded.”

This also is a stage where psychiatrists could help individuals prepare for release by getting them into a GED program or other training.

Intercept 4 (reentry). With appropriate intervention at this stage, Joe would have his benefits, such as Medicaid and Supplemental Security Income, reinstated prior to reentry to the community. Also, his psychiatrist and treatment program would be contacted. He would be welcomed back into treatment, and he would have assistance finding a permanent place to live with services provided in the community.

Intercept 5 (community corrections). At this stage, community behavioral health clinicians would maintain awareness of their biases and fears about people involved in the criminal justice system and avoid making assumptions about Joe. His risks, needs, and priorities would be assessed and addressed, and he would be asked about his experiences with the system and about what could be done to help him avoid incarceration in the future.

He would receive help in incorporating alternative behaviors and thinking to address dynamic criminogenic risk, and evidence-based practices would be used in treatment.

The sequential intercept model reflects the fact that the criminal justice system and the people it serves are part of the community, Dr. Le Melle said.

“The community and the behavioral health system and the criminal justice system are partners in our shared mission of public safety and public health, so we are one and we can’t expect that our responsibility for providing people with the best care and services ends if someone is in the criminal justice system,” she said.

Dr. Champion, Dr. Osher, and Dr. Le Melle reported having no disclosures.

[email protected]

NEW YORK – The overrepresentation of people with serious mental illness (SMI) in the criminal justice system has led to creation of a resource from the Judges’ and Psychiatrists’ Leadership Initiative (JPLI) aimed at helping psychiatry and law enforcement address the problem.

belchonock/Thinkstock

The resource, “Supporting People with Serious Mental Illnesses and Reducing Their Risk of Contact with the Criminal Justice System: A Primer for Psychiatrists,” released last year, was designed to provide psychiatrists with specific knowledge and tools, according to Michael Champion, MD, forensic chief at the Hawaii State Department of Health, Adult Mental Health Division, Honolulu, and a member of the JPLI executive leadership team.

In developing the primer, the JPLI, which was created about 10 years ago by the American Psychiatric Association Foundation in partnership with the Council of State Governments Justice Center in response to the growing problem of such overrepresentation, sought to teach psychiatrists about what the criminal justice literature has dubbed “criminogenic risk” and to explore strategies to address those risks in community treatment settings, Dr. Champion said at the annual meeting of the American Psychiatric Association.

“The fact is that one in three Americans has a criminal record, and people with serious mental illness and criminal justice involvement are frequently part of our patient population – particularly in the public mental health sector,” Dr. Champion said. “Part of the challenge is that psychiatrists ... aren’t typically trained in these principles ... so the JPLI saw that this as an area that we could try to make some traction in and try to make a difference.”

The JPLI’s goals in publishing this resource are to reduce the risk of patient involvement in the criminal justice system, and to improve clinical and recovery outcomes by educating community psychiatrists about Risk-Need-Responsivity (RNR) principles. The JPLI also seeks to provide strategies for collaborating with criminal justice partners, incorporating criminal justice history into screening and assessment, and integrating criminogenic risk needs of patients into comprehensive treatment plans, Dr. Champion said.

Criminogenic risk and RNR

Many factors contribute to the involvement of people with serious mental illnesses in the criminal justice system, including higher rates of arrest, longer stays, recidivism, and limited access to health care, said Fred C. Osher, MD, former director of health systems and services policy for the Council of State Governments Justice Center.

“We used to think that ... if we could just get folks the health care that they need, they wouldn’t get involved with the criminal justice system. It turns out that that’s a gross oversimplification, in that their needs are terribly complex, and while treatment is a necessary component, it isn’t often sufficient for a large number of individuals,” said Dr. Osher, now a member of the JPLI executive leadership team.

Criminogenic risk – the likelihood that a person who has been arrested and jailed will commit a new crime after release or return to custody – helps explain why that is the case, he said, adding: “We have ways in which we can understand those risks.”

The risks are measured via static factors (unchanging conditions such as criminal history, age at first arrest, current age, and gender) and dynamic factors, he explained.

“It’s the dynamic factors that we really want to focus on; [they are] dynamic in that they’re changeable,” he said, noting that the research has shown there are eight specific criminogenic risk factors: substance abuse, history of antisocial behavior, antisocial personality pattern, antisocial cognition, antisocial associates, family and/or marital discord, poor school and/or work output, and having few leisure/recreation outlets.

Notably, mental illness is not a part of that list, he said.

“The reason for that is it’s not explanatory in and of itself,” he added.

However, research shows that people with mental illness have more of these dynamic risk factors, and research by Jennifer L. Skeem, PhD, and others shows that those with mental illness were coming back to jail not for new criminal activity, but for failing to comply with their conditions of release.

“These risks, then, have been brought into a paradigm that is central to our criminal justice operations, and it’s called the Risk-Need-Responsivity model,” Dr. Osher said. “This paradigm is what allows a criminal justice system to think about how to prioritize the resources – to think about who really needs to be wrapped tight, who needs to have close supervision, frequent reporting, lots of contact.”

The risk principle in the RNR model says that resources should be focused on high-risk cases, with limited supervision in lower-risk cases. This is based on experience demonstrating that recidivism is lower in high-risk individuals with close supervision but higher in low-risk individuals with close supervision.

The needs principle suggests that dynamic needs are “the issues that get folks in trouble,” he said.

“So, if we’re going to intervene, if we’re going to provide programming, if we’re going to try and help that individual stay out of jail or prison, we need to address these criminogenic needs,” he said, adding that the “big four” are related to their antisocial thinking and personality and friends.

Targeted interventions can help those individuals make better choices going forward, he noted.

The responsivity principle is an acknowledgment that individuals have different ways of learning, different cultural factors and backgrounds that influence them, and social determinants that are important to understand if they predict the ability to stay out of trouble.

“This is where mental illness fits in,” Dr. Osher said. “It’s absolutely important that we understand that.”

Examples would be patients with severe major depressive disorder who need their depression treated before they can participate in a group treatment setting designed to address criminogenic risks.

Dynamic risk factors are best treated with cognitive-behavioral interventions, Dr. Osher said, noting that the most effective interventions provide opportunities for participants to practice new behavior patterns and skills with feedback from program staff.

In many states, those interventions are being provided by criminal justice personnel, including probation officers, partly because of “an absence of [psychiatrists’] understanding, willingness, or ability to step forward.” The JPLI primer is designed to “really amp up our own excitement about, and willingness to learn how to develop interventions to help that individual stay out of trouble,” and it includes detailed descriptions of numerous well-researched, standardized, manualized interventions that people can access that make it less likely for them to have criminal justice access going forward, he said.

Those include programs such as “Thinking for a Change,” “Reasoning and Rehabilitation,” “Moral Reconation Therapy,” and “Interactive Journaling.”

A focus on the Sequential Intercept Model, which describes how individuals move through the criminal justice system, illustrates multiple points where psychiatrists can “do things better and differently to intervene,” he said, noting that the primer includes a framework for prioritizing the target population, and validated screening and assessment tools, including tools to help corrections officers identify mental health/substance abuse/criminogenic issues at the time individuals are booked into jail so they can be referred for appropriate interventions.

Achieving positive public health and safety outcomes requires changes to policy and practice, Dr. Osher said.

The JPLI primer is a step toward making such changes, and with it comes a set of four principles:

1. Conduct universal risk, substance use, and mental health screening at booking, and full assessments as appropriate, he said, noting that “13 million times this year (9 million unduplicated count), 2 million folks with serious mental illness are going to be arrested and brought to jail. Let’s make sure they get assessed, identified, and then a plan can be made.”

2. Get relevant information into the hands of decision makers in time to inform pretrial release decisions. For example, knowing if someone is eligible for a mental health court could lead to that person’s receiving necessary support and supervision, he said.

3. Use assessment information to connect people to appropriate jail-based services and post-release services and supervision, and ensure that there is communication between the two.

4. Ensure services and supervision are evidence based and hold systems accountable by measuring outcomes.

In addition, the goal is to partner with the criminal justice system through information-sharing agreements and integrating dynamic criminogenic risk factors into treatment plans, he said.
 

The intercepts

To demonstrate ways in which psychiatrists can intervene over the course of a patients’ journey toward involvement in the criminal justice system, Stephanie Le Melle, MD, provided a case example involving a 30-year-old African American man diagnosed with schizophrenia at age 18 years.

Courtesy Dr. Stephanie Le Melle

As a child, “Joe” was neglected and abused; both parents had a history of mental illness and substance use. He experienced homelessness, never finished high school, and was hospitalized or visited the emergency department more than 15 times after going off medications or because of intoxication.

His history with the legal system involved a first arrest at age 14 years for gang-related fighting and assault (after being bullied as a child and seeking safety in a gang), followed by 3 years in juvenile detention. He was released with supervision at age 17 years, was arrested several times after that for public intoxication and loitering, and was held for several days or weeks each time – then released with time served or summons paid. His first hospitalization occurred at age 18, when he was diagnosed with psychosis.

Subsequent experiences included treatment in a community mental health program at age 25 for heroin use and drinking. However, he was denied admission to a substance abuse program because of his history of psychosis and violence. After stopping his medications because of side effects, he tried to buy heroin, got into a fight, and was arrested for assault with a pocket knife. He resisted arrest and was tasered, handcuffed, and taken to prison, where he was held because he could not afford bail. Involvement in gang activity while in prison led to sanctions, including time in solitary confinement.

During all of his time in the criminal justice system, Joe refused treatment, because he was afraid he’d be considered “crazy” and would be preyed upon even more by other inmates. After about 3 years, he was released to a Forensic Assertive Community Treatment team for 2 years and completed that program, and is now receiving treatment in the community. He lives alone in supported housing and has Supplemental Security Income. He does not engage in clinic-related activities and has a lack of trust in the clinical team. He often is agitated and disruptive in the clinic. Staff members have concerns about his history of violence and drug use, and were reluctant to bring him into the program.

“Going back to ... the sequential intercept model, we can think about things, as psychiatrists, that we could have done for Joe all along the way to help him not get into the criminal justice system in the first place,” said Dr. Le Melle, director of public psychiatry education at Columbia University/New York State Psychiatric Institute, New York.

This is a framework for thinking through treatment for a patient like Joe:

Intercept 0 (community services). At this early stage, Joe would have been screened for adverse childhood experiences, and that could have led to trauma treatment, substance abuse treatment, and educational and vocational services. Awareness of his family illness, discord, and poverty would have led to parenting interventions, early school involvement, and promotion of meaningful activities, she said.

“These are things, again, that we can address as clinicians ... to intervene with families and with schools and communities to try to give young people an opportunity to not get into the criminal justice system,” she said, adding that providing early co-occurring treatment for mental health and substance use is particularly important.

Intercept 1 (law enforcement) also is a stage during which a psychiatrist can intervene by giving pertinent information when 911 is called by providing police or corrections with contact information for follow-up. For Joe, psychiatrist involvement at this intercept could have allowed for treatment recommendations or assessment for diversion programs, and in fact, at some point during his care, did allow for communication about his treatment needs, Dr. Le Melle said.

In general, psychiatrists also can participate at this stage through provision of crisis intervention team training for first responders or by being part of a co-response team, she said.

Intercept 2 (initial detention/initial court hearings). Attending court on behalf of a patient can make a real difference in outcomes, she noted.

“Judges want to know that someone is out there who can help, and they want to know that there’s a team of people who can intervene and try to get someone out of the criminal justice system,” she said.

At this stage, psychiatrists can help by recommending a treatment plan for a diversion program, and – within HIPAA guidelines – can share pertinent information about treatment needs and preferences.

Intercept 3 (jails/courts). At this in-the-system stage, information shared between corrections and community behavioral health would have led to Joe’s transfer to a mental health/observation unit; he would have been offered mental health treatment and been started on substance use treatment; and he would have participated in motivational treatment and cognitive-behavioral therapy targeting his criminogenic needs, she said.

Meeting with individuals while they are incarcerated can be helpful for “keeping them grounded.”

This also is a stage where psychiatrists could help individuals prepare for release by getting them into a GED program or other training.

Intercept 4 (reentry). With appropriate intervention at this stage, Joe would have his benefits, such as Medicaid and Supplemental Security Income, reinstated prior to reentry to the community. Also, his psychiatrist and treatment program would be contacted. He would be welcomed back into treatment, and he would have assistance finding a permanent place to live with services provided in the community.

Intercept 5 (community corrections). At this stage, community behavioral health clinicians would maintain awareness of their biases and fears about people involved in the criminal justice system and avoid making assumptions about Joe. His risks, needs, and priorities would be assessed and addressed, and he would be asked about his experiences with the system and about what could be done to help him avoid incarceration in the future.

He would receive help in incorporating alternative behaviors and thinking to address dynamic criminogenic risk, and evidence-based practices would be used in treatment.

The sequential intercept model reflects the fact that the criminal justice system and the people it serves are part of the community, Dr. Le Melle said.

“The community and the behavioral health system and the criminal justice system are partners in our shared mission of public safety and public health, so we are one and we can’t expect that our responsibility for providing people with the best care and services ends if someone is in the criminal justice system,” she said.

Dr. Champion, Dr. Osher, and Dr. Le Melle reported having no disclosures.

[email protected]

NEW YORK – The overrepresentation of people with serious mental illness (SMI) in the criminal justice system has led to creation of a resource from the Judges’ and Psychiatrists’ Leadership Initiative (JPLI) aimed at helping psychiatry and law enforcement address the problem.

belchonock/Thinkstock

The resource, “Supporting People with Serious Mental Illnesses and Reducing Their Risk of Contact with the Criminal Justice System: A Primer for Psychiatrists,” released last year, was designed to provide psychiatrists with specific knowledge and tools, according to Michael Champion, MD, forensic chief at the Hawaii State Department of Health, Adult Mental Health Division, Honolulu, and a member of the JPLI executive leadership team.

In developing the primer, the JPLI, which was created about 10 years ago by the American Psychiatric Association Foundation in partnership with the Council of State Governments Justice Center in response to the growing problem of such overrepresentation, sought to teach psychiatrists about what the criminal justice literature has dubbed “criminogenic risk” and to explore strategies to address those risks in community treatment settings, Dr. Champion said at the annual meeting of the American Psychiatric Association.

“The fact is that one in three Americans has a criminal record, and people with serious mental illness and criminal justice involvement are frequently part of our patient population – particularly in the public mental health sector,” Dr. Champion said. “Part of the challenge is that psychiatrists ... aren’t typically trained in these principles ... so the JPLI saw that this as an area that we could try to make some traction in and try to make a difference.”

The JPLI’s goals in publishing this resource are to reduce the risk of patient involvement in the criminal justice system, and to improve clinical and recovery outcomes by educating community psychiatrists about Risk-Need-Responsivity (RNR) principles. The JPLI also seeks to provide strategies for collaborating with criminal justice partners, incorporating criminal justice history into screening and assessment, and integrating criminogenic risk needs of patients into comprehensive treatment plans, Dr. Champion said.

Criminogenic risk and RNR

Many factors contribute to the involvement of people with serious mental illnesses in the criminal justice system, including higher rates of arrest, longer stays, recidivism, and limited access to health care, said Fred C. Osher, MD, former director of health systems and services policy for the Council of State Governments Justice Center.

“We used to think that ... if we could just get folks the health care that they need, they wouldn’t get involved with the criminal justice system. It turns out that that’s a gross oversimplification, in that their needs are terribly complex, and while treatment is a necessary component, it isn’t often sufficient for a large number of individuals,” said Dr. Osher, now a member of the JPLI executive leadership team.

Criminogenic risk – the likelihood that a person who has been arrested and jailed will commit a new crime after release or return to custody – helps explain why that is the case, he said, adding: “We have ways in which we can understand those risks.”

The risks are measured via static factors (unchanging conditions such as criminal history, age at first arrest, current age, and gender) and dynamic factors, he explained.

“It’s the dynamic factors that we really want to focus on; [they are] dynamic in that they’re changeable,” he said, noting that the research has shown there are eight specific criminogenic risk factors: substance abuse, history of antisocial behavior, antisocial personality pattern, antisocial cognition, antisocial associates, family and/or marital discord, poor school and/or work output, and having few leisure/recreation outlets.

Notably, mental illness is not a part of that list, he said.

“The reason for that is it’s not explanatory in and of itself,” he added.

However, research shows that people with mental illness have more of these dynamic risk factors, and research by Jennifer L. Skeem, PhD, and others shows that those with mental illness were coming back to jail not for new criminal activity, but for failing to comply with their conditions of release.

“These risks, then, have been brought into a paradigm that is central to our criminal justice operations, and it’s called the Risk-Need-Responsivity model,” Dr. Osher said. “This paradigm is what allows a criminal justice system to think about how to prioritize the resources – to think about who really needs to be wrapped tight, who needs to have close supervision, frequent reporting, lots of contact.”

The risk principle in the RNR model says that resources should be focused on high-risk cases, with limited supervision in lower-risk cases. This is based on experience demonstrating that recidivism is lower in high-risk individuals with close supervision but higher in low-risk individuals with close supervision.

The needs principle suggests that dynamic needs are “the issues that get folks in trouble,” he said.

“So, if we’re going to intervene, if we’re going to provide programming, if we’re going to try and help that individual stay out of jail or prison, we need to address these criminogenic needs,” he said, adding that the “big four” are related to their antisocial thinking and personality and friends.

Targeted interventions can help those individuals make better choices going forward, he noted.

The responsivity principle is an acknowledgment that individuals have different ways of learning, different cultural factors and backgrounds that influence them, and social determinants that are important to understand if they predict the ability to stay out of trouble.

“This is where mental illness fits in,” Dr. Osher said. “It’s absolutely important that we understand that.”

Examples would be patients with severe major depressive disorder who need their depression treated before they can participate in a group treatment setting designed to address criminogenic risks.

Dynamic risk factors are best treated with cognitive-behavioral interventions, Dr. Osher said, noting that the most effective interventions provide opportunities for participants to practice new behavior patterns and skills with feedback from program staff.

In many states, those interventions are being provided by criminal justice personnel, including probation officers, partly because of “an absence of [psychiatrists’] understanding, willingness, or ability to step forward.” The JPLI primer is designed to “really amp up our own excitement about, and willingness to learn how to develop interventions to help that individual stay out of trouble,” and it includes detailed descriptions of numerous well-researched, standardized, manualized interventions that people can access that make it less likely for them to have criminal justice access going forward, he said.

Those include programs such as “Thinking for a Change,” “Reasoning and Rehabilitation,” “Moral Reconation Therapy,” and “Interactive Journaling.”

A focus on the Sequential Intercept Model, which describes how individuals move through the criminal justice system, illustrates multiple points where psychiatrists can “do things better and differently to intervene,” he said, noting that the primer includes a framework for prioritizing the target population, and validated screening and assessment tools, including tools to help corrections officers identify mental health/substance abuse/criminogenic issues at the time individuals are booked into jail so they can be referred for appropriate interventions.

Achieving positive public health and safety outcomes requires changes to policy and practice, Dr. Osher said.

The JPLI primer is a step toward making such changes, and with it comes a set of four principles:

1. Conduct universal risk, substance use, and mental health screening at booking, and full assessments as appropriate, he said, noting that “13 million times this year (9 million unduplicated count), 2 million folks with serious mental illness are going to be arrested and brought to jail. Let’s make sure they get assessed, identified, and then a plan can be made.”

2. Get relevant information into the hands of decision makers in time to inform pretrial release decisions. For example, knowing if someone is eligible for a mental health court could lead to that person’s receiving necessary support and supervision, he said.

3. Use assessment information to connect people to appropriate jail-based services and post-release services and supervision, and ensure that there is communication between the two.

4. Ensure services and supervision are evidence based and hold systems accountable by measuring outcomes.

In addition, the goal is to partner with the criminal justice system through information-sharing agreements and integrating dynamic criminogenic risk factors into treatment plans, he said.
 

The intercepts

To demonstrate ways in which psychiatrists can intervene over the course of a patients’ journey toward involvement in the criminal justice system, Stephanie Le Melle, MD, provided a case example involving a 30-year-old African American man diagnosed with schizophrenia at age 18 years.

Courtesy Dr. Stephanie Le Melle

As a child, “Joe” was neglected and abused; both parents had a history of mental illness and substance use. He experienced homelessness, never finished high school, and was hospitalized or visited the emergency department more than 15 times after going off medications or because of intoxication.

His history with the legal system involved a first arrest at age 14 years for gang-related fighting and assault (after being bullied as a child and seeking safety in a gang), followed by 3 years in juvenile detention. He was released with supervision at age 17 years, was arrested several times after that for public intoxication and loitering, and was held for several days or weeks each time – then released with time served or summons paid. His first hospitalization occurred at age 18, when he was diagnosed with psychosis.

Subsequent experiences included treatment in a community mental health program at age 25 for heroin use and drinking. However, he was denied admission to a substance abuse program because of his history of psychosis and violence. After stopping his medications because of side effects, he tried to buy heroin, got into a fight, and was arrested for assault with a pocket knife. He resisted arrest and was tasered, handcuffed, and taken to prison, where he was held because he could not afford bail. Involvement in gang activity while in prison led to sanctions, including time in solitary confinement.

During all of his time in the criminal justice system, Joe refused treatment, because he was afraid he’d be considered “crazy” and would be preyed upon even more by other inmates. After about 3 years, he was released to a Forensic Assertive Community Treatment team for 2 years and completed that program, and is now receiving treatment in the community. He lives alone in supported housing and has Supplemental Security Income. He does not engage in clinic-related activities and has a lack of trust in the clinical team. He often is agitated and disruptive in the clinic. Staff members have concerns about his history of violence and drug use, and were reluctant to bring him into the program.

“Going back to ... the sequential intercept model, we can think about things, as psychiatrists, that we could have done for Joe all along the way to help him not get into the criminal justice system in the first place,” said Dr. Le Melle, director of public psychiatry education at Columbia University/New York State Psychiatric Institute, New York.

This is a framework for thinking through treatment for a patient like Joe:

Intercept 0 (community services). At this early stage, Joe would have been screened for adverse childhood experiences, and that could have led to trauma treatment, substance abuse treatment, and educational and vocational services. Awareness of his family illness, discord, and poverty would have led to parenting interventions, early school involvement, and promotion of meaningful activities, she said.

“These are things, again, that we can address as clinicians ... to intervene with families and with schools and communities to try to give young people an opportunity to not get into the criminal justice system,” she said, adding that providing early co-occurring treatment for mental health and substance use is particularly important.

Intercept 1 (law enforcement) also is a stage during which a psychiatrist can intervene by giving pertinent information when 911 is called by providing police or corrections with contact information for follow-up. For Joe, psychiatrist involvement at this intercept could have allowed for treatment recommendations or assessment for diversion programs, and in fact, at some point during his care, did allow for communication about his treatment needs, Dr. Le Melle said.

In general, psychiatrists also can participate at this stage through provision of crisis intervention team training for first responders or by being part of a co-response team, she said.

Intercept 2 (initial detention/initial court hearings). Attending court on behalf of a patient can make a real difference in outcomes, she noted.

“Judges want to know that someone is out there who can help, and they want to know that there’s a team of people who can intervene and try to get someone out of the criminal justice system,” she said.

At this stage, psychiatrists can help by recommending a treatment plan for a diversion program, and – within HIPAA guidelines – can share pertinent information about treatment needs and preferences.

Intercept 3 (jails/courts). At this in-the-system stage, information shared between corrections and community behavioral health would have led to Joe’s transfer to a mental health/observation unit; he would have been offered mental health treatment and been started on substance use treatment; and he would have participated in motivational treatment and cognitive-behavioral therapy targeting his criminogenic needs, she said.

Meeting with individuals while they are incarcerated can be helpful for “keeping them grounded.”

This also is a stage where psychiatrists could help individuals prepare for release by getting them into a GED program or other training.

Intercept 4 (reentry). With appropriate intervention at this stage, Joe would have his benefits, such as Medicaid and Supplemental Security Income, reinstated prior to reentry to the community. Also, his psychiatrist and treatment program would be contacted. He would be welcomed back into treatment, and he would have assistance finding a permanent place to live with services provided in the community.

Intercept 5 (community corrections). At this stage, community behavioral health clinicians would maintain awareness of their biases and fears about people involved in the criminal justice system and avoid making assumptions about Joe. His risks, needs, and priorities would be assessed and addressed, and he would be asked about his experiences with the system and about what could be done to help him avoid incarceration in the future.

He would receive help in incorporating alternative behaviors and thinking to address dynamic criminogenic risk, and evidence-based practices would be used in treatment.

The sequential intercept model reflects the fact that the criminal justice system and the people it serves are part of the community, Dr. Le Melle said.

“The community and the behavioral health system and the criminal justice system are partners in our shared mission of public safety and public health, so we are one and we can’t expect that our responsibility for providing people with the best care and services ends if someone is in the criminal justice system,” she said.

Dr. Champion, Dr. Osher, and Dr. Le Melle reported having no disclosures.

[email protected]

ORLANDO – Patient-centered decision making and support, along with improved diet and exercise, constitute the foundation of all glycemic management, according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).

Patients with ASCVD or heart failure

Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.

“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.

The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.

“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.

However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.

“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.

“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.

That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).

These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).

Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.

If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.

In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.

“Then we suggest that if you are still not at [hemoglobin A_1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.

In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.

The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
 

Lifestyle management and medication

With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.

In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.

In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.

“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.

In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.

The hope is that the final consensus statement will make it easier to navigate them, she said.

Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.

The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m² or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.

Decision making and injectable therapies

The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA_1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA_1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).

The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.

This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA_1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.

The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
 

Knowledge gaps

In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”

Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.

These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.

“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
 

Consensus statement development

The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).

The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.

The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.

The updates were mainly based on research generated over the past 2 years, Dr. Davies said.

The final draft will be submitted for publication to Diabetes Care and Diabetologia.

Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.

[email protected]

ORLANDO – Patient-centered decision making and support, along with improved diet and exercise, constitute the foundation of all glycemic management, according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).

Patients with ASCVD or heart failure

Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.

“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.

The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.

“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.

However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.

“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.

“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.

That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).

These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).

Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.

If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.

In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.

“Then we suggest that if you are still not at [hemoglobin A_1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.

In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.

The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
 

Lifestyle management and medication

With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.

In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.

In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.

“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.

In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.

The hope is that the final consensus statement will make it easier to navigate them, she said.

Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.

The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m² or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.

Decision making and injectable therapies

The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA_1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA_1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).

The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.

This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA_1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.

The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
 

Knowledge gaps

In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”

Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.

These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.

“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
 

Consensus statement development

The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).

The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.

The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.

The updates were mainly based on research generated over the past 2 years, Dr. Davies said.

The final draft will be submitted for publication to Diabetes Care and Diabetologia.

Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.

[email protected]

ORLANDO – Patient-centered decision making and support, along with improved diet and exercise, constitute the foundation of all glycemic management, according to a draft consensus report on the management of hyperglycemia in patients with type 2 diabetes mellitus (T2DM).

Patients with ASCVD or heart failure

Given new evidence from trials such as EMPA-REG and LEADER showing outcomes benefits with the use of specific antihyperglycemic medications in patients with established atherosclerotic cardiovascular disease (ASCVD), an important early step in the proposed approach is to consider the presence or absence of ASCVD and heart failure, said Dr. Wexler of Massachusetts General Hospital, Boston.

“The presence of cardiovascular disease is a compelling indication for the selection of certain glucose-lowering drugs,” she said.

The draft consensus recommendation in this regard – a new recommendation since the last consensus report in 2015 – differentiates between T2DM patients in whom ASCVD predominates and those in whom heart failure predominates.

“What’s new since 2015 is that we recommend that these comorbidities be considered first and foremost because they do influence the choice of a particular glucose-lowering medication, and the recommendation is that, among patients with type 2 diabetes with established ASCVD, sodium-glucose cotransporter 2 [SGLT2] inhibitors or glucagonlike peptide 1 [GLP-1] receptor agonists with proven cardiovascular benefit are recommended as part of glycemic management,” she said.

However, it is important to note that ASCVD is defined differently across trials, and patients considered in the development of these recommendations are those with much higher cardiovascular risk than the average patient with T2DM, she added.

“It’s also important to keep in mind that each cardiovascular outcomes trial, while large, is but a single experiment ... and we don’t have the benefit of replication,” she said, noting that it is not always clear whether differences in trial findings within a drug class are related to trial design or true differences in individual medications.

“So we try to read into them and interpret these data, but it’s just important to consider that ... and when evidence suggests a hierarchy, we noted that,” she said.

That said, if ASCVD predominates, the recommendation is for treatment with either a GLP-1 receptor agonist with proven cardiovascular benefit (favoring liraglutide over semaglutide and over long-acting exenatide) or an SGLT2 inhibitor with proven cardiovascular benefit if estimated glomerular filtration (eGFR) is adequate (favoring empagliflozin over canagliflozin).

These recommendations are based on the LEADER trial finding of significant improvement in the primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with liraglutide vs. placebo (hazard ratio, 0.87; number needed to treat [NNT], 52 over 3.8 years) and on the EMPA-REG trial finding of significant improvement in the same primary outcome with empagliflozin vs. placebo (HR, 0.86; NNT, 62 over 3.1 years).

Keep in mind that there is no evidence of cardiovascular benefit from these treatments in patients at lower risk and also that the “expensive and complicated” combination of an SGLT2 inhibitor and a GLP-1 receptor agonist has not been tested in cardiovascular outcomes trials and there is no evidence of additional benefit from a cardiovascular perspective with this combination, Dr. Wexler said.

If heart failure predominates, the recommendations call for consideration of an SGLT2 inhibitor as part of the treatment strategy because patients with T2DM are at increased risk for heart failure with reduced or preserved ejection fraction and because significant, consistent reduction in hospitalizations for heart failure were seen in SGLT2 inhibitor trials, writing group member Peter Rossing, MD, explained during the session; he noted, however, that the trials were not designed to adjudicate heart failure and that most patients did not have clinical heart failure at baseline.

In those in whom SGLT2 inhibitors are contraindicated – because of impaired renal function, for example – a GLP-1 receptor agonist with proven cardiovascular benefit is recommended.

“Then we suggest that if you are still not at [hemoglobin A_1c] target, you should avoid thiazolidinediones [TZD] because of the risk of fluid overload, and you could then consider, if needed, combining an SGLT2-inhibitor and a GLP-1 receptor agonist ... or you could use a [dipeptidyl peptidase–4 (DPP-4) inhibitor] if you are not on an GLP-1 receptor agonist. And we point out that saxagliptin has unfavorable data on heart failure,” Dr. Rossing of Steno Diabetes Center, Copenhagen, said, noting that basal insulin or sulfonylurea are other alternative options.

In EMPA-REG, hospitalization for heart failure was reduced by 35% with empagliflozin vs. placebo (HR, 0.65; NNT, 71 over 3 years), and similar findings were seen in the CANVAS trial. In LEADER, a nonsignificant 13% reduction was seen in hospitalization for heart failure with liraglutide vs. placebo (HR, 0.87). However, this was a secondary outcome; ongoing studies are addressing heart failure as a primary outcome, Dr. Rossing said.

The report also includes a recommendation that, for patients with chronic kidney disease and high cardiovascular risk, GLP-1 receptor agonists and SGLT2 inhibitors can be used but with dose reductions for some medications – several of which have demonstrated renal benefit and cardiovascular benefits in those populations and can be considered as part of treatment.
 

Lifestyle management and medication

With respect to lifestyle management and pharmacologic treatment, the proposed recommendations, which are based on several large trials, state that an individualized program of medical nutritional therapy should be offered to all patients and that all overweight and obese patients with diabetes should be advised of the health benefits of weight loss. They also should be encouraged to engage in a program of intensive lifestyle management, which may include food substitution, writing group member Walter Kernan, MD, said at the meeting.

In the DiRECT Trial, the average weight loss was about 10 kg in an intervention group that had complete food replacement for 3 months followed by gradual food reintroduction and ongoing counseling versus about 1 kg in controls, and the diabetes remission rate at 1 year was 46% versus 4%, respectively, said Dr. Kernan of Yale University, New Haven, Conn.

In addition, intentional physical activity is known to improve glycemic control and should be encouraged in all patients with T2DM, he said.

“The foundation of hyperglycemia treatment in type 2 diabetes is, for sure, lifestyle modification,” said group member Geltrude Mingrone, MD, of Catholic University of the Sacred Heart in Rome. “Those patients who are very well motivated and adherent to the [recommendations] can achieve very good results,” she added.

In those in whom lifestyle modification fails to lead to adequate improvement, “a pretty large medication portfolio is available,” she said, adding that the choice of treatment should be based on safety, efficacy, cost, and convenience, factors which are described in the statement.

The hope is that the final consensus statement will make it easier to navigate them, she said.

Finally, bariatric surgery can be considered a very effective salvage therapy, Dr. Mingrone said, noting that only lifestyle modification or bariatric surgery will lead to diabetes remission.

The draft consensus recommendation for bariatric surgery is to consider it in patients with T2DM and a body mass index of 40 kg/m² or greater (37.5 or greater in those of Asian ancestry), regardless of the level of glycemic control, and in those with BMI of 35-39.9 (32.5-37.4 in those of Asian ancestry) when hyperglycemia is inadequately controlled despite lifestyle and optimal medical therapy.

Decision making and injectable therapies

The statement includes decision-making strategies and algorithms for treatment and addresses issues such as choosing antihyperglycemic medications when weight is a concern (consider an SGLT2 inhibitor or a GLP-1 receptor agonist with good efficacy for weight loss to start – or a combination of both if HbA_1c is not on target), when minimizing hypoglycemia is the priority (consider adding an SGLT2 inhibitors, GLP-1 receptor agonist, a TZD, or a DPP-4 inhibitor to metformin therapy to start, followed by reintensification of lifestyle modifications and combination therapies if HbA_1c is above target), and when drug costs need to be minimized, as well as when and how to initiate injectable therapies, according to writing group members David D’Alessio, MD, of Duke University, Durham, N.C, and Chantal Mathieu, MD, of Katholieke Universteit Leuven (Belgium).

The draft consensus recommendation regarding the latter is that, in patients who need the greater glucose-lowering effect of an injectable medication, GLP-1 receptor agonists should be considered as the first choice and that, when insulin is the medication of choice on the basis of clinical characteristics, basal insulin is preferred. Additionally, in patients who are unable to maintain glycemic targets on basal insulin in combination with oral medication, intensification with a GLP-1 receptor agonist, SGLT2 inhibitor, or prandial insulin can be considered.

This recommendation is based on “overwhelming evidence that GLP-1 receptor agonists give you HbA_1c lowering in the same range as basal insulin but can do so without hypoglycemia and with weight loss, in contrast to weight gain with most insulin preparations,” Dr. Mathieu noted.

The bottom line, however, is that “the patient is at the center of everything and ... should become an integral part of the team treating this patient,” Dr. Mathieu said.
 

Knowledge gaps

In a review of remaining knowledge gaps regarding glycemic control in T2DM, Dr. Buse said that, while the tools available to treat and prevent diabetes are vastly improved, implementation of effective innovation has lagged behind and “requires fundamental changes in health care policy and societal approaches to wellness.”

Additionally, the management of overweight and obesity is clearly inadequate and requires much greater emphasis on lifestyle techniques, behavioral approaches, medication, and surgery, said Dr. Buse, who is the Verne S. Caviness distinguished professor and chief of the division of endocrinology, as well as director of the Diabetes Center, at the University of North Carolina, Chapel Hill.

These and numerous other knowledge gaps (with respect to preserving and enhancing beta-cell function, incorporating personalized medicine, the value of combinations for additive benefit, the identification of biomarkers, the use of early intensive therapy, metabolic surgery decision making, the value of self-monitoring of blood glucose, and the need for better drugs – including those for the primary prevention of cardiovascular disease) need to be addressed and “require additional investment in basic, translational, clinical, and implementation research,” he said.

“More time- and cost-efficient research paradigms to address patient-centered endpoints are needed through regulatory reform and leveraging informatics and coordinated learning health care systems. Additionally, the increasing burden of cardiometabolic disease is an existential threat to society,” he said, stressing that “urgent attention to improve prevention and treatment is of the essence.”
 

Consensus statement development

The draft consensus statement is the work of group members selected by the ADA and EASD to ensure regional representation (five each from the United States and Europe). The group had two face-to-face meetings, as well as regular teleconferences; the members also conducted a “robust evidence review, which informed the content,” said group cochair Melanie J. Davies, MD, of the University of Leicester (U.K.).

The group reviewed randomized controlled trials, systematic reviews, and meta-analyses published from Jan. 1, 2014, (to capture research that may have been missed during development of the 2015 statement) through Feb. 28, 2018.

The process was based on consensus among members; areas of disagreement were voted on and the group proceeded according to 60% supermajority votes.

The updates were mainly based on research generated over the past 2 years, Dr. Davies said.

The final draft will be submitted for publication to Diabetes Care and Diabetologia.

Dr. Buse reported relationships (research support, stock ownership, and/or advisory roles) with Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon Pharmaceuticals, Mellitus Health, Metavention, NovaTarg Therapeutics, Novo Nordisk, PhaseBio Pharmaceuticals, Sanofi, Senseonics, Theracos, and vTv Therapeutics; Dr. Wexler reported having no disclosures; Dr. Rossing reported relationships (consultancy and/or speaking fees, research grants, stock ownership) with AbbVie, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MDS Medical, Novo Nordisk, and Sanofi; Dr. Kernan reported having no disclosures; Dr. Mingrone is a consultant for Novo Nordisk, Fractyl, and Johnson & Johnson; Dr. D’Alessio reported advisory board membership with and/or research support from Eli Lilly, Intarcia Therapeutics, Merck, and Novo Nordisk; Dr. Mathieu reported relationships (advisory board membership, speaker’s bureau, and/or research support) with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Hanmi Pharmaceuticals, Intrexon, Janssen Pharmaceuticals, MannKind, Medtronic, Merck Sharp & Dohme (MSD), Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, and UCB; Dr. Davies reported relationships (advisory panel, consulting, research support, and/or speaker’s bureau) with AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Intarcia Therapeutics, Janssen Pharmaceuticals, MSD, Mitsubishi Tanabi Pharma, Novo Nordisk, Sanofi, and Servier.

[email protected]

ORLANDO – Improvements in cardiovascular and renal outcomes seen after nearly 10 years of improved glucose control among participants in the Veterans Affairs Diabetes Trial (VADT) who received intensive glucose-lowering therapy dissipated by year 15, according to final results from the VADT follow-up study (VADT-F).

Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).

This was despite a rapid and statistically significant separation of hemoglobin A_1c (HbA_1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.

Approximately 6 months after the start of the VADT, median HbA_1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.

“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
 

10-year outcomes

However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.

The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m², sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.

At that 10-year follow-up, HbA_1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.

“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA_1c levels over time ... illustrating the difficulty of controlling HbA_1c values to this level in this advanced diabetes population,” Dr. Reaven said.
 

15-year outcomes

At the final 15-year follow up, with the HbA_1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).

Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.

The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.

Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.

There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.

Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.

In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.

Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.

The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.

“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.

That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA_1c levels achieved during those intervening 10 years of follow-up.

For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA_1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA_1c), he said, noting that similar findings have been reported from prior trials.

The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.

Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA_1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m², had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.

A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA_1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.

“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.

All patients with a BMI of 27 kg/m² or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m² were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA_1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.

Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.

“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.



The VADT-F design

The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.

“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.

The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.

The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.

“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”

Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.

However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA_1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA_1c less than 7%, albeit “with all sorts of caveats.”

“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.

He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA_1c control goals in patients with T2DM.

“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A_1c targets should be personalized to maximize benefits while limiting risks.”

Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.

“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.

The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.

[email protected]

ORLANDO – Improvements in cardiovascular and renal outcomes seen after nearly 10 years of improved glucose control among participants in the Veterans Affairs Diabetes Trial (VADT) who received intensive glucose-lowering therapy dissipated by year 15, according to final results from the VADT follow-up study (VADT-F).

Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).

This was despite a rapid and statistically significant separation of hemoglobin A_1c (HbA_1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.

Approximately 6 months after the start of the VADT, median HbA_1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.

“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
 

10-year outcomes

However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.

The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m², sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.

At that 10-year follow-up, HbA_1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.

“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA_1c levels over time ... illustrating the difficulty of controlling HbA_1c values to this level in this advanced diabetes population,” Dr. Reaven said.
 

15-year outcomes

At the final 15-year follow up, with the HbA_1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).

Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.

The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.

Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.

There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.

Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.

In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.

Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.

The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.

“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.

That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA_1c levels achieved during those intervening 10 years of follow-up.

For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA_1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA_1c), he said, noting that similar findings have been reported from prior trials.

The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.

Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA_1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m², had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.

A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA_1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.

“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.

All patients with a BMI of 27 kg/m² or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m² were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA_1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.

Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.

“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.



The VADT-F design

The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.

“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.

The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.

The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.

“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”

Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.

However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA_1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA_1c less than 7%, albeit “with all sorts of caveats.”

“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.

He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA_1c control goals in patients with T2DM.

“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A_1c targets should be personalized to maximize benefits while limiting risks.”

Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.

“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.

The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.

[email protected]

ORLANDO – Improvements in cardiovascular and renal outcomes seen after nearly 10 years of improved glucose control among participants in the Veterans Affairs Diabetes Trial (VADT) who received intensive glucose-lowering therapy dissipated by year 15, according to final results from the VADT follow-up study (VADT-F).

Participants in the randomized, controlled VADT, which compared the effects of intensive versus standard glucose control in more than 1,700 patients with type 2 diabetes mellitus (T2DM), did not experience a significant improvement in the primary cardiovascular disease (CVD) outcome – a composite of myocardial infarction, stroke, cardiovascular death, new congestive heart failure, cardiovascular surgery or inoperable coronary artery disease, and ischemic amputation – after a median of 5.6 years of active treatment (hazard ratio, 0.88; P = .14). Nor did they experience significant improvement in secondary cardiovascular outcomes, including cardiovascular death and death from any cause (HRs, 1.32 and 1.07, respectively), or in a renal composite outcome (HR, 0.85), according to the findings published in 2009 (N Engl J Med. 2009 Jan 8;360[2]:129-39).

This was despite a rapid and statistically significant separation of hemoglobin A_1c (HbA_1c) levels between the treatment groups, Peter Reaven, MD, noted during a presentation of the final follow-up data at the annual scientific sessions of the American Diabetes Association.

Approximately 6 months after the start of the VADT, median HbA_1c levels decreased from more than 9% in both groups to 6.9% and 8.4% in intensive and standard treatment groups, respectively (a median separation of 1.5%), said Dr. Reaven, director of the diabetes research program at the Phoenix VA Health Care System and a professor of clinical medicine at the University of Arizona in Phoenix.

“This was maintained throughout the study period,” he said. “All other risk factors during this period of time were equal between the two treatment groups.”
 

10-year outcomes

However, 10-year interim data from VADT-F, published in the New England Journal of Medicine (2015 Jun 4;372[23]:2197-206), showed a delayed benefit in these outcomes among those in the intensive control group: The incidence of the primary CVD composite outcome was reduced by 17% (HR, 0.83; P = .04) in favor of the intensive therapy at that time, Dr. Reaven said.

The incidence of the renal composite outcome, which included estimated glomerular filtration rate less than 54 mL/min per 1.73m², sustained macroalbuminuria, and end-stage renal disease, was reduced by 32% (HR, 0.68; P = .008), said Nicholas Emanuele, MD, who presented the VADT-F renal and microvascular outcomes at the ADA meeting.

At that 10-year follow-up, HbA_1c levels in the intensive and standard treatment groups had nearly equalized (although they remained slightly better in the intensive treatment group), and eventually, the levels stabilized at about 8.2% in both groups through the end of the 15-year follow-up, the investigators said.

“So it was still lower by nearly 1.2 hemoglobin percent units, compared to baseline values nearly 15 years earlier, and despite ending the study in very good control, after we released these patients to the primary care providers for their diabetes care, there was a substantial rise in HbA_1c levels over time ... illustrating the difficulty of controlling HbA_1c values to this level in this advanced diabetes population,” Dr. Reaven said.
 

15-year outcomes

At the final 15-year follow up, with the HbA_1c levels similar in the groups, nearly all benefits seen at 10 years were lost. Event rates for the CVD primary composite outcome were 51.8 and 47.3 per 1,000 patient-years in the intensive care and standard care groups, respectively (HR, 0.91; P = .23), and event rates for the renal composite outcome were 88 and 85 per 1,000 patient-years (HR, 0.90; P = .55).

Similarly, no differences were seen at 15 years in the secondary VADT-F outcomes of any major diabetes outcome, (HR, 0.90; P = .16), cardiovascular death (HR, 0.94; P = .61), or death from any cause (HR 1.02; P = .81), and no differences were seen in the individual components of the composite outcomes, the investigators said.

The same was true for other outcomes, including hospitalizations and health-related quality of life, Dr. Reaven said.

Ocular events studied in the VADT-F included cataract extraction, laster photocoagulation, vitrectomy, and intravitreal injections, with the latter three constituting a retinal event composite for which there was a difference of “very borderline significance (HR, 0.84; P = .053),” said Dr. Emanuele of Hines (Ill.) VA Hospital and Loyola University of Chicago.

There was no difference between groups for cataract extraction. (HR, 1.16; P = .30) or in participants’ self reported vision at 15 years, he added.

Additional analyses showed that there were no treatment interactions for results based on baseline differences in diabetes duration, prior CV events, or risk scores.

In essence, there was no evidence of a legacy effect, Dr. Reaven said, noting that the findings are “relatively consistent” with those from other recent glucose-lowering trials, including ACCORDION and ADVANCE-ON, which also showed no legacy benefits of intensive glucose lowering.

Dr. Emanuele also concluded that no prolonged legacy effect was apparent for renal and other microvascular outcomes.

The lack of a legacy effect at 15 years, however, shouldn’t discount the benefits seen at the 10-year follow-up because there are other ways to look at “legacy,” Hertzel C. Gerstein, MD, said during an independent “clinical perspective” commentary on the VADT and VADT-F findings.

“Another way to define ‘legacy’ is what happens after the active clinical trial ends, and if you think of it that way, there is a legacy,” said Dr. Gerstein, a professor and Population Health Institute chair in diabetes research at McMaster University and Hamilton Health Sciences, Ontario, Canada.

That is, the intensive glycemic control led to significant improvements at 10-year follow-up. While he acknowledged “that’s just semantics,” he stressed that a number of important lessons have been learned from the VADT and VADT-F – not the least of which relate to mediation analyses that showed the benefit seen at 10 years can be explained, at least statistically, by the differences in HbA_1c levels achieved during those intervening 10 years of follow-up.

For example, the 10-year cardiovascular outcome hazard ratios changed from 0.83 with a P value of .04 to 0.86 with a P value of .12 (after controlling for time-varying HbA_1c levels) and to 0.94 with a P value of .53 (after controlling for time-varying cumulative mean HbA_1c), he said, noting that similar findings have been reported from prior trials.

The VADT was designed to evaluate whether an intensive glycemic control regimen could reduce the incidence of major cardiovascular events compared with standard care in patients with T2DM; secondary objectives included differences in additional cardiovascular, renal, and other outcomes.

Subjects, who were enrolled from 20 VA medical centers beginning in December 2000, were aged 41 years or older (mean of about 60 years) and had failed to respond to a maximum dose of at least one oral agent and/or daily insulin. Patients were excluded if they had HbA_1c less than 7.5%, had had a cardiovascular event in the previous 6 months, had advanced congestive heart failure, had severe angina, had a life expectancy of less than 7 years, had a body mass index over 40 kg/m², had serum creatinine less than 1.6 mg/dL, or had an alanine transaminase level greater than 3 times the upper limit of normal, according to Wyndy L. Wiitala, PhD, of the VA Center for Clinical Management Research in Ann Arbor, Michigan.

A total of 818 patients in the standard care group and 837 in the intensive treatment group completed the study with up to 7.5 years of total follow-up (median, 5.6 years). The groups were similar in age; both were mostly male, which is expected for a VA population; and the average HbA_1c level was 9.4% in both groups. Other clinical measures, including lipids, blood pressure, and estimated cardiovascular risk were also similar between the two groups.

“The VADT was designed so that the only planned difference between the treatment groups was the level of glycemic control,” Dr. Wiitala said.

All patients with a BMI of 27 kg/m² or greater were started on metformin plus rosiglitazone, and those with a BMI less than 27 kg/m² were started on glimepiride plus rosiglitazone. Those in the intensive therapy arm were started on maximal doses, and those in the standard therapy arm were started on half the maximal doses. Insulin was added for patients in the intensive-therapy group who did not achieve HbA_1c below 6%, as well as for those in the standard-therapy group with a level of less than 9%.

Any subsequent medication changes were determined according to protocol guidelines and local assessment, and investigators were allowed to use any approved drug at their discretion.

“The use of medications between the two groups was similar, with differences in dose and insulin intensity only,” Dr. Wiitala said, adding that all other aspects of treatment, including blood pressure control, lipid control, aspirin therapy, diet, and nutrition, were “nearly identical” in the two groups.



The VADT-F design

The negative findings from the VADT raised “a number of questions, which really provided the rationale for the VADT follow-up study,” Dr. Reaven said.

“Would the post-VADT follow-up reveal an emerging cardiovascular benefit? This was particularly relevant as there was an indication that the group differences were increasing toward the end of the study, and benefits in cardiovascular outcomes, as we know, take a fair amount of time,” he said, adding that since the glucose separation seen in the treatment groups was greater than that seen in other recent studies involving patients with advanced T2DM and remained that way for an extended period of time, the follow-up study provided an excellent opportunity to examine whether there was a legacy or other effects.

The VADT-F continued to follow the VADT patients after the intervention ended in 2008; at that time, patients returned to normal care with no further intervention by the research team, Dr. Wiitala said, noting that participants were followed using national data sources, annual mail surveys, and targeted chart reviews.

The 10-year interim analysis was reported in 2015, and the 15-year final analysis, which is currently under review, represents the longest follow-up of patients with advanced T2DM with high risk for cardiovascular disease, she said.

“These results suggest that there are modest long-term cardiovascular disease benefits of therapies directed toward bringing glucose control to near-normal range in high-risk type 2 diabetes and that substantial and continuous glucose separation may be required to maintain these improvements,” Dr. Reaven concluded, adding that “recent studies demonstrating cardiovascular benefit with diabetes agents that only achieve modest improvements in glycemic control highlight the importance of also considering nonglycemic approaches to reducing cardiovascular disease events and mortality in these patients.”

Similarly, Dr. Emanuele concluded that there is a delayed beneficial effect of intensive glycemic control on kidney outcomes but that the effect dissipates as glycemic separation wanes.

However, in his commentary at the meeting, Dr. Gerstein stressed that the findings add value; in addition to showing, via mediation analyses, that HbA_1c levels statistically explain the differences seen between the intensive and standard therapy arms at 10 years, the VADT and VADT-F findings also underscore the veracity of the ADA’s recommended target of HbA_1c less than 7%, albeit “with all sorts of caveats.”

“But one point to make is that clinical trials do not tell you how to treat the patient in front of you. [They] just tell you what works on average for the average patient. ... You have to take the information you get from randomized trials and put it into your brain as a doctor and treat the patient,” he said.

He and several colleagues further explained this concept in a recent editorial (Diabetes Care. 2018 Jun;41[6]:1121-4) penned in response to new guidance statements published by the American College of Physicians advocating for relaxation of HbA_1c control goals in patients with T2DM.

“The ACP proposal may encourage a step backward at a time when accumulating evidence from randomized, controlled trials calls for movement forward in the treatment of diabetes,” they wrote in the editorial entitled “A_1c targets should be personalized to maximize benefits while limiting risks.”

Findings from those trials, including the VADT and VADT-F, continue to increase diabetes insights and inform care, and while there is not yet a statin-like “prescribe-and-go” treatment for diabetes, the findings represent a step in the right direction, Dr Gerstein said.

“All you have to do is look at all the clinical trials that are happening. We’re going to get there. ... This is not the end of the end, this is the beginning of the next phase,” he said.

The VADT and VADT-F were funded by the VA Cooperative Studies Program, the ADA, and the National Institutes of Health/National Eye Institute. Medication and additional support were provided by Aventis, GlaxoSmithKline, and Novo Nordisk Pharmaceuticals, which provided funding and supplies, and by Abbott Laboratory, Amylin, Eli Lily, Kos, Roche, and the University of Chicago, which also provided supplies. Dr. Reaven is an advisory panel member for Sanofi and has received research support from AstraZeneca and Novo Nordisk. Dr. Gerstein has received grants or other research support, honoraria, and/or consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Novo Nordisk, and Sanofi. Dr. Wiitala and Dr. Emanuele reported having no disclosures.

[email protected]

LOS ANGELES – A novel scoring system based on six readily available seizure risk factors from a patient’s history and continuous electroencephalogram (cEEG) monitoring appears to accurately predict seizures in acutely ill hospitalized patients.

The final model of the system, dubbed the 2HELPS2B score, has an area under the curve (AUC) of 0.821, suggesting a “good overall fit,” Aaron Struck, MD, reported at the annual meeting of the American Academy of Neurology.

However, more relevant than the AUC and suggestive of high classification accuracy is the low calibration error of 2.7%, which shows that the actual incidence of seizures within a particular risk group is, on average, within 2.7% of predicted incidence, Dr. Struck of the University of Wisconsin, Madison, explained in an interview.

The use of cEEG has expanded, largely because of a high incidence of subclinical seizures in hospitalized patients with encephalopathy; EEG features believed to predict seizures include epileptiform discharges and periodic discharges, but the ways in which these variables may jointly affect seizure risk have not been studied, he said.

He and his colleagues used a prospective database to derive a dataset containing 24 clinical and electroencephalographic variables for 5,427 cEEG sessions of at least 24 hours each, and then, using a machine-learning method known as RiskSLIM, created a scoring system model to estimate seizure risk in patients undergoing cEEG.

The name of the scoring system – 2HELPS2B – represents the six variables included in the final model:

• 2 H is for frequency greater than 2.0 Hz for any periodic rhythmic pattern (1 point).
• E is for sporadic epileptiform discharges (1 point).
• L is for the presence of lateralized periodic discharges, lateralized rhythmic delta activity, or bilateral independent periodic discharges (1 point).
• P is for the presence of “plus” features, including superimposed, rhythmic, sharp, or fast activity (1 point).
• S is for prior seizure (1 point).
• 2B is for brief, potentially ictal, rhythmic discharges (2 points).

The predicted seizure risk rose with score, such that the seizure risk was less than 5% for a score of 0, 12% for 1, 27% for 2, 50% for 3, 73% for 4, 88% for 5, and greater than 95% for 6-7, Dr. Struck said. “Really, anything over 2 points, you’re at substantial risk for having seizures.”

Limitations of the study, which are being addressed in an ongoing, multicenter, prospective validation trial through the Critical Care EEG Monitoring Research Consortium, are mainly related to the constraints of the database; the duration of EEG needed to accurately calculate the 2HELPS2B score wasn’t defined, and cEEGs were of varying length.

“So in our validation study moving forward, these are two things we will address,” he said. “We also want to show that this is something that’s useful on a day-to-day basis – that it accurately gauges the degree of variability or potential severity of the ictal-interictal continuum pattern.”

With validation, Dr. Struck said that the 2HELPS2B score could ultimately be used to rapidly communicate seizure potential based on EEG severity and to guide decision making with respect to initiation of empiric antiseizure medication.

Findings from the validation study are “trending in the right direction,” but the confidence intervals are wide, as only 404 patients have been included at this point, Dr. Struck said.

This study was supported by a research infrastructure award from the American Epilepsy Society and the Epilepsy Foundation.

[email protected]

SOURCE: Struck A et al. Neurology. 2018 Apr 90(15 Suppl.):S11.002.

LOS ANGELES – A novel scoring system based on six readily available seizure risk factors from a patient’s history and continuous electroencephalogram (cEEG) monitoring appears to accurately predict seizures in acutely ill hospitalized patients.

The final model of the system, dubbed the 2HELPS2B score, has an area under the curve (AUC) of 0.821, suggesting a “good overall fit,” Aaron Struck, MD, reported at the annual meeting of the American Academy of Neurology.

However, more relevant than the AUC and suggestive of high classification accuracy is the low calibration error of 2.7%, which shows that the actual incidence of seizures within a particular risk group is, on average, within 2.7% of predicted incidence, Dr. Struck of the University of Wisconsin, Madison, explained in an interview.

The use of cEEG has expanded, largely because of a high incidence of subclinical seizures in hospitalized patients with encephalopathy; EEG features believed to predict seizures include epileptiform discharges and periodic discharges, but the ways in which these variables may jointly affect seizure risk have not been studied, he said.

He and his colleagues used a prospective database to derive a dataset containing 24 clinical and electroencephalographic variables for 5,427 cEEG sessions of at least 24 hours each, and then, using a machine-learning method known as RiskSLIM, created a scoring system model to estimate seizure risk in patients undergoing cEEG.

The name of the scoring system – 2HELPS2B – represents the six variables included in the final model:

• 2 H is for frequency greater than 2.0 Hz for any periodic rhythmic pattern (1 point).
• E is for sporadic epileptiform discharges (1 point).
• L is for the presence of lateralized periodic discharges, lateralized rhythmic delta activity, or bilateral independent periodic discharges (1 point).
• P is for the presence of “plus” features, including superimposed, rhythmic, sharp, or fast activity (1 point).
• S is for prior seizure (1 point).
• 2B is for brief, potentially ictal, rhythmic discharges (2 points).

The predicted seizure risk rose with score, such that the seizure risk was less than 5% for a score of 0, 12% for 1, 27% for 2, 50% for 3, 73% for 4, 88% for 5, and greater than 95% for 6-7, Dr. Struck said. “Really, anything over 2 points, you’re at substantial risk for having seizures.”

Limitations of the study, which are being addressed in an ongoing, multicenter, prospective validation trial through the Critical Care EEG Monitoring Research Consortium, are mainly related to the constraints of the database; the duration of EEG needed to accurately calculate the 2HELPS2B score wasn’t defined, and cEEGs were of varying length.

“So in our validation study moving forward, these are two things we will address,” he said. “We also want to show that this is something that’s useful on a day-to-day basis – that it accurately gauges the degree of variability or potential severity of the ictal-interictal continuum pattern.”

With validation, Dr. Struck said that the 2HELPS2B score could ultimately be used to rapidly communicate seizure potential based on EEG severity and to guide decision making with respect to initiation of empiric antiseizure medication.

Findings from the validation study are “trending in the right direction,” but the confidence intervals are wide, as only 404 patients have been included at this point, Dr. Struck said.

This study was supported by a research infrastructure award from the American Epilepsy Society and the Epilepsy Foundation.

[email protected]

SOURCE: Struck A et al. Neurology. 2018 Apr 90(15 Suppl.):S11.002.

LOS ANGELES – A novel scoring system based on six readily available seizure risk factors from a patient’s history and continuous electroencephalogram (cEEG) monitoring appears to accurately predict seizures in acutely ill hospitalized patients.

The final model of the system, dubbed the 2HELPS2B score, has an area under the curve (AUC) of 0.821, suggesting a “good overall fit,” Aaron Struck, MD, reported at the annual meeting of the American Academy of Neurology.

However, more relevant than the AUC and suggestive of high classification accuracy is the low calibration error of 2.7%, which shows that the actual incidence of seizures within a particular risk group is, on average, within 2.7% of predicted incidence, Dr. Struck of the University of Wisconsin, Madison, explained in an interview.

The use of cEEG has expanded, largely because of a high incidence of subclinical seizures in hospitalized patients with encephalopathy; EEG features believed to predict seizures include epileptiform discharges and periodic discharges, but the ways in which these variables may jointly affect seizure risk have not been studied, he said.

He and his colleagues used a prospective database to derive a dataset containing 24 clinical and electroencephalographic variables for 5,427 cEEG sessions of at least 24 hours each, and then, using a machine-learning method known as RiskSLIM, created a scoring system model to estimate seizure risk in patients undergoing cEEG.

The name of the scoring system – 2HELPS2B – represents the six variables included in the final model:

• 2 H is for frequency greater than 2.0 Hz for any periodic rhythmic pattern (1 point).
• E is for sporadic epileptiform discharges (1 point).
• L is for the presence of lateralized periodic discharges, lateralized rhythmic delta activity, or bilateral independent periodic discharges (1 point).
• P is for the presence of “plus” features, including superimposed, rhythmic, sharp, or fast activity (1 point).
• S is for prior seizure (1 point).
• 2B is for brief, potentially ictal, rhythmic discharges (2 points).

The predicted seizure risk rose with score, such that the seizure risk was less than 5% for a score of 0, 12% for 1, 27% for 2, 50% for 3, 73% for 4, 88% for 5, and greater than 95% for 6-7, Dr. Struck said. “Really, anything over 2 points, you’re at substantial risk for having seizures.”

Limitations of the study, which are being addressed in an ongoing, multicenter, prospective validation trial through the Critical Care EEG Monitoring Research Consortium, are mainly related to the constraints of the database; the duration of EEG needed to accurately calculate the 2HELPS2B score wasn’t defined, and cEEGs were of varying length.

“So in our validation study moving forward, these are two things we will address,” he said. “We also want to show that this is something that’s useful on a day-to-day basis – that it accurately gauges the degree of variability or potential severity of the ictal-interictal continuum pattern.”

With validation, Dr. Struck said that the 2HELPS2B score could ultimately be used to rapidly communicate seizure potential based on EEG severity and to guide decision making with respect to initiation of empiric antiseizure medication.

Findings from the validation study are “trending in the right direction,” but the confidence intervals are wide, as only 404 patients have been included at this point, Dr. Struck said.

This study was supported by a research infrastructure award from the American Epilepsy Society and the Epilepsy Foundation.

[email protected]

SOURCE: Struck A et al. Neurology. 2018 Apr 90(15 Suppl.):S11.002.

LOS ANGELES – The commercially available Fitbit Flex accelerometer proved useful and feasible for longitudinal measurement of average daily steps in a prospective, 1-year study of patients with multiple sclerosis.

The wrist-worn device was well received, with 79 of 96 participants (82%) completing follow-up, and it revealed changes in daily functioning that were not captured using more traditional disability metrics, Valerie J. Block, DPTSc, reported at the annual meeting of the American Academy of Neurology.

The study involved 61 adults with relapsing multiple sclerosis (MS) and 35 with progressive MS who were recruited into the University of California, San Francisco (UCSF) FITriMS cohort. All were able to walk at least 2 minutes at baseline, and their daily physical activity was recorded continuously by the device over 1 year. Performance-based measures, including the Expanded Disability Status Scale (EDSS) and timed 25-foot walk test, were evaluated at baseline and at 1 year, and patient-reported outcomes such as the 12-item MS walking scale were completed at baseline and at 1.5, 3, 6, 9, and 12 months. Nine patients withdrew, and eight were lost to follow-up.

“This was a fairly stable, actively treated cohort, and overall, there was no significant change in average daily steps (STEPS) over 1 year. However, there was a trend toward a decrease (–315 steps/day; P = .117), and 53% of patients had a decrease of more than 800 steps per day, which is a proposed minimal clinically important difference threshold,” Dr. Block, a postdoctoral scholar at UCSF, said in an interview.

Despite the modest, gradual reduction in STEPS over the year, most participants were able to complete the study, providing at least 1 valid week of STEPS data per month throughout the year, she said, noting that there was no difference in device use between relapsing MS and progressive MS participants.

A significant association between decreasing STEPS and worsening of clinic-based and patient-reported outcomes was demonstrated, but declining STEPS occurred even when disability levels, as measured by the EDSS, remained stable.

“Participants who started off the study with lower STEPS, below the cohort median of 4,766 STEPS, had fourfold higher odds of clinically-meaningful disability worsening at 1 year after adjusting for age, sex, and disease duration,” she said.

Further, earlier data published by Dr. Block and her colleagues showed there is wide variability in the change in steps over 1 year. In that study, the change in step count in patients whose EDSS score remained unchanged ranged from +814 to –3,718, suggesting that popular mainstream wearable technology is not only feasible but also can provide a more detailed and nuanced measure of how patients are functioning in their daily lives, she said.

Together, these findings suggest that remote accelerometry provides useful continuous information about physical activity in real-world setting, she said, concluding that “these results support the possibility of using STEPS as a more sensitive and granular outcome measure in clinical trials and for targeted interventions in clinical care.”

This study was supported by the National Center for Advancing Translational Sciences. Dr. Block reported having no disclosures.

[email protected]

SOURCE: Block VJ et al. Neurology. 2018 Apr 10;90(15 Suppl):N5.001.

LOS ANGELES – The commercially available Fitbit Flex accelerometer proved useful and feasible for longitudinal measurement of average daily steps in a prospective, 1-year study of patients with multiple sclerosis.

The wrist-worn device was well received, with 79 of 96 participants (82%) completing follow-up, and it revealed changes in daily functioning that were not captured using more traditional disability metrics, Valerie J. Block, DPTSc, reported at the annual meeting of the American Academy of Neurology.

The study involved 61 adults with relapsing multiple sclerosis (MS) and 35 with progressive MS who were recruited into the University of California, San Francisco (UCSF) FITriMS cohort. All were able to walk at least 2 minutes at baseline, and their daily physical activity was recorded continuously by the device over 1 year. Performance-based measures, including the Expanded Disability Status Scale (EDSS) and timed 25-foot walk test, were evaluated at baseline and at 1 year, and patient-reported outcomes such as the 12-item MS walking scale were completed at baseline and at 1.5, 3, 6, 9, and 12 months. Nine patients withdrew, and eight were lost to follow-up.

“This was a fairly stable, actively treated cohort, and overall, there was no significant change in average daily steps (STEPS) over 1 year. However, there was a trend toward a decrease (–315 steps/day; P = .117), and 53% of patients had a decrease of more than 800 steps per day, which is a proposed minimal clinically important difference threshold,” Dr. Block, a postdoctoral scholar at UCSF, said in an interview.

Despite the modest, gradual reduction in STEPS over the year, most participants were able to complete the study, providing at least 1 valid week of STEPS data per month throughout the year, she said, noting that there was no difference in device use between relapsing MS and progressive MS participants.

A significant association between decreasing STEPS and worsening of clinic-based and patient-reported outcomes was demonstrated, but declining STEPS occurred even when disability levels, as measured by the EDSS, remained stable.

“Participants who started off the study with lower STEPS, below the cohort median of 4,766 STEPS, had fourfold higher odds of clinically-meaningful disability worsening at 1 year after adjusting for age, sex, and disease duration,” she said.

Further, earlier data published by Dr. Block and her colleagues showed there is wide variability in the change in steps over 1 year. In that study, the change in step count in patients whose EDSS score remained unchanged ranged from +814 to –3,718, suggesting that popular mainstream wearable technology is not only feasible but also can provide a more detailed and nuanced measure of how patients are functioning in their daily lives, she said.

Together, these findings suggest that remote accelerometry provides useful continuous information about physical activity in real-world setting, she said, concluding that “these results support the possibility of using STEPS as a more sensitive and granular outcome measure in clinical trials and for targeted interventions in clinical care.”

This study was supported by the National Center for Advancing Translational Sciences. Dr. Block reported having no disclosures.

[email protected]

SOURCE: Block VJ et al. Neurology. 2018 Apr 10;90(15 Suppl):N5.001.

LOS ANGELES – The commercially available Fitbit Flex accelerometer proved useful and feasible for longitudinal measurement of average daily steps in a prospective, 1-year study of patients with multiple sclerosis.

The wrist-worn device was well received, with 79 of 96 participants (82%) completing follow-up, and it revealed changes in daily functioning that were not captured using more traditional disability metrics, Valerie J. Block, DPTSc, reported at the annual meeting of the American Academy of Neurology.

The study involved 61 adults with relapsing multiple sclerosis (MS) and 35 with progressive MS who were recruited into the University of California, San Francisco (UCSF) FITriMS cohort. All were able to walk at least 2 minutes at baseline, and their daily physical activity was recorded continuously by the device over 1 year. Performance-based measures, including the Expanded Disability Status Scale (EDSS) and timed 25-foot walk test, were evaluated at baseline and at 1 year, and patient-reported outcomes such as the 12-item MS walking scale were completed at baseline and at 1.5, 3, 6, 9, and 12 months. Nine patients withdrew, and eight were lost to follow-up.

“This was a fairly stable, actively treated cohort, and overall, there was no significant change in average daily steps (STEPS) over 1 year. However, there was a trend toward a decrease (–315 steps/day; P = .117), and 53% of patients had a decrease of more than 800 steps per day, which is a proposed minimal clinically important difference threshold,” Dr. Block, a postdoctoral scholar at UCSF, said in an interview.

Despite the modest, gradual reduction in STEPS over the year, most participants were able to complete the study, providing at least 1 valid week of STEPS data per month throughout the year, she said, noting that there was no difference in device use between relapsing MS and progressive MS participants.

A significant association between decreasing STEPS and worsening of clinic-based and patient-reported outcomes was demonstrated, but declining STEPS occurred even when disability levels, as measured by the EDSS, remained stable.

“Participants who started off the study with lower STEPS, below the cohort median of 4,766 STEPS, had fourfold higher odds of clinically-meaningful disability worsening at 1 year after adjusting for age, sex, and disease duration,” she said.

Further, earlier data published by Dr. Block and her colleagues showed there is wide variability in the change in steps over 1 year. In that study, the change in step count in patients whose EDSS score remained unchanged ranged from +814 to –3,718, suggesting that popular mainstream wearable technology is not only feasible but also can provide a more detailed and nuanced measure of how patients are functioning in their daily lives, she said.

Together, these findings suggest that remote accelerometry provides useful continuous information about physical activity in real-world setting, she said, concluding that “these results support the possibility of using STEPS as a more sensitive and granular outcome measure in clinical trials and for targeted interventions in clinical care.”

This study was supported by the National Center for Advancing Translational Sciences. Dr. Block reported having no disclosures.

[email protected]

SOURCE: Block VJ et al. Neurology. 2018 Apr 10;90(15 Suppl):N5.001.

CHICAGO – A dendritic cell vaccine improved progression-free survival when administered sequentially after chemotherapy in patients with epithelial ovarian carcinoma who have undergone primary debulking surgery, according to interim findings from a randomized, phase 2, open-label trial.

Of 99 patients enrolled in the international, multicenter trial between November 2013 and March 2016, 92 received at least one dose of therapy and had a postbaseline endpoint assessment (the modified intention-to-treat population). Median progression-free survival was 18.3 months in the 31 patients who received autologous dendritic cell vaccine (DCVAC) given concomitantly with chemotherapy (group A), 24.3 months in the 30 patients who received DCVAC given sequentially as maintenance therapy after chemotherapy (group B), and 18.6 months in the 31 controls who received chemotherapy alone (group C), Lukas Rob, MD, reported at the annual meeting of the American Society of Clinical Oncology.

“When DCVAC was administered as maintenance [therapy] after the chemotherapy, the time to disease progression was prolonged by almost 6 months. Based on the hazard ratio, there was a 57% decrease in the hazard of progression in favor of arm B,” said Dr. Rob, of University Hospital Kralovske Vinohrady, Prague.

Compared with group C, progression-free survival hazard ratios were 0.64 and 0.43 in the modified intention-to-treat population in groups A and B, respectively, he said.

“These results are statistically significant and the clinical benefit is even more significant in patients who received more doses of DCVAC,” he added, explaining that the hazard ratios for patients in groups A and B who received at least eight doses of DCVAC and/or three cycles of chemotherapy (the per protocol population, including 87 patients) were 1.01 and 0.32, respectively.

Although the overall survival data in this study is immature, there is “a strong trend in favor of DCVAC in the maintenance treatment arm,” he said.

Study participants had FIGO stage III epithelial ovarian cancer (EOC) and a performance status score of 0-2. All had undergone primary debulking surgery and had less than 1 cm maximal residuum and no prior systemic therapy. Patients were randomized up to 6 weeks after surgery. Chemotherapy in all three groups included six cycles of carboplatin and paclitaxel, and DCVAC was given at doses of 1 x 107 dendritic cells per dose for a planned 10 doses.

Most patients with EOC – about 70% of those with stage III/IV disease – relapse after optimal debulking surgery and chemotherapy.

“There is no doubt that we need a new treatment modality,” he said. Because autologous DCVAC can present tumor antigens to elicit a durable immune response, he and his colleagues hypothesized that adding DCVAC to chemotherapy could improve outcomes – either when used concomitantly to target tumor-induced immune suppression and allowing for partial recovery of the immune system after each cycle, or when used sequentially as maintenance therapy, as minimal tumor burden after chemotherapy would provide optimal conditions for immune stimulation and the immune system would be fully recovered after completing cytotoxic therapy.

The treatments in this study were well tolerated; no grade 3 or greater adverse events were related solely to DCVAC, and the vaccine did not worsen the side effects of chemotherapy, Dr. Rob said.

The findings suggested that sequential DCVAC after chemotherapy in patients with EOC is a promising maintenance treatment option that can delay disease progression, he concluded, noting that “due to the excellent result in the maintenance arm we decided ... to enroll more patients in arms B and C to increase the power of this study.”

Additionally, a phase 3 trial is planned and enrollment should begin in early 2019, he said.

Dr. Rob reported having no disclosures.

SOURCE: Rob L et al. ASCO 2018, Abstract 5509.

CHICAGO – A dendritic cell vaccine improved progression-free survival when administered sequentially after chemotherapy in patients with epithelial ovarian carcinoma who have undergone primary debulking surgery, according to interim findings from a randomized, phase 2, open-label trial.

Of 99 patients enrolled in the international, multicenter trial between November 2013 and March 2016, 92 received at least one dose of therapy and had a postbaseline endpoint assessment (the modified intention-to-treat population). Median progression-free survival was 18.3 months in the 31 patients who received autologous dendritic cell vaccine (DCVAC) given concomitantly with chemotherapy (group A), 24.3 months in the 30 patients who received DCVAC given sequentially as maintenance therapy after chemotherapy (group B), and 18.6 months in the 31 controls who received chemotherapy alone (group C), Lukas Rob, MD, reported at the annual meeting of the American Society of Clinical Oncology.

“When DCVAC was administered as maintenance [therapy] after the chemotherapy, the time to disease progression was prolonged by almost 6 months. Based on the hazard ratio, there was a 57% decrease in the hazard of progression in favor of arm B,” said Dr. Rob, of University Hospital Kralovske Vinohrady, Prague.

Compared with group C, progression-free survival hazard ratios were 0.64 and 0.43 in the modified intention-to-treat population in groups A and B, respectively, he said.

“These results are statistically significant and the clinical benefit is even more significant in patients who received more doses of DCVAC,” he added, explaining that the hazard ratios for patients in groups A and B who received at least eight doses of DCVAC and/or three cycles of chemotherapy (the per protocol population, including 87 patients) were 1.01 and 0.32, respectively.

Although the overall survival data in this study is immature, there is “a strong trend in favor of DCVAC in the maintenance treatment arm,” he said.

Study participants had FIGO stage III epithelial ovarian cancer (EOC) and a performance status score of 0-2. All had undergone primary debulking surgery and had less than 1 cm maximal residuum and no prior systemic therapy. Patients were randomized up to 6 weeks after surgery. Chemotherapy in all three groups included six cycles of carboplatin and paclitaxel, and DCVAC was given at doses of 1 x 107 dendritic cells per dose for a planned 10 doses.

Most patients with EOC – about 70% of those with stage III/IV disease – relapse after optimal debulking surgery and chemotherapy.

“There is no doubt that we need a new treatment modality,” he said. Because autologous DCVAC can present tumor antigens to elicit a durable immune response, he and his colleagues hypothesized that adding DCVAC to chemotherapy could improve outcomes – either when used concomitantly to target tumor-induced immune suppression and allowing for partial recovery of the immune system after each cycle, or when used sequentially as maintenance therapy, as minimal tumor burden after chemotherapy would provide optimal conditions for immune stimulation and the immune system would be fully recovered after completing cytotoxic therapy.

The treatments in this study were well tolerated; no grade 3 or greater adverse events were related solely to DCVAC, and the vaccine did not worsen the side effects of chemotherapy, Dr. Rob said.

The findings suggested that sequential DCVAC after chemotherapy in patients with EOC is a promising maintenance treatment option that can delay disease progression, he concluded, noting that “due to the excellent result in the maintenance arm we decided ... to enroll more patients in arms B and C to increase the power of this study.”

Additionally, a phase 3 trial is planned and enrollment should begin in early 2019, he said.

Dr. Rob reported having no disclosures.

SOURCE: Rob L et al. ASCO 2018, Abstract 5509.

CHICAGO – A dendritic cell vaccine improved progression-free survival when administered sequentially after chemotherapy in patients with epithelial ovarian carcinoma who have undergone primary debulking surgery, according to interim findings from a randomized, phase 2, open-label trial.

Of 99 patients enrolled in the international, multicenter trial between November 2013 and March 2016, 92 received at least one dose of therapy and had a postbaseline endpoint assessment (the modified intention-to-treat population). Median progression-free survival was 18.3 months in the 31 patients who received autologous dendritic cell vaccine (DCVAC) given concomitantly with chemotherapy (group A), 24.3 months in the 30 patients who received DCVAC given sequentially as maintenance therapy after chemotherapy (group B), and 18.6 months in the 31 controls who received chemotherapy alone (group C), Lukas Rob, MD, reported at the annual meeting of the American Society of Clinical Oncology.

“When DCVAC was administered as maintenance [therapy] after the chemotherapy, the time to disease progression was prolonged by almost 6 months. Based on the hazard ratio, there was a 57% decrease in the hazard of progression in favor of arm B,” said Dr. Rob, of University Hospital Kralovske Vinohrady, Prague.

Compared with group C, progression-free survival hazard ratios were 0.64 and 0.43 in the modified intention-to-treat population in groups A and B, respectively, he said.

“These results are statistically significant and the clinical benefit is even more significant in patients who received more doses of DCVAC,” he added, explaining that the hazard ratios for patients in groups A and B who received at least eight doses of DCVAC and/or three cycles of chemotherapy (the per protocol population, including 87 patients) were 1.01 and 0.32, respectively.

Although the overall survival data in this study is immature, there is “a strong trend in favor of DCVAC in the maintenance treatment arm,” he said.

Study participants had FIGO stage III epithelial ovarian cancer (EOC) and a performance status score of 0-2. All had undergone primary debulking surgery and had less than 1 cm maximal residuum and no prior systemic therapy. Patients were randomized up to 6 weeks after surgery. Chemotherapy in all three groups included six cycles of carboplatin and paclitaxel, and DCVAC was given at doses of 1 x 107 dendritic cells per dose for a planned 10 doses.

Most patients with EOC – about 70% of those with stage III/IV disease – relapse after optimal debulking surgery and chemotherapy.

“There is no doubt that we need a new treatment modality,” he said. Because autologous DCVAC can present tumor antigens to elicit a durable immune response, he and his colleagues hypothesized that adding DCVAC to chemotherapy could improve outcomes – either when used concomitantly to target tumor-induced immune suppression and allowing for partial recovery of the immune system after each cycle, or when used sequentially as maintenance therapy, as minimal tumor burden after chemotherapy would provide optimal conditions for immune stimulation and the immune system would be fully recovered after completing cytotoxic therapy.

The treatments in this study were well tolerated; no grade 3 or greater adverse events were related solely to DCVAC, and the vaccine did not worsen the side effects of chemotherapy, Dr. Rob said.

The findings suggested that sequential DCVAC after chemotherapy in patients with EOC is a promising maintenance treatment option that can delay disease progression, he concluded, noting that “due to the excellent result in the maintenance arm we decided ... to enroll more patients in arms B and C to increase the power of this study.”

Additionally, a phase 3 trial is planned and enrollment should begin in early 2019, he said.

Dr. Rob reported having no disclosures.

SOURCE: Rob L et al. ASCO 2018, Abstract 5509.

CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.

The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.

In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.

Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IV_indolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.

For example, median OS in patients with stage IV_indolent vs. stage IV_aggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IV_indolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.

In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.

“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.

This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.

SOURCE: Davis A et al., ASCO 2018 Poster 1019.

CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.

The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.

In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.

Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IV_indolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.

For example, median OS in patients with stage IV_indolent vs. stage IV_aggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IV_indolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.

In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.

“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.

This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.

SOURCE: Davis A et al., ASCO 2018 Poster 1019.

CHICAGO – A circulating tumor cell (CTC) count less than 5 per 7.5 mL of blood in patients with metastatic breast cancer indicates an indolent disease subset, according to a pooled analysis of individual patient data from two large cohorts.

The findings, which were independent of molecular subtype, disease location, or line of treatment, have important implications for CTC-based staging of metastatic breast cancer (MBC), which in turn could guide treatment decision making and drug development, Andrew A. Davis, MD, of Northwestern University, Chicago, and his colleagues reported in a poster at the annual meeting of the American Society of Clinical Oncology.

In 1,944 patients from the European Pooled Analysis Consortium (EPAC) and 492 from MD Anderson Cancer Center, CTC counts of 5 per 7.5mL or greater were associated with worse outcomes overall (hazard ratio, 2.43), the investigators said.

Median overall survival (OS) among all patients with CTC counts less than 5, who were considered to have stage IV indolent disease (stage IV_indolent), was 36.3 months, and OS among those with de novo disease and CDC counts less than 5 was greater than 5.5 years, they said, noting that the survival benefit persisted across all disease subtypes.

For example, median OS in patients with stage IV_indolent vs. stage IV_aggressive (those with CTC counts of 5 or greater ) was 44.0 vs. 17.3 months in patients with hormone receptor–positive disease, 23.8 vs. 9.0 months in triple negative breast cancer patients, and 36.7 vs. 20.4 months in patients with HER2+ disease, respectively, they explained.They also noted that stage IV_indolent disease could discriminate a less aggressive cohort both for patients with and without prior treatment; the hazard ratios were 0.40 and 0.42 favoring indolent disease for both first-line treatment and treatment beyond the first line, respectively.

In early-stage breast cancer, diagnostic tools have been incorporated into practice to help identify patients who will benefit from conservative vs. aggressive therapy, and the current findings suggest that CTC counts could be used in that manner for staging MBC.

“We propose a CTC-based staging system for MBC based on indolent and aggressive disease to incorporate into the American Joint Committee on Cancer [tumor node metastasis] staging classification,” they wrote, adding that prospective studies of single-agent, cost-effective treatments for stage IVindolent disease in the first-line setting are needed.

This study was supported by the Lynn Sage Breast Cancer Research OncoSET Program at Robert H. Lurie Cancer Center. Dr. Davis reported having no disclosures.

SOURCE: Davis A et al., ASCO 2018 Poster 1019.

ORLANDO – Sodium-glucose transporter 2 inhibitors, including dapagliflozin, have a beneficial class effect on major adverse cardiac events, all-cause mortality, and renal function, a post hoc analysis of data from the EXSCEL trial suggested.

Sharon Worcester/MDedge News

The findings are consistent with those from published cardiovascular outcomes trials (CVOTs) of sodium-glucose transporter 2 (SGLT2) inhibitors other than dapagliflozin, real-world data, and findings from non-CVOTs of dapagliflozin, Lindsay Clegg, PhD, reported in a late-breaking poster at the annual scientific sessions of the American Diabetes Association.

In EXSCEL – a CVOT of once-weekly treatment with the glucagonlike peptide–1 receptor agonist exenatide added to usual care in patients with type 2 diabetes mellitus – 10% of patients took an SGLT2 inhibitor, and about half of those took dapagliflozin. For the current analysis, the effects of all SGLT2 inhibitors and dapagliflozin alone were evaluated in EXSCEL patients who received placebo.

“Just looking at that placebo data, we wanted to ask what the impact of SGLT2 inhibition was on the adjudicated cardiovascular events, as well as all-cause death and eGFR [estimated glomerular filtration rate] in this population,” Dr. Clegg, a postdoctoral fellow with the AstraZeneca Quantitative Clinical Pharmacology Group in Gaithersburg, Md., said in an interview.

In two propensity-matched cohorts, including a cohort of 709 SGLT2 inhibitor users and a cohort of 709 non-SGLT2 inhibitor users, SGLT2 inhibitors and dapagliflozin alone were found to numerically decrease the major adverse cardiac event (MACE) hazard ratio, and SGLT2 inhibitors significantly reduced all-cause mortality risk, she explained.

MACE events – a composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke – occurred in 28 versus 44 patients in the SGLT2 and non-SGLT2 inhibitor groups, respectively (event rate per 100 patient-years, 3.41 vs. 4.45; adjusted HR, 0.79). Dr. Clegg noted that this hazard ratio is “very consistent with what has been seen in the CVOTs for [the SGLT2 inhibitors] empagliflozin and canagliflozin in literature.”

The corresponding figures for dapagliflozin were 11 versus 22 events (event rate per 100 patient-years, 2.69 vs. 4.54; aHR, 0.55).

“So those weren’t statistically significant, but those point estimates were very similar to literature,” she said.

All-cause mortality events occurred in 14 versus 37 patients in the SGLT2 and non-SGLT2 inhibitor groups, respectively (event rate per 100 patient-years, 1.61 vs. 3.34; aHR, 0.50), and in 7 versus 13 dapagliflozin patients within these groups, respectively (event rate per 100 patient-years, 1.62 vs. 2.42; aHR, 0.66).

The overall SGLT2 inhibitor all-cause mortality findings were very similar to what was seen in CVD-REAL, a real-world evidence trial which looked at cardiovascular outcomes in new users of SGLT-2 inhibitors, and the differences were statistically significant for the treatment effect.

“For dapagliflozin, the numbers were pretty similar as well. Not statistically significant, because the number of subjects was smaller, but similar,” Dr. Clegg said.

“On eGFR looking at renal function ... subjects not using an SGLT2 inhibitor had about a 1 mL/min per year decline, which is what we would expect for this population. At baseline the median eGFR was about 80, so it’s a fairly healthy population, because exenatide isn’t used in people with poor renal function,” she explained.

The effects of SGLT2 inhibitors overall, and dapagliflozin alone, were associated with the statistically significant increase in the eGFR slope over time – an outcome that the Food and Drug Administration now recognizes as a surrogate endpoint for renal outcomes, she added. “And again, that’s very consistent with what was seen for [the SGLT2 inhibitor empagliflozin] in the literature.”

Empagliflozin and canagliflozin (another SGLT2 inhibitor) have been shown to reduce MACE, all-cause mortality, and renal events in CVOTs, and real-world evidence suggests a class effect benefit, but dapagliflozin CVOT data have not yet been published.

“Overall this was a nice dataset where we had these adjudicated events to look at outcomes with SGLT2 inhibitors and with [dapagliflozin] specifically, and what we see is very encouraging and suggestive of a class effect,” she concluded, noting that findings from the ongoing phase 3 DECLARE-TIMI58 dapagliflozin CVOT should be released later this year.

Dr. Clegg is employed by AstraZeneca. She reported having no other disclosures.

[email protected]

SOURCE: Clegg L et al. ADA 2018, Abstract 130-LB.

ORLANDO – Sodium-glucose transporter 2 inhibitors, including dapagliflozin, have a beneficial class effect on major adverse cardiac events, all-cause mortality, and renal function, a post hoc analysis of data from the EXSCEL trial suggested.

Sharon Worcester/MDedge News

The findings are consistent with those from published cardiovascular outcomes trials (CVOTs) of sodium-glucose transporter 2 (SGLT2) inhibitors other than dapagliflozin, real-world data, and findings from non-CVOTs of dapagliflozin, Lindsay Clegg, PhD, reported in a late-breaking poster at the annual scientific sessions of the American Diabetes Association.

In EXSCEL – a CVOT of once-weekly treatment with the glucagonlike peptide–1 receptor agonist exenatide added to usual care in patients with type 2 diabetes mellitus – 10% of patients took an SGLT2 inhibitor, and about half of those took dapagliflozin. For the current analysis, the effects of all SGLT2 inhibitors and dapagliflozin alone were evaluated in EXSCEL patients who received placebo.

“Just looking at that placebo data, we wanted to ask what the impact of SGLT2 inhibition was on the adjudicated cardiovascular events, as well as all-cause death and eGFR [estimated glomerular filtration rate] in this population,” Dr. Clegg, a postdoctoral fellow with the AstraZeneca Quantitative Clinical Pharmacology Group in Gaithersburg, Md., said in an interview.

In two propensity-matched cohorts, including a cohort of 709 SGLT2 inhibitor users and a cohort of 709 non-SGLT2 inhibitor users, SGLT2 inhibitors and dapagliflozin alone were found to numerically decrease the major adverse cardiac event (MACE) hazard ratio, and SGLT2 inhibitors significantly reduced all-cause mortality risk, she explained.

MACE events – a composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke – occurred in 28 versus 44 patients in the SGLT2 and non-SGLT2 inhibitor groups, respectively (event rate per 100 patient-years, 3.41 vs. 4.45; adjusted HR, 0.79). Dr. Clegg noted that this hazard ratio is “very consistent with what has been seen in the CVOTs for [the SGLT2 inhibitors] empagliflozin and canagliflozin in literature.”

The corresponding figures for dapagliflozin were 11 versus 22 events (event rate per 100 patient-years, 2.69 vs. 4.54; aHR, 0.55).

“So those weren’t statistically significant, but those point estimates were very similar to literature,” she said.

All-cause mortality events occurred in 14 versus 37 patients in the SGLT2 and non-SGLT2 inhibitor groups, respectively (event rate per 100 patient-years, 1.61 vs. 3.34; aHR, 0.50), and in 7 versus 13 dapagliflozin patients within these groups, respectively (event rate per 100 patient-years, 1.62 vs. 2.42; aHR, 0.66).

The overall SGLT2 inhibitor all-cause mortality findings were very similar to what was seen in CVD-REAL, a real-world evidence trial which looked at cardiovascular outcomes in new users of SGLT-2 inhibitors, and the differences were statistically significant for the treatment effect.

“For dapagliflozin, the numbers were pretty similar as well. Not statistically significant, because the number of subjects was smaller, but similar,” Dr. Clegg said.

“On eGFR looking at renal function ... subjects not using an SGLT2 inhibitor had about a 1 mL/min per year decline, which is what we would expect for this population. At baseline the median eGFR was about 80, so it’s a fairly healthy population, because exenatide isn’t used in people with poor renal function,” she explained.

The effects of SGLT2 inhibitors overall, and dapagliflozin alone, were associated with the statistically significant increase in the eGFR slope over time – an outcome that the Food and Drug Administration now recognizes as a surrogate endpoint for renal outcomes, she added. “And again, that’s very consistent with what was seen for [the SGLT2 inhibitor empagliflozin] in the literature.”

Empagliflozin and canagliflozin (another SGLT2 inhibitor) have been shown to reduce MACE, all-cause mortality, and renal events in CVOTs, and real-world evidence suggests a class effect benefit, but dapagliflozin CVOT data have not yet been published.

“Overall this was a nice dataset where we had these adjudicated events to look at outcomes with SGLT2 inhibitors and with [dapagliflozin] specifically, and what we see is very encouraging and suggestive of a class effect,” she concluded, noting that findings from the ongoing phase 3 DECLARE-TIMI58 dapagliflozin CVOT should be released later this year.

Dr. Clegg is employed by AstraZeneca. She reported having no other disclosures.

[email protected]

SOURCE: Clegg L et al. ADA 2018, Abstract 130-LB.

ORLANDO – Sodium-glucose transporter 2 inhibitors, including dapagliflozin, have a beneficial class effect on major adverse cardiac events, all-cause mortality, and renal function, a post hoc analysis of data from the EXSCEL trial suggested.

Sharon Worcester/MDedge News

The findings are consistent with those from published cardiovascular outcomes trials (CVOTs) of sodium-glucose transporter 2 (SGLT2) inhibitors other than dapagliflozin, real-world data, and findings from non-CVOTs of dapagliflozin, Lindsay Clegg, PhD, reported in a late-breaking poster at the annual scientific sessions of the American Diabetes Association.

In EXSCEL – a CVOT of once-weekly treatment with the glucagonlike peptide–1 receptor agonist exenatide added to usual care in patients with type 2 diabetes mellitus – 10% of patients took an SGLT2 inhibitor, and about half of those took dapagliflozin. For the current analysis, the effects of all SGLT2 inhibitors and dapagliflozin alone were evaluated in EXSCEL patients who received placebo.

“Just looking at that placebo data, we wanted to ask what the impact of SGLT2 inhibition was on the adjudicated cardiovascular events, as well as all-cause death and eGFR [estimated glomerular filtration rate] in this population,” Dr. Clegg, a postdoctoral fellow with the AstraZeneca Quantitative Clinical Pharmacology Group in Gaithersburg, Md., said in an interview.

In two propensity-matched cohorts, including a cohort of 709 SGLT2 inhibitor users and a cohort of 709 non-SGLT2 inhibitor users, SGLT2 inhibitors and dapagliflozin alone were found to numerically decrease the major adverse cardiac event (MACE) hazard ratio, and SGLT2 inhibitors significantly reduced all-cause mortality risk, she explained.

MACE events – a composite endpoint of cardiovascular death, nonfatal MI, or nonfatal stroke – occurred in 28 versus 44 patients in the SGLT2 and non-SGLT2 inhibitor groups, respectively (event rate per 100 patient-years, 3.41 vs. 4.45; adjusted HR, 0.79). Dr. Clegg noted that this hazard ratio is “very consistent with what has been seen in the CVOTs for [the SGLT2 inhibitors] empagliflozin and canagliflozin in literature.”

The corresponding figures for dapagliflozin were 11 versus 22 events (event rate per 100 patient-years, 2.69 vs. 4.54; aHR, 0.55).

“So those weren’t statistically significant, but those point estimates were very similar to literature,” she said.

All-cause mortality events occurred in 14 versus 37 patients in the SGLT2 and non-SGLT2 inhibitor groups, respectively (event rate per 100 patient-years, 1.61 vs. 3.34; aHR, 0.50), and in 7 versus 13 dapagliflozin patients within these groups, respectively (event rate per 100 patient-years, 1.62 vs. 2.42; aHR, 0.66).

The overall SGLT2 inhibitor all-cause mortality findings were very similar to what was seen in CVD-REAL, a real-world evidence trial which looked at cardiovascular outcomes in new users of SGLT-2 inhibitors, and the differences were statistically significant for the treatment effect.

“For dapagliflozin, the numbers were pretty similar as well. Not statistically significant, because the number of subjects was smaller, but similar,” Dr. Clegg said.

“On eGFR looking at renal function ... subjects not using an SGLT2 inhibitor had about a 1 mL/min per year decline, which is what we would expect for this population. At baseline the median eGFR was about 80, so it’s a fairly healthy population, because exenatide isn’t used in people with poor renal function,” she explained.

The effects of SGLT2 inhibitors overall, and dapagliflozin alone, were associated with the statistically significant increase in the eGFR slope over time – an outcome that the Food and Drug Administration now recognizes as a surrogate endpoint for renal outcomes, she added. “And again, that’s very consistent with what was seen for [the SGLT2 inhibitor empagliflozin] in the literature.”

Empagliflozin and canagliflozin (another SGLT2 inhibitor) have been shown to reduce MACE, all-cause mortality, and renal events in CVOTs, and real-world evidence suggests a class effect benefit, but dapagliflozin CVOT data have not yet been published.

“Overall this was a nice dataset where we had these adjudicated events to look at outcomes with SGLT2 inhibitors and with [dapagliflozin] specifically, and what we see is very encouraging and suggestive of a class effect,” she concluded, noting that findings from the ongoing phase 3 DECLARE-TIMI58 dapagliflozin CVOT should be released later this year.

Dr. Clegg is employed by AstraZeneca. She reported having no other disclosures.

[email protected]

SOURCE: Clegg L et al. ADA 2018, Abstract 130-LB.

ORLANDO – Initiation of treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor is associated with significantly lower risks of death, cardiovascular events, and stroke, compared with initiation of dipeptidyl peptidase–4 (DPP-4) inhibitor treatment in patients with type 2 diabetes mellitus, according to findings from the CVD-REAL 2 study.

CVD-REAL 2 is a real-world, observational cohort study involving the analysis of health records for two matched cohorts of patients with T2DM from 12 countries across the globe, including 181,620 SGLT-2 inhibitor recipients and 181,620 DPP-4 inhibitor recipients who were newly initiated on their respective treatments between December 2012 and November 2017. The respective rates of all-cause death were 0.83 and 1.33 per 100 patient-years (4,768 events; hazard ratio, 0.51), Shun Kohsaka, MD, of Keio University School of Medicine, Tokyo, and his colleagues reported in a late-breaking poster at the annual scientific sessions of the American Diabetes Association.

“HRs for all-cause death consistently favored SGLT-2 inhibitor vs. DPP-4 inhibitor in each country,” the investigators noted. “Directionally, the same results were observed in other cardiovascular outcomes, including [hospitalization for heart failure (HHF)], and the composite of all-cause death or HHF but modestly for [myocardial infarction] and stroke.”

The rates of hospitalization for heart failure per 100 patient-years were 0.80 and 1.08 in the SGLT-2 inhibitor and DPP-4 inhibitor groups (3,875 events; HR, 0.68), and for HHF plus all-cause death, they were 1.55 and 2.22 per 100 patient-years (7,807 events; HR, 0.67), respectively. The rates of myocardial infarction in the groups, respectively, were 0.53 and 0.58 per 100 patient-years (2,298 events; HR, 0.90), and for stroke, they were 0.82 and 0.99 per 100 patient-years (3,747 events; HR, 0.84), the investigators reported.

Study subjects in both cohorts had a mean age of 58 years, and 30% and 29% in the SGLT-2 inhibitor and DPP-4 inhibitor groups, respectively, had established cardiovascular disease. Only those newly initiated on either an SGLT-2 inhibitor or DPP-4 inhibitor were selected from each data source; fixed-dose combinations were allowed as long as there was no use of either drug during the year prior to enrollment.

In the SGLT-2 inhibitor cohort, most exposures (60.1%) were to dapagliflozin, followed by canagliflozin (23.8%) and empagliflozin (12.1%). The remaining exposures were to ipragliflozin, tofogliflozin, or luseogliflozin (0.3-2.8%). In the DPP-4 inhibitor group, most exposures (49.7%) were to sitagliptin, 18.9% were to linagliptin, 10.4% were to saxagliptin, and the remaining exposures were to alogliptin, gemigliptin, teneligliptin, anagliptin, evogliptin, and trelagliptin (0.1%-4.7%).

Those in the SGLT-2 inhibitor group were followed for a mean of 439 days, and those in the DPP-4 inhibitor group were followed for a mean of 446 days.

“The results were consistent across the subgroups of patients with and without established [cardiovascular disease], favoring SGLT-2 inhibitor vs. DPP-4 inhibitor for all outcomes,” they noted.

Both DPP-4 inhibitors and SGLT2 inhibitors are widely used in T2DM, and although clinical trials demonstrated lower risk of cardiovascular events with SGLT-2 inhibitors and a neutral effect on cardiovascular events with DPP-4 inhibitors, large comparative studies are lacking, the investigators explained.

Though limited by the possibility of residual, unmeasured confounding, as well as by a lack of mortality data in Japan and Singapore apart from the inpatient setting, the findings of this “large, contemporary analysis of real-world administrative data” are complementary to those from previous observational studies and clinical trials, they concluded, noting that “SGLT-2 inhibitor experience in real-world practice is still relatively short and longer-term follow-up is required to examine whether effects are sustained over time.”

The CVD-REAL studies are sponsored by AstraZeneca. Dr. Kohsaka reported receiving research support from Bayer Yakuhin and Daiichi Sankyo and serving on the speaker’s bureau for Bayer Yakuhin and Bristol-Myers Squibb.

[email protected]

SOURCE: Kohsaka S et al. ADA 2018, Abstract 124-LB.

ORLANDO – Initiation of treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor is associated with significantly lower risks of death, cardiovascular events, and stroke, compared with initiation of dipeptidyl peptidase–4 (DPP-4) inhibitor treatment in patients with type 2 diabetes mellitus, according to findings from the CVD-REAL 2 study.

CVD-REAL 2 is a real-world, observational cohort study involving the analysis of health records for two matched cohorts of patients with T2DM from 12 countries across the globe, including 181,620 SGLT-2 inhibitor recipients and 181,620 DPP-4 inhibitor recipients who were newly initiated on their respective treatments between December 2012 and November 2017. The respective rates of all-cause death were 0.83 and 1.33 per 100 patient-years (4,768 events; hazard ratio, 0.51), Shun Kohsaka, MD, of Keio University School of Medicine, Tokyo, and his colleagues reported in a late-breaking poster at the annual scientific sessions of the American Diabetes Association.

“HRs for all-cause death consistently favored SGLT-2 inhibitor vs. DPP-4 inhibitor in each country,” the investigators noted. “Directionally, the same results were observed in other cardiovascular outcomes, including [hospitalization for heart failure (HHF)], and the composite of all-cause death or HHF but modestly for [myocardial infarction] and stroke.”

The rates of hospitalization for heart failure per 100 patient-years were 0.80 and 1.08 in the SGLT-2 inhibitor and DPP-4 inhibitor groups (3,875 events; HR, 0.68), and for HHF plus all-cause death, they were 1.55 and 2.22 per 100 patient-years (7,807 events; HR, 0.67), respectively. The rates of myocardial infarction in the groups, respectively, were 0.53 and 0.58 per 100 patient-years (2,298 events; HR, 0.90), and for stroke, they were 0.82 and 0.99 per 100 patient-years (3,747 events; HR, 0.84), the investigators reported.

Study subjects in both cohorts had a mean age of 58 years, and 30% and 29% in the SGLT-2 inhibitor and DPP-4 inhibitor groups, respectively, had established cardiovascular disease. Only those newly initiated on either an SGLT-2 inhibitor or DPP-4 inhibitor were selected from each data source; fixed-dose combinations were allowed as long as there was no use of either drug during the year prior to enrollment.

In the SGLT-2 inhibitor cohort, most exposures (60.1%) were to dapagliflozin, followed by canagliflozin (23.8%) and empagliflozin (12.1%). The remaining exposures were to ipragliflozin, tofogliflozin, or luseogliflozin (0.3-2.8%). In the DPP-4 inhibitor group, most exposures (49.7%) were to sitagliptin, 18.9% were to linagliptin, 10.4% were to saxagliptin, and the remaining exposures were to alogliptin, gemigliptin, teneligliptin, anagliptin, evogliptin, and trelagliptin (0.1%-4.7%).

Those in the SGLT-2 inhibitor group were followed for a mean of 439 days, and those in the DPP-4 inhibitor group were followed for a mean of 446 days.

“The results were consistent across the subgroups of patients with and without established [cardiovascular disease], favoring SGLT-2 inhibitor vs. DPP-4 inhibitor for all outcomes,” they noted.

Both DPP-4 inhibitors and SGLT2 inhibitors are widely used in T2DM, and although clinical trials demonstrated lower risk of cardiovascular events with SGLT-2 inhibitors and a neutral effect on cardiovascular events with DPP-4 inhibitors, large comparative studies are lacking, the investigators explained.

Though limited by the possibility of residual, unmeasured confounding, as well as by a lack of mortality data in Japan and Singapore apart from the inpatient setting, the findings of this “large, contemporary analysis of real-world administrative data” are complementary to those from previous observational studies and clinical trials, they concluded, noting that “SGLT-2 inhibitor experience in real-world practice is still relatively short and longer-term follow-up is required to examine whether effects are sustained over time.”

The CVD-REAL studies are sponsored by AstraZeneca. Dr. Kohsaka reported receiving research support from Bayer Yakuhin and Daiichi Sankyo and serving on the speaker’s bureau for Bayer Yakuhin and Bristol-Myers Squibb.

[email protected]

SOURCE: Kohsaka S et al. ADA 2018, Abstract 124-LB.

ORLANDO – Initiation of treatment with a sodium-glucose cotransporter 2 (SGLT2) inhibitor is associated with significantly lower risks of death, cardiovascular events, and stroke, compared with initiation of dipeptidyl peptidase–4 (DPP-4) inhibitor treatment in patients with type 2 diabetes mellitus, according to findings from the CVD-REAL 2 study.

CVD-REAL 2 is a real-world, observational cohort study involving the analysis of health records for two matched cohorts of patients with T2DM from 12 countries across the globe, including 181,620 SGLT-2 inhibitor recipients and 181,620 DPP-4 inhibitor recipients who were newly initiated on their respective treatments between December 2012 and November 2017. The respective rates of all-cause death were 0.83 and 1.33 per 100 patient-years (4,768 events; hazard ratio, 0.51), Shun Kohsaka, MD, of Keio University School of Medicine, Tokyo, and his colleagues reported in a late-breaking poster at the annual scientific sessions of the American Diabetes Association.

“HRs for all-cause death consistently favored SGLT-2 inhibitor vs. DPP-4 inhibitor in each country,” the investigators noted. “Directionally, the same results were observed in other cardiovascular outcomes, including [hospitalization for heart failure (HHF)], and the composite of all-cause death or HHF but modestly for [myocardial infarction] and stroke.”

The rates of hospitalization for heart failure per 100 patient-years were 0.80 and 1.08 in the SGLT-2 inhibitor and DPP-4 inhibitor groups (3,875 events; HR, 0.68), and for HHF plus all-cause death, they were 1.55 and 2.22 per 100 patient-years (7,807 events; HR, 0.67), respectively. The rates of myocardial infarction in the groups, respectively, were 0.53 and 0.58 per 100 patient-years (2,298 events; HR, 0.90), and for stroke, they were 0.82 and 0.99 per 100 patient-years (3,747 events; HR, 0.84), the investigators reported.

Study subjects in both cohorts had a mean age of 58 years, and 30% and 29% in the SGLT-2 inhibitor and DPP-4 inhibitor groups, respectively, had established cardiovascular disease. Only those newly initiated on either an SGLT-2 inhibitor or DPP-4 inhibitor were selected from each data source; fixed-dose combinations were allowed as long as there was no use of either drug during the year prior to enrollment.

In the SGLT-2 inhibitor cohort, most exposures (60.1%) were to dapagliflozin, followed by canagliflozin (23.8%) and empagliflozin (12.1%). The remaining exposures were to ipragliflozin, tofogliflozin, or luseogliflozin (0.3-2.8%). In the DPP-4 inhibitor group, most exposures (49.7%) were to sitagliptin, 18.9% were to linagliptin, 10.4% were to saxagliptin, and the remaining exposures were to alogliptin, gemigliptin, teneligliptin, anagliptin, evogliptin, and trelagliptin (0.1%-4.7%).

Those in the SGLT-2 inhibitor group were followed for a mean of 439 days, and those in the DPP-4 inhibitor group were followed for a mean of 446 days.

“The results were consistent across the subgroups of patients with and without established [cardiovascular disease], favoring SGLT-2 inhibitor vs. DPP-4 inhibitor for all outcomes,” they noted.

Both DPP-4 inhibitors and SGLT2 inhibitors are widely used in T2DM, and although clinical trials demonstrated lower risk of cardiovascular events with SGLT-2 inhibitors and a neutral effect on cardiovascular events with DPP-4 inhibitors, large comparative studies are lacking, the investigators explained.

Though limited by the possibility of residual, unmeasured confounding, as well as by a lack of mortality data in Japan and Singapore apart from the inpatient setting, the findings of this “large, contemporary analysis of real-world administrative data” are complementary to those from previous observational studies and clinical trials, they concluded, noting that “SGLT-2 inhibitor experience in real-world practice is still relatively short and longer-term follow-up is required to examine whether effects are sustained over time.”

The CVD-REAL studies are sponsored by AstraZeneca. Dr. Kohsaka reported receiving research support from Bayer Yakuhin and Daiichi Sankyo and serving on the speaker’s bureau for Bayer Yakuhin and Bristol-Myers Squibb.

[email protected]

SOURCE: Kohsaka S et al. ADA 2018, Abstract 124-LB.