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Whatever the substance, adolescents’ abuse shares common links
SAN DIEGO – Among adolescent daily cigarette smokers, the individual and concomitant use of alcohol, marijuana, and tobacco have unique and common associations with reinforcement sensitivity, with negative affect, and with electrophysiological signatures of reward function, results from a novel study demonstrated.
“The co-use of alcohol, marijuana, and tobacco in youth are associated bidirectionally with higher rates of substance use, higher levels of addiction severity, and with poorer treatment outcomes for youth who present for treatment,” lead study author Christopher J. Hammond, MD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
Currently, the effects of combined alcohol, marijuana, and tobacco use on brain function are poorly understood, noted Dr. Hammond of the division of child and adolescent psychiatry at Johns Hopkins Bayview Medical Center, Baltimore.
Published studies to date suggest that alcohol, marijuana, and tobacco use disorders are linked separately to dysfunction in the neural substrates of reward and punishment processing, but none has examined co-use or comorbid disorders in adolescents.
In a cross-sectional, single-visit study, Dr. Hammond and his associates examined a population of 36 adolescent non-deprived daily cigarette smokers and 29 healthy controls from the greater New Haven, Conn., area, matched for age, gender, and grade level. The subjects ranged in age from 14 to 20 years and were administered self-report measures characterizing tobacco, marijuana, and alcohol use. The researchers also collected urine and breathalyzer measures to characterize tobacco and cannabis use.
All subjects completed a number of self-report questionnaires characterizing their substance use patterns, their addiction severity, impulsivity, sensitivity to reward and punishment, and depression. They also underwent a 45-minute EEG, during which they completed a resting EEG test and completed a reward task.
The adolescent daily cigarette smoker group had blunted or decreased sensitivity to punishment and increased impulsivity, compared with the healthy controls, Dr. Hammond reported.
Co-occurring drug use was high in the adolescent daily smoker group, with 80% reporting heavy marijuana use (defined as using it over 100 times during adolescence), and 67% reporting heavy episodic binge drinking (defined as consuming greater than four alcoholic beverages for females during one sitting and greater than five for males at least two or more times a month).
One out of two of the daily cigarette smokers were also daily marijuana smokers, and about 75% of the adolescent smokers had a positive urine drug screen for marijuana. They smoked an average of eight cigarettes per day, used cannabis about 17 days out of the month, and they had about 1.5 binge drinking episodes per month.
Next, the researchers used linear regression analyses to examine which of the psychological variables were associated with alcohol, marijuana, and tobacco use severity within the smoker group, after co-varying for age, gender, race/ethnicity, and full-scale IQ.
“For alcohol use, we found that depression, sensitivity to reward, and impulsivity were significantly associated with alcohol problem severity scores, even after controlling for sociodemographics and other drug use (P less than .05),” Dr. Hammond said.
“For marijuana use, we found that sensitivity to reward and impulsivity were significantly associated with cannabis problem severity, even after controlling for demographics and alcohol and other drug use (P less than .01),” he continued. “For tobacco use, we found that anxiety sensitivity was significantly associated with nicotine dependence scores, even after controlling for demographics and alcohol and marijuana use (P less than .001).”
On EEG analyses, the researchers found no main effects for group or group by condition for the feedback-related negativity (FRN) signal or for the event-related Theta oscillation between the adolescent non-deprived smokers and the healthy controls.
However, examination of the smoker subgroups revealed a unique and shared association between alcohol, marijuana, and tobacco and the EEG signals.
“With regard to substance use associations with the FRN smokers, regression analyses showed that cannabis use problem severity was associated with an increased FRN amplitude during the reward condition only,” Dr. Hammond said. “This finding remained significant after co-varying for demographics, for other drug use, for nicotine dependence and alcohol severity as well.
“We also found an association between alcohol problem severity and mean FRN amplitude, but with no differences across conditions,” he added. There was an association also “ between nicotine dependence and decreased FRN latency, but only during the reward and draw conditions, suggesting a nicotine severity association with speed of processing salient reward and stimuli.”
While the findings need to be better studied and replicated, “these associations may be leveraged to better personalize our interventions for these different substances of abuse,” Dr. Hammond observed. “The study also provides preliminary evidence for a dual-process model of substance use, specifically for cannabis. Cannabis severity in adolescent smokers is associated with increased bottom-up reward signaling and impaired top-down cognitive control over a salient or rewarding stimulus.”
The study was supported by the American Academy of Child and Adolescent Psychiatry and the National Institute on Drug Abuse. Dr. Hammond disclosed that he receives research funding from both organizations.
SOURCE: Hammond et al. AAAP 2017. Paper session A3.
SAN DIEGO – Among adolescent daily cigarette smokers, the individual and concomitant use of alcohol, marijuana, and tobacco have unique and common associations with reinforcement sensitivity, with negative affect, and with electrophysiological signatures of reward function, results from a novel study demonstrated.
“The co-use of alcohol, marijuana, and tobacco in youth are associated bidirectionally with higher rates of substance use, higher levels of addiction severity, and with poorer treatment outcomes for youth who present for treatment,” lead study author Christopher J. Hammond, MD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
Currently, the effects of combined alcohol, marijuana, and tobacco use on brain function are poorly understood, noted Dr. Hammond of the division of child and adolescent psychiatry at Johns Hopkins Bayview Medical Center, Baltimore.
Published studies to date suggest that alcohol, marijuana, and tobacco use disorders are linked separately to dysfunction in the neural substrates of reward and punishment processing, but none has examined co-use or comorbid disorders in adolescents.
In a cross-sectional, single-visit study, Dr. Hammond and his associates examined a population of 36 adolescent non-deprived daily cigarette smokers and 29 healthy controls from the greater New Haven, Conn., area, matched for age, gender, and grade level. The subjects ranged in age from 14 to 20 years and were administered self-report measures characterizing tobacco, marijuana, and alcohol use. The researchers also collected urine and breathalyzer measures to characterize tobacco and cannabis use.
All subjects completed a number of self-report questionnaires characterizing their substance use patterns, their addiction severity, impulsivity, sensitivity to reward and punishment, and depression. They also underwent a 45-minute EEG, during which they completed a resting EEG test and completed a reward task.
The adolescent daily cigarette smoker group had blunted or decreased sensitivity to punishment and increased impulsivity, compared with the healthy controls, Dr. Hammond reported.
Co-occurring drug use was high in the adolescent daily smoker group, with 80% reporting heavy marijuana use (defined as using it over 100 times during adolescence), and 67% reporting heavy episodic binge drinking (defined as consuming greater than four alcoholic beverages for females during one sitting and greater than five for males at least two or more times a month).
One out of two of the daily cigarette smokers were also daily marijuana smokers, and about 75% of the adolescent smokers had a positive urine drug screen for marijuana. They smoked an average of eight cigarettes per day, used cannabis about 17 days out of the month, and they had about 1.5 binge drinking episodes per month.
Next, the researchers used linear regression analyses to examine which of the psychological variables were associated with alcohol, marijuana, and tobacco use severity within the smoker group, after co-varying for age, gender, race/ethnicity, and full-scale IQ.
“For alcohol use, we found that depression, sensitivity to reward, and impulsivity were significantly associated with alcohol problem severity scores, even after controlling for sociodemographics and other drug use (P less than .05),” Dr. Hammond said.
“For marijuana use, we found that sensitivity to reward and impulsivity were significantly associated with cannabis problem severity, even after controlling for demographics and alcohol and other drug use (P less than .01),” he continued. “For tobacco use, we found that anxiety sensitivity was significantly associated with nicotine dependence scores, even after controlling for demographics and alcohol and marijuana use (P less than .001).”
On EEG analyses, the researchers found no main effects for group or group by condition for the feedback-related negativity (FRN) signal or for the event-related Theta oscillation between the adolescent non-deprived smokers and the healthy controls.
However, examination of the smoker subgroups revealed a unique and shared association between alcohol, marijuana, and tobacco and the EEG signals.
“With regard to substance use associations with the FRN smokers, regression analyses showed that cannabis use problem severity was associated with an increased FRN amplitude during the reward condition only,” Dr. Hammond said. “This finding remained significant after co-varying for demographics, for other drug use, for nicotine dependence and alcohol severity as well.
“We also found an association between alcohol problem severity and mean FRN amplitude, but with no differences across conditions,” he added. There was an association also “ between nicotine dependence and decreased FRN latency, but only during the reward and draw conditions, suggesting a nicotine severity association with speed of processing salient reward and stimuli.”
While the findings need to be better studied and replicated, “these associations may be leveraged to better personalize our interventions for these different substances of abuse,” Dr. Hammond observed. “The study also provides preliminary evidence for a dual-process model of substance use, specifically for cannabis. Cannabis severity in adolescent smokers is associated with increased bottom-up reward signaling and impaired top-down cognitive control over a salient or rewarding stimulus.”
The study was supported by the American Academy of Child and Adolescent Psychiatry and the National Institute on Drug Abuse. Dr. Hammond disclosed that he receives research funding from both organizations.
SOURCE: Hammond et al. AAAP 2017. Paper session A3.
SAN DIEGO – Among adolescent daily cigarette smokers, the individual and concomitant use of alcohol, marijuana, and tobacco have unique and common associations with reinforcement sensitivity, with negative affect, and with electrophysiological signatures of reward function, results from a novel study demonstrated.
“The co-use of alcohol, marijuana, and tobacco in youth are associated bidirectionally with higher rates of substance use, higher levels of addiction severity, and with poorer treatment outcomes for youth who present for treatment,” lead study author Christopher J. Hammond, MD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
Currently, the effects of combined alcohol, marijuana, and tobacco use on brain function are poorly understood, noted Dr. Hammond of the division of child and adolescent psychiatry at Johns Hopkins Bayview Medical Center, Baltimore.
Published studies to date suggest that alcohol, marijuana, and tobacco use disorders are linked separately to dysfunction in the neural substrates of reward and punishment processing, but none has examined co-use or comorbid disorders in adolescents.
In a cross-sectional, single-visit study, Dr. Hammond and his associates examined a population of 36 adolescent non-deprived daily cigarette smokers and 29 healthy controls from the greater New Haven, Conn., area, matched for age, gender, and grade level. The subjects ranged in age from 14 to 20 years and were administered self-report measures characterizing tobacco, marijuana, and alcohol use. The researchers also collected urine and breathalyzer measures to characterize tobacco and cannabis use.
All subjects completed a number of self-report questionnaires characterizing their substance use patterns, their addiction severity, impulsivity, sensitivity to reward and punishment, and depression. They also underwent a 45-minute EEG, during which they completed a resting EEG test and completed a reward task.
The adolescent daily cigarette smoker group had blunted or decreased sensitivity to punishment and increased impulsivity, compared with the healthy controls, Dr. Hammond reported.
Co-occurring drug use was high in the adolescent daily smoker group, with 80% reporting heavy marijuana use (defined as using it over 100 times during adolescence), and 67% reporting heavy episodic binge drinking (defined as consuming greater than four alcoholic beverages for females during one sitting and greater than five for males at least two or more times a month).
One out of two of the daily cigarette smokers were also daily marijuana smokers, and about 75% of the adolescent smokers had a positive urine drug screen for marijuana. They smoked an average of eight cigarettes per day, used cannabis about 17 days out of the month, and they had about 1.5 binge drinking episodes per month.
Next, the researchers used linear regression analyses to examine which of the psychological variables were associated with alcohol, marijuana, and tobacco use severity within the smoker group, after co-varying for age, gender, race/ethnicity, and full-scale IQ.
“For alcohol use, we found that depression, sensitivity to reward, and impulsivity were significantly associated with alcohol problem severity scores, even after controlling for sociodemographics and other drug use (P less than .05),” Dr. Hammond said.
“For marijuana use, we found that sensitivity to reward and impulsivity were significantly associated with cannabis problem severity, even after controlling for demographics and alcohol and other drug use (P less than .01),” he continued. “For tobacco use, we found that anxiety sensitivity was significantly associated with nicotine dependence scores, even after controlling for demographics and alcohol and marijuana use (P less than .001).”
On EEG analyses, the researchers found no main effects for group or group by condition for the feedback-related negativity (FRN) signal or for the event-related Theta oscillation between the adolescent non-deprived smokers and the healthy controls.
However, examination of the smoker subgroups revealed a unique and shared association between alcohol, marijuana, and tobacco and the EEG signals.
“With regard to substance use associations with the FRN smokers, regression analyses showed that cannabis use problem severity was associated with an increased FRN amplitude during the reward condition only,” Dr. Hammond said. “This finding remained significant after co-varying for demographics, for other drug use, for nicotine dependence and alcohol severity as well.
“We also found an association between alcohol problem severity and mean FRN amplitude, but with no differences across conditions,” he added. There was an association also “ between nicotine dependence and decreased FRN latency, but only during the reward and draw conditions, suggesting a nicotine severity association with speed of processing salient reward and stimuli.”
While the findings need to be better studied and replicated, “these associations may be leveraged to better personalize our interventions for these different substances of abuse,” Dr. Hammond observed. “The study also provides preliminary evidence for a dual-process model of substance use, specifically for cannabis. Cannabis severity in adolescent smokers is associated with increased bottom-up reward signaling and impaired top-down cognitive control over a salient or rewarding stimulus.”
The study was supported by the American Academy of Child and Adolescent Psychiatry and the National Institute on Drug Abuse. Dr. Hammond disclosed that he receives research funding from both organizations.
SOURCE: Hammond et al. AAAP 2017. Paper session A3.
REPORTING FROM AAAP
Key clinical point:
Major finding: Among adolescents who smoked cigarettes daily, 80% reported co-occurring heavy marijuana use, and 67% reported heavy episodic binge drinking.
Study details: A cross-sectional, single visit study of 36 adolescent nondeprived daily cigarette smokers and 29 healthy, age-matched controls.
Disclosures: The study was supported by the American Academy of Child and Adolescent Psychiatry and the National Institute on Drug Abuse. Dr. Hammond disclosed that he receives research funding from both organizations.
Source: Hammond et al. AAAP 2017. Paper session A3.
FDA clears assay for myeloma patients
The US Food and Drug Administration (FDA) has granted 510(k) clearance for Sebia’s Hydrashift 2/4 daratumumab immunofixation assay.
This in vitro diagnostic test allows for assessment of response in patients with multiple myeloma by mitigating potential interference caused by the anti-CD38 antibody daratumumab (Darzalex®).
Daratumumab can interfere with the visualization of M-proteins in immunofixation electrophoresis.
The Hydrashift 2/4 daratumumab assay is intended to be used with Sebia’s Hydragel IF kit to provide qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis.
The assay is performed on Sebia’s Hydrasys 2 agarose gel platform.
The Hydrashift 2/4 daratumumab assay is the result of a collaboration between Sebia and Janssen Biotech, Inc. Sebia received development rights from Janssen and is the worldwide supplier of this assay.
The Hydrashift 2/4 daratumumab assay received the CE mark in November 2016. 
The US Food and Drug Administration (FDA) has granted 510(k) clearance for Sebia’s Hydrashift 2/4 daratumumab immunofixation assay.
This in vitro diagnostic test allows for assessment of response in patients with multiple myeloma by mitigating potential interference caused by the anti-CD38 antibody daratumumab (Darzalex®).
Daratumumab can interfere with the visualization of M-proteins in immunofixation electrophoresis.
The Hydrashift 2/4 daratumumab assay is intended to be used with Sebia’s Hydragel IF kit to provide qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis.
The assay is performed on Sebia’s Hydrasys 2 agarose gel platform.
The Hydrashift 2/4 daratumumab assay is the result of a collaboration between Sebia and Janssen Biotech, Inc. Sebia received development rights from Janssen and is the worldwide supplier of this assay.
The Hydrashift 2/4 daratumumab assay received the CE mark in November 2016.
The US Food and Drug Administration (FDA) has granted 510(k) clearance for Sebia’s Hydrashift 2/4 daratumumab immunofixation assay.
This in vitro diagnostic test allows for assessment of response in patients with multiple myeloma by mitigating potential interference caused by the anti-CD38 antibody daratumumab (Darzalex®).
Daratumumab can interfere with the visualization of M-proteins in immunofixation electrophoresis.
The Hydrashift 2/4 daratumumab assay is intended to be used with Sebia’s Hydragel IF kit to provide qualitative detection of monoclonal proteins in human serum by immunofixation electrophoresis.
The assay is performed on Sebia’s Hydrasys 2 agarose gel platform.
The Hydrashift 2/4 daratumumab assay is the result of a collaboration between Sebia and Janssen Biotech, Inc. Sebia received development rights from Janssen and is the worldwide supplier of this assay.
The Hydrashift 2/4 daratumumab assay received the CE mark in November 2016.
How to prioritize CVD reduction in type 2 diabetes
LOS ANGELES – In the opinion of Mikhail N. Kosiborod, MD, the paradigm of treating patients with type 2 diabetes should shift from a narrow focus on hemoglobin A1c control to a broader strategy of reducing cardiovascular risk.
“We already know that the number one killer of patients with diabetes is cardiovascular disease, and we already know that lowering HbA1c as a general strategy does not substantially lower the risk of most important CVD events,” Dr. Kosiborod, a cardiologist at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
Physicians know that some medications lower the risk of cardiovascular events – including cardiovascular death – substantially, and other drugs don’t. “The bottom line is that we are not talking about ignoring HbA1c, but it’s how you get there that’s important – how you do it and in whom,” Dr. Kosiborod explained.
He pointed to a meta-analysis of four large diabetes trials involving 27,049 participants and 2,370 major vascular events (Diabetologia. 2009 Nov;52[11]:2288-98). It found that the general strategy of targeting more-intensive glucose lowering modestly reduced nonfatal myocardial infarction and increased major hypoglycemia over 4.4 years in people with type 2 diabetes – yet there was no difference in the effect of intensive glucose control on cardiovascular death or hospitalization for heart failure.
“Some point to the benefit of glucose control on the risk of nonfatal myocardial infarction, but that’s a modest benefit,” he said. “It’s observed beyond the randomization phase of clinical trials and takes many years to see it. It’s a large, very long-term investment for a modest reduction in MI risk, with no benefit in death or heart failure. So, when you test intensive glucose control as a general strategy, it has not been successful in reducing cardiovascular complications of type 2 diabetes.”
However, there is now evidence that specific classes of medications, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for glucose lowering in type 2 diabetes, can significantly reduce cardiovascular risk within a relatively short time frame.
In EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), the first trial to demonstrate such benefits, all patients had established CVD, compared with 67% of patients in CANVAS (Canagliflozin Cardiovascular Assessment Study), a second RCT program to report cardiovascular outcomes with SGLT2 inhibitors. In the meantime, about 15%-20% of patients in real-world clinical practice have established CVD.
This led Dr. Kosiborod and his associates to launch CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors), a real-world comparative effectiveness study that evaluated hospitalization for heart failure and total mortality among new users of SGLT2 inhibitors, compared with other glucose-lowering drugs.
In all, 154,528 patients in six countries were initiated on an SGLT2 inhibitor, and 154,528 were initiated on other glucose-lowering drugs (Circulation. 2017 May 18. doi: 10/1161/circulationaha.117.029190). The greatest exposure time was observed from canagliflozin (53%) followed by dapagliflozin (42%) and empagliflozin (5%).
The pooled analysis showed that initiation of SGLT2 inhibitors was associated with a significantly lower risk of heart failure events, compared with other glucose-lowering drugs (risk ratio, 0.61; P less than .001). The researchers observed an overall 39% lower risk of heart failure hospitalization, 51% reduction in total death, and 46% reduction in the composite of heart failure hospitalization or death.
“There was no heterogeneity across countries, despite the fact that the health care systems were very different and the prescribing patterns were very different,” he said.
Dr. Kosiborod, who is also professor of medicine at the University of Missouri-Kansas City, noted that 13% of patients from CVD-REAL had established CVD, while 87% did not. When comparing the results within these two key subgroups, “what’s striking is the difference in event rates, stratified by treatment allocation,” he said of the unpublished data.
“If you look at the composite outcome of heart failure or death, you see an almost seven-fold difference in annualized event rates – about 7% per year in patients with established CVD, compared with about 1% per year in the primary prevention cohort,” he explained. “But the relative risk reduction associated with SGLT2 inhibitors versus other glucose-lowering drugs is identical across both patient groups. That’s a good lesson in epidemiology: You can have patients with dramatically different absolute risks, dramatically different absolute risk reductions, and therefore dramatically different numbers needed to treat, but identical relative risk reductions.”
Dr. Kosiborod also pointed out that heart failure is emerging as one of the most important outcomes in trials patents with type 2 diabetes.
“That’s because people with diabetes who develop heart failure have very poor outcomes,” he said. “Among elderly patients with type 2 diabetes who develop new heart failure, there’s less than 25% survival at 5 years. That’s the reason, I think, that if you really want to impact survival and complication rates in people with diabetes, preventing and treating heart failure is one of the surest ways of doing so.
“You shouldn’t just think of the patient in front of you as someone who has an A1c of 7%, 8%, or 9%,” he cautioned. “You should also start thinking of where the patient is on the spectrum of cardiovascular disease, all the way from CVD risk factors only to symptomatic heart failure.”
Some evidence already exists to help clinicians make treatment decisions based on where the patients fall on that spectrum, he continued.
For example, clinical trials have demonstrated that in patients with established atherosclerotic cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors can reduce the risk of cardiovascular events, including, in some cases, cardiovascular death.
“We don’t have a lot of data demonstrating benefit for patients with recent acute coronary syndrome,” he said. “Some compounds have proven to be neutral, but none has been proven to save lives in this patient group.
“Now, we also have data for people with prior stroke that pioglitazone may be beneficial in managing those patients to prevent recurrent stroke and MI, based on the recent IRIS Trial, provided they don’t have heart failure at baseline,” Dr. Kosiborod added. “We don’t have definitive data yet in people with established heart failure, but those studies are ongoing.”
Dr. Kosiborod disclosed that he is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Glytec, GSK, Intarcia, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and ZS Pharma. He has also received research grants from AstraZeneca and Boehringer Ingelheim.
LOS ANGELES – In the opinion of Mikhail N. Kosiborod, MD, the paradigm of treating patients with type 2 diabetes should shift from a narrow focus on hemoglobin A1c control to a broader strategy of reducing cardiovascular risk.
“We already know that the number one killer of patients with diabetes is cardiovascular disease, and we already know that lowering HbA1c as a general strategy does not substantially lower the risk of most important CVD events,” Dr. Kosiborod, a cardiologist at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
Physicians know that some medications lower the risk of cardiovascular events – including cardiovascular death – substantially, and other drugs don’t. “The bottom line is that we are not talking about ignoring HbA1c, but it’s how you get there that’s important – how you do it and in whom,” Dr. Kosiborod explained.
He pointed to a meta-analysis of four large diabetes trials involving 27,049 participants and 2,370 major vascular events (Diabetologia. 2009 Nov;52[11]:2288-98). It found that the general strategy of targeting more-intensive glucose lowering modestly reduced nonfatal myocardial infarction and increased major hypoglycemia over 4.4 years in people with type 2 diabetes – yet there was no difference in the effect of intensive glucose control on cardiovascular death or hospitalization for heart failure.
“Some point to the benefit of glucose control on the risk of nonfatal myocardial infarction, but that’s a modest benefit,” he said. “It’s observed beyond the randomization phase of clinical trials and takes many years to see it. It’s a large, very long-term investment for a modest reduction in MI risk, with no benefit in death or heart failure. So, when you test intensive glucose control as a general strategy, it has not been successful in reducing cardiovascular complications of type 2 diabetes.”
However, there is now evidence that specific classes of medications, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for glucose lowering in type 2 diabetes, can significantly reduce cardiovascular risk within a relatively short time frame.
In EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), the first trial to demonstrate such benefits, all patients had established CVD, compared with 67% of patients in CANVAS (Canagliflozin Cardiovascular Assessment Study), a second RCT program to report cardiovascular outcomes with SGLT2 inhibitors. In the meantime, about 15%-20% of patients in real-world clinical practice have established CVD.
This led Dr. Kosiborod and his associates to launch CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors), a real-world comparative effectiveness study that evaluated hospitalization for heart failure and total mortality among new users of SGLT2 inhibitors, compared with other glucose-lowering drugs.
In all, 154,528 patients in six countries were initiated on an SGLT2 inhibitor, and 154,528 were initiated on other glucose-lowering drugs (Circulation. 2017 May 18. doi: 10/1161/circulationaha.117.029190). The greatest exposure time was observed from canagliflozin (53%) followed by dapagliflozin (42%) and empagliflozin (5%).
The pooled analysis showed that initiation of SGLT2 inhibitors was associated with a significantly lower risk of heart failure events, compared with other glucose-lowering drugs (risk ratio, 0.61; P less than .001). The researchers observed an overall 39% lower risk of heart failure hospitalization, 51% reduction in total death, and 46% reduction in the composite of heart failure hospitalization or death.
“There was no heterogeneity across countries, despite the fact that the health care systems were very different and the prescribing patterns were very different,” he said.
Dr. Kosiborod, who is also professor of medicine at the University of Missouri-Kansas City, noted that 13% of patients from CVD-REAL had established CVD, while 87% did not. When comparing the results within these two key subgroups, “what’s striking is the difference in event rates, stratified by treatment allocation,” he said of the unpublished data.
“If you look at the composite outcome of heart failure or death, you see an almost seven-fold difference in annualized event rates – about 7% per year in patients with established CVD, compared with about 1% per year in the primary prevention cohort,” he explained. “But the relative risk reduction associated with SGLT2 inhibitors versus other glucose-lowering drugs is identical across both patient groups. That’s a good lesson in epidemiology: You can have patients with dramatically different absolute risks, dramatically different absolute risk reductions, and therefore dramatically different numbers needed to treat, but identical relative risk reductions.”
Dr. Kosiborod also pointed out that heart failure is emerging as one of the most important outcomes in trials patents with type 2 diabetes.
“That’s because people with diabetes who develop heart failure have very poor outcomes,” he said. “Among elderly patients with type 2 diabetes who develop new heart failure, there’s less than 25% survival at 5 years. That’s the reason, I think, that if you really want to impact survival and complication rates in people with diabetes, preventing and treating heart failure is one of the surest ways of doing so.
“You shouldn’t just think of the patient in front of you as someone who has an A1c of 7%, 8%, or 9%,” he cautioned. “You should also start thinking of where the patient is on the spectrum of cardiovascular disease, all the way from CVD risk factors only to symptomatic heart failure.”
Some evidence already exists to help clinicians make treatment decisions based on where the patients fall on that spectrum, he continued.
For example, clinical trials have demonstrated that in patients with established atherosclerotic cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors can reduce the risk of cardiovascular events, including, in some cases, cardiovascular death.
“We don’t have a lot of data demonstrating benefit for patients with recent acute coronary syndrome,” he said. “Some compounds have proven to be neutral, but none has been proven to save lives in this patient group.
“Now, we also have data for people with prior stroke that pioglitazone may be beneficial in managing those patients to prevent recurrent stroke and MI, based on the recent IRIS Trial, provided they don’t have heart failure at baseline,” Dr. Kosiborod added. “We don’t have definitive data yet in people with established heart failure, but those studies are ongoing.”
Dr. Kosiborod disclosed that he is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Glytec, GSK, Intarcia, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and ZS Pharma. He has also received research grants from AstraZeneca and Boehringer Ingelheim.
LOS ANGELES – In the opinion of Mikhail N. Kosiborod, MD, the paradigm of treating patients with type 2 diabetes should shift from a narrow focus on hemoglobin A1c control to a broader strategy of reducing cardiovascular risk.
“We already know that the number one killer of patients with diabetes is cardiovascular disease, and we already know that lowering HbA1c as a general strategy does not substantially lower the risk of most important CVD events,” Dr. Kosiborod, a cardiologist at Saint Luke’s Mid-America Heart Institute, Kansas City, Mo., said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.
Physicians know that some medications lower the risk of cardiovascular events – including cardiovascular death – substantially, and other drugs don’t. “The bottom line is that we are not talking about ignoring HbA1c, but it’s how you get there that’s important – how you do it and in whom,” Dr. Kosiborod explained.
He pointed to a meta-analysis of four large diabetes trials involving 27,049 participants and 2,370 major vascular events (Diabetologia. 2009 Nov;52[11]:2288-98). It found that the general strategy of targeting more-intensive glucose lowering modestly reduced nonfatal myocardial infarction and increased major hypoglycemia over 4.4 years in people with type 2 diabetes – yet there was no difference in the effect of intensive glucose control on cardiovascular death or hospitalization for heart failure.
“Some point to the benefit of glucose control on the risk of nonfatal myocardial infarction, but that’s a modest benefit,” he said. “It’s observed beyond the randomization phase of clinical trials and takes many years to see it. It’s a large, very long-term investment for a modest reduction in MI risk, with no benefit in death or heart failure. So, when you test intensive glucose control as a general strategy, it has not been successful in reducing cardiovascular complications of type 2 diabetes.”
However, there is now evidence that specific classes of medications, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, initially developed for glucose lowering in type 2 diabetes, can significantly reduce cardiovascular risk within a relatively short time frame.
In EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), the first trial to demonstrate such benefits, all patients had established CVD, compared with 67% of patients in CANVAS (Canagliflozin Cardiovascular Assessment Study), a second RCT program to report cardiovascular outcomes with SGLT2 inhibitors. In the meantime, about 15%-20% of patients in real-world clinical practice have established CVD.
This led Dr. Kosiborod and his associates to launch CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT2 Inhibitors), a real-world comparative effectiveness study that evaluated hospitalization for heart failure and total mortality among new users of SGLT2 inhibitors, compared with other glucose-lowering drugs.
In all, 154,528 patients in six countries were initiated on an SGLT2 inhibitor, and 154,528 were initiated on other glucose-lowering drugs (Circulation. 2017 May 18. doi: 10/1161/circulationaha.117.029190). The greatest exposure time was observed from canagliflozin (53%) followed by dapagliflozin (42%) and empagliflozin (5%).
The pooled analysis showed that initiation of SGLT2 inhibitors was associated with a significantly lower risk of heart failure events, compared with other glucose-lowering drugs (risk ratio, 0.61; P less than .001). The researchers observed an overall 39% lower risk of heart failure hospitalization, 51% reduction in total death, and 46% reduction in the composite of heart failure hospitalization or death.
“There was no heterogeneity across countries, despite the fact that the health care systems were very different and the prescribing patterns were very different,” he said.
Dr. Kosiborod, who is also professor of medicine at the University of Missouri-Kansas City, noted that 13% of patients from CVD-REAL had established CVD, while 87% did not. When comparing the results within these two key subgroups, “what’s striking is the difference in event rates, stratified by treatment allocation,” he said of the unpublished data.
“If you look at the composite outcome of heart failure or death, you see an almost seven-fold difference in annualized event rates – about 7% per year in patients with established CVD, compared with about 1% per year in the primary prevention cohort,” he explained. “But the relative risk reduction associated with SGLT2 inhibitors versus other glucose-lowering drugs is identical across both patient groups. That’s a good lesson in epidemiology: You can have patients with dramatically different absolute risks, dramatically different absolute risk reductions, and therefore dramatically different numbers needed to treat, but identical relative risk reductions.”
Dr. Kosiborod also pointed out that heart failure is emerging as one of the most important outcomes in trials patents with type 2 diabetes.
“That’s because people with diabetes who develop heart failure have very poor outcomes,” he said. “Among elderly patients with type 2 diabetes who develop new heart failure, there’s less than 25% survival at 5 years. That’s the reason, I think, that if you really want to impact survival and complication rates in people with diabetes, preventing and treating heart failure is one of the surest ways of doing so.
“You shouldn’t just think of the patient in front of you as someone who has an A1c of 7%, 8%, or 9%,” he cautioned. “You should also start thinking of where the patient is on the spectrum of cardiovascular disease, all the way from CVD risk factors only to symptomatic heart failure.”
Some evidence already exists to help clinicians make treatment decisions based on where the patients fall on that spectrum, he continued.
For example, clinical trials have demonstrated that in patients with established atherosclerotic cardiovascular disease, GLP-1 receptor agonists and SGLT2 inhibitors can reduce the risk of cardiovascular events, including, in some cases, cardiovascular death.
“We don’t have a lot of data demonstrating benefit for patients with recent acute coronary syndrome,” he said. “Some compounds have proven to be neutral, but none has been proven to save lives in this patient group.
“Now, we also have data for people with prior stroke that pioglitazone may be beneficial in managing those patients to prevent recurrent stroke and MI, based on the recent IRIS Trial, provided they don’t have heart failure at baseline,” Dr. Kosiborod added. “We don’t have definitive data yet in people with established heart failure, but those studies are ongoing.”
Dr. Kosiborod disclosed that he is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eisai, Glytec, GSK, Intarcia, Merck (Diabetes), Novartis, Novo Nordisk, Sanofi, and ZS Pharma. He has also received research grants from AstraZeneca and Boehringer Ingelheim.
EXPERT ANALYSIS FROM WCIRDC 2017
Heart attacks bring 12 weeks of higher stroke risk
LOS ANGELES – , based on a sample of Medicare beneficiaries.
The period of elevated stroke risk following an MI extends beyond the 30-day window that has traditionally been considered the interval of highest risk, Alexander E. Merkler, MD, said at the International Stroke Conference, sponsored by the American Heart Association.
Beyond 12 weeks after MI discharge, the stroke incidence showed no significant difference compared with people without a recent MI history, said Dr. Merkler, a neurologist at Weill Cornell Medicine in New York.
He calculated these statistically significant elevated risk rates after adjusting for demographic measures, stroke risk factors, and the comorbidities included in the Charlson Comorbidity Index.
These increased stroke rates were independent of periprocedural strokes that might have happened during MI interventions, as the analysis excluded MI patients with a history of a stroke either before or during their MI hospitalization.
To run this analysis, Dr. Merkler and his associates used data collected in a 5% sample of Medicare beneficiaries who were at least 66 years old during 2008-2015. Among these 1.7 million people were 46,182 who were hospitalized for an MI.
Several factors associated with an acute MI likely contribute to an elevated stroke risk, including stasis in the heart and generation of microthrombi, and a possibly systemic proinflammatory state, Dr. Merkler suggested.
Dr. Merkler had no disclosures.
SOURCE: Merkler AE et al., International Stroke Conference abstract 172 (Stroke. 2018 Jan; 49[Suppl 1]:A172).
LOS ANGELES – , based on a sample of Medicare beneficiaries.
The period of elevated stroke risk following an MI extends beyond the 30-day window that has traditionally been considered the interval of highest risk, Alexander E. Merkler, MD, said at the International Stroke Conference, sponsored by the American Heart Association.
Beyond 12 weeks after MI discharge, the stroke incidence showed no significant difference compared with people without a recent MI history, said Dr. Merkler, a neurologist at Weill Cornell Medicine in New York.
He calculated these statistically significant elevated risk rates after adjusting for demographic measures, stroke risk factors, and the comorbidities included in the Charlson Comorbidity Index.
These increased stroke rates were independent of periprocedural strokes that might have happened during MI interventions, as the analysis excluded MI patients with a history of a stroke either before or during their MI hospitalization.
To run this analysis, Dr. Merkler and his associates used data collected in a 5% sample of Medicare beneficiaries who were at least 66 years old during 2008-2015. Among these 1.7 million people were 46,182 who were hospitalized for an MI.
Several factors associated with an acute MI likely contribute to an elevated stroke risk, including stasis in the heart and generation of microthrombi, and a possibly systemic proinflammatory state, Dr. Merkler suggested.
Dr. Merkler had no disclosures.
SOURCE: Merkler AE et al., International Stroke Conference abstract 172 (Stroke. 2018 Jan; 49[Suppl 1]:A172).
LOS ANGELES – , based on a sample of Medicare beneficiaries.
The period of elevated stroke risk following an MI extends beyond the 30-day window that has traditionally been considered the interval of highest risk, Alexander E. Merkler, MD, said at the International Stroke Conference, sponsored by the American Heart Association.
Beyond 12 weeks after MI discharge, the stroke incidence showed no significant difference compared with people without a recent MI history, said Dr. Merkler, a neurologist at Weill Cornell Medicine in New York.
He calculated these statistically significant elevated risk rates after adjusting for demographic measures, stroke risk factors, and the comorbidities included in the Charlson Comorbidity Index.
These increased stroke rates were independent of periprocedural strokes that might have happened during MI interventions, as the analysis excluded MI patients with a history of a stroke either before or during their MI hospitalization.
To run this analysis, Dr. Merkler and his associates used data collected in a 5% sample of Medicare beneficiaries who were at least 66 years old during 2008-2015. Among these 1.7 million people were 46,182 who were hospitalized for an MI.
Several factors associated with an acute MI likely contribute to an elevated stroke risk, including stasis in the heart and generation of microthrombi, and a possibly systemic proinflammatory state, Dr. Merkler suggested.
Dr. Merkler had no disclosures.
SOURCE: Merkler AE et al., International Stroke Conference abstract 172 (Stroke. 2018 Jan; 49[Suppl 1]:A172).
REPORTING FROM ISC 2018
Key clinical point: A patient’s stroke risk is elevated for 12 weeks following a myocardial infarction.
Major finding: The stroke rate was 2.7-fold, 2.0-fold, and 1.6-fold above background at 4, 8, and 12 weeks after an MI.
Study details: A review of 1.7 million Medicare beneficiaries during 2008-2015.
Disclosures: Dr. Merkler had no disclosures.
Source: Merkler AE et al., International Stroke Conference abstract 172 (Stroke. 2018 Jan;49[Suppl 1]:A172).
Pembrolizumab plus SBRT shows promise for advanced solid tumors
SAN FRANCISCO – Pembrolizumab immunotherapy with multi-site stereotactic body radiotherapy (SBRT) appears to be a safe and effective treatment in patients with advanced solid tumors, according to findings from a phase 1 study.
Of 79 patients with metastatic solid tumors who progressed on standard treatment and who were enrolled in the study, 68 underwent multi-site SBRT, received at least one cycle of pembrolizumab (Keytruda), and had imaging follow-up. The overall objective response rate in those 68 patients was 13.2%, Jeffrey Lemons, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
When responses in the non-irradiated lesions (out-of-field responses) were measured based on a 30% reduction in any single lesion, the rate was 26.9%. But when defined by a 30% reduction in aggregate diameter of the non-irradiated measurable lesions, the rate was 13.5%, he said. While both approaches for measuring response are acceptable, Dr. Lemons noted, it’s important to be sure which one is being used in a given study.
Overall, 73 patients received both SBRT and pembrolizumab (5 had no imaging follow-up). They had a mean age of 62 years and a median of five prior therapies. Cancer types included ovarian/fallopian tube cancer (12.3%), non–small cell lung cancer (9.6%), breast cancer (8.2%), cholangiocarcinoma (8.2%), endometrial cancer (8.2%), colorectal cancer (6.8%), head and neck cancer (5.5%), and other tumors, each with less than 5% accrual (41.2%).
The number of sites treated with SBRT was two in 94.5% of patients, three in 4.1%, and four in 1.3%; 151 lesions in total were treated.
The premise for combining pembrolizumab and SBRT is that response to anti-programmed cell death-1 (PD1) therapy seems to correspond with interferon-gamma signaling, and that SBRT can stimulate innate and adaptive immunity to potentially augment immunotherapy, Dr. Lemons explained. In addition, anti-PD1 treatment outcomes are improved with lower disease burden.
Multi-site radiation is an emerging paradigm for eradicating metastatic disease, he said.
Patients included in the study had metastatic solid tumors and had progressed on standard treatment. They had measurable disease by RECIST, and metastases amenable to SBRT with 0.25 cc to 65 cc of viable tumor.
Tumors larger than 65 cc were partially targeted with radiotherapy. Radiation doses were adapted from recently completed and ongoing National Cancer Institute trials and ranged from 30-50 Gy (3-5 fractions) based on anatomic location.
Pembrolizumab was initiated within 7 days of the final SBRT treatment.
Dose-limiting toxicities, all grade 3, occurred in six patients during a median follow-up of 5.5 months, and included pneumonitis in three patients, hepatic failure in one patient, and colitis in two patients, but there were no radiation dose reductions, Dr. Lemons said.
“This is the first and largest prospective trial to determine the safety of this combination,” he explained. “There was some intriguing clinical activity ... and we feel that this justifies further randomized studies
The University of Chicago sponsored the study. Dr. Lemons reported having no disclosures.
sworcester@frontlinemedcom.com
SOURCE: Lemons J et al., ASCO-SITC abstract #20.
SAN FRANCISCO – Pembrolizumab immunotherapy with multi-site stereotactic body radiotherapy (SBRT) appears to be a safe and effective treatment in patients with advanced solid tumors, according to findings from a phase 1 study.
Of 79 patients with metastatic solid tumors who progressed on standard treatment and who were enrolled in the study, 68 underwent multi-site SBRT, received at least one cycle of pembrolizumab (Keytruda), and had imaging follow-up. The overall objective response rate in those 68 patients was 13.2%, Jeffrey Lemons, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
When responses in the non-irradiated lesions (out-of-field responses) were measured based on a 30% reduction in any single lesion, the rate was 26.9%. But when defined by a 30% reduction in aggregate diameter of the non-irradiated measurable lesions, the rate was 13.5%, he said. While both approaches for measuring response are acceptable, Dr. Lemons noted, it’s important to be sure which one is being used in a given study.
Overall, 73 patients received both SBRT and pembrolizumab (5 had no imaging follow-up). They had a mean age of 62 years and a median of five prior therapies. Cancer types included ovarian/fallopian tube cancer (12.3%), non–small cell lung cancer (9.6%), breast cancer (8.2%), cholangiocarcinoma (8.2%), endometrial cancer (8.2%), colorectal cancer (6.8%), head and neck cancer (5.5%), and other tumors, each with less than 5% accrual (41.2%).
The number of sites treated with SBRT was two in 94.5% of patients, three in 4.1%, and four in 1.3%; 151 lesions in total were treated.
The premise for combining pembrolizumab and SBRT is that response to anti-programmed cell death-1 (PD1) therapy seems to correspond with interferon-gamma signaling, and that SBRT can stimulate innate and adaptive immunity to potentially augment immunotherapy, Dr. Lemons explained. In addition, anti-PD1 treatment outcomes are improved with lower disease burden.
Multi-site radiation is an emerging paradigm for eradicating metastatic disease, he said.
Patients included in the study had metastatic solid tumors and had progressed on standard treatment. They had measurable disease by RECIST, and metastases amenable to SBRT with 0.25 cc to 65 cc of viable tumor.
Tumors larger than 65 cc were partially targeted with radiotherapy. Radiation doses were adapted from recently completed and ongoing National Cancer Institute trials and ranged from 30-50 Gy (3-5 fractions) based on anatomic location.
Pembrolizumab was initiated within 7 days of the final SBRT treatment.
Dose-limiting toxicities, all grade 3, occurred in six patients during a median follow-up of 5.5 months, and included pneumonitis in three patients, hepatic failure in one patient, and colitis in two patients, but there were no radiation dose reductions, Dr. Lemons said.
“This is the first and largest prospective trial to determine the safety of this combination,” he explained. “There was some intriguing clinical activity ... and we feel that this justifies further randomized studies
The University of Chicago sponsored the study. Dr. Lemons reported having no disclosures.
sworcester@frontlinemedcom.com
SOURCE: Lemons J et al., ASCO-SITC abstract #20.
SAN FRANCISCO – Pembrolizumab immunotherapy with multi-site stereotactic body radiotherapy (SBRT) appears to be a safe and effective treatment in patients with advanced solid tumors, according to findings from a phase 1 study.
Of 79 patients with metastatic solid tumors who progressed on standard treatment and who were enrolled in the study, 68 underwent multi-site SBRT, received at least one cycle of pembrolizumab (Keytruda), and had imaging follow-up. The overall objective response rate in those 68 patients was 13.2%, Jeffrey Lemons, MD, reported at the ASCO-SITC Clinical Immuno-Oncology Symposium.
When responses in the non-irradiated lesions (out-of-field responses) were measured based on a 30% reduction in any single lesion, the rate was 26.9%. But when defined by a 30% reduction in aggregate diameter of the non-irradiated measurable lesions, the rate was 13.5%, he said. While both approaches for measuring response are acceptable, Dr. Lemons noted, it’s important to be sure which one is being used in a given study.
Overall, 73 patients received both SBRT and pembrolizumab (5 had no imaging follow-up). They had a mean age of 62 years and a median of five prior therapies. Cancer types included ovarian/fallopian tube cancer (12.3%), non–small cell lung cancer (9.6%), breast cancer (8.2%), cholangiocarcinoma (8.2%), endometrial cancer (8.2%), colorectal cancer (6.8%), head and neck cancer (5.5%), and other tumors, each with less than 5% accrual (41.2%).
The number of sites treated with SBRT was two in 94.5% of patients, three in 4.1%, and four in 1.3%; 151 lesions in total were treated.
The premise for combining pembrolizumab and SBRT is that response to anti-programmed cell death-1 (PD1) therapy seems to correspond with interferon-gamma signaling, and that SBRT can stimulate innate and adaptive immunity to potentially augment immunotherapy, Dr. Lemons explained. In addition, anti-PD1 treatment outcomes are improved with lower disease burden.
Multi-site radiation is an emerging paradigm for eradicating metastatic disease, he said.
Patients included in the study had metastatic solid tumors and had progressed on standard treatment. They had measurable disease by RECIST, and metastases amenable to SBRT with 0.25 cc to 65 cc of viable tumor.
Tumors larger than 65 cc were partially targeted with radiotherapy. Radiation doses were adapted from recently completed and ongoing National Cancer Institute trials and ranged from 30-50 Gy (3-5 fractions) based on anatomic location.
Pembrolizumab was initiated within 7 days of the final SBRT treatment.
Dose-limiting toxicities, all grade 3, occurred in six patients during a median follow-up of 5.5 months, and included pneumonitis in three patients, hepatic failure in one patient, and colitis in two patients, but there were no radiation dose reductions, Dr. Lemons said.
“This is the first and largest prospective trial to determine the safety of this combination,” he explained. “There was some intriguing clinical activity ... and we feel that this justifies further randomized studies
The University of Chicago sponsored the study. Dr. Lemons reported having no disclosures.
sworcester@frontlinemedcom.com
SOURCE: Lemons J et al., ASCO-SITC abstract #20.
REPORTING FROM THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Key clinical point: Pembrolizumab plus multi-site SBRT appears safe and effective for advanced solid tumors.
Major finding: The overall objective response rate was 13.2%.
Study details: A phase 1 study of 79 patients.
Disclosures: The University of Chicago sponsored the study. Dr. Lemons reported having no disclosures
Source: Lemons J et al. ASCO-SITC abstract #20.
Trial seeks improved regimens for pregnant women with HIV
A new phase 3 trial will compare the safety and efficacy of the current first-line antiretroviral regimen for pregnant women with HIV to that of two other regimens, each of which include the newer antiretroviral drug dolutegravir (DTG).
The World Health Organization recommends efavirenz /emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) for pregnant women who have HIV and live in low-resource settings, but the regimen is not well tolerated.
The new phase 3 trial, known as IMPAACT 2010 or VESTED (Virologic Efficacy and Safety of Antiretroviral Therapy Combinations with TAF/TDF, EFV, and DTG), will compare the recommended regimen with DTG plus emtricitabine/tenofovir alafenamide (FTC/TAF) and DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in hopes of finding a better alternative.
The trial has sites open in Zimbabwe and the United States, but more sites are expected to open over the coming months in Botswana, Brazil, Haiti, India, Malawi, South Africa, Tanzania, Thailand, Uganda, the United States, and Zimbabwe, according to a statement from the U.S. National Institutes of Health.
The study is receiving funding in part from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, as well as from the National Institute of Allergy and Infectious Diseases. The drugs used in the study have been provided by Gilead Sciences, Mylan, and ViiV Healthcare. ViiV is also covering nonparticipant costs for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network, which is conducting the study.
A new phase 3 trial will compare the safety and efficacy of the current first-line antiretroviral regimen for pregnant women with HIV to that of two other regimens, each of which include the newer antiretroviral drug dolutegravir (DTG).
The World Health Organization recommends efavirenz /emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) for pregnant women who have HIV and live in low-resource settings, but the regimen is not well tolerated.
The new phase 3 trial, known as IMPAACT 2010 or VESTED (Virologic Efficacy and Safety of Antiretroviral Therapy Combinations with TAF/TDF, EFV, and DTG), will compare the recommended regimen with DTG plus emtricitabine/tenofovir alafenamide (FTC/TAF) and DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in hopes of finding a better alternative.
The trial has sites open in Zimbabwe and the United States, but more sites are expected to open over the coming months in Botswana, Brazil, Haiti, India, Malawi, South Africa, Tanzania, Thailand, Uganda, the United States, and Zimbabwe, according to a statement from the U.S. National Institutes of Health.
The study is receiving funding in part from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, as well as from the National Institute of Allergy and Infectious Diseases. The drugs used in the study have been provided by Gilead Sciences, Mylan, and ViiV Healthcare. ViiV is also covering nonparticipant costs for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network, which is conducting the study.
A new phase 3 trial will compare the safety and efficacy of the current first-line antiretroviral regimen for pregnant women with HIV to that of two other regimens, each of which include the newer antiretroviral drug dolutegravir (DTG).
The World Health Organization recommends efavirenz /emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) for pregnant women who have HIV and live in low-resource settings, but the regimen is not well tolerated.
The new phase 3 trial, known as IMPAACT 2010 or VESTED (Virologic Efficacy and Safety of Antiretroviral Therapy Combinations with TAF/TDF, EFV, and DTG), will compare the recommended regimen with DTG plus emtricitabine/tenofovir alafenamide (FTC/TAF) and DTG plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in hopes of finding a better alternative.
The trial has sites open in Zimbabwe and the United States, but more sites are expected to open over the coming months in Botswana, Brazil, Haiti, India, Malawi, South Africa, Tanzania, Thailand, Uganda, the United States, and Zimbabwe, according to a statement from the U.S. National Institutes of Health.
The study is receiving funding in part from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, as well as from the National Institute of Allergy and Infectious Diseases. The drugs used in the study have been provided by Gilead Sciences, Mylan, and ViiV Healthcare. ViiV is also covering nonparticipant costs for the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) network, which is conducting the study.
Cerebrospinal tract may help decide mild stroke treatment
LOS ANGELES – In acute ischemic stroke patients with small perfusion lesions of less than 15 mL, involvement of the corticospinal tract (CST) may help guide the decision whether to treat with alteplase.
Specifically, patients with hypoperfusion in the CST, but without CST infarction, were more likely to have a modified Rankin Scale score (mRS) of 0-2 at 90 days after treatment with alteplase. Patients with no CST involvement, or with a CST infarct, had worse outcomes with treatment.
The better outcomes “might indicate that hypoperfused CST tissue at baseline could be salvaged by timely reperfusion,” said Min Lou, MD, PhD, vice chair of neurology at Zhejiang University, Hangzhou, China, during her presentation of the study at the International Stroke Conference sponsored by the American Heart Association.
Previous studies have left physicians uncertain what to do with patients presenting with mild stroke, especially strokes that are judged to be potentially disabling despite a low National Institutes of Health Stroke Scale (NIHSS) score. These patients have a lower risk of hemorrhagic conversion, estimated at 0%-2%.
A meta-analysis showed that alteplase treatment in patients with a baseline NIHSS score of 0-4 was associated with a 48% increase in the chance of an excellent outcome. But another study showed that, among patients with a perfusion lesion smaller than 15 mL, treatment with alteplase was less likely than no treatment at all to confer an excellent outcome.
“The challenge is to identify what kind of minor stroke patient would benefit from thrombolysis therapy,” said Dr. Lou.
The researchers analyzed data from the International Stroke Perfusion Imaging Registry (INSPIRE) database, selecting 412 patients with an acute perfusion lesion less than 15 mL who had undergone computed tomography perfusion or magnetic resonance perfusion imaging within 4.5 hours of symptom onset, had had the scan repeated at 24 hours, and who were followed up at 90 days.
Among the patients, 248 were treated with alteplase, and 164 were not. The alteplase-treated group had a mean NIHSS score of 5.0, compared with 4.0 in the untreated group (P = .001). CST hypoperfusion was more common in the treated group (32.3% versus 15.9%, P less than .001), as was CST infarction (14.9% versus 5.5%, P = .004) and 24-hour intracerebral hemorrhage (ICH) (9.3% versus 0.6%, P less than .001).
The researchers divided subjects into three groups: no CST lesion (306 patients), CST hypoperfusion with no CST infarct (60), and CST infarct (46). The 24-hour ICH frequency varied between the groups, with the highest frequency in the CST infarct group (15.2%), followed by the CST hypoperfusion with no infarct group (10.0%), and the no CST lesion group (3.6%, P = .002).
At 90 days, higher frequency of an mRS score of 0-1 was only associated with alteplase treatment in the CST hypoperfusion with no infarct group (76.7% versus 47.1%, P = .035).
The reverse was true in the other groups: No treatment was associated with better odds of an mRS score of 0-1 in the group with no CST lesion (87.7% versus 79.8%, P = .067) and particularly in the group with CST infarct (88.9% versus 32.4%, P = .006).
The study is limited by the fact that it is a retrospective analysis, the investigators cautioned.
The National Natural Science Foundation of China funded the study. Dr. Lou reported having no financial disclosures.
LOS ANGELES – In acute ischemic stroke patients with small perfusion lesions of less than 15 mL, involvement of the corticospinal tract (CST) may help guide the decision whether to treat with alteplase.
Specifically, patients with hypoperfusion in the CST, but without CST infarction, were more likely to have a modified Rankin Scale score (mRS) of 0-2 at 90 days after treatment with alteplase. Patients with no CST involvement, or with a CST infarct, had worse outcomes with treatment.
The better outcomes “might indicate that hypoperfused CST tissue at baseline could be salvaged by timely reperfusion,” said Min Lou, MD, PhD, vice chair of neurology at Zhejiang University, Hangzhou, China, during her presentation of the study at the International Stroke Conference sponsored by the American Heart Association.
Previous studies have left physicians uncertain what to do with patients presenting with mild stroke, especially strokes that are judged to be potentially disabling despite a low National Institutes of Health Stroke Scale (NIHSS) score. These patients have a lower risk of hemorrhagic conversion, estimated at 0%-2%.
A meta-analysis showed that alteplase treatment in patients with a baseline NIHSS score of 0-4 was associated with a 48% increase in the chance of an excellent outcome. But another study showed that, among patients with a perfusion lesion smaller than 15 mL, treatment with alteplase was less likely than no treatment at all to confer an excellent outcome.
“The challenge is to identify what kind of minor stroke patient would benefit from thrombolysis therapy,” said Dr. Lou.
The researchers analyzed data from the International Stroke Perfusion Imaging Registry (INSPIRE) database, selecting 412 patients with an acute perfusion lesion less than 15 mL who had undergone computed tomography perfusion or magnetic resonance perfusion imaging within 4.5 hours of symptom onset, had had the scan repeated at 24 hours, and who were followed up at 90 days.
Among the patients, 248 were treated with alteplase, and 164 were not. The alteplase-treated group had a mean NIHSS score of 5.0, compared with 4.0 in the untreated group (P = .001). CST hypoperfusion was more common in the treated group (32.3% versus 15.9%, P less than .001), as was CST infarction (14.9% versus 5.5%, P = .004) and 24-hour intracerebral hemorrhage (ICH) (9.3% versus 0.6%, P less than .001).
The researchers divided subjects into three groups: no CST lesion (306 patients), CST hypoperfusion with no CST infarct (60), and CST infarct (46). The 24-hour ICH frequency varied between the groups, with the highest frequency in the CST infarct group (15.2%), followed by the CST hypoperfusion with no infarct group (10.0%), and the no CST lesion group (3.6%, P = .002).
At 90 days, higher frequency of an mRS score of 0-1 was only associated with alteplase treatment in the CST hypoperfusion with no infarct group (76.7% versus 47.1%, P = .035).
The reverse was true in the other groups: No treatment was associated with better odds of an mRS score of 0-1 in the group with no CST lesion (87.7% versus 79.8%, P = .067) and particularly in the group with CST infarct (88.9% versus 32.4%, P = .006).
The study is limited by the fact that it is a retrospective analysis, the investigators cautioned.
The National Natural Science Foundation of China funded the study. Dr. Lou reported having no financial disclosures.
LOS ANGELES – In acute ischemic stroke patients with small perfusion lesions of less than 15 mL, involvement of the corticospinal tract (CST) may help guide the decision whether to treat with alteplase.
Specifically, patients with hypoperfusion in the CST, but without CST infarction, were more likely to have a modified Rankin Scale score (mRS) of 0-2 at 90 days after treatment with alteplase. Patients with no CST involvement, or with a CST infarct, had worse outcomes with treatment.
The better outcomes “might indicate that hypoperfused CST tissue at baseline could be salvaged by timely reperfusion,” said Min Lou, MD, PhD, vice chair of neurology at Zhejiang University, Hangzhou, China, during her presentation of the study at the International Stroke Conference sponsored by the American Heart Association.
Previous studies have left physicians uncertain what to do with patients presenting with mild stroke, especially strokes that are judged to be potentially disabling despite a low National Institutes of Health Stroke Scale (NIHSS) score. These patients have a lower risk of hemorrhagic conversion, estimated at 0%-2%.
A meta-analysis showed that alteplase treatment in patients with a baseline NIHSS score of 0-4 was associated with a 48% increase in the chance of an excellent outcome. But another study showed that, among patients with a perfusion lesion smaller than 15 mL, treatment with alteplase was less likely than no treatment at all to confer an excellent outcome.
“The challenge is to identify what kind of minor stroke patient would benefit from thrombolysis therapy,” said Dr. Lou.
The researchers analyzed data from the International Stroke Perfusion Imaging Registry (INSPIRE) database, selecting 412 patients with an acute perfusion lesion less than 15 mL who had undergone computed tomography perfusion or magnetic resonance perfusion imaging within 4.5 hours of symptom onset, had had the scan repeated at 24 hours, and who were followed up at 90 days.
Among the patients, 248 were treated with alteplase, and 164 were not. The alteplase-treated group had a mean NIHSS score of 5.0, compared with 4.0 in the untreated group (P = .001). CST hypoperfusion was more common in the treated group (32.3% versus 15.9%, P less than .001), as was CST infarction (14.9% versus 5.5%, P = .004) and 24-hour intracerebral hemorrhage (ICH) (9.3% versus 0.6%, P less than .001).
The researchers divided subjects into three groups: no CST lesion (306 patients), CST hypoperfusion with no CST infarct (60), and CST infarct (46). The 24-hour ICH frequency varied between the groups, with the highest frequency in the CST infarct group (15.2%), followed by the CST hypoperfusion with no infarct group (10.0%), and the no CST lesion group (3.6%, P = .002).
At 90 days, higher frequency of an mRS score of 0-1 was only associated with alteplase treatment in the CST hypoperfusion with no infarct group (76.7% versus 47.1%, P = .035).
The reverse was true in the other groups: No treatment was associated with better odds of an mRS score of 0-1 in the group with no CST lesion (87.7% versus 79.8%, P = .067) and particularly in the group with CST infarct (88.9% versus 32.4%, P = .006).
The study is limited by the fact that it is a retrospective analysis, the investigators cautioned.
The National Natural Science Foundation of China funded the study. Dr. Lou reported having no financial disclosures.
AT ISC 2018
Key clinical point:
Major finding: 76.7% of patients with cerebrospinal tract hypoperfusion but no infarct achieved a modified Rankin Scale score of 0-1, compared with 47.1% of untreated patients.
Data source: A retrospective analysis of 412 patients drawn from the International Stroke Perfusion Imaging Registry.
Disclosures: The National Natural Science Foundation of China funded the study. Dr. Lou reported having no financial disclosures.
Elderly at highest CV risk get short-statined
ANAHEIM, CALIF. – Adults older than age 75 years with known atherosclerotic cardiovascular disease are significantly less likely than younger patients to receive a high-intensity statin for secondary prevention, even though they actually tolerate statin therapy better, Michael G. Nanna, MD, said at the American Heart Association scientific sessions.
This was among the eye-opening findings from his analysis of data from the PALM (Patient and Provider Assessment of Lipid Management) Registry, a national registry that provides a snapshot of how cardiologists, primary care physicians, and endocrinologists in real-world community practice care for their patients with known atherosclerotic cardiovascular disease (ASCVD) or at high risk for it.
The impetus for this study was the dearth of information about what’s going on in everyday clinical practice in terms of statin utilization and side effects in the elderly since release of the 2013 American College of Cardiology and American Heart Association cholesterol guidelines. Those guidelines highlighted the lack of randomized clinical trial data to support the use of statins in patients over age 75, who had typically been excluded from participation in the major studies.
The guidelines recommended moderate-intensity statin therapy for secondary prevention in the elderly, and didn’t take a firm position regarding statins for primary prevention in older patients.
What’s happening in community practice
For primary prevention in the elderly, physicians appear to be extrapolating from their practice patterns in younger at-risk patients. Sixty-three percent of patients younger than age 75 at high risk for ASCVD were on a statin for primary prevention, as were an equal percentage of older patients. Moreover, 10.2% of older patients were on a high-intensity statin for primary prevention, a rate not significantly different from the 12.3% in younger at-risk patients.
Statin therapy for secondary prevention in the elderly was a different story. Older patients were significantly less likely to receive any statin for secondary prevention. And they were much less likely to get a high-intensity statin, by a margin of 23.5% to 36.2%.
Indeed, in a multivariate regression analysis adjusted for patient demographics, diabetes, smoking, heart failure, body mass index, insurance type, income, and whether a patient saw a cardiologist, older patients with ASCVD were 42% less likely to receive a high-intensity statin than patients younger than age 75.
“It’s interesting that older patients who have ASCVD are actually the group at highest risk of events, yet they’re the least likely to receive a high-intensity statin,” Dr. Nanna observed in an interview.
Of note, older patients were significantly less likely to report any side effect on a statin, by a margin of 41.3% to 46.6%. They were also markedly less likely to report myalgias, by a margin of 23.3% to 33.3%.
“One of the reasons why folks have shied away from treating older patients with statins, and especially with high-intensity statins, is the theoretical risk of more side effects and drug interactions. We didn’t see that,” Dr. Nanna said.
What’s next
“My dream is that studies like this will motivate folks to fund a randomized clinical trial looking at high-intensity statins in older adults,” Dr. Nanna said. “I think there are funding challenges because both rosuvastatin and atorvastatin are generic at this point. But I think it needs to be done.”
Rumor has it, he added, that the first randomized trial of statin therapy in the elderly will be in the primary prevention setting. “That’s an area where we’re all essentially operating in an evidence-free zone,” Dr. Nanna said.
Regeneron and Sanofi fund the PALM Registry. Dr. Nanna reported having no relevant financial conflicts of interest.
ANAHEIM, CALIF. – Adults older than age 75 years with known atherosclerotic cardiovascular disease are significantly less likely than younger patients to receive a high-intensity statin for secondary prevention, even though they actually tolerate statin therapy better, Michael G. Nanna, MD, said at the American Heart Association scientific sessions.
This was among the eye-opening findings from his analysis of data from the PALM (Patient and Provider Assessment of Lipid Management) Registry, a national registry that provides a snapshot of how cardiologists, primary care physicians, and endocrinologists in real-world community practice care for their patients with known atherosclerotic cardiovascular disease (ASCVD) or at high risk for it.
The impetus for this study was the dearth of information about what’s going on in everyday clinical practice in terms of statin utilization and side effects in the elderly since release of the 2013 American College of Cardiology and American Heart Association cholesterol guidelines. Those guidelines highlighted the lack of randomized clinical trial data to support the use of statins in patients over age 75, who had typically been excluded from participation in the major studies.
The guidelines recommended moderate-intensity statin therapy for secondary prevention in the elderly, and didn’t take a firm position regarding statins for primary prevention in older patients.
What’s happening in community practice
For primary prevention in the elderly, physicians appear to be extrapolating from their practice patterns in younger at-risk patients. Sixty-three percent of patients younger than age 75 at high risk for ASCVD were on a statin for primary prevention, as were an equal percentage of older patients. Moreover, 10.2% of older patients were on a high-intensity statin for primary prevention, a rate not significantly different from the 12.3% in younger at-risk patients.
Statin therapy for secondary prevention in the elderly was a different story. Older patients were significantly less likely to receive any statin for secondary prevention. And they were much less likely to get a high-intensity statin, by a margin of 23.5% to 36.2%.
Indeed, in a multivariate regression analysis adjusted for patient demographics, diabetes, smoking, heart failure, body mass index, insurance type, income, and whether a patient saw a cardiologist, older patients with ASCVD were 42% less likely to receive a high-intensity statin than patients younger than age 75.
“It’s interesting that older patients who have ASCVD are actually the group at highest risk of events, yet they’re the least likely to receive a high-intensity statin,” Dr. Nanna observed in an interview.
Of note, older patients were significantly less likely to report any side effect on a statin, by a margin of 41.3% to 46.6%. They were also markedly less likely to report myalgias, by a margin of 23.3% to 33.3%.
“One of the reasons why folks have shied away from treating older patients with statins, and especially with high-intensity statins, is the theoretical risk of more side effects and drug interactions. We didn’t see that,” Dr. Nanna said.
What’s next
“My dream is that studies like this will motivate folks to fund a randomized clinical trial looking at high-intensity statins in older adults,” Dr. Nanna said. “I think there are funding challenges because both rosuvastatin and atorvastatin are generic at this point. But I think it needs to be done.”
Rumor has it, he added, that the first randomized trial of statin therapy in the elderly will be in the primary prevention setting. “That’s an area where we’re all essentially operating in an evidence-free zone,” Dr. Nanna said.
Regeneron and Sanofi fund the PALM Registry. Dr. Nanna reported having no relevant financial conflicts of interest.
ANAHEIM, CALIF. – Adults older than age 75 years with known atherosclerotic cardiovascular disease are significantly less likely than younger patients to receive a high-intensity statin for secondary prevention, even though they actually tolerate statin therapy better, Michael G. Nanna, MD, said at the American Heart Association scientific sessions.
This was among the eye-opening findings from his analysis of data from the PALM (Patient and Provider Assessment of Lipid Management) Registry, a national registry that provides a snapshot of how cardiologists, primary care physicians, and endocrinologists in real-world community practice care for their patients with known atherosclerotic cardiovascular disease (ASCVD) or at high risk for it.
The impetus for this study was the dearth of information about what’s going on in everyday clinical practice in terms of statin utilization and side effects in the elderly since release of the 2013 American College of Cardiology and American Heart Association cholesterol guidelines. Those guidelines highlighted the lack of randomized clinical trial data to support the use of statins in patients over age 75, who had typically been excluded from participation in the major studies.
The guidelines recommended moderate-intensity statin therapy for secondary prevention in the elderly, and didn’t take a firm position regarding statins for primary prevention in older patients.
What’s happening in community practice
For primary prevention in the elderly, physicians appear to be extrapolating from their practice patterns in younger at-risk patients. Sixty-three percent of patients younger than age 75 at high risk for ASCVD were on a statin for primary prevention, as were an equal percentage of older patients. Moreover, 10.2% of older patients were on a high-intensity statin for primary prevention, a rate not significantly different from the 12.3% in younger at-risk patients.
Statin therapy for secondary prevention in the elderly was a different story. Older patients were significantly less likely to receive any statin for secondary prevention. And they were much less likely to get a high-intensity statin, by a margin of 23.5% to 36.2%.
Indeed, in a multivariate regression analysis adjusted for patient demographics, diabetes, smoking, heart failure, body mass index, insurance type, income, and whether a patient saw a cardiologist, older patients with ASCVD were 42% less likely to receive a high-intensity statin than patients younger than age 75.
“It’s interesting that older patients who have ASCVD are actually the group at highest risk of events, yet they’re the least likely to receive a high-intensity statin,” Dr. Nanna observed in an interview.
Of note, older patients were significantly less likely to report any side effect on a statin, by a margin of 41.3% to 46.6%. They were also markedly less likely to report myalgias, by a margin of 23.3% to 33.3%.
“One of the reasons why folks have shied away from treating older patients with statins, and especially with high-intensity statins, is the theoretical risk of more side effects and drug interactions. We didn’t see that,” Dr. Nanna said.
What’s next
“My dream is that studies like this will motivate folks to fund a randomized clinical trial looking at high-intensity statins in older adults,” Dr. Nanna said. “I think there are funding challenges because both rosuvastatin and atorvastatin are generic at this point. But I think it needs to be done.”
Rumor has it, he added, that the first randomized trial of statin therapy in the elderly will be in the primary prevention setting. “That’s an area where we’re all essentially operating in an evidence-free zone,” Dr. Nanna said.
Regeneron and Sanofi fund the PALM Registry. Dr. Nanna reported having no relevant financial conflicts of interest.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: Patients over age 75 with known cardiovascular disease were 42% less likely to receive a high-intensity statin for secondary prevention.
Study details: This was an analysis of more than 7,700 patients in the observational PALM Registry conducted in 138 U.S. community cardiology, primary care, and endocrinology practices.
Disclosures: Regeneron and Sanofi fund the PALM Registry. The presenter reported having no financial conflicts of interest.
APOE4 may drive tau deposition in Alzheimer’s
SAN DIEGO – The apolipoprotein E e4 allele is well known for its association with amyloid deposition in Alzheimer’s disease, but now it also appears to help drive the other key pathological process in the disease: deposition of hyperphosphorylated tau protein.
That’s according to the authors of a PET neuroimaging study presented at the annual meeting of the American Neurological Association.
The finding suggests a pathophysiologic mechanism for Alzheimer’s disease cases that predominantly affect memory.
The team then compared the results with uptake of the radiotracers in 71 cognitively normal control subjects who were a mean age of 79 years, 23 of whom (32%) were APOE4 carriers.
APOE4 was associated with higher cortical amyloid in the controls, but not tau deposition. Although AV1451 uptake in the temporal lobe was increased in e4 carriers, the effect was not statistically significant after controlling for PiB uptake.
“We saw an APOE4 effect on amyloid but not on tau in normal people,” said senior investigator Gil Rabinovici, MD, a neurologist and professor of memory and aging at the University of California, San Francisco.
All the AD patients had PiB uptake, with no difference in uptake between e4 carriers and noncarriers. However, APOE4 carriers had higher AV1451 uptake in their anterior medial temporal lobes (MTL), a difference that remained unchanged after controlling for PiB.
Carriers of the e4 allele who had AV1451 uptake in their MTLs had a harder time than other AD patients on a test in which they were asked to recall a series of words after a 10-minute break (California Verbal Learning Test), but they did not perform worse on other cognitive measures.
“In cognitively normal individuals, the effect of APOE4 on tau pathology seems to be mediated by the effect of e4 on Ab [amyloid-beta] deposition,” the investigators noted. “However, when assessing amyloid-positive symptomatic AD patients, APOE4 was associated with increased AV1451 binding in the MTL.
“This suggests that, in addition to its effect on Ab pathology, APOE4 might influence the topographical distribution of tau pathology and, potentially, the cognitive symptoms in patients,” the researchers concluded.
“We are very interested in heterogeneity in Alzheimer’s disease – age of onset, rate of progression, which brain areas are affected,” Dr. Rabinovici said. “This study is beginning to dig into some of the factors that might explain that; APOE4 is one potential modifier. It may have a direct effect on tau phosphorylation, and it changes where tau is located in the setting of Alzheimer’s disease.”
The finding of increased MTL tau in APOE4-positive Alzheimer’s patients helps explain why patients who carry the allele tend to have more memory problems, he said, while AD patients who don’t carry the allele tend to have more of a cortical-predominant presentation, with more visual-spatial and language problems.
“I think it’s very likely that APOE4-related disease may be driven by a different mechanism than APOE4-negative disease,” Dr. Rabinovici said. “In the future, APOE4-positive or APOE4-negative might be used to stratify therapy and the measurements used for disease progression. APOE4 itself may be an interesting therapeutic target because it has downstream effects on amyloid and tau.”
Meanwhile, there’s just not a lot of tau pathology in cognitively normal people, which is likely why the effect didn’t show up in the controls, noted lead investigator Renaud La Joie, PhD, a neuroimaging researcher at UCSF.
The work was funded in part by the National Institutes of Health. Avid Pharmaceuticals provided the AV1451. Dr. Rabinovici is an advisor for Genentech, Merck, and Roche, and has research support from Avid Radiopharmaceuticals and Eli Lilly, among others.
SOURCE: La Joie R, et al. Abstract M183, American Neurological Association 2017 annual meeting.
SAN DIEGO – The apolipoprotein E e4 allele is well known for its association with amyloid deposition in Alzheimer’s disease, but now it also appears to help drive the other key pathological process in the disease: deposition of hyperphosphorylated tau protein.
That’s according to the authors of a PET neuroimaging study presented at the annual meeting of the American Neurological Association.
The finding suggests a pathophysiologic mechanism for Alzheimer’s disease cases that predominantly affect memory.
The team then compared the results with uptake of the radiotracers in 71 cognitively normal control subjects who were a mean age of 79 years, 23 of whom (32%) were APOE4 carriers.
APOE4 was associated with higher cortical amyloid in the controls, but not tau deposition. Although AV1451 uptake in the temporal lobe was increased in e4 carriers, the effect was not statistically significant after controlling for PiB uptake.
“We saw an APOE4 effect on amyloid but not on tau in normal people,” said senior investigator Gil Rabinovici, MD, a neurologist and professor of memory and aging at the University of California, San Francisco.
All the AD patients had PiB uptake, with no difference in uptake between e4 carriers and noncarriers. However, APOE4 carriers had higher AV1451 uptake in their anterior medial temporal lobes (MTL), a difference that remained unchanged after controlling for PiB.
Carriers of the e4 allele who had AV1451 uptake in their MTLs had a harder time than other AD patients on a test in which they were asked to recall a series of words after a 10-minute break (California Verbal Learning Test), but they did not perform worse on other cognitive measures.
“In cognitively normal individuals, the effect of APOE4 on tau pathology seems to be mediated by the effect of e4 on Ab [amyloid-beta] deposition,” the investigators noted. “However, when assessing amyloid-positive symptomatic AD patients, APOE4 was associated with increased AV1451 binding in the MTL.
“This suggests that, in addition to its effect on Ab pathology, APOE4 might influence the topographical distribution of tau pathology and, potentially, the cognitive symptoms in patients,” the researchers concluded.
“We are very interested in heterogeneity in Alzheimer’s disease – age of onset, rate of progression, which brain areas are affected,” Dr. Rabinovici said. “This study is beginning to dig into some of the factors that might explain that; APOE4 is one potential modifier. It may have a direct effect on tau phosphorylation, and it changes where tau is located in the setting of Alzheimer’s disease.”
The finding of increased MTL tau in APOE4-positive Alzheimer’s patients helps explain why patients who carry the allele tend to have more memory problems, he said, while AD patients who don’t carry the allele tend to have more of a cortical-predominant presentation, with more visual-spatial and language problems.
“I think it’s very likely that APOE4-related disease may be driven by a different mechanism than APOE4-negative disease,” Dr. Rabinovici said. “In the future, APOE4-positive or APOE4-negative might be used to stratify therapy and the measurements used for disease progression. APOE4 itself may be an interesting therapeutic target because it has downstream effects on amyloid and tau.”
Meanwhile, there’s just not a lot of tau pathology in cognitively normal people, which is likely why the effect didn’t show up in the controls, noted lead investigator Renaud La Joie, PhD, a neuroimaging researcher at UCSF.
The work was funded in part by the National Institutes of Health. Avid Pharmaceuticals provided the AV1451. Dr. Rabinovici is an advisor for Genentech, Merck, and Roche, and has research support from Avid Radiopharmaceuticals and Eli Lilly, among others.
SOURCE: La Joie R, et al. Abstract M183, American Neurological Association 2017 annual meeting.
SAN DIEGO – The apolipoprotein E e4 allele is well known for its association with amyloid deposition in Alzheimer’s disease, but now it also appears to help drive the other key pathological process in the disease: deposition of hyperphosphorylated tau protein.
That’s according to the authors of a PET neuroimaging study presented at the annual meeting of the American Neurological Association.
The finding suggests a pathophysiologic mechanism for Alzheimer’s disease cases that predominantly affect memory.
The team then compared the results with uptake of the radiotracers in 71 cognitively normal control subjects who were a mean age of 79 years, 23 of whom (32%) were APOE4 carriers.
APOE4 was associated with higher cortical amyloid in the controls, but not tau deposition. Although AV1451 uptake in the temporal lobe was increased in e4 carriers, the effect was not statistically significant after controlling for PiB uptake.
“We saw an APOE4 effect on amyloid but not on tau in normal people,” said senior investigator Gil Rabinovici, MD, a neurologist and professor of memory and aging at the University of California, San Francisco.
All the AD patients had PiB uptake, with no difference in uptake between e4 carriers and noncarriers. However, APOE4 carriers had higher AV1451 uptake in their anterior medial temporal lobes (MTL), a difference that remained unchanged after controlling for PiB.
Carriers of the e4 allele who had AV1451 uptake in their MTLs had a harder time than other AD patients on a test in which they were asked to recall a series of words after a 10-minute break (California Verbal Learning Test), but they did not perform worse on other cognitive measures.
“In cognitively normal individuals, the effect of APOE4 on tau pathology seems to be mediated by the effect of e4 on Ab [amyloid-beta] deposition,” the investigators noted. “However, when assessing amyloid-positive symptomatic AD patients, APOE4 was associated with increased AV1451 binding in the MTL.
“This suggests that, in addition to its effect on Ab pathology, APOE4 might influence the topographical distribution of tau pathology and, potentially, the cognitive symptoms in patients,” the researchers concluded.
“We are very interested in heterogeneity in Alzheimer’s disease – age of onset, rate of progression, which brain areas are affected,” Dr. Rabinovici said. “This study is beginning to dig into some of the factors that might explain that; APOE4 is one potential modifier. It may have a direct effect on tau phosphorylation, and it changes where tau is located in the setting of Alzheimer’s disease.”
The finding of increased MTL tau in APOE4-positive Alzheimer’s patients helps explain why patients who carry the allele tend to have more memory problems, he said, while AD patients who don’t carry the allele tend to have more of a cortical-predominant presentation, with more visual-spatial and language problems.
“I think it’s very likely that APOE4-related disease may be driven by a different mechanism than APOE4-negative disease,” Dr. Rabinovici said. “In the future, APOE4-positive or APOE4-negative might be used to stratify therapy and the measurements used for disease progression. APOE4 itself may be an interesting therapeutic target because it has downstream effects on amyloid and tau.”
Meanwhile, there’s just not a lot of tau pathology in cognitively normal people, which is likely why the effect didn’t show up in the controls, noted lead investigator Renaud La Joie, PhD, a neuroimaging researcher at UCSF.
The work was funded in part by the National Institutes of Health. Avid Pharmaceuticals provided the AV1451. Dr. Rabinovici is an advisor for Genentech, Merck, and Roche, and has research support from Avid Radiopharmaceuticals and Eli Lilly, among others.
SOURCE: La Joie R, et al. Abstract M183, American Neurological Association 2017 annual meeting.
REPORTING FROM ANA 2017
Key clinical point:
Major finding: APOE4 carriers had higher AV1451-uptake in their anterior medial temporal lobes, a difference that remained unchanged after controlling for Pittsburgh compound B.
Study details: An analysis of radiotracer PET imaging in 67 Alzheimer’s disease patients and 71 controls.
Disclosures: The work was funded in part by the National Institutes of Health. Avid Pharmaceuticals provided the AV1451. The senior investigator is an advisor for Genentech, Merck, and Roche, and has research support from Avid Radiopharmaceuticals and Eli Lilly, among others.
Source: La Joie R, et al. Abstract M183, American Neurological Association 2017 annual meeting.
FDA approves irritable bowel syndrome treatment
(IBS-C).
Plecanatide had previously been approved to treat adults with chronic idiopathic constipation (CIC).
Plecanatide met both of its primary endpoints, with reductions in abdominal pain in both studies, compared with placebo (30.2% vs. 17.8% in study 1, P < .001; 21.5% vs. 14.2% in study 2, P = .009).
Plecanatide is the only prescription, once-daily medication that treats both CIC and IBS-C in adults. The drug should be available in the first quarter of 2018.
(IBS-C).
Plecanatide had previously been approved to treat adults with chronic idiopathic constipation (CIC).
Plecanatide met both of its primary endpoints, with reductions in abdominal pain in both studies, compared with placebo (30.2% vs. 17.8% in study 1, P < .001; 21.5% vs. 14.2% in study 2, P = .009).
Plecanatide is the only prescription, once-daily medication that treats both CIC and IBS-C in adults. The drug should be available in the first quarter of 2018.
(IBS-C).
Plecanatide had previously been approved to treat adults with chronic idiopathic constipation (CIC).
Plecanatide met both of its primary endpoints, with reductions in abdominal pain in both studies, compared with placebo (30.2% vs. 17.8% in study 1, P < .001; 21.5% vs. 14.2% in study 2, P = .009).
Plecanatide is the only prescription, once-daily medication that treats both CIC and IBS-C in adults. The drug should be available in the first quarter of 2018.