User login
‘Sit less, move more’ to reduce stroke risk
in a population-based study of middle aged and older adults.
The study also found relatively short periods of moderate to vigorous exercise were associated with reduced stroke risk.
“Our results suggest there are a number of ways to reduce stroke risk simply by moving about,” said lead author Steven P. Hooker, PhD, San Diego State University. “This could be with short periods of moderate to vigorous activity each day, longer periods of light activity, or just sedentary for shorter periods of time. All these things can make a difference.”
Dr. Hooker explained that, while it has been found previously that moderate to vigorous exercise reduces stroke risk, this study gives more information on light-intensity activities and sedentary behavior and the risk of stroke.
“Our results suggest that you don’t have to be a chronic exerciser to reduce stroke risk. Replacing sedentary time with light-intensity activity will be beneficial. Just go for a short walk, get up from your desk and move around the house at regular intervals. That can help to reduce stroke risk,” Dr. Hooker said.
“Our message is basically to sit less and move more,” he added.
The study was published online in JAMA Network Open.
The study involved 7,607 U.S. individuals without a history of stroke, with oversampling from the southeastern “Stroke Belt,” who were participating in the REGARDS cohort study.
The participants wore an accelerometer to measure physical activity and sedentary behavior for 7 consecutive days. The mean age of the individuals was 63 years; 54% were female, 32% were Black.
Over a mean follow-up of 7.4 years, 286 incident stroke cases occurred.
Results showed that increased levels of physical activity were associated with reduced risk of stroke.
For moderate to vigorous activity, compared with participants in the lowest tertile, those in the highest tertile of total daily time in moderate to vigorous activity had a 43% lower risk of stroke.
In the current study, the amount of moderate to vigorous activity associated with a significant reduction in stroke risk was approximately 25 minutes per day (3 hours per week).
Dr. Hooker noted that moderate to vigorous activity included things such as brisk walking, jogging, bike riding, swimming, or playing tennis or soccer. “Doing such activities for just 25 minutes per day reduced risk of stroke by 43%. This is very doable. Just commuting to work by bicycle would cover you here,” he said.
In terms of light-intensity activity, individuals who did 4-5 hours of light activities each day had a 26% reduced risk for first stroke, compared with those doing less than 3 hours of such light activities.
Dr. Hooker explained that examples of light activity included household chores, such as vacuuming, washing dishes, or going for a gentle stroll. “These activities do not require heaving breathing, increased heart rate or breaking into a sweat. They are activities of daily living and relatively easy to engage in.”
But he pointed out that the 4-5 hours of light activity every day linked to a reduction in stroke risk may be more difficult to achieve than the 25 minutes of moderate to vigorous activity, saying: “You have to have some intentionality here.”
Long bouts of sedentary time are harmful
The study also showed that sedentary time was associated with a higher risk for stroke.
The authors noted that time spent in sedentary behavior is of interest because most adults spend most of their awake time being physically inactive.
They report that participants in the highest tertile of sedentary time (more than 13 hours/day) exhibited a 44% increase in risk of stroke, compared with those in the lowest tertile (less than 11 hours/day), and the association remained significant when adjusted for several covariates, including moderate to vigorous activity.
“Even when controlling for the amount of other physical activity, sedentary behavior is still highly associated with risk of stroke. So even if you are active, long bouts of sedentary behavior are harmful,” Dr. Hooker commented.
They also found that longer bouts of sedentary time (more than 17 minutes at a time) were associated with a 54% higher risk of stroke than shorter bouts (less than 8 minutes).
“This suggests that breaking up periods of sedentary behavior into shorter bouts would be beneficial,” Dr. Hooker said.
“If you are going to spend the evening on the couch watching television, try to stand up and walk around every few minutes. Same for if you are sitting at a computer all day – try having a standing workstation, or at least take regular breaks to walk around,” he added.
This research was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Additional funding was provided by an unrestricted grant from the Coca-Cola Company. The authors report no disclosures.
A version of this article first appeared on Medscape.com.
in a population-based study of middle aged and older adults.
The study also found relatively short periods of moderate to vigorous exercise were associated with reduced stroke risk.
“Our results suggest there are a number of ways to reduce stroke risk simply by moving about,” said lead author Steven P. Hooker, PhD, San Diego State University. “This could be with short periods of moderate to vigorous activity each day, longer periods of light activity, or just sedentary for shorter periods of time. All these things can make a difference.”
Dr. Hooker explained that, while it has been found previously that moderate to vigorous exercise reduces stroke risk, this study gives more information on light-intensity activities and sedentary behavior and the risk of stroke.
“Our results suggest that you don’t have to be a chronic exerciser to reduce stroke risk. Replacing sedentary time with light-intensity activity will be beneficial. Just go for a short walk, get up from your desk and move around the house at regular intervals. That can help to reduce stroke risk,” Dr. Hooker said.
“Our message is basically to sit less and move more,” he added.
The study was published online in JAMA Network Open.
The study involved 7,607 U.S. individuals without a history of stroke, with oversampling from the southeastern “Stroke Belt,” who were participating in the REGARDS cohort study.
The participants wore an accelerometer to measure physical activity and sedentary behavior for 7 consecutive days. The mean age of the individuals was 63 years; 54% were female, 32% were Black.
Over a mean follow-up of 7.4 years, 286 incident stroke cases occurred.
Results showed that increased levels of physical activity were associated with reduced risk of stroke.
For moderate to vigorous activity, compared with participants in the lowest tertile, those in the highest tertile of total daily time in moderate to vigorous activity had a 43% lower risk of stroke.
In the current study, the amount of moderate to vigorous activity associated with a significant reduction in stroke risk was approximately 25 minutes per day (3 hours per week).
Dr. Hooker noted that moderate to vigorous activity included things such as brisk walking, jogging, bike riding, swimming, or playing tennis or soccer. “Doing such activities for just 25 minutes per day reduced risk of stroke by 43%. This is very doable. Just commuting to work by bicycle would cover you here,” he said.
In terms of light-intensity activity, individuals who did 4-5 hours of light activities each day had a 26% reduced risk for first stroke, compared with those doing less than 3 hours of such light activities.
Dr. Hooker explained that examples of light activity included household chores, such as vacuuming, washing dishes, or going for a gentle stroll. “These activities do not require heaving breathing, increased heart rate or breaking into a sweat. They are activities of daily living and relatively easy to engage in.”
But he pointed out that the 4-5 hours of light activity every day linked to a reduction in stroke risk may be more difficult to achieve than the 25 minutes of moderate to vigorous activity, saying: “You have to have some intentionality here.”
Long bouts of sedentary time are harmful
The study also showed that sedentary time was associated with a higher risk for stroke.
The authors noted that time spent in sedentary behavior is of interest because most adults spend most of their awake time being physically inactive.
They report that participants in the highest tertile of sedentary time (more than 13 hours/day) exhibited a 44% increase in risk of stroke, compared with those in the lowest tertile (less than 11 hours/day), and the association remained significant when adjusted for several covariates, including moderate to vigorous activity.
“Even when controlling for the amount of other physical activity, sedentary behavior is still highly associated with risk of stroke. So even if you are active, long bouts of sedentary behavior are harmful,” Dr. Hooker commented.
They also found that longer bouts of sedentary time (more than 17 minutes at a time) were associated with a 54% higher risk of stroke than shorter bouts (less than 8 minutes).
“This suggests that breaking up periods of sedentary behavior into shorter bouts would be beneficial,” Dr. Hooker said.
“If you are going to spend the evening on the couch watching television, try to stand up and walk around every few minutes. Same for if you are sitting at a computer all day – try having a standing workstation, or at least take regular breaks to walk around,” he added.
This research was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Additional funding was provided by an unrestricted grant from the Coca-Cola Company. The authors report no disclosures.
A version of this article first appeared on Medscape.com.
in a population-based study of middle aged and older adults.
The study also found relatively short periods of moderate to vigorous exercise were associated with reduced stroke risk.
“Our results suggest there are a number of ways to reduce stroke risk simply by moving about,” said lead author Steven P. Hooker, PhD, San Diego State University. “This could be with short periods of moderate to vigorous activity each day, longer periods of light activity, or just sedentary for shorter periods of time. All these things can make a difference.”
Dr. Hooker explained that, while it has been found previously that moderate to vigorous exercise reduces stroke risk, this study gives more information on light-intensity activities and sedentary behavior and the risk of stroke.
“Our results suggest that you don’t have to be a chronic exerciser to reduce stroke risk. Replacing sedentary time with light-intensity activity will be beneficial. Just go for a short walk, get up from your desk and move around the house at regular intervals. That can help to reduce stroke risk,” Dr. Hooker said.
“Our message is basically to sit less and move more,” he added.
The study was published online in JAMA Network Open.
The study involved 7,607 U.S. individuals without a history of stroke, with oversampling from the southeastern “Stroke Belt,” who were participating in the REGARDS cohort study.
The participants wore an accelerometer to measure physical activity and sedentary behavior for 7 consecutive days. The mean age of the individuals was 63 years; 54% were female, 32% were Black.
Over a mean follow-up of 7.4 years, 286 incident stroke cases occurred.
Results showed that increased levels of physical activity were associated with reduced risk of stroke.
For moderate to vigorous activity, compared with participants in the lowest tertile, those in the highest tertile of total daily time in moderate to vigorous activity had a 43% lower risk of stroke.
In the current study, the amount of moderate to vigorous activity associated with a significant reduction in stroke risk was approximately 25 minutes per day (3 hours per week).
Dr. Hooker noted that moderate to vigorous activity included things such as brisk walking, jogging, bike riding, swimming, or playing tennis or soccer. “Doing such activities for just 25 minutes per day reduced risk of stroke by 43%. This is very doable. Just commuting to work by bicycle would cover you here,” he said.
In terms of light-intensity activity, individuals who did 4-5 hours of light activities each day had a 26% reduced risk for first stroke, compared with those doing less than 3 hours of such light activities.
Dr. Hooker explained that examples of light activity included household chores, such as vacuuming, washing dishes, or going for a gentle stroll. “These activities do not require heaving breathing, increased heart rate or breaking into a sweat. They are activities of daily living and relatively easy to engage in.”
But he pointed out that the 4-5 hours of light activity every day linked to a reduction in stroke risk may be more difficult to achieve than the 25 minutes of moderate to vigorous activity, saying: “You have to have some intentionality here.”
Long bouts of sedentary time are harmful
The study also showed that sedentary time was associated with a higher risk for stroke.
The authors noted that time spent in sedentary behavior is of interest because most adults spend most of their awake time being physically inactive.
They report that participants in the highest tertile of sedentary time (more than 13 hours/day) exhibited a 44% increase in risk of stroke, compared with those in the lowest tertile (less than 11 hours/day), and the association remained significant when adjusted for several covariates, including moderate to vigorous activity.
“Even when controlling for the amount of other physical activity, sedentary behavior is still highly associated with risk of stroke. So even if you are active, long bouts of sedentary behavior are harmful,” Dr. Hooker commented.
They also found that longer bouts of sedentary time (more than 17 minutes at a time) were associated with a 54% higher risk of stroke than shorter bouts (less than 8 minutes).
“This suggests that breaking up periods of sedentary behavior into shorter bouts would be beneficial,” Dr. Hooker said.
“If you are going to spend the evening on the couch watching television, try to stand up and walk around every few minutes. Same for if you are sitting at a computer all day – try having a standing workstation, or at least take regular breaks to walk around,” he added.
This research was supported by grants from the National Institute of Neurological Disorders and Stroke and the National Institute on Aging. Additional funding was provided by an unrestricted grant from the Coca-Cola Company. The authors report no disclosures.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
‘Remission is possible’ for patients with type 2 diabetes
A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.
Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.
This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.
Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.
An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.
Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.
Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).
These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
Remission is not reversal or cure ...
“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission
Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.
However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.
“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”
This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”
The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”
“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
How the intervention works
The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.
The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.
The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.
The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.
The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.
The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.
The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.
U.S. clinical trial, health insurance coverage
The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.
The company has started a clinical trial in the United States, with 5-year results expected in 2027.
“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”
The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.
A version of this article first appeared on Medscape.com.
A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.
Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.
This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.
Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.
An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.
Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.
Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).
These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
Remission is not reversal or cure ...
“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission
Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.
However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.
“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”
This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”
The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”
“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
How the intervention works
The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.
The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.
The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.
The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.
The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.
The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.
The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.
U.S. clinical trial, health insurance coverage
The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.
The company has started a clinical trial in the United States, with 5-year results expected in 2027.
“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”
The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.
A version of this article first appeared on Medscape.com.
A novel approach that involves sensors, artificial intelligence, and real-time individualized lifestyle guidance from an app and live coaches led to a high rate of remission of type 2 diabetes in a new study.
Specifically, among 199 patients with type 2 diabetes in India who received the app-delivered lifestyle guidance developed by Twin Health, Mountain View, Calif., mean hemoglobin A1c dropped from 9.0% to 5.7% at 6 months.
This is “huge,” Paramesh Shamanna, MD, told a press briefing at the annual scientific sessions of the American Diabetes Association. The research was presented as three posters by the group at the meeting.
Patients were a mean age of 43 and had diabetes for a mean of 3.7 years and up to 8 years.
An “unprecedented” 84% of patients had remission of diabetes at 6 months, Dr. Shamanna, medical director at Twin Health, noted.
Diabetes remission was defined according to the 2021 joint consensus statement from the ADA and other organizations as an A1c less than 6.5% without the use of diabetes medications for at least 3 months.
Importantly, patients’ time in range (percentage of time spent in target blood glucose range) increased from 53% to 81%, Dr. Shamanna pointed out. On average, patients’ waist circumference decreased by 10 cm (3.9 inches) and their weight dropped from 79 kg (approximately 174 lb) to 68 kg (150 lb).
These results are driven by “the continuous individualized and precise guidance regarding nutrition, activity, and sleep,” Dr. Shamanna said in an interview.
Remission is not reversal or cure ...
“Remission” from type 2 diabetes is not “reversal” or a “cure,” Robert A. Gabbay, MD, PhD, chief scientific and medical officer of the ADA, stressed to the press. Just like cancer, diabetes can return after remission
Therefore, it is important to follow the lifestyle guidance. Patients may still be at risk for diabetes complications after diabetes remission, so it’s also important to continue to be screened for eye disease, nerve damage, and lipid levels.
However, “remission can be made to last,” Dr. Shamanna said, by continuing to follow the lifestyle advice and getting back on track after a relapse.
“We’re in a different time right now,” Lisa Shah, MD, chief medical officer, Twin Health, noted. “This is very different from management of blood glucose to a certain number.”
This study shows that “remission [from type 2 diabetes] is possible. How you achieve it can be precise for you.”
The program is designed to consider the health and happiness of the patient, added Shashank R. Joshi, MD, chief scientist, Twin Health. “We want remission to be complication free. These findings give patients hope.”
“It’s exciting now that we can really start thinking about remission as an option for people with [type 2] diabetes, and that just provides such incredible hope for all of those living with [type 2] diabetes,” Dr. Gabbay said in an interview.
How the intervention works
The Twin Precision Treatment (TPT) intervention integrates multiple data – glucose values from a continuous glucose monitor (CGM); heart rate, activity, and sleep time from a fitness tracker; blood pressure values from a blood pressure cuff; food intake from the patient’s food log; and weight and body fat data from a smart scale – and provides the patient with precise, individualized nutrition and health guidance.
The four most critical sensors are the CGM, the fitness tracker, the smart scale, and the blood pressure cuff, Dr. Shah explained. The system gathers thousands of signals combined with patient self-reported data including mood or anxiety.
The CGM is used to build the initial nutrition guidance during the first 30 days. Once a patient is in remission, he or she can just keep the fitness tracker and smart scale.
The coaches who are part of this program include dietitians who are trained to provide compassionate patient education and help patients avoid diabetes relapse, and they are overseen by a licensed provider.
The program does not restrict calories. “It is not a diet,” Dr. Shah stressed.
The algorithm makes mini adjustments to the food a person is already eating to improve nutrition, Dr. Joshi explained. “This is personalized medicine at its best.” Patients eat food that they like and are guided to make small changes to get glucose under control and avoid glucose spikes.
The program is designed to safely deescalate diabetes medications as A1c decreases, Dr. Shamanna added.
U.S. clinical trial, health insurance coverage
The 1-year results of the current trial are expected in August, and the trial will continue for 2-=5 years, Dr. Shamanna said.
The company has started a clinical trial in the United States, with 5-year results expected in 2027.
“Currently, in the United States, we are partnering with self-insured employers and select health plans that offer [Twin Precision Treatment ] as an available benefit for their members,” Dr. Shah said. It “is suitable for most members living with type 2 diabetes, with rare exclusion situations.”
The study was funded by Twin Health. Dr. Shamanna, Dr. Shah, and Dr. Joshi are employees of Twin Health.
A version of this article first appeared on Medscape.com.
FROM ADA 2022
Blood-based assay may offer new way of diagnosing Parkinson’s disease
A novel blood-based assay could one day be used to diagnose Parkinson’s disease and possibly other chronic inflammatory conditions, according to investigators. In addition to being highly accurate, the assay, which detects changes in expression of cytochrome P450s, is faster and easier to perform than other Parkinson’s disease assays under investigation, reported lead author Kohei Ihara, PhD, of Kobe University, Japan, and colleagues.
“Effective diagnostic systems and biomarkers for patients without subjective motor symptoms have not yet been established,” the investigators wrote in Nature Scientific Reports. “Consequently, the poor diagnostic options for Parkinson’s disease delay the development of therapeutic approaches and medication. Therefore, the development of efficient diagnostic systems and biomarkers is crucial for overcoming Parkinson’s disease.”
According to Dr. Ihara and colleagues, various cytochrome P450 expression patterns and associated serum metabolites correlate with chronic conditions, making them possible markers of disease. To detect these changes, they developed the present assay. It relies upon recombinant P450s expressed on the surface of Escherichia coli. By mixing the E. coli with serum and Vivid, a fluorescent substrate, the investigators can measure “the inhibition rate of the Vivid decomposition reaction” that was driven by “serum metabolites associated with P450s,” revealing underlying expression and, if present, disease.
After some promising initial experiments with mouse models of ulcerative colitis and diabetes, Dr. Ihara and colleagues focused on a rat model of Parkinson’s disease. Evaluating inhibition rates associated with four P450s revealed area-under-the-curve (AUC) values of 0.814-0.914. Two of those P450s were also associated with progression of disease symptoms.
“Therefore, we concluded that the P450 inhibition assay could discriminate between Parkinson’s disease model rats and control rats,” the investigators wrote.
Next, the investigators tested the approach with a case-control study involving 20 patients with Parkinson’s disease and 20 healthy volunteers. Twelve P450s were analyzed, three of which revealed significant differences between patients with Parkinson’s disease and controls, with AUCs ranging from 0.740-0.775. Each of the three P450 enzymes also correlated significantly with stage of disease on the Hoehn & Yahr scale, although severity and frequency of symptoms were not reported.
To increase accuracy of the technique, the investigators developed a logistic regression model using two of the three P450s, generating an AUC of 0.910. Further testing showed that the P450 inhibition assay could distinguish between patients with Parkinson’s disease and Alzheimer’s disease, as well as other chronic inflammatory diseases.
“The P450 inhibition assay is easier to perform and is faster than other assays because this assay does not require pretreatment, such as purification of exosomes, and it involves a single enzymatic reaction,” the investigators wrote, suggesting that the assay may be suitable for real-world diagnosis.
‘Promising’ findings need replication
According to Douglas Galasko, MD, a neurologist and professor of neurosciences at UC San Diego Health, the reported accuracy of the assay “seems spectacular,” and the findings are “promising,” but they need to be replicated, “particularly in early-stage patients where the diagnosis [of Parkinson’s disease] is more difficult and important to make.” In practice, the assay would likely see greatest usage for “early diagnosis or diagnosis of unusual or challenging cases,” so accuracy testing needs to be conducted in this setting, he said.
Dr. Galasko, who was not involved in the study, predicted that liquid biopsy for detecting Parkinson’s disease is unlikely to hit the clinic floor anytime soon. “We’re not really close with blood-based biomarkers for Parkinson’s disease,” he said, “unlike the situation for Alzheimer’s disease, where there are several promising blood-based biomarkers.”
For diagnosing Parkinson’s disease, Dr. Galasko suggested that assays using skin biopsies to measure alpha-synuclein accumulation may be closer to approval.
The study was supported by JSPS KAKENHI Grant Number 20K20223 and the Sumitomo Electric Industries Group Corporate Social Responsibility Foundation. The investigators disclosed no conflicts of interest.
A novel blood-based assay could one day be used to diagnose Parkinson’s disease and possibly other chronic inflammatory conditions, according to investigators. In addition to being highly accurate, the assay, which detects changes in expression of cytochrome P450s, is faster and easier to perform than other Parkinson’s disease assays under investigation, reported lead author Kohei Ihara, PhD, of Kobe University, Japan, and colleagues.
“Effective diagnostic systems and biomarkers for patients without subjective motor symptoms have not yet been established,” the investigators wrote in Nature Scientific Reports. “Consequently, the poor diagnostic options for Parkinson’s disease delay the development of therapeutic approaches and medication. Therefore, the development of efficient diagnostic systems and biomarkers is crucial for overcoming Parkinson’s disease.”
According to Dr. Ihara and colleagues, various cytochrome P450 expression patterns and associated serum metabolites correlate with chronic conditions, making them possible markers of disease. To detect these changes, they developed the present assay. It relies upon recombinant P450s expressed on the surface of Escherichia coli. By mixing the E. coli with serum and Vivid, a fluorescent substrate, the investigators can measure “the inhibition rate of the Vivid decomposition reaction” that was driven by “serum metabolites associated with P450s,” revealing underlying expression and, if present, disease.
After some promising initial experiments with mouse models of ulcerative colitis and diabetes, Dr. Ihara and colleagues focused on a rat model of Parkinson’s disease. Evaluating inhibition rates associated with four P450s revealed area-under-the-curve (AUC) values of 0.814-0.914. Two of those P450s were also associated with progression of disease symptoms.
“Therefore, we concluded that the P450 inhibition assay could discriminate between Parkinson’s disease model rats and control rats,” the investigators wrote.
Next, the investigators tested the approach with a case-control study involving 20 patients with Parkinson’s disease and 20 healthy volunteers. Twelve P450s were analyzed, three of which revealed significant differences between patients with Parkinson’s disease and controls, with AUCs ranging from 0.740-0.775. Each of the three P450 enzymes also correlated significantly with stage of disease on the Hoehn & Yahr scale, although severity and frequency of symptoms were not reported.
To increase accuracy of the technique, the investigators developed a logistic regression model using two of the three P450s, generating an AUC of 0.910. Further testing showed that the P450 inhibition assay could distinguish between patients with Parkinson’s disease and Alzheimer’s disease, as well as other chronic inflammatory diseases.
“The P450 inhibition assay is easier to perform and is faster than other assays because this assay does not require pretreatment, such as purification of exosomes, and it involves a single enzymatic reaction,” the investigators wrote, suggesting that the assay may be suitable for real-world diagnosis.
‘Promising’ findings need replication
According to Douglas Galasko, MD, a neurologist and professor of neurosciences at UC San Diego Health, the reported accuracy of the assay “seems spectacular,” and the findings are “promising,” but they need to be replicated, “particularly in early-stage patients where the diagnosis [of Parkinson’s disease] is more difficult and important to make.” In practice, the assay would likely see greatest usage for “early diagnosis or diagnosis of unusual or challenging cases,” so accuracy testing needs to be conducted in this setting, he said.
Dr. Galasko, who was not involved in the study, predicted that liquid biopsy for detecting Parkinson’s disease is unlikely to hit the clinic floor anytime soon. “We’re not really close with blood-based biomarkers for Parkinson’s disease,” he said, “unlike the situation for Alzheimer’s disease, where there are several promising blood-based biomarkers.”
For diagnosing Parkinson’s disease, Dr. Galasko suggested that assays using skin biopsies to measure alpha-synuclein accumulation may be closer to approval.
The study was supported by JSPS KAKENHI Grant Number 20K20223 and the Sumitomo Electric Industries Group Corporate Social Responsibility Foundation. The investigators disclosed no conflicts of interest.
A novel blood-based assay could one day be used to diagnose Parkinson’s disease and possibly other chronic inflammatory conditions, according to investigators. In addition to being highly accurate, the assay, which detects changes in expression of cytochrome P450s, is faster and easier to perform than other Parkinson’s disease assays under investigation, reported lead author Kohei Ihara, PhD, of Kobe University, Japan, and colleagues.
“Effective diagnostic systems and biomarkers for patients without subjective motor symptoms have not yet been established,” the investigators wrote in Nature Scientific Reports. “Consequently, the poor diagnostic options for Parkinson’s disease delay the development of therapeutic approaches and medication. Therefore, the development of efficient diagnostic systems and biomarkers is crucial for overcoming Parkinson’s disease.”
According to Dr. Ihara and colleagues, various cytochrome P450 expression patterns and associated serum metabolites correlate with chronic conditions, making them possible markers of disease. To detect these changes, they developed the present assay. It relies upon recombinant P450s expressed on the surface of Escherichia coli. By mixing the E. coli with serum and Vivid, a fluorescent substrate, the investigators can measure “the inhibition rate of the Vivid decomposition reaction” that was driven by “serum metabolites associated with P450s,” revealing underlying expression and, if present, disease.
After some promising initial experiments with mouse models of ulcerative colitis and diabetes, Dr. Ihara and colleagues focused on a rat model of Parkinson’s disease. Evaluating inhibition rates associated with four P450s revealed area-under-the-curve (AUC) values of 0.814-0.914. Two of those P450s were also associated with progression of disease symptoms.
“Therefore, we concluded that the P450 inhibition assay could discriminate between Parkinson’s disease model rats and control rats,” the investigators wrote.
Next, the investigators tested the approach with a case-control study involving 20 patients with Parkinson’s disease and 20 healthy volunteers. Twelve P450s were analyzed, three of which revealed significant differences between patients with Parkinson’s disease and controls, with AUCs ranging from 0.740-0.775. Each of the three P450 enzymes also correlated significantly with stage of disease on the Hoehn & Yahr scale, although severity and frequency of symptoms were not reported.
To increase accuracy of the technique, the investigators developed a logistic regression model using two of the three P450s, generating an AUC of 0.910. Further testing showed that the P450 inhibition assay could distinguish between patients with Parkinson’s disease and Alzheimer’s disease, as well as other chronic inflammatory diseases.
“The P450 inhibition assay is easier to perform and is faster than other assays because this assay does not require pretreatment, such as purification of exosomes, and it involves a single enzymatic reaction,” the investigators wrote, suggesting that the assay may be suitable for real-world diagnosis.
‘Promising’ findings need replication
According to Douglas Galasko, MD, a neurologist and professor of neurosciences at UC San Diego Health, the reported accuracy of the assay “seems spectacular,” and the findings are “promising,” but they need to be replicated, “particularly in early-stage patients where the diagnosis [of Parkinson’s disease] is more difficult and important to make.” In practice, the assay would likely see greatest usage for “early diagnosis or diagnosis of unusual or challenging cases,” so accuracy testing needs to be conducted in this setting, he said.
Dr. Galasko, who was not involved in the study, predicted that liquid biopsy for detecting Parkinson’s disease is unlikely to hit the clinic floor anytime soon. “We’re not really close with blood-based biomarkers for Parkinson’s disease,” he said, “unlike the situation for Alzheimer’s disease, where there are several promising blood-based biomarkers.”
For diagnosing Parkinson’s disease, Dr. Galasko suggested that assays using skin biopsies to measure alpha-synuclein accumulation may be closer to approval.
The study was supported by JSPS KAKENHI Grant Number 20K20223 and the Sumitomo Electric Industries Group Corporate Social Responsibility Foundation. The investigators disclosed no conflicts of interest.
FROM NATURE SCIENTIFIC REPORTS
Antidiabetes drug costs keep patients away
NEW ORLEANS – , according to findings from two separate studies.
One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.
A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.
“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.
Prevention drug lists can help
Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.
One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.
The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.
PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”
Newer, more effective drugs cost a lot
“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”
About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.
The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.
People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.
In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.
Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.
“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.
Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.
NEW ORLEANS – , according to findings from two separate studies.
One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.
A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.
“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.
Prevention drug lists can help
Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.
One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.
The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.
PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”
Newer, more effective drugs cost a lot
“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”
About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.
The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.
People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.
In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.
Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.
“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.
Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.
NEW ORLEANS – , according to findings from two separate studies.
One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.
A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.
“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.
Prevention drug lists can help
Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.
One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.
The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.
PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”
Newer, more effective drugs cost a lot
“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”
About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.
The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.
People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.
In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.
Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.
“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.
Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.
AT ADA 2022
‘Exciting’ new gene therapy yields promising results
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
In the first-in-human, phase 1 open-label study, known as ANTLER, 5 out of 5 patients with relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL) responded to a single dose of CB-010, an allogeneic CAR-T cell therapy designed to boost antitumor activity, according to the company.
The use of chimeric antigen receptor (CAR) T-cell therapy involves taking T cells out of the body, reprogramming them with CAR to better equip them to kill cancer cells, and putting them back into the body.
The study consists of two sections: an initial dose escalation following a 3 + 3 design, with prespecified, increasing doses, followed by an expanded trial in which all patients receive CB-010 at the dose determined in the first section.
The study population included 6 adults with r/r B-NHL who had relapsed after previous treatment with a median of 3 prior therapies. At baseline, all 6 patients underwent a lymphodepletion regimen consisting of cyclophosphamide at 60 mg/kg/day for 2 days, followed by 5 days of fludarabine at 25 mg/m2/day.
Then all patients received a single dose of 40x106 CAR-T cells. As of the Feb. 23, 2022, data cutoff date, 5 of the 6 patients had completed the 28-day dose-limiting toxicity (DLT) evaluation period. All 5 patients (100%) achieved a response; 4 achieved complete response and 1 achieved partial response. All 4 of the complete responders had ongoing complete response at 3 months, and the longest measured complete response was 6 months, according to the company.
“We are excited to see a 100% overall response rate with CB-010 at dose level 1 for these patients who have limited treatment options,” said Dr. Syed Rizvi, chief medical officer for Caribou Biosciences, in the press release. “We believe this initial level of activity is unparalleled for a single, starting dose of cell therapy. CB-010 was generally well-tolerated, with adverse events routinely observed in autologous or allogeneic anti-CD19 CAR-T cell therapies,” he said.
Based on the promising safety and efficacy results, the company is enrolling patients in a second cohort for treatment at dose level 2 (80x106 CAR-T cells), according to the news release.
Another allogeneic CAR-T cell therapy known as ALLO-501A is being studied in a similar trial conducted by the Moffitt Cancer Center.
Overall, CB-010 was well-tolerated, according to Caribou Biosciences. No cases of graft-versus-host disease were reported. A total of 3 patients developed grade 3 or 4 adverse events (AEs) within the first 28 days; the most common were neutropenia (50%), thrombocytopenia (33%), anemia (17%), and hypogammaglobulinemia (17%). One patient experienced both grade 1 cytokine release syndrome (CRS) and grade 3 Immune effector cell-Associated Neurotoxicity Syndrome (ICANS). This response was characterized as a dose-limiting toxicity. The patient was treated with tocilizumab and steroids, recovered within 39 hours, and went on to achieve a complete response, according to the company.
Although the safety profile in the current study was promising, prior research suggest that concerns associated with CRS and ICANS should not be ignored and may be barriers to treatment.
In an article published in Bone Marrow Transplant in 2021, Dr. Vipul Sheth and Dr. Jordan Gauthier of the Fred Hutchinson Cancer Center, Seattle, noted that adverse effects may remain a challenge to widespread use of CAR-T in patients with refractory or relapsed acute lymphoblastic leukemia, for which it has been approved by the U.S. Food and Drug Administration and several European agencies. However, “there is mounting evidence that earlier, and potentially more targeted, interventions can reduce these toxicities,” they wrote.
Study provides solid stepping stone
“CRS and ICANS are mild in most patients but can be severe and sometimes life-threatening in a subset of patients undergoing CD19 CAR T-cell therapy,” Dr. Gauthier said in an interview. “Different strategies are being investigated to mitigate or treat severe toxicities, such as the use of prophylactic corticosteroids, anakinra, lenzilumab, itacitinib. I am hopeful we will soon manage to prevent toxicities while maintaining potent anti-tumor effects,” he said.
“While autologous CD19 CAR-T cells have high efficacy in patients with refractory/relapsed large B-cell lymphoma, product manufacturing remains a complicated and lengthy process in the autologous setting,” Dr. Gauthier noted. “Commercial CAR T-cell manufacturing takes approximately 3-4 weeks, sometimes longer. Some patients won’t survive long enough to receive their infusion. In some patients, T-cell function is dramatically impaired, due to prior therapies or to the disease itself,” he said.
Dr. Gauthier said he was not surprised but that he was encouraged by the apparent early success of the ANTLER study. “The proof-of-concept that allogeneic CD19-targeted CAR T cells can induce high response rates in r/r LBCL has already been established,” he said. “Having said that, it is comforting to see prior findings confirmed by this new study, and those results are exciting for the field,” he added.
As for additional research, “we need longer follow-up after allogeneic CD19-targeted CAR T-cell therapy to ensure responses are durable,” Dr. Gauthier explained. “We also need to better understand the biology driving the antitumor effects and the side effects of CAR T-cells. This will help us build more efficacious and safer CAR T-cell therapies,” he said.
Response and side effects show promise for future research
The therapy is “the best CAR-T product” that clinicians can provide for patients knowing that autologous CAR-T works, said Dr. Ahmed Galal, of Duke University, Durham, N.C., in an interview. The current research supports the use of this treatment immediately for patients, he added.
Dr. Galal said he was somewhat surprised, but pleasantly so, by the 100% response rate. This rate is likely because of the small number of patients and may not hold up in further research, but “even 90% would be an amazing achievement,” he said. The tolerable safety profile is encouraging as well, he emphasized. Dr. Galal said that he did not foresee any real barriers to expanded use of the therapy and that technology should make it easier to deliver at authorized centers.
Limitations to the current study are those common to all phase 1 trials, such as the strict inclusion criteria, Dr. Galal said. As research progresses to phase 2, “I don’t think it will be an obstacle to find patients,” he said. However, patients should be aware of side effects, and clinicians should maintain a culture of education to help them understand the value of the therapy, he added.
The complete data from the preliminary findings are scheduled to be presented at the European Hematology Association (EHA) 2022 Hybrid Congress, Vienna, in June, as abstract P1455, titled “First-in-human trial of CB-010, a CRISPR-edited allogeneic anti-CD19 CAR-T cell therapy with a PD-1 knock out, in patients with relapsed or refractory B cell non-Hodgkin lymphoma (ANTLER study).” The findings are scheduled to be presented by Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, according to Caribou Biosciences.
Dr. Gauthier had no financial conflicts to disclose. Dr. Galal had no financial conflicts to disclose.
Weekly dulaglutide promising in youth with type 2 diabetes
Another glucagonlike peptide-1 (GLP1) agonist, dulaglutide (Trulicity, Lilly), is poised to be a new option for glycemic control in youth aged 10-18 years with type 2 diabetes, given as a weekly injection, based on the AWARD-PEDS clinical trial.
The U.S. Food and Drug Administration has already approved daily injection liraglutide (Victoza, Novo Nordisk) in 2019 and weekly exenatide (Bydureon/Bydureon BCise, AstraZeneca) in 2021 for glycemic control in young patients with type 2 diabetes, both of which are also GLP-1 agonists.
AWARD-PEDS showed that youth with type 2 diabetes and obesity treated with or without metformin or basal insulin who received weekly injections of 0.75 mg or 1.5 mg of dulaglutide had lower hemoglobin A1c at 26 weeks than patients who received placebo.
Eli Lilly is now submitting these trial results to the FDA for this indication.
Dulaglutide was cleared for use in adults with type 2 diabetes in the United States in 2014 and was additionally approved for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes at high risk of such events in 2020.
The most common adverse symptoms were gastrointestinal, and the safety profile was consistent with that in adults. However, the drug had no effect on body mass index.
The study was simultaneously published in the New England Journal of Medicine and presented as a late-breaking poster at the annual scientific sessions of the American Diabetes Association in New Orleans.
Might dulaglutide target pathophysiologic impairments in youth?
Dulaglutide would “offer a new treatment that targets the pathophysiologic impairments of type 2 diabetes in youth,” Silva A. Arslanian, MD, lead investigator, told this news organization.
Exenatide is also given as a weekly injection but is associated with a smaller decrease in A1c and does not improve fasting glucose concentrations, plus it requires more steps compared with the dulaglutide single-use pen, said Dr. Arslanian, who is scientific director at the Center for Pediatric Research in Obesity & Metabolism, UPMC Children’s Hospital of Pittsburgh.
“Liraglutide is a daily injection, and I believe most patients, particularly adolescents, would prefer a weekly injection,” she added. 
Invited to comment, Elvira Isganaitis, MD, MPH, said “the significance of this paper lies in the fact that options for treating type 2 diabetes in children are currently much more limited than in adults – which is a major problem given recent studies that show that type 2 diabetes in youth is much more aggressive and more likely to cause complications early in the disease course.”
Dr. Isganaitis was not involved with the trial but is an investigator for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
“With supply chain shortages and health insurance coverage issues that are common in the U.S., it would be helpful to have more than one FDA-approved option for a weekly GLP-1 receptor agonist in children [and] access to other classes of medications,” added Dr. Isganaitis, a pediatric endocrinologist at the Joslin Diabetes Center, Boston.
Phase 3 trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in youth with type 2 diabetes are also ongoing, Dr. Arslanian noted, “but as always, recruitment is slow with adolescents.”
“I am not optimistic that DPP4 inhibitors will have a place in the treatment of youth with type 2 diabetes,” she said. A recent study showed the addition of sitagliptin to metformin in youth with type 2 diabetes did not provide durable improvement in glycemic control.
Potentially promising therapy
In their published article, Dr. Arslanian and colleagues write that “considering the progressive increase in [A1c] over time that was observed in the TODAY trial, with 34% of youths having [an A1c] of at least 10% after up to 15 years of follow-up, we believe that the effects of dulaglutide therapy appear to be potentially promising.”
The TODAY trial showed that more than 50% of youth with type 2 diabetes taking metformin failed to maintain glycemic control within a median of 11.5 months, Dr. Arslanian elaborated, and over time their A1c escalated while their beta-cell function deteriorated rapidly, and complications progressed quickly.
“Therefore,” she noted, “considering that dulaglutide and the GLP-1 receptor agonist class of drugs improve A1c, improve beta-cell function, suppress glucagon concentrations, and improve insulin sensitivity, dulaglutide would provide a promising new treatment option for youth with type 2 diabetes.”
Phase 3 superiority trial
The AWARD-PEDS trial included 154 youth with type 2 diabetes and a BMI greater than the 85th percentile for their age and sex at 46 centers in nine countries. Researchers randomized participants 1:1:1 to the two doses of dulaglutide or placebo for 26 weeks, followed by a 26-week open-label study (during which the placebo group received 0.75 mg dulaglutide) and a 4-week safety extension.
Participants were a mean age of 14.5 years and had a mean BMI of 34 kg/m2.
In each of the dulaglutide groups, roughly 66% of patients were female and 58% were White, 18% were Black, and about 57% were Hispanic. They had a mean weight of 91 kg (200 lb) and a mean A1c of about 8%; 62% were taking metformin only, 27% were taking metformin plus basal insulin, 3% were taking basal insulin only, and 10% were on diet and exercise only.
At 26 weeks, mean A1c increased by 0.6% in the placebo group but decreased by 0.6% in the 0.75-mg dulaglutide group and by 0.9% in the 1.5-mg dulaglutide group (P < .001 for both comparisons versus placebo).
Also at 26 weeks, more participants in the pooled dulaglutide groups than in the placebo group had an A1c <7.0% (51% vs. 14%; P < .001).
Fasting glucose concentration increased in the placebo group (+17.1 mg/dL ) and decreased in the pooled dulaglutide groups (–18.9 mg/dL; P < .001).
There were no group differences in BMI or adiposity-related parameters even at 52 weeks.
“I believe adolescents may be somewhat resistant to the weight-reducing effects of GLP-1 agonists in diabetes trials (liraglutide and exenatide youth type 2 diabetes trials showed the same thing) and they may need higher doses,” Dr. Arslanian speculated.
“Only future studies will be able to address this issue,” she concluded.
The study was funded by Eli Lilly. Dr. Arslanian has disclosed being a consultant for Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals; participating in data safety monitoring for AstraZeneca and Eli Lilly trials; and receiving institutional research funding from Eli Lilly and Novo Nordisk. Dr. Isganaitis has disclosed receiving research funding (paid to her institution) from Dexcom and AstraZeneca.
A version of this article first appeared on Medscape.com.
Another glucagonlike peptide-1 (GLP1) agonist, dulaglutide (Trulicity, Lilly), is poised to be a new option for glycemic control in youth aged 10-18 years with type 2 diabetes, given as a weekly injection, based on the AWARD-PEDS clinical trial.
The U.S. Food and Drug Administration has already approved daily injection liraglutide (Victoza, Novo Nordisk) in 2019 and weekly exenatide (Bydureon/Bydureon BCise, AstraZeneca) in 2021 for glycemic control in young patients with type 2 diabetes, both of which are also GLP-1 agonists.
AWARD-PEDS showed that youth with type 2 diabetes and obesity treated with or without metformin or basal insulin who received weekly injections of 0.75 mg or 1.5 mg of dulaglutide had lower hemoglobin A1c at 26 weeks than patients who received placebo.
Eli Lilly is now submitting these trial results to the FDA for this indication.
Dulaglutide was cleared for use in adults with type 2 diabetes in the United States in 2014 and was additionally approved for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes at high risk of such events in 2020.
The most common adverse symptoms were gastrointestinal, and the safety profile was consistent with that in adults. However, the drug had no effect on body mass index.
The study was simultaneously published in the New England Journal of Medicine and presented as a late-breaking poster at the annual scientific sessions of the American Diabetes Association in New Orleans.
Might dulaglutide target pathophysiologic impairments in youth?
Dulaglutide would “offer a new treatment that targets the pathophysiologic impairments of type 2 diabetes in youth,” Silva A. Arslanian, MD, lead investigator, told this news organization.
Exenatide is also given as a weekly injection but is associated with a smaller decrease in A1c and does not improve fasting glucose concentrations, plus it requires more steps compared with the dulaglutide single-use pen, said Dr. Arslanian, who is scientific director at the Center for Pediatric Research in Obesity & Metabolism, UPMC Children’s Hospital of Pittsburgh.
“Liraglutide is a daily injection, and I believe most patients, particularly adolescents, would prefer a weekly injection,” she added.
Invited to comment, Elvira Isganaitis, MD, MPH, said “the significance of this paper lies in the fact that options for treating type 2 diabetes in children are currently much more limited than in adults – which is a major problem given recent studies that show that type 2 diabetes in youth is much more aggressive and more likely to cause complications early in the disease course.”
Dr. Isganaitis was not involved with the trial but is an investigator for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
“With supply chain shortages and health insurance coverage issues that are common in the U.S., it would be helpful to have more than one FDA-approved option for a weekly GLP-1 receptor agonist in children [and] access to other classes of medications,” added Dr. Isganaitis, a pediatric endocrinologist at the Joslin Diabetes Center, Boston.
Phase 3 trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in youth with type 2 diabetes are also ongoing, Dr. Arslanian noted, “but as always, recruitment is slow with adolescents.”
“I am not optimistic that DPP4 inhibitors will have a place in the treatment of youth with type 2 diabetes,” she said. A recent study showed the addition of sitagliptin to metformin in youth with type 2 diabetes did not provide durable improvement in glycemic control.
Potentially promising therapy
In their published article, Dr. Arslanian and colleagues write that “considering the progressive increase in [A1c] over time that was observed in the TODAY trial, with 34% of youths having [an A1c] of at least 10% after up to 15 years of follow-up, we believe that the effects of dulaglutide therapy appear to be potentially promising.”
The TODAY trial showed that more than 50% of youth with type 2 diabetes taking metformin failed to maintain glycemic control within a median of 11.5 months, Dr. Arslanian elaborated, and over time their A1c escalated while their beta-cell function deteriorated rapidly, and complications progressed quickly.
“Therefore,” she noted, “considering that dulaglutide and the GLP-1 receptor agonist class of drugs improve A1c, improve beta-cell function, suppress glucagon concentrations, and improve insulin sensitivity, dulaglutide would provide a promising new treatment option for youth with type 2 diabetes.”
Phase 3 superiority trial
The AWARD-PEDS trial included 154 youth with type 2 diabetes and a BMI greater than the 85th percentile for their age and sex at 46 centers in nine countries. Researchers randomized participants 1:1:1 to the two doses of dulaglutide or placebo for 26 weeks, followed by a 26-week open-label study (during which the placebo group received 0.75 mg dulaglutide) and a 4-week safety extension.
Participants were a mean age of 14.5 years and had a mean BMI of 34 kg/m2.
In each of the dulaglutide groups, roughly 66% of patients were female and 58% were White, 18% were Black, and about 57% were Hispanic. They had a mean weight of 91 kg (200 lb) and a mean A1c of about 8%; 62% were taking metformin only, 27% were taking metformin plus basal insulin, 3% were taking basal insulin only, and 10% were on diet and exercise only.
At 26 weeks, mean A1c increased by 0.6% in the placebo group but decreased by 0.6% in the 0.75-mg dulaglutide group and by 0.9% in the 1.5-mg dulaglutide group (P < .001 for both comparisons versus placebo).
Also at 26 weeks, more participants in the pooled dulaglutide groups than in the placebo group had an A1c <7.0% (51% vs. 14%; P < .001).
Fasting glucose concentration increased in the placebo group (+17.1 mg/dL ) and decreased in the pooled dulaglutide groups (–18.9 mg/dL; P < .001).
There were no group differences in BMI or adiposity-related parameters even at 52 weeks.
“I believe adolescents may be somewhat resistant to the weight-reducing effects of GLP-1 agonists in diabetes trials (liraglutide and exenatide youth type 2 diabetes trials showed the same thing) and they may need higher doses,” Dr. Arslanian speculated.
“Only future studies will be able to address this issue,” she concluded.
The study was funded by Eli Lilly. Dr. Arslanian has disclosed being a consultant for Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals; participating in data safety monitoring for AstraZeneca and Eli Lilly trials; and receiving institutional research funding from Eli Lilly and Novo Nordisk. Dr. Isganaitis has disclosed receiving research funding (paid to her institution) from Dexcom and AstraZeneca.
A version of this article first appeared on Medscape.com.
Another glucagonlike peptide-1 (GLP1) agonist, dulaglutide (Trulicity, Lilly), is poised to be a new option for glycemic control in youth aged 10-18 years with type 2 diabetes, given as a weekly injection, based on the AWARD-PEDS clinical trial.
The U.S. Food and Drug Administration has already approved daily injection liraglutide (Victoza, Novo Nordisk) in 2019 and weekly exenatide (Bydureon/Bydureon BCise, AstraZeneca) in 2021 for glycemic control in young patients with type 2 diabetes, both of which are also GLP-1 agonists.
AWARD-PEDS showed that youth with type 2 diabetes and obesity treated with or without metformin or basal insulin who received weekly injections of 0.75 mg or 1.5 mg of dulaglutide had lower hemoglobin A1c at 26 weeks than patients who received placebo.
Eli Lilly is now submitting these trial results to the FDA for this indication.
Dulaglutide was cleared for use in adults with type 2 diabetes in the United States in 2014 and was additionally approved for reducing the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes at high risk of such events in 2020.
The most common adverse symptoms were gastrointestinal, and the safety profile was consistent with that in adults. However, the drug had no effect on body mass index.
The study was simultaneously published in the New England Journal of Medicine and presented as a late-breaking poster at the annual scientific sessions of the American Diabetes Association in New Orleans.
Might dulaglutide target pathophysiologic impairments in youth?
Dulaglutide would “offer a new treatment that targets the pathophysiologic impairments of type 2 diabetes in youth,” Silva A. Arslanian, MD, lead investigator, told this news organization.
Exenatide is also given as a weekly injection but is associated with a smaller decrease in A1c and does not improve fasting glucose concentrations, plus it requires more steps compared with the dulaglutide single-use pen, said Dr. Arslanian, who is scientific director at the Center for Pediatric Research in Obesity & Metabolism, UPMC Children’s Hospital of Pittsburgh.
“Liraglutide is a daily injection, and I believe most patients, particularly adolescents, would prefer a weekly injection,” she added.
Invited to comment, Elvira Isganaitis, MD, MPH, said “the significance of this paper lies in the fact that options for treating type 2 diabetes in children are currently much more limited than in adults – which is a major problem given recent studies that show that type 2 diabetes in youth is much more aggressive and more likely to cause complications early in the disease course.”
Dr. Isganaitis was not involved with the trial but is an investigator for the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study.
“With supply chain shortages and health insurance coverage issues that are common in the U.S., it would be helpful to have more than one FDA-approved option for a weekly GLP-1 receptor agonist in children [and] access to other classes of medications,” added Dr. Isganaitis, a pediatric endocrinologist at the Joslin Diabetes Center, Boston.
Phase 3 trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors in youth with type 2 diabetes are also ongoing, Dr. Arslanian noted, “but as always, recruitment is slow with adolescents.”
“I am not optimistic that DPP4 inhibitors will have a place in the treatment of youth with type 2 diabetes,” she said. A recent study showed the addition of sitagliptin to metformin in youth with type 2 diabetes did not provide durable improvement in glycemic control.
Potentially promising therapy
In their published article, Dr. Arslanian and colleagues write that “considering the progressive increase in [A1c] over time that was observed in the TODAY trial, with 34% of youths having [an A1c] of at least 10% after up to 15 years of follow-up, we believe that the effects of dulaglutide therapy appear to be potentially promising.”
The TODAY trial showed that more than 50% of youth with type 2 diabetes taking metformin failed to maintain glycemic control within a median of 11.5 months, Dr. Arslanian elaborated, and over time their A1c escalated while their beta-cell function deteriorated rapidly, and complications progressed quickly.
“Therefore,” she noted, “considering that dulaglutide and the GLP-1 receptor agonist class of drugs improve A1c, improve beta-cell function, suppress glucagon concentrations, and improve insulin sensitivity, dulaglutide would provide a promising new treatment option for youth with type 2 diabetes.”
Phase 3 superiority trial
The AWARD-PEDS trial included 154 youth with type 2 diabetes and a BMI greater than the 85th percentile for their age and sex at 46 centers in nine countries. Researchers randomized participants 1:1:1 to the two doses of dulaglutide or placebo for 26 weeks, followed by a 26-week open-label study (during which the placebo group received 0.75 mg dulaglutide) and a 4-week safety extension.
Participants were a mean age of 14.5 years and had a mean BMI of 34 kg/m2.
In each of the dulaglutide groups, roughly 66% of patients were female and 58% were White, 18% were Black, and about 57% were Hispanic. They had a mean weight of 91 kg (200 lb) and a mean A1c of about 8%; 62% were taking metformin only, 27% were taking metformin plus basal insulin, 3% were taking basal insulin only, and 10% were on diet and exercise only.
At 26 weeks, mean A1c increased by 0.6% in the placebo group but decreased by 0.6% in the 0.75-mg dulaglutide group and by 0.9% in the 1.5-mg dulaglutide group (P < .001 for both comparisons versus placebo).
Also at 26 weeks, more participants in the pooled dulaglutide groups than in the placebo group had an A1c <7.0% (51% vs. 14%; P < .001).
Fasting glucose concentration increased in the placebo group (+17.1 mg/dL ) and decreased in the pooled dulaglutide groups (–18.9 mg/dL; P < .001).
There were no group differences in BMI or adiposity-related parameters even at 52 weeks.
“I believe adolescents may be somewhat resistant to the weight-reducing effects of GLP-1 agonists in diabetes trials (liraglutide and exenatide youth type 2 diabetes trials showed the same thing) and they may need higher doses,” Dr. Arslanian speculated.
“Only future studies will be able to address this issue,” she concluded.
The study was funded by Eli Lilly. Dr. Arslanian has disclosed being a consultant for Eli Lilly, Novo Nordisk, and Rhythm Pharmaceuticals; participating in data safety monitoring for AstraZeneca and Eli Lilly trials; and receiving institutional research funding from Eli Lilly and Novo Nordisk. Dr. Isganaitis has disclosed receiving research funding (paid to her institution) from Dexcom and AstraZeneca.
A version of this article first appeared on Medscape.com.
FROM ADA 2022
Adagrasib shows durable benefit in KRAS-mutated NSCLC
with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.
“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.
“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.
New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.
Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.
If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.
Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
Published clinical data
The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.
It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.
Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.
On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.
Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.
Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.
“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.
Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
CNS metastases
At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.
As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.
The study was funded by Mirati Therapeutics.
A version of this article first appeared on Medscape.com.
with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.
“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.
“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.
New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.
Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.
If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.
Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
Published clinical data
The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.
It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.
Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.
On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.
Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.
Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.
“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.
Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
CNS metastases
At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.
As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.
The study was funded by Mirati Therapeutics.
A version of this article first appeared on Medscape.com.
with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.
“KRAS G12C mutations occur in over 10% of patients with NSCL [and] remain difficult to target, and outcomes for this patient population have remained poor,” co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, said in a statement.
“Our patients benefited clinically from this agent, and it appears to have improved overall survival (OS), compared with historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting,” he added.
New data on adagrasib were presented at the annual meeting of the American Society for Clinical Oncology and simultaneously published in the New England Journal of Medicine.
Adagrasib (developed by Mirati) is currently awaiting approval from the U.S. Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.
If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the U.S. Food and Drug Administration in May 2021.
Dr. Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.
Published clinical data
The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.
It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.
Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.
On Oct. 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.
Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one-third of the group were still receiving treatment, the authors note.
Median progression-free survival (PFS) was 6.5 months and median OS was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months, and the estimated OS at 1 year was close to 51%.
“The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence,” Dr. Sabari noted.
Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.
CNS metastases
At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one-third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.
As Dr. Sabari noted, CNS metastases from KRAS mutant NSCLC are common. “Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C-mutant NSCLC and active, untreated CNS metastases,” he said.
The study was funded by Mirati Therapeutics.
A version of this article first appeared on Medscape.com.
FROM ASCO 2022
Will tirzepatide slow kidney function decline in type 2 diabetes?
The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.
“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.
The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.
Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.
40% reduced risk of kidney function decline
The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.
Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).
“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).
“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.
The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.
“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”
Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).
“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.
“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.
Strongest reduction seen in risk of new macroalbuminuria
One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.
The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.
The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.
Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m2.
Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m2). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).
The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:
- Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
- Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.
During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.
In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.
Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.
Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”
The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.
Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.
A version of this article first appeared on Medscape.com.
The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.
“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.
The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.
Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.
40% reduced risk of kidney function decline
The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.
Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).
“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).
“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.
The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.
“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”
Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).
“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.
“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.
Strongest reduction seen in risk of new macroalbuminuria
One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.
The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.
The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.
Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m2.
Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m2). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).
The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:
- Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
- Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.
During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.
In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.
Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.
Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”
The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.
Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.
A version of this article first appeared on Medscape.com.
The “twincretin” tirzepatide might become part of the “arsenal” against diabetic kidney disease, new research suggests. Notably, the drug significantly reduced the likelihood of macroalbuminuria, in a prespecified subanalysis of the SURPASS-4 clinical trial.
“Once-per-week tirzepatide compared to [daily] insulin glargine treatment resulted in a meaningful improvement in estimated glomerular filtration rate (eGFR) decline and reduced urine albumin-to-creatinine ratio (UACR) and the risk of end stage kidney disease (ESKD) – with low risk of clinically relevant hypoglycemia in participants with type 2 diabetes at high cardiovascular risk and varying degrees of chronic kidney disease (CKD),” lead investigator Hiddo J. L. Heerspink, PhD, PharmD, summarized in an email to this news organization.
The U.S. Food and Drug Administration has just approved tirzepatide (Mounjaro, Eli Lilly) – a novel, glucose-dependent insulinotropic polypeptide (GIP) combined with a glucagonlike peptide-1 (GLP-1) receptor agonist – to treat glycemia in patients with type 2 diabetes, based on five pivotal SURPASS trials.
Dr. Heerspink presented the new findings about tirzepatide’s impact on kidney function in an oral session at the annual scientific sessions of the American Diabetes Association.
40% reduced risk of kidney function decline
The main results of SURPASS-4 were published in the Lancet in October 2021, and showed that tirzepatide appeared superior to insulin glargine in lowering hemoglobin A1c in patients with type 2 diabetes at high cardiovascular risk who were inadequately controlled on oral diabetes treatments.
Now, Dr. Heerspink has shown that patients who received tirzepatide as opposed to insulin glargine were significantly less likely to have kidney function decline that included new-onset macroalbuminuria (hazard ratio, 0.59; P < .05).
“These are very large benefits and clearly indicate the potential of tirzepatide to be a very strong kidney protective drug,” said Dr. Heerspink, from the department of clinical pharmacy and pharmacology, University Medical Center Groningen (the Netherlands).
“Based on results from the SURPASS-4 trial, tirzepatide has significant kidney-protective effects in adults with type 2 diabetes with high cardiovascular risk and largely normal kidney function,” Christine Limonte, MD, chair of the session in which the analysis was presented, agreed, in an email to this news organization.
The approximate 40% reduced risk of kidney function decline in this population “is important because it suggests that this novel agent may contribute to the growing arsenal for preventing and treating diabetic kidney disease,” added Dr. Limonte, a clinical research fellow in the division of nephrology, University of Washington, Seattle.
“Over the last several years,” she noted, “sodium glucose cotransporter-2 [SGLT2] inhibitors and GLP-1 receptor agonists have been identified as having significant kidney-protective effects in type 2 diabetes, and as such are becoming first-line agents in the treatment of diabetic kidney disease.”
Additional studies are needed, she added, to assess the impacts of tirzepatide compared to these agents (particularly GLP-1 receptor agonists, which overlap in their mechanism of action).
“With the growing number of therapeutic options for diabetic kidney disease, future research should also focus on identifying combinations of agents which benefit individuals in a ‘targeted’ manner,” according to Dr. Limonte.
“Ensuring accessibility to kidney-protective agents by promoting access to health care and reducing drug costs is essential to improving outcomes in diabetic kidney disease,” she added.
Strongest reduction seen in risk of new macroalbuminuria
One in three adults with diabetes has CKD, according to a press release issued by the ADA. Therefore, there is a need for therapies to reduce the development and progression of CKD in patients with type 2 diabetes.
The prespecified analysis of SUPRESS-4 investigated potential renoprotective effects of tirzepatide.
The trial enrolled 1,995 patients with type 2 diabetes who were at increased risk of cardiovascular disease. The patients had a mean age of 63.6 years and a mean hemoglobin A1c of 8.5%.
Most patients had normal kidney function. The mean eGFR based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was 81.3 mL/min per 1.73 m2.
Few patients (17%) had moderately or severely reduced kidney function (eGFR <60 mL/min per 1.73 m2). Around a quarter of the patients (28%) had microalbuminuria (UACR 30-300 mg/g) and 8% had macroalbuminuria (UACR >300 mg/g).
The patients were randomized to receive a weekly injection of 5, 10, or 15 mg tirzepatide or a daily individualized injection of insulin glargine starting at 10 IU/day at bedtime, titrated to a fasting blood glucose <100 mg/dL, in addition to existing oral glucose-lowering agents. The primary outcomes in the subanalysis were:
- Endpoint 1: a composite of ≥40% decline in eGFR from baseline, renal death, progression to ESKD, and new-onset macroalbuminuria.
- Endpoint 2: the same as endpoint 1 excluding new-onset macroalbuminuria.
During a median follow up of 85 weeks and up to 104 weeks, patients who received tirzepatide versus insulin glargine were significantly less likely to reach endpoint 1 but not endpoint 2.
In addition, tirzepatide “very strongly” reduced the risk of new-onset macroalbuminuria, compared to insulin glargine, by approximately 60% in the complete study cohort (hazard ratio, 0.41; P < .05), Dr. Limonte noted.
Tirzepatide also reduced the risk of a >40% decline in eGFR, but this effect was not statistically significant, possibly because this outcome was underpowered. There were also too few kidney deaths and progressions to ESKD to meaningfully assess the effects of tirzepatide on these outcomes.
Therefore, Dr. Limonte noted, “it is likely that tirzepatide’s significant benefit on composite endpoint 1 was largely driven by this agent’s impact on reducing macroalbuminuria onset [explaining why a significant benefit was not seen with composite endpoint 2, which excluded new-onset macroalbuminuria].”
The study was funded by Eli Lilly. Dr. Heerspink disclosed that he is a consultant for AstraZeneca, Bayer AG, Boehringer Ingelheim, Chinook Therapeutics, CSL Behring, Gilead Sciences, Goldfinch Bio, Janssen Research & Development, Mitsubishi Tanabe Pharma, Mundipharma, and Traveere Pharmaceuticals, and has received research support from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk.
Dr. Limonte disclosed that she receives funds from the American Kidney Fund’s Clinical Scientist in Nephrology Award.
A version of this article first appeared on Medscape.com.
FROM ADA 2022
B-cell level may affect COVID booster efficacy in MS
Patients with multiple sclerosis (MS) treated with the B-cell-depleting medication rituximab who have not yet been vaccinated against COVID-19 should get the initial vaccination as soon as possible but wait to get a booster shot until B-cell levels increase, new research suggests.
In a prospective cohort study, 90% of patients taking rituximab whose B-cell level was at least 40 cells/mcL had a sufficient antibody response to the Pfizer vaccine, whereas among those with lower levels, the antibody response was significantly lower.
Results also showed a wide variation in the length of time needed for adequate B-cell restoration. Some patients needed a year or longer for levels to become adequate.
The findings led the hospital where the study was conducted to suspend rituximab therapy until patients could be vaccinated. The findings also prompted researchers to call for new guidelines on vaccine scheduling that are based on B-cell levels and not on the current criteria of length of time since last treatment.
“It’s meaningless to just go by some recommendation covering time since the last treatment,” study investigator Joachim Burman, MD, PhD, a consultant neurologist at Uppsala University Hospital and an associate professor at Uppsala University, both in Sweden, told this news organization.
“It’s misleading and potentially harmful for patients,” Dr. Burman said.
The findings were published online in JAMA Network Open.
Finding the cutoff
Drugs such as rituximab target CD20, a protein found on the surface of B cells, resulting in B-cell depletion.
Rituximab is the most common MS therapy used in Sweden. The drug is approved in the United States to treat rheumatoid arthritis and some forms of cancer, but it is not approved for treatment of MS.
Prior research showed that antibody response to COVID-19 vaccines was lower in patients receiving B-cell therapy than in the general population. That was not altogether surprising, given the fact that studies have found a similarly weakened antibody response to other vaccines.
But before now, there was no known B-cell threshold sufficient to mount an acceptable antibody response following COVID vaccination.
Researchers enrolled 67 patients in the study. Of those patients, 60 had received rituximab treatment, and seven had not.
Approximately 6 months after the last rituximab dose, the B-cell count was lower than 10/mcL for 40% of patients. In that group, rituximab treatment duration was the only factor significantly associated with slower B-cell mobilization (median duration, 4.0 years, vs. 2.1; P = .002).
Close monitoring needed
Six weeks after vaccination with tozinameran, the mRNA vaccine manufactured by Pfizer, 28% of patients failed to generate a sufficient antibody response. Among those patients, the median B-cell count was 22/mcL, versus 51/mcL for the remainder of the cohort (P < .001).
A cutoff value of 40/mcL rendered adequate levels of anti-spike immunoglobulin G antibodies in 90% of patients and a strong response in anti-RBD antibodies in 72%.
Study participants did register an adequate T-cell response to the vaccine, suggesting at least some level of protection.
Because MS patients are at increased risk for serious illness from SARS-CoV-2 infection, the investigators recommend that patients with MS receive their initial COVID vaccines as soon as possible – but that they should hold off on receiving a booster until their B-cell counts reach 40/mcL.
Regarding when a clinician should re-vaccinate, “the results from our study strongly suggest that you should not do that right away or just follow some generic guideline,” Dr. Burman said.
“You should closely monitor the B-cell values, and re-vaccinate once those B- cells hit the level of 40 cells/mcL” he added.
Dr. Burman said he would expect that their findings would hold with the other mRNA vaccine and with any other B-cell therapy.
Too soon for B-cell measures?
Commenting for this news organization, Robert J. Fox, MD, staff neurologist at the Mellen Center for MS and vice-chair for research at the Neurological Institute at Cleveland Clinic, Ohio, said the B-cell threshold identified in the study is much higher than what is typically seen in patients who undergo treatment with ocrelizumab, an anti-CD20 B-cell therapy approved in the United States for treating MS.
“Decisions about treatment interval need to balance efficacy in treating MS with safety, including response to vaccines,” said Dr. Fox, who was not involved with the research.
“Given the unknown efficacy of these extended intervals, I don’t think we’re at the point of making management recommendations based upon B-cell counts,” he added.
And yet, Uppsala University Hospital, where the study was conducted, and other centers in Sweden decided to do just that. They suspended administering rituximab to patients with MS until the patients were vaccinated. For patients newly diagnosed with MS, therapy was initiated using another disease-modifying treatment, and for those who were due for a rituximab infusion, that treatment was delayed.
Only one patient experienced a mild MS relapse during the rituximab suspension, and that case went into remission within a week, Dr. Burman reported.
“Ever since the Bar-Or report showing that the humeral response to vaccines is markedly diminished in MS patients treated with anti-CD20 therapies, clinicians have been struggling to balance those safety concerns related to anti-CD20 monoclonal antibody treatments and the clinical benefit of this treatment class,” Dr. Fox said.
“Given the uncharted waters of the COVID pandemic, clinicians made judgments and decisions as best they could, given the paucity of data,” he noted.
“At this point, we don’t know which decisions were right or wrong, but I certainly don’t think we should judge clinicians for making decisions the best they could.”
The study was funded by the Engkvist Foundation, the Marianne and Marcus Wallenberg Foundation, and the Swedish Society for Medical Research. Dr. Burman reported no relevant financial relationships. Dr. Fox has received consulting fees from Genentech/Roche, Biogen, and other companies that promote MS therapies.
A version of this article first appeared on Medscape.com.
Patients with multiple sclerosis (MS) treated with the B-cell-depleting medication rituximab who have not yet been vaccinated against COVID-19 should get the initial vaccination as soon as possible but wait to get a booster shot until B-cell levels increase, new research suggests.
In a prospective cohort study, 90% of patients taking rituximab whose B-cell level was at least 40 cells/mcL had a sufficient antibody response to the Pfizer vaccine, whereas among those with lower levels, the antibody response was significantly lower.
Results also showed a wide variation in the length of time needed for adequate B-cell restoration. Some patients needed a year or longer for levels to become adequate.
The findings led the hospital where the study was conducted to suspend rituximab therapy until patients could be vaccinated. The findings also prompted researchers to call for new guidelines on vaccine scheduling that are based on B-cell levels and not on the current criteria of length of time since last treatment.
“It’s meaningless to just go by some recommendation covering time since the last treatment,” study investigator Joachim Burman, MD, PhD, a consultant neurologist at Uppsala University Hospital and an associate professor at Uppsala University, both in Sweden, told this news organization.
“It’s misleading and potentially harmful for patients,” Dr. Burman said.
The findings were published online in JAMA Network Open.
Finding the cutoff
Drugs such as rituximab target CD20, a protein found on the surface of B cells, resulting in B-cell depletion.
Rituximab is the most common MS therapy used in Sweden. The drug is approved in the United States to treat rheumatoid arthritis and some forms of cancer, but it is not approved for treatment of MS.
Prior research showed that antibody response to COVID-19 vaccines was lower in patients receiving B-cell therapy than in the general population. That was not altogether surprising, given the fact that studies have found a similarly weakened antibody response to other vaccines.
But before now, there was no known B-cell threshold sufficient to mount an acceptable antibody response following COVID vaccination.
Researchers enrolled 67 patients in the study. Of those patients, 60 had received rituximab treatment, and seven had not.
Approximately 6 months after the last rituximab dose, the B-cell count was lower than 10/mcL for 40% of patients. In that group, rituximab treatment duration was the only factor significantly associated with slower B-cell mobilization (median duration, 4.0 years, vs. 2.1; P = .002).
Close monitoring needed
Six weeks after vaccination with tozinameran, the mRNA vaccine manufactured by Pfizer, 28% of patients failed to generate a sufficient antibody response. Among those patients, the median B-cell count was 22/mcL, versus 51/mcL for the remainder of the cohort (P < .001).
A cutoff value of 40/mcL rendered adequate levels of anti-spike immunoglobulin G antibodies in 90% of patients and a strong response in anti-RBD antibodies in 72%.
Study participants did register an adequate T-cell response to the vaccine, suggesting at least some level of protection.
Because MS patients are at increased risk for serious illness from SARS-CoV-2 infection, the investigators recommend that patients with MS receive their initial COVID vaccines as soon as possible – but that they should hold off on receiving a booster until their B-cell counts reach 40/mcL.
Regarding when a clinician should re-vaccinate, “the results from our study strongly suggest that you should not do that right away or just follow some generic guideline,” Dr. Burman said.
“You should closely monitor the B-cell values, and re-vaccinate once those B- cells hit the level of 40 cells/mcL” he added.
Dr. Burman said he would expect that their findings would hold with the other mRNA vaccine and with any other B-cell therapy.
Too soon for B-cell measures?
Commenting for this news organization, Robert J. Fox, MD, staff neurologist at the Mellen Center for MS and vice-chair for research at the Neurological Institute at Cleveland Clinic, Ohio, said the B-cell threshold identified in the study is much higher than what is typically seen in patients who undergo treatment with ocrelizumab, an anti-CD20 B-cell therapy approved in the United States for treating MS.
“Decisions about treatment interval need to balance efficacy in treating MS with safety, including response to vaccines,” said Dr. Fox, who was not involved with the research.
“Given the unknown efficacy of these extended intervals, I don’t think we’re at the point of making management recommendations based upon B-cell counts,” he added.
And yet, Uppsala University Hospital, where the study was conducted, and other centers in Sweden decided to do just that. They suspended administering rituximab to patients with MS until the patients were vaccinated. For patients newly diagnosed with MS, therapy was initiated using another disease-modifying treatment, and for those who were due for a rituximab infusion, that treatment was delayed.
Only one patient experienced a mild MS relapse during the rituximab suspension, and that case went into remission within a week, Dr. Burman reported.
“Ever since the Bar-Or report showing that the humeral response to vaccines is markedly diminished in MS patients treated with anti-CD20 therapies, clinicians have been struggling to balance those safety concerns related to anti-CD20 monoclonal antibody treatments and the clinical benefit of this treatment class,” Dr. Fox said.
“Given the uncharted waters of the COVID pandemic, clinicians made judgments and decisions as best they could, given the paucity of data,” he noted.
“At this point, we don’t know which decisions were right or wrong, but I certainly don’t think we should judge clinicians for making decisions the best they could.”
The study was funded by the Engkvist Foundation, the Marianne and Marcus Wallenberg Foundation, and the Swedish Society for Medical Research. Dr. Burman reported no relevant financial relationships. Dr. Fox has received consulting fees from Genentech/Roche, Biogen, and other companies that promote MS therapies.
A version of this article first appeared on Medscape.com.
Patients with multiple sclerosis (MS) treated with the B-cell-depleting medication rituximab who have not yet been vaccinated against COVID-19 should get the initial vaccination as soon as possible but wait to get a booster shot until B-cell levels increase, new research suggests.
In a prospective cohort study, 90% of patients taking rituximab whose B-cell level was at least 40 cells/mcL had a sufficient antibody response to the Pfizer vaccine, whereas among those with lower levels, the antibody response was significantly lower.
Results also showed a wide variation in the length of time needed for adequate B-cell restoration. Some patients needed a year or longer for levels to become adequate.
The findings led the hospital where the study was conducted to suspend rituximab therapy until patients could be vaccinated. The findings also prompted researchers to call for new guidelines on vaccine scheduling that are based on B-cell levels and not on the current criteria of length of time since last treatment.
“It’s meaningless to just go by some recommendation covering time since the last treatment,” study investigator Joachim Burman, MD, PhD, a consultant neurologist at Uppsala University Hospital and an associate professor at Uppsala University, both in Sweden, told this news organization.
“It’s misleading and potentially harmful for patients,” Dr. Burman said.
The findings were published online in JAMA Network Open.
Finding the cutoff
Drugs such as rituximab target CD20, a protein found on the surface of B cells, resulting in B-cell depletion.
Rituximab is the most common MS therapy used in Sweden. The drug is approved in the United States to treat rheumatoid arthritis and some forms of cancer, but it is not approved for treatment of MS.
Prior research showed that antibody response to COVID-19 vaccines was lower in patients receiving B-cell therapy than in the general population. That was not altogether surprising, given the fact that studies have found a similarly weakened antibody response to other vaccines.
But before now, there was no known B-cell threshold sufficient to mount an acceptable antibody response following COVID vaccination.
Researchers enrolled 67 patients in the study. Of those patients, 60 had received rituximab treatment, and seven had not.
Approximately 6 months after the last rituximab dose, the B-cell count was lower than 10/mcL for 40% of patients. In that group, rituximab treatment duration was the only factor significantly associated with slower B-cell mobilization (median duration, 4.0 years, vs. 2.1; P = .002).
Close monitoring needed
Six weeks after vaccination with tozinameran, the mRNA vaccine manufactured by Pfizer, 28% of patients failed to generate a sufficient antibody response. Among those patients, the median B-cell count was 22/mcL, versus 51/mcL for the remainder of the cohort (P < .001).
A cutoff value of 40/mcL rendered adequate levels of anti-spike immunoglobulin G antibodies in 90% of patients and a strong response in anti-RBD antibodies in 72%.
Study participants did register an adequate T-cell response to the vaccine, suggesting at least some level of protection.
Because MS patients are at increased risk for serious illness from SARS-CoV-2 infection, the investigators recommend that patients with MS receive their initial COVID vaccines as soon as possible – but that they should hold off on receiving a booster until their B-cell counts reach 40/mcL.
Regarding when a clinician should re-vaccinate, “the results from our study strongly suggest that you should not do that right away or just follow some generic guideline,” Dr. Burman said.
“You should closely monitor the B-cell values, and re-vaccinate once those B- cells hit the level of 40 cells/mcL” he added.
Dr. Burman said he would expect that their findings would hold with the other mRNA vaccine and with any other B-cell therapy.
Too soon for B-cell measures?
Commenting for this news organization, Robert J. Fox, MD, staff neurologist at the Mellen Center for MS and vice-chair for research at the Neurological Institute at Cleveland Clinic, Ohio, said the B-cell threshold identified in the study is much higher than what is typically seen in patients who undergo treatment with ocrelizumab, an anti-CD20 B-cell therapy approved in the United States for treating MS.
“Decisions about treatment interval need to balance efficacy in treating MS with safety, including response to vaccines,” said Dr. Fox, who was not involved with the research.
“Given the unknown efficacy of these extended intervals, I don’t think we’re at the point of making management recommendations based upon B-cell counts,” he added.
And yet, Uppsala University Hospital, where the study was conducted, and other centers in Sweden decided to do just that. They suspended administering rituximab to patients with MS until the patients were vaccinated. For patients newly diagnosed with MS, therapy was initiated using another disease-modifying treatment, and for those who were due for a rituximab infusion, that treatment was delayed.
Only one patient experienced a mild MS relapse during the rituximab suspension, and that case went into remission within a week, Dr. Burman reported.
“Ever since the Bar-Or report showing that the humeral response to vaccines is markedly diminished in MS patients treated with anti-CD20 therapies, clinicians have been struggling to balance those safety concerns related to anti-CD20 monoclonal antibody treatments and the clinical benefit of this treatment class,” Dr. Fox said.
“Given the uncharted waters of the COVID pandemic, clinicians made judgments and decisions as best they could, given the paucity of data,” he noted.
“At this point, we don’t know which decisions were right or wrong, but I certainly don’t think we should judge clinicians for making decisions the best they could.”
The study was funded by the Engkvist Foundation, the Marianne and Marcus Wallenberg Foundation, and the Swedish Society for Medical Research. Dr. Burman reported no relevant financial relationships. Dr. Fox has received consulting fees from Genentech/Roche, Biogen, and other companies that promote MS therapies.
A version of this article first appeared on Medscape.com.
Pfizer asks FDA to authorize COVID vaccine for children younger than 5
The FDA has accepted Pfizer’s application for a COVID-19 vaccine for children under age 5, which clears the way for approval and distribution in June.
Pfizer announced June 1 that it completed the application for a three-dose vaccine for kids between 6 months and 5 years old, and the FDA said it received the emergency use application.
Children in this age group – the last to be eligible for COVID-19 vaccines – could begin getting shots as early as June 21, according to White House COVID-19 response coordinator Ashish Jha, MD.
Meanwhile, COVID-19 cases are still high – an average of 100,000 cases a day – but death numbers are about 90% lower than they were when President Joe Biden first took office, Dr. Jha said.
The FDA’s advisory group, the Vaccines and Related Biological Products Advisory Committee, is scheduled to meet June 14 and June 15 to discuss data submitted by both Pfizer and Moderna.
If the FDA gives them the green light, the CDC will then weigh in.
“We know that many, many parents are eager to vaccinate their youngest kids, and it’s important to do this right,” Dr. Jha said at a White House press briefing on June 2. “We expect that vaccinations will begin in earnest as early as June 21 and really roll on throughout that week.”
States can place their orders as early as June 3, Dr. Jha said, and there will initially be 10 million doses available. If the FDA gives emergency use authorization for the vaccines, the government will begin shipping doses to thousands of sites across the country.
“The good news is we have plenty of supply of Pfizer and Moderna vaccines,” Dr. Jha said. “We’ve asked states to distribute to their highest priority sites, serving the highest risk and hardest to reach areas.”
Pfizer’s clinical trials found that three doses of the vaccine for children 6 months to under 5 years were safe and effective and proved to be 80% effective against Omicron.
The FDA announced its meeting information with a conversation about the Moderna vaccine for ages 6-17 scheduled for June 14 and a conversation about the Pfizer and Moderna vaccines for young children scheduled for June 15.
Moderna applied for FDA authorization of its two-dose vaccine for children under age 6 on April 28. The company said the vaccine was 51% effective against infections with symptoms for children ages 6 months to 2 years and 37% effective for ages 2-5.
Pfizer’s 3-microgram dose is one-tenth of its adult dose. Moderna’s 25-microgram dose is one-quarter of its adult dose.
A version of this article first appeared on Medscape.com.
The FDA has accepted Pfizer’s application for a COVID-19 vaccine for children under age 5, which clears the way for approval and distribution in June.
Pfizer announced June 1 that it completed the application for a three-dose vaccine for kids between 6 months and 5 years old, and the FDA said it received the emergency use application.
Children in this age group – the last to be eligible for COVID-19 vaccines – could begin getting shots as early as June 21, according to White House COVID-19 response coordinator Ashish Jha, MD.
Meanwhile, COVID-19 cases are still high – an average of 100,000 cases a day – but death numbers are about 90% lower than they were when President Joe Biden first took office, Dr. Jha said.
The FDA’s advisory group, the Vaccines and Related Biological Products Advisory Committee, is scheduled to meet June 14 and June 15 to discuss data submitted by both Pfizer and Moderna.
If the FDA gives them the green light, the CDC will then weigh in.
“We know that many, many parents are eager to vaccinate their youngest kids, and it’s important to do this right,” Dr. Jha said at a White House press briefing on June 2. “We expect that vaccinations will begin in earnest as early as June 21 and really roll on throughout that week.”
States can place their orders as early as June 3, Dr. Jha said, and there will initially be 10 million doses available. If the FDA gives emergency use authorization for the vaccines, the government will begin shipping doses to thousands of sites across the country.
“The good news is we have plenty of supply of Pfizer and Moderna vaccines,” Dr. Jha said. “We’ve asked states to distribute to their highest priority sites, serving the highest risk and hardest to reach areas.”
Pfizer’s clinical trials found that three doses of the vaccine for children 6 months to under 5 years were safe and effective and proved to be 80% effective against Omicron.
The FDA announced its meeting information with a conversation about the Moderna vaccine for ages 6-17 scheduled for June 14 and a conversation about the Pfizer and Moderna vaccines for young children scheduled for June 15.
Moderna applied for FDA authorization of its two-dose vaccine for children under age 6 on April 28. The company said the vaccine was 51% effective against infections with symptoms for children ages 6 months to 2 years and 37% effective for ages 2-5.
Pfizer’s 3-microgram dose is one-tenth of its adult dose. Moderna’s 25-microgram dose is one-quarter of its adult dose.
A version of this article first appeared on Medscape.com.
The FDA has accepted Pfizer’s application for a COVID-19 vaccine for children under age 5, which clears the way for approval and distribution in June.
Pfizer announced June 1 that it completed the application for a three-dose vaccine for kids between 6 months and 5 years old, and the FDA said it received the emergency use application.
Children in this age group – the last to be eligible for COVID-19 vaccines – could begin getting shots as early as June 21, according to White House COVID-19 response coordinator Ashish Jha, MD.
Meanwhile, COVID-19 cases are still high – an average of 100,000 cases a day – but death numbers are about 90% lower than they were when President Joe Biden first took office, Dr. Jha said.
The FDA’s advisory group, the Vaccines and Related Biological Products Advisory Committee, is scheduled to meet June 14 and June 15 to discuss data submitted by both Pfizer and Moderna.
If the FDA gives them the green light, the CDC will then weigh in.
“We know that many, many parents are eager to vaccinate their youngest kids, and it’s important to do this right,” Dr. Jha said at a White House press briefing on June 2. “We expect that vaccinations will begin in earnest as early as June 21 and really roll on throughout that week.”
States can place their orders as early as June 3, Dr. Jha said, and there will initially be 10 million doses available. If the FDA gives emergency use authorization for the vaccines, the government will begin shipping doses to thousands of sites across the country.
“The good news is we have plenty of supply of Pfizer and Moderna vaccines,” Dr. Jha said. “We’ve asked states to distribute to their highest priority sites, serving the highest risk and hardest to reach areas.”
Pfizer’s clinical trials found that three doses of the vaccine for children 6 months to under 5 years were safe and effective and proved to be 80% effective against Omicron.
The FDA announced its meeting information with a conversation about the Moderna vaccine for ages 6-17 scheduled for June 14 and a conversation about the Pfizer and Moderna vaccines for young children scheduled for June 15.
Moderna applied for FDA authorization of its two-dose vaccine for children under age 6 on April 28. The company said the vaccine was 51% effective against infections with symptoms for children ages 6 months to 2 years and 37% effective for ages 2-5.
Pfizer’s 3-microgram dose is one-tenth of its adult dose. Moderna’s 25-microgram dose is one-quarter of its adult dose.
A version of this article first appeared on Medscape.com.