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Doug Brunk is a San Diego-based award-winning reporter who began covering health care in 1991. Before joining the company, he wrote for the health sciences division of Columbia University and was an associate editor at Contemporary Long Term Care magazine when it won a Jesse H. Neal Award. His work has been syndicated by the Los Angeles Times and he is the author of two books related to the University of Kentucky Wildcats men's basketball program. Doug has a master’s degree in magazine journalism from the S.I. Newhouse School of Public Communications at Syracuse University. Follow him on Twitter @dougbrunk.
Hospitalization risk twice as likely for veterans with mental illness
SAN DIEGO – compared with their peers who had no psychiatric or addiction diagnosis, according to results of a large VA database study.
“Our patients sit at the center of two public health crises,” David T. Moore, MD, PhD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry. “One is the incredibly reduced life expectancy for adults with mental illnesses. There may be a 20-year reduced life expectancy. Their mortality rate for chronic medical conditions such as heart disease and COPD is increased by two- to fourfold, and is associated with greater hospitalization rates, longer lengths of stay, and increased readmission rates. The second part of this crisis is the incredible cost associated with medical hospitalizations. About 1 in every $20 in the entire U.S. economy goes toward inpatient medical hospitalization.”
The final analysis included 952,252 veterans with a mental illness and 1,064,140 without a psychiatric or addiction diagnosis. Dr. Moore reported that among veterans with mental illness, 100,191 (7.1%) were hospitalized on a medical unit at some point during the study period, compared with only 31,759 (2.9%) of veterans with no psychiatric or addiction diagnosis. The Charlson Comorbidity Index was significantly increased in veterans with mental health diagnoses, compared with those who did not have mental health diagnoses.
“There was more tobacco use; they were much more likely to receive an opioid prescription; [and] they used more outpatient medical services, whether it be primary care visits or specialty care visits,” Dr. Moore said of the hospitalized veterans. “They are sicker, but they also use more outpatient medical services, suggesting that they do not lack access to adequate outpatient medical care.”
Next, the researchers performed a subset analysis of all veterans with any mental health diagnosis. Compared with those who were not hospitalized during the study period, those hospitalized were older (a mean age of 52 vs. 45 years, respectively), more likely to be homeless (21% vs. 12%; relative risk, 1.8), and receive a VA pension, which is correlated with poor functioning and disability (7.1% vs. 2.9%; RR, 2.4). The only psychiatric disorder correlated with correlated with medical hospitalization was personality disorder (6.3% vs. 3.7%; RR, 1.7). The researchers also observed that a higher proportion of hospitalized patients had an alcohol use disorder (34% vs. 23%; RR, 1.7) and drug use (31% vs. 17%; RR, 1.8). “The use of benzodiazepines had the greatest relative risk for medical hospitalizations,” Dr. Moore said.
In unadjusted analyses, veterans with the following diagnoses were at increased risk for hospitalization: drug use disorder (odds ratio, 4.58), alcohol use disorder (OR, 3.84), bipolar disorder (OR, 3.29), major depressive disorder (OR, 3.04), schizophrenia (OR, 2.98), and posttraumatic stress disorder (OR, 1.91).
After adjusting for other health factors in multiple regression, alcohol use disorder was the only psychiatric or addiction disorder strongly associated with medical hospitalizations (OR, 1.95). After accounting for sociodemographic characteristics, medical comorbidities, use of outpatient medical services, and alcohol use, the OR for medical hospitalizations among veterans with mental illness decreased from 2.52 to 1.24.
“It looks like a lot of the folks with drug use disorders who are being hospitalized may also have co-occurring alcohol use disorders,” Dr. Moore said. “That may partly account for their hospitalization risk.”
He concluded that the study’s overall findings “leave us with a lot of questions about what to do. The majority of patients who are hospitalized have a mental illness. Is this a setting where we should be engaging them and trying to connect them with outpatient services?”
Dr. Moore reported having no financial disclosures.
SOURCE: Moore et al. AAAP 2017. Paper session A1.
SAN DIEGO – compared with their peers who had no psychiatric or addiction diagnosis, according to results of a large VA database study.
“Our patients sit at the center of two public health crises,” David T. Moore, MD, PhD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry. “One is the incredibly reduced life expectancy for adults with mental illnesses. There may be a 20-year reduced life expectancy. Their mortality rate for chronic medical conditions such as heart disease and COPD is increased by two- to fourfold, and is associated with greater hospitalization rates, longer lengths of stay, and increased readmission rates. The second part of this crisis is the incredible cost associated with medical hospitalizations. About 1 in every $20 in the entire U.S. economy goes toward inpatient medical hospitalization.”
The final analysis included 952,252 veterans with a mental illness and 1,064,140 without a psychiatric or addiction diagnosis. Dr. Moore reported that among veterans with mental illness, 100,191 (7.1%) were hospitalized on a medical unit at some point during the study period, compared with only 31,759 (2.9%) of veterans with no psychiatric or addiction diagnosis. The Charlson Comorbidity Index was significantly increased in veterans with mental health diagnoses, compared with those who did not have mental health diagnoses.
“There was more tobacco use; they were much more likely to receive an opioid prescription; [and] they used more outpatient medical services, whether it be primary care visits or specialty care visits,” Dr. Moore said of the hospitalized veterans. “They are sicker, but they also use more outpatient medical services, suggesting that they do not lack access to adequate outpatient medical care.”
Next, the researchers performed a subset analysis of all veterans with any mental health diagnosis. Compared with those who were not hospitalized during the study period, those hospitalized were older (a mean age of 52 vs. 45 years, respectively), more likely to be homeless (21% vs. 12%; relative risk, 1.8), and receive a VA pension, which is correlated with poor functioning and disability (7.1% vs. 2.9%; RR, 2.4). The only psychiatric disorder correlated with correlated with medical hospitalization was personality disorder (6.3% vs. 3.7%; RR, 1.7). The researchers also observed that a higher proportion of hospitalized patients had an alcohol use disorder (34% vs. 23%; RR, 1.7) and drug use (31% vs. 17%; RR, 1.8). “The use of benzodiazepines had the greatest relative risk for medical hospitalizations,” Dr. Moore said.
In unadjusted analyses, veterans with the following diagnoses were at increased risk for hospitalization: drug use disorder (odds ratio, 4.58), alcohol use disorder (OR, 3.84), bipolar disorder (OR, 3.29), major depressive disorder (OR, 3.04), schizophrenia (OR, 2.98), and posttraumatic stress disorder (OR, 1.91).
After adjusting for other health factors in multiple regression, alcohol use disorder was the only psychiatric or addiction disorder strongly associated with medical hospitalizations (OR, 1.95). After accounting for sociodemographic characteristics, medical comorbidities, use of outpatient medical services, and alcohol use, the OR for medical hospitalizations among veterans with mental illness decreased from 2.52 to 1.24.
“It looks like a lot of the folks with drug use disorders who are being hospitalized may also have co-occurring alcohol use disorders,” Dr. Moore said. “That may partly account for their hospitalization risk.”
He concluded that the study’s overall findings “leave us with a lot of questions about what to do. The majority of patients who are hospitalized have a mental illness. Is this a setting where we should be engaging them and trying to connect them with outpatient services?”
Dr. Moore reported having no financial disclosures.
SOURCE: Moore et al. AAAP 2017. Paper session A1.
SAN DIEGO – compared with their peers who had no psychiatric or addiction diagnosis, according to results of a large VA database study.
“Our patients sit at the center of two public health crises,” David T. Moore, MD, PhD, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry. “One is the incredibly reduced life expectancy for adults with mental illnesses. There may be a 20-year reduced life expectancy. Their mortality rate for chronic medical conditions such as heart disease and COPD is increased by two- to fourfold, and is associated with greater hospitalization rates, longer lengths of stay, and increased readmission rates. The second part of this crisis is the incredible cost associated with medical hospitalizations. About 1 in every $20 in the entire U.S. economy goes toward inpatient medical hospitalization.”
The final analysis included 952,252 veterans with a mental illness and 1,064,140 without a psychiatric or addiction diagnosis. Dr. Moore reported that among veterans with mental illness, 100,191 (7.1%) were hospitalized on a medical unit at some point during the study period, compared with only 31,759 (2.9%) of veterans with no psychiatric or addiction diagnosis. The Charlson Comorbidity Index was significantly increased in veterans with mental health diagnoses, compared with those who did not have mental health diagnoses.
“There was more tobacco use; they were much more likely to receive an opioid prescription; [and] they used more outpatient medical services, whether it be primary care visits or specialty care visits,” Dr. Moore said of the hospitalized veterans. “They are sicker, but they also use more outpatient medical services, suggesting that they do not lack access to adequate outpatient medical care.”
Next, the researchers performed a subset analysis of all veterans with any mental health diagnosis. Compared with those who were not hospitalized during the study period, those hospitalized were older (a mean age of 52 vs. 45 years, respectively), more likely to be homeless (21% vs. 12%; relative risk, 1.8), and receive a VA pension, which is correlated with poor functioning and disability (7.1% vs. 2.9%; RR, 2.4). The only psychiatric disorder correlated with correlated with medical hospitalization was personality disorder (6.3% vs. 3.7%; RR, 1.7). The researchers also observed that a higher proportion of hospitalized patients had an alcohol use disorder (34% vs. 23%; RR, 1.7) and drug use (31% vs. 17%; RR, 1.8). “The use of benzodiazepines had the greatest relative risk for medical hospitalizations,” Dr. Moore said.
In unadjusted analyses, veterans with the following diagnoses were at increased risk for hospitalization: drug use disorder (odds ratio, 4.58), alcohol use disorder (OR, 3.84), bipolar disorder (OR, 3.29), major depressive disorder (OR, 3.04), schizophrenia (OR, 2.98), and posttraumatic stress disorder (OR, 1.91).
After adjusting for other health factors in multiple regression, alcohol use disorder was the only psychiatric or addiction disorder strongly associated with medical hospitalizations (OR, 1.95). After accounting for sociodemographic characteristics, medical comorbidities, use of outpatient medical services, and alcohol use, the OR for medical hospitalizations among veterans with mental illness decreased from 2.52 to 1.24.
“It looks like a lot of the folks with drug use disorders who are being hospitalized may also have co-occurring alcohol use disorders,” Dr. Moore said. “That may partly account for their hospitalization risk.”
He concluded that the study’s overall findings “leave us with a lot of questions about what to do. The majority of patients who are hospitalized have a mental illness. Is this a setting where we should be engaging them and trying to connect them with outpatient services?”
Dr. Moore reported having no financial disclosures.
SOURCE: Moore et al. AAAP 2017. Paper session A1.
REPORTING FROM AAAP
Key clinical point: In order to improve the health of veterans with mental illness, more efforts are needed to target alcohol use.
Major finding: Among veterans with mental illnesses, 7.1% were hospitalized, compared with 2.9% of their peers with no psychiatric or addiction diagnosis.
Study details: A database analysis of 952,252 veterans with a mental illness and 1,064,140 without a psychiatric or addiction diagnosis.
Disclosures: Dr. Moore reported having no financial disclosures.
Source: Moore et al. AAAP 2017. Paper session A1.
Long-acting naltrexone tied to fewer detox admissions, more treatment engagement
SAN DIEGO – Persistence with long-acting naltrexone treatment was associated with significantly reduced detoxification admissions and concurrent engagement in treatment, a retrospective study of veterans found.
The Food and Drug Administration has approved long-acting naltrexone hydrochloride for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD), but little is known about the patients who initiate and continue this therapy, Grace Chang, MD, MPH, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry. In an effort to evaluate the characteristics associated with long-term naltrexone treatment persistence, Dr. Chang, chief of consultation-liaison psychiatry at the VA Boston Healthcare System, and her associates studied 154 veterans who initiated long-acting naltrexone therapy for AUD or OUD between 2014 and 2015.
Among those who died in the study year after the index shot, no difference in the average number of long-acting naltrexone injections was observed (5.3 in the OUD group vs. 6.8 in the AUD group, P = .62). There was a long interval between the last known injection of long-acting naltrexone and the date of death (381 days in the OUD group vs. 326 days in the AUD group, P = .67). The cause of death was unknown in 57% of cases, while 21% were from natural causes, and 21% were tied to overdose or self-inflicted injury.
The rates of posttraumatic stress disorder in the OUD and AUD groups were about the same, but the AUD patients had higher rates of mood disorder and anxiety disorder. The AUD patients had higher rates of cardiac disease and pulmonary disease, while the OUD patients had higher rates of musculoskeletal problems. Renal disease was relatively rare in both groups. “The AUD patients started using their drug of choice earlier, but the groups were comparable in being able to attain over 2 years of abstinence at some point,” said Dr. Chang, who is also professor of psychiatry at Harvard Medical School, Boston. “Both groups had about two detoxes in the year prior to the index shot.
“ We were also curious about what other drugs they were using prior to starting naltrexone. The OUD patients used more stimulants, more cocaine, and more sedative hypnotics. Smoking was endemic in both of these groups, as was marijuana use.”
The average interval from the time patients in both groups made the decision to start long-acting naltrexone to the time they received their first shot was about 2 months. “It’s safe to say that no one rushed into this,” Dr. Chang said. “The mean number of injections for the study year was about 5, which was very high, and the range was from 1 to 13, which suggests that some people got a shot every single month. Both of the groups had similar numbers of individual treatment sessions, which was about one. They had almost two residential admissions after the index shot and at least one other appointment with a prescribing psychiatrist.”
On Poisson regression analysis, factors associated with increased medication persistence included percent service connection and number of individual, group, residential, and other treatment modalities attended (P less than .05 for all associations). For each unit increase in the number of individual sessions, the number of long-acting naltrexone shots would go up by 7%, Dr. Chang said. For each unit increase in the number of group sessions, the number of long-acting naltrexone therapy shots would go up by 5%, while for each residential admission session, the number of long-acting naltrexone shots would go up by 14%.
“Keep in mind that our patients had an average of two residential admissions, so the number of shots went up by 28%,” she said. “For the number of other appointments with the addiction psychiatrist, the number of shots went up by 6%.”
Dr. Chang acknowledged certain limitations of the study, including its retrospective design and the relatively small sample size. “What was good to see is that the number of inpatient detox admissions was halved, when comparing the year before and the year after the shot,” she said. “This was highly statistically significant. Concurrent psychosocial treatment is highly important in the treatment persistence with this modality.”
Dr. Chang reported having no relevant financial disclosures.
SAN DIEGO – Persistence with long-acting naltrexone treatment was associated with significantly reduced detoxification admissions and concurrent engagement in treatment, a retrospective study of veterans found.
The Food and Drug Administration has approved long-acting naltrexone hydrochloride for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD), but little is known about the patients who initiate and continue this therapy, Grace Chang, MD, MPH, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry. In an effort to evaluate the characteristics associated with long-term naltrexone treatment persistence, Dr. Chang, chief of consultation-liaison psychiatry at the VA Boston Healthcare System, and her associates studied 154 veterans who initiated long-acting naltrexone therapy for AUD or OUD between 2014 and 2015.
Among those who died in the study year after the index shot, no difference in the average number of long-acting naltrexone injections was observed (5.3 in the OUD group vs. 6.8 in the AUD group, P = .62). There was a long interval between the last known injection of long-acting naltrexone and the date of death (381 days in the OUD group vs. 326 days in the AUD group, P = .67). The cause of death was unknown in 57% of cases, while 21% were from natural causes, and 21% were tied to overdose or self-inflicted injury.
The rates of posttraumatic stress disorder in the OUD and AUD groups were about the same, but the AUD patients had higher rates of mood disorder and anxiety disorder. The AUD patients had higher rates of cardiac disease and pulmonary disease, while the OUD patients had higher rates of musculoskeletal problems. Renal disease was relatively rare in both groups. “The AUD patients started using their drug of choice earlier, but the groups were comparable in being able to attain over 2 years of abstinence at some point,” said Dr. Chang, who is also professor of psychiatry at Harvard Medical School, Boston. “Both groups had about two detoxes in the year prior to the index shot.
“ We were also curious about what other drugs they were using prior to starting naltrexone. The OUD patients used more stimulants, more cocaine, and more sedative hypnotics. Smoking was endemic in both of these groups, as was marijuana use.”
The average interval from the time patients in both groups made the decision to start long-acting naltrexone to the time they received their first shot was about 2 months. “It’s safe to say that no one rushed into this,” Dr. Chang said. “The mean number of injections for the study year was about 5, which was very high, and the range was from 1 to 13, which suggests that some people got a shot every single month. Both of the groups had similar numbers of individual treatment sessions, which was about one. They had almost two residential admissions after the index shot and at least one other appointment with a prescribing psychiatrist.”
On Poisson regression analysis, factors associated with increased medication persistence included percent service connection and number of individual, group, residential, and other treatment modalities attended (P less than .05 for all associations). For each unit increase in the number of individual sessions, the number of long-acting naltrexone shots would go up by 7%, Dr. Chang said. For each unit increase in the number of group sessions, the number of long-acting naltrexone therapy shots would go up by 5%, while for each residential admission session, the number of long-acting naltrexone shots would go up by 14%.
“Keep in mind that our patients had an average of two residential admissions, so the number of shots went up by 28%,” she said. “For the number of other appointments with the addiction psychiatrist, the number of shots went up by 6%.”
Dr. Chang acknowledged certain limitations of the study, including its retrospective design and the relatively small sample size. “What was good to see is that the number of inpatient detox admissions was halved, when comparing the year before and the year after the shot,” she said. “This was highly statistically significant. Concurrent psychosocial treatment is highly important in the treatment persistence with this modality.”
Dr. Chang reported having no relevant financial disclosures.
SAN DIEGO – Persistence with long-acting naltrexone treatment was associated with significantly reduced detoxification admissions and concurrent engagement in treatment, a retrospective study of veterans found.
The Food and Drug Administration has approved long-acting naltrexone hydrochloride for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD), but little is known about the patients who initiate and continue this therapy, Grace Chang, MD, MPH, said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry. In an effort to evaluate the characteristics associated with long-term naltrexone treatment persistence, Dr. Chang, chief of consultation-liaison psychiatry at the VA Boston Healthcare System, and her associates studied 154 veterans who initiated long-acting naltrexone therapy for AUD or OUD between 2014 and 2015.
Among those who died in the study year after the index shot, no difference in the average number of long-acting naltrexone injections was observed (5.3 in the OUD group vs. 6.8 in the AUD group, P = .62). There was a long interval between the last known injection of long-acting naltrexone and the date of death (381 days in the OUD group vs. 326 days in the AUD group, P = .67). The cause of death was unknown in 57% of cases, while 21% were from natural causes, and 21% were tied to overdose or self-inflicted injury.
The rates of posttraumatic stress disorder in the OUD and AUD groups were about the same, but the AUD patients had higher rates of mood disorder and anxiety disorder. The AUD patients had higher rates of cardiac disease and pulmonary disease, while the OUD patients had higher rates of musculoskeletal problems. Renal disease was relatively rare in both groups. “The AUD patients started using their drug of choice earlier, but the groups were comparable in being able to attain over 2 years of abstinence at some point,” said Dr. Chang, who is also professor of psychiatry at Harvard Medical School, Boston. “Both groups had about two detoxes in the year prior to the index shot.
“ We were also curious about what other drugs they were using prior to starting naltrexone. The OUD patients used more stimulants, more cocaine, and more sedative hypnotics. Smoking was endemic in both of these groups, as was marijuana use.”
The average interval from the time patients in both groups made the decision to start long-acting naltrexone to the time they received their first shot was about 2 months. “It’s safe to say that no one rushed into this,” Dr. Chang said. “The mean number of injections for the study year was about 5, which was very high, and the range was from 1 to 13, which suggests that some people got a shot every single month. Both of the groups had similar numbers of individual treatment sessions, which was about one. They had almost two residential admissions after the index shot and at least one other appointment with a prescribing psychiatrist.”
On Poisson regression analysis, factors associated with increased medication persistence included percent service connection and number of individual, group, residential, and other treatment modalities attended (P less than .05 for all associations). For each unit increase in the number of individual sessions, the number of long-acting naltrexone shots would go up by 7%, Dr. Chang said. For each unit increase in the number of group sessions, the number of long-acting naltrexone therapy shots would go up by 5%, while for each residential admission session, the number of long-acting naltrexone shots would go up by 14%.
“Keep in mind that our patients had an average of two residential admissions, so the number of shots went up by 28%,” she said. “For the number of other appointments with the addiction psychiatrist, the number of shots went up by 6%.”
Dr. Chang acknowledged certain limitations of the study, including its retrospective design and the relatively small sample size. “What was good to see is that the number of inpatient detox admissions was halved, when comparing the year before and the year after the shot,” she said. “This was highly statistically significant. Concurrent psychosocial treatment is highly important in the treatment persistence with this modality.”
Dr. Chang reported having no relevant financial disclosures.
REPORTING FROM AAAP
Key clinical point: The number of inpatient detoxification admissions was halved when the year before and the year after the start of long-term naltrexone were compared.
Major finding: Factors associated with increased medication persistence included percent service connection and the number of individual, group, residential, and other treatment modalities attended (P less than .05 for all associations).
Study details: A retrospective analysis of 154 veterans who initiated long-acting naltrexone therapy between 2014 and 2015.
Disclosures: Dr. Chang reported having no relevant financial disclosures.
Personal omics profiling here to stay
LOS ANGELES – Michael Snyder, PhD, wears his research on his sleeve, so to speak. On any given day, he wears up to eight devices on his body that measure everything from radiation exposure to fasting glucose and sleep activity.
The way he sees it,wearables to monitor physiomes, plus personal omics profiling technology, give a high-resolution view of how health changes over periods of wellness and disease.
“We know intuitively that your health state is influenced by many things, including your genome and all of the things you’re exposed to, from pathogens to food, stress, and exercise,” Dr. Snyder said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They all impact your health state, but in a future not far away, people will be born with their genome sequenced, and we will understand in a probabilistic fashion how, with a set of variants in your genome, if you are exposed to certain environmental conditions, you will have certain health outcomes. As an example, if you’re at risk for Parkinson’s disease, you probably shouldn’t be a pesticide worker, because that greatly increases the chances by which you get Parkinson’s.”
About 8 years ago, he and his associates launched an ongoing longitudinal personal omics profiling project of 105 individuals, 55% of whom are prediabetic. After undergoing genome sequencing, each person undergoes measurement of 14 different omics every 3 months, including their RNA, proteins, lipidomics, cytokines, and microbiome (Cell Host Microbe. 2014 Sep 10;16[3]:276-89).
When a perturbation comes along, like a viral infection or positive results from a colonoscopy, the researchers gather additional samples. “We are trying to understand how the different omics relate to one another,” said Dr. Snyder, who in 2012 used his own genome sequence to predict and help diagnose his own type 2 diabetes, a story that received international media attention. “If you know the inputs into a system, you should be able to calculate the outputs, no matter how complex the system is. You should be able to make meaningful associations. In this case, the inputs are your genome, your epigenome and your microbiome, and the foods you eat. The outputs would be the metabolome, and things like that. We try to understand how responses to, say, viral infections or other perturbations are similar to one another, like congestion and fever, but also why some people get more ill than others, or have varying disease-specific symptoms.”
To date, Dr. Snyder and his associates have collected about 1,800 time points and roughly 10,000 samples. The first 1,000 of those time points have been analyzed. Of the first 70 people who underwent genome sequencing, 12 had pathogenic mutations that are clinically actionable, including mutations in BRCA1, which is associated with breast and ovarian cancer; APC and MUTYH, which are associated with colon cancer; SHBD, which is associated with a high frequency of neuroendocrine tumors; and RBM20, which is associated with dilated cardiomyopathy. One such person “underwent stress testing, and it turns out he does have a heart defect,” noted Dr. Snyder, who is also the author of Genomics and Personalized Medicine: What Everyone Needs to Know (New York: Oxford University Press, 2016). “So some of this information is extremely valuable. This is why we argue that genome sequencing, much like family history, will one day move into the clinic for those who want to use it.”
So far, the longitudinal personal omics analysis has revealed other important diagnoses that likely would have flown under the radar of conventional Western medicine, including a heart defect in one person that was detected by a simple wearable device, a case of early lymphoma, and a case of MGUS (monoclonal gammopathy of unknown significance), which is a precancerous condition.
“We have also had many metabolic cases; a lot of folks were prediabetic and others were diabetic,” Dr. Snyder said. “It’s hard to predict exactly what you’re going to see for any one person. But when you collect a lot of this data, you do find things that are important for their health.”
Of the current study participants, 23 underwent a dietary perturbation. Of these, 13 were insulin resistant and 10 were healthy controls, matched for body mass index. The subjects consumed an extra 1,000 calories per day for 30 days, maintained their peak weight for 7 days, and embarked on a weight loss program for 60 days. “We looked at the effects of weight gain and weight loss in incredible molecular detail,” Dr. Snyder explained, noting that the work will appear in a forthcoming edition of Cell Systems. “At baseline, we can tell the insulin-resistant from the -sensitive folks. After people gain and lose weight, we can identify all the compounds and biochemical pathways that change by using integrative c-means clustering to identify pattern recognition across RNA sequencing, proteome, metabolome, microbiome, and cytokines. From blood, we can actually see these compounds changing. We also can tease out differences between resistance and sensitivity in their reaction to weight gain and weight loss. For example, in the microbiome, the insulin-resistant folks were more resistant to changes in weight gain and weight loss, while insulin-sensitive folks go up and down pretty well.”
The researchers also observed that the omics profile of each person who participated in the dietary perturbation study was different at baseline. “So everybody is special, and not just to our mothers,” Dr. Snyder said. “That is to say, if I profile you, you will not look like anyone sitting next to you. If you go through a perturbation, you will still look more like you than the person sitting next to you.” Going forward, he predicted that personal omics profiling “will build a personal dashboard that relays into your smartphone and can measure your health. Just like your car dashboard, we hope that you’ll have indicators of health, which will be your command center of the future.”
He disclosed that he is a scientific adviser to Personalis, Genapsys, SensOmics, and Qbio.
LOS ANGELES – Michael Snyder, PhD, wears his research on his sleeve, so to speak. On any given day, he wears up to eight devices on his body that measure everything from radiation exposure to fasting glucose and sleep activity.
The way he sees it,wearables to monitor physiomes, plus personal omics profiling technology, give a high-resolution view of how health changes over periods of wellness and disease.
“We know intuitively that your health state is influenced by many things, including your genome and all of the things you’re exposed to, from pathogens to food, stress, and exercise,” Dr. Snyder said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They all impact your health state, but in a future not far away, people will be born with their genome sequenced, and we will understand in a probabilistic fashion how, with a set of variants in your genome, if you are exposed to certain environmental conditions, you will have certain health outcomes. As an example, if you’re at risk for Parkinson’s disease, you probably shouldn’t be a pesticide worker, because that greatly increases the chances by which you get Parkinson’s.”
About 8 years ago, he and his associates launched an ongoing longitudinal personal omics profiling project of 105 individuals, 55% of whom are prediabetic. After undergoing genome sequencing, each person undergoes measurement of 14 different omics every 3 months, including their RNA, proteins, lipidomics, cytokines, and microbiome (Cell Host Microbe. 2014 Sep 10;16[3]:276-89).
When a perturbation comes along, like a viral infection or positive results from a colonoscopy, the researchers gather additional samples. “We are trying to understand how the different omics relate to one another,” said Dr. Snyder, who in 2012 used his own genome sequence to predict and help diagnose his own type 2 diabetes, a story that received international media attention. “If you know the inputs into a system, you should be able to calculate the outputs, no matter how complex the system is. You should be able to make meaningful associations. In this case, the inputs are your genome, your epigenome and your microbiome, and the foods you eat. The outputs would be the metabolome, and things like that. We try to understand how responses to, say, viral infections or other perturbations are similar to one another, like congestion and fever, but also why some people get more ill than others, or have varying disease-specific symptoms.”
To date, Dr. Snyder and his associates have collected about 1,800 time points and roughly 10,000 samples. The first 1,000 of those time points have been analyzed. Of the first 70 people who underwent genome sequencing, 12 had pathogenic mutations that are clinically actionable, including mutations in BRCA1, which is associated with breast and ovarian cancer; APC and MUTYH, which are associated with colon cancer; SHBD, which is associated with a high frequency of neuroendocrine tumors; and RBM20, which is associated with dilated cardiomyopathy. One such person “underwent stress testing, and it turns out he does have a heart defect,” noted Dr. Snyder, who is also the author of Genomics and Personalized Medicine: What Everyone Needs to Know (New York: Oxford University Press, 2016). “So some of this information is extremely valuable. This is why we argue that genome sequencing, much like family history, will one day move into the clinic for those who want to use it.”
So far, the longitudinal personal omics analysis has revealed other important diagnoses that likely would have flown under the radar of conventional Western medicine, including a heart defect in one person that was detected by a simple wearable device, a case of early lymphoma, and a case of MGUS (monoclonal gammopathy of unknown significance), which is a precancerous condition.
“We have also had many metabolic cases; a lot of folks were prediabetic and others were diabetic,” Dr. Snyder said. “It’s hard to predict exactly what you’re going to see for any one person. But when you collect a lot of this data, you do find things that are important for their health.”
Of the current study participants, 23 underwent a dietary perturbation. Of these, 13 were insulin resistant and 10 were healthy controls, matched for body mass index. The subjects consumed an extra 1,000 calories per day for 30 days, maintained their peak weight for 7 days, and embarked on a weight loss program for 60 days. “We looked at the effects of weight gain and weight loss in incredible molecular detail,” Dr. Snyder explained, noting that the work will appear in a forthcoming edition of Cell Systems. “At baseline, we can tell the insulin-resistant from the -sensitive folks. After people gain and lose weight, we can identify all the compounds and biochemical pathways that change by using integrative c-means clustering to identify pattern recognition across RNA sequencing, proteome, metabolome, microbiome, and cytokines. From blood, we can actually see these compounds changing. We also can tease out differences between resistance and sensitivity in their reaction to weight gain and weight loss. For example, in the microbiome, the insulin-resistant folks were more resistant to changes in weight gain and weight loss, while insulin-sensitive folks go up and down pretty well.”
The researchers also observed that the omics profile of each person who participated in the dietary perturbation study was different at baseline. “So everybody is special, and not just to our mothers,” Dr. Snyder said. “That is to say, if I profile you, you will not look like anyone sitting next to you. If you go through a perturbation, you will still look more like you than the person sitting next to you.” Going forward, he predicted that personal omics profiling “will build a personal dashboard that relays into your smartphone and can measure your health. Just like your car dashboard, we hope that you’ll have indicators of health, which will be your command center of the future.”
He disclosed that he is a scientific adviser to Personalis, Genapsys, SensOmics, and Qbio.
LOS ANGELES – Michael Snyder, PhD, wears his research on his sleeve, so to speak. On any given day, he wears up to eight devices on his body that measure everything from radiation exposure to fasting glucose and sleep activity.
The way he sees it,wearables to monitor physiomes, plus personal omics profiling technology, give a high-resolution view of how health changes over periods of wellness and disease.
“We know intuitively that your health state is influenced by many things, including your genome and all of the things you’re exposed to, from pathogens to food, stress, and exercise,” Dr. Snyder said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “They all impact your health state, but in a future not far away, people will be born with their genome sequenced, and we will understand in a probabilistic fashion how, with a set of variants in your genome, if you are exposed to certain environmental conditions, you will have certain health outcomes. As an example, if you’re at risk for Parkinson’s disease, you probably shouldn’t be a pesticide worker, because that greatly increases the chances by which you get Parkinson’s.”
About 8 years ago, he and his associates launched an ongoing longitudinal personal omics profiling project of 105 individuals, 55% of whom are prediabetic. After undergoing genome sequencing, each person undergoes measurement of 14 different omics every 3 months, including their RNA, proteins, lipidomics, cytokines, and microbiome (Cell Host Microbe. 2014 Sep 10;16[3]:276-89).
When a perturbation comes along, like a viral infection or positive results from a colonoscopy, the researchers gather additional samples. “We are trying to understand how the different omics relate to one another,” said Dr. Snyder, who in 2012 used his own genome sequence to predict and help diagnose his own type 2 diabetes, a story that received international media attention. “If you know the inputs into a system, you should be able to calculate the outputs, no matter how complex the system is. You should be able to make meaningful associations. In this case, the inputs are your genome, your epigenome and your microbiome, and the foods you eat. The outputs would be the metabolome, and things like that. We try to understand how responses to, say, viral infections or other perturbations are similar to one another, like congestion and fever, but also why some people get more ill than others, or have varying disease-specific symptoms.”
To date, Dr. Snyder and his associates have collected about 1,800 time points and roughly 10,000 samples. The first 1,000 of those time points have been analyzed. Of the first 70 people who underwent genome sequencing, 12 had pathogenic mutations that are clinically actionable, including mutations in BRCA1, which is associated with breast and ovarian cancer; APC and MUTYH, which are associated with colon cancer; SHBD, which is associated with a high frequency of neuroendocrine tumors; and RBM20, which is associated with dilated cardiomyopathy. One such person “underwent stress testing, and it turns out he does have a heart defect,” noted Dr. Snyder, who is also the author of Genomics and Personalized Medicine: What Everyone Needs to Know (New York: Oxford University Press, 2016). “So some of this information is extremely valuable. This is why we argue that genome sequencing, much like family history, will one day move into the clinic for those who want to use it.”
So far, the longitudinal personal omics analysis has revealed other important diagnoses that likely would have flown under the radar of conventional Western medicine, including a heart defect in one person that was detected by a simple wearable device, a case of early lymphoma, and a case of MGUS (monoclonal gammopathy of unknown significance), which is a precancerous condition.
“We have also had many metabolic cases; a lot of folks were prediabetic and others were diabetic,” Dr. Snyder said. “It’s hard to predict exactly what you’re going to see for any one person. But when you collect a lot of this data, you do find things that are important for their health.”
Of the current study participants, 23 underwent a dietary perturbation. Of these, 13 were insulin resistant and 10 were healthy controls, matched for body mass index. The subjects consumed an extra 1,000 calories per day for 30 days, maintained their peak weight for 7 days, and embarked on a weight loss program for 60 days. “We looked at the effects of weight gain and weight loss in incredible molecular detail,” Dr. Snyder explained, noting that the work will appear in a forthcoming edition of Cell Systems. “At baseline, we can tell the insulin-resistant from the -sensitive folks. After people gain and lose weight, we can identify all the compounds and biochemical pathways that change by using integrative c-means clustering to identify pattern recognition across RNA sequencing, proteome, metabolome, microbiome, and cytokines. From blood, we can actually see these compounds changing. We also can tease out differences between resistance and sensitivity in their reaction to weight gain and weight loss. For example, in the microbiome, the insulin-resistant folks were more resistant to changes in weight gain and weight loss, while insulin-sensitive folks go up and down pretty well.”
The researchers also observed that the omics profile of each person who participated in the dietary perturbation study was different at baseline. “So everybody is special, and not just to our mothers,” Dr. Snyder said. “That is to say, if I profile you, you will not look like anyone sitting next to you. If you go through a perturbation, you will still look more like you than the person sitting next to you.” Going forward, he predicted that personal omics profiling “will build a personal dashboard that relays into your smartphone and can measure your health. Just like your car dashboard, we hope that you’ll have indicators of health, which will be your command center of the future.”
He disclosed that he is a scientific adviser to Personalis, Genapsys, SensOmics, and Qbio.
EXPERT ANALYSIS FROM WCIRDC 2017
Link between glucose control and CVD risk: It’s complicated
EXPERT ANALYSIS FROM WCIRDC 2017
LOS ANGELES – If you think the link between glucose control and cardiovascular disease is complicated, you’re not alone.
“Glucose is not the only risk factor for CVD, and it may not be the most important risk factor,” Peter Reaven, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Controlling blood pressure and lipids is also quite important. In current studies, patients with diabetes are aggressively treated for other risk factors with many vascular-acting medications, so it’s difficult to show the benefits of glucose lowering on its own. That is pertinent because it’s becoming clear that the benefits of glucose lowering may take a long time. How, and in whom, one controls glucose may influence the outcome.
Medications, hypoglycemia, glucose variation, and extent of disease all may influence vascular responses to glucose lowering.”
Dr. Reaven, an endocrinologist who directs the Diabetes Research Program at the University of Arizona and VA Health Care System, Phoenix, noted that, while a consistent body of evidence supports an association between higher levels of glucose and increased risk for CVD, it’s not as clear that tight control efforts decrease a patient’s risk for CVD at the microvascular and macrovascular level. “We also appreciate that complications from intensive glucose lowering – such as hypoglycemia, weight gain, time and cost, and increased mortality – are not minimal,” he said.
A meta-analysis of 27,049 patients with type 2 diabetes enrolled in four major trials found that those who were allocated to more-intensive, compared with less-intensive, glucose control had a reduced risk of major cardiovascular events by 9% (hazard ratio, 0.91), primarily because of a 15% reduced risk of myocardial infarction (Diabetologia 2009;52[11] 2288-98). “None of these studies actually achieved statistical significance, but they all showed a modest trend,” said Dr. Reaven, who was not involved in the meta-analysis. At the same time, interim data from the Veterans Affairs Diabetes Trial follow-up study (VADT-F) showed that, after about 10 years, the median HbA1c levels were similar between patients who had received either intensive or standard glucose for a median of 5.6 years in the initial VADT trial (N Engl J Med. 2009;360[2]:129-39). Other risk factors between the two groups were similar, including LDL and systolic and diastolic blood pressures.
In this extended follow-up of the VADT, a 17% reduction in CVD was observed among patients who were treated more intensively, compared with those on standard therapy, after about 12 years of treatment (P = .04; N Engl J Med. 2015;372:2197-206). “Why does it take so long?” he asked. “Why does it take 10-plus years of mean follow-up with an HbA1c separation of 1.5% to start to lead to cardiovascular events? The reality is, we don’t know the answer.”
It’s possible that many years of hyperglycemia created enough vascular injury and long-term consequences that are not easily turned around in short intervals, but Dr. Reaven noted that advanced glycation and oxidation products might also be contributing to long-term vascular legacy events. In an analysis of patients from the VADT-F, he and his associates found that specific advanced glycation end products and oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing type 2 diabetes mellitus (Diabetes Care 2017;40[4]:591-8). In particular, the combination of 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone and 2-aminoadipic acid was strongly associated with all measures of subclinical atherosclerosis.
In the initial VADT trial, severe hypoglycemia occurred nearly three times more commonly in the intensively treated group, compared with the standard therapy group. Severe hypoglycemia was defined as an episode of low blood glucose that was accompanied by confusion requiring assistance from another person or loss of consciousness. In related analyses, the hazard ratio for CV events, CV mortality, and overall mortality with severe hypoglycemia within the preceding 3 months was also increased. “So this is a consistent finding across multiple studies of the danger of severe hypoglycemia occurring during your efforts to improve glucose lowering,” Dr. Reaven said. “Interestingly, it appears that the risk for CVD events following severe hypoglycemia increases with higher baseline CV risk, based on the United Kingdom Prospective Diabetes Study 10-year CV risk score. So, how great your risk is begins to influence how well you do after severe hypoglycemia.”
In a separate stratified analysis of VADT data, the risk for CVD after severe hypoglycemia was more prominent in the standard treatment group, compared with the intensive treatment group. “There’s nearly a sevenfold increased risk for all-cause mortality following severe hypoglycemia in the preceding 3 months,” he said. “The same pattern is present for cardiovascular mortality and, somewhat, for cardiovascular events, although not statistically significant. The association between symptomatic, severe hypoglycemia and mortality in type 2 diabetes was seen in the ACCORD [Action to Control Cardiovascular Risk in Diabetes] population as well.”
A subset of patients in the VADT study showed that individuals in the standard therapy group who had a prior serious hypoglycemic episode actually had greater coronary calcium progression during the study, compared with the intensively treated group (P = .02; Diabetes Care 2016;39[3]:448-54). “One possibility is that serious hypoglycemia contributed to the development of atherosclerosis in this group,” Dr. Reaven said. “This held true when one examined high and lower glucose levels on average in the study. Those individuals that had A1c levels of 7.5% or above were the ones that appeared to show coronary calcium progression during the study following episodes of severe hypoglycemia, whereas it did not appear to be an issue among those with good glucose control. Another finding was that severe hypoglycemia is associated with increased glucose variability from office visit to office visit.”
He concluded his remarks by noting that being “glucose centric” is not the right approach to treating patients with diabetes. “Other risk factors may offer bigger and more rapid benefits,” he said. “The benefits of glucose lowering are likely most relevant in type 1 diabetes and in early type 2 diabetes, and the benefits of glucose lowering on vascular disease appear to take a long time. Avoid severe hypoglycemia, especially in older patients with type 2 diabetes. This last point may be particularly relevant for those in poor control.”
Dr. Reaven reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM WCIRDC 2017
LOS ANGELES – If you think the link between glucose control and cardiovascular disease is complicated, you’re not alone.
“Glucose is not the only risk factor for CVD, and it may not be the most important risk factor,” Peter Reaven, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Controlling blood pressure and lipids is also quite important. In current studies, patients with diabetes are aggressively treated for other risk factors with many vascular-acting medications, so it’s difficult to show the benefits of glucose lowering on its own. That is pertinent because it’s becoming clear that the benefits of glucose lowering may take a long time. How, and in whom, one controls glucose may influence the outcome.
Medications, hypoglycemia, glucose variation, and extent of disease all may influence vascular responses to glucose lowering.”
Dr. Reaven, an endocrinologist who directs the Diabetes Research Program at the University of Arizona and VA Health Care System, Phoenix, noted that, while a consistent body of evidence supports an association between higher levels of glucose and increased risk for CVD, it’s not as clear that tight control efforts decrease a patient’s risk for CVD at the microvascular and macrovascular level. “We also appreciate that complications from intensive glucose lowering – such as hypoglycemia, weight gain, time and cost, and increased mortality – are not minimal,” he said.
A meta-analysis of 27,049 patients with type 2 diabetes enrolled in four major trials found that those who were allocated to more-intensive, compared with less-intensive, glucose control had a reduced risk of major cardiovascular events by 9% (hazard ratio, 0.91), primarily because of a 15% reduced risk of myocardial infarction (Diabetologia 2009;52[11] 2288-98). “None of these studies actually achieved statistical significance, but they all showed a modest trend,” said Dr. Reaven, who was not involved in the meta-analysis. At the same time, interim data from the Veterans Affairs Diabetes Trial follow-up study (VADT-F) showed that, after about 10 years, the median HbA1c levels were similar between patients who had received either intensive or standard glucose for a median of 5.6 years in the initial VADT trial (N Engl J Med. 2009;360[2]:129-39). Other risk factors between the two groups were similar, including LDL and systolic and diastolic blood pressures.
In this extended follow-up of the VADT, a 17% reduction in CVD was observed among patients who were treated more intensively, compared with those on standard therapy, after about 12 years of treatment (P = .04; N Engl J Med. 2015;372:2197-206). “Why does it take so long?” he asked. “Why does it take 10-plus years of mean follow-up with an HbA1c separation of 1.5% to start to lead to cardiovascular events? The reality is, we don’t know the answer.”
It’s possible that many years of hyperglycemia created enough vascular injury and long-term consequences that are not easily turned around in short intervals, but Dr. Reaven noted that advanced glycation and oxidation products might also be contributing to long-term vascular legacy events. In an analysis of patients from the VADT-F, he and his associates found that specific advanced glycation end products and oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing type 2 diabetes mellitus (Diabetes Care 2017;40[4]:591-8). In particular, the combination of 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone and 2-aminoadipic acid was strongly associated with all measures of subclinical atherosclerosis.
In the initial VADT trial, severe hypoglycemia occurred nearly three times more commonly in the intensively treated group, compared with the standard therapy group. Severe hypoglycemia was defined as an episode of low blood glucose that was accompanied by confusion requiring assistance from another person or loss of consciousness. In related analyses, the hazard ratio for CV events, CV mortality, and overall mortality with severe hypoglycemia within the preceding 3 months was also increased. “So this is a consistent finding across multiple studies of the danger of severe hypoglycemia occurring during your efforts to improve glucose lowering,” Dr. Reaven said. “Interestingly, it appears that the risk for CVD events following severe hypoglycemia increases with higher baseline CV risk, based on the United Kingdom Prospective Diabetes Study 10-year CV risk score. So, how great your risk is begins to influence how well you do after severe hypoglycemia.”
In a separate stratified analysis of VADT data, the risk for CVD after severe hypoglycemia was more prominent in the standard treatment group, compared with the intensive treatment group. “There’s nearly a sevenfold increased risk for all-cause mortality following severe hypoglycemia in the preceding 3 months,” he said. “The same pattern is present for cardiovascular mortality and, somewhat, for cardiovascular events, although not statistically significant. The association between symptomatic, severe hypoglycemia and mortality in type 2 diabetes was seen in the ACCORD [Action to Control Cardiovascular Risk in Diabetes] population as well.”
A subset of patients in the VADT study showed that individuals in the standard therapy group who had a prior serious hypoglycemic episode actually had greater coronary calcium progression during the study, compared with the intensively treated group (P = .02; Diabetes Care 2016;39[3]:448-54). “One possibility is that serious hypoglycemia contributed to the development of atherosclerosis in this group,” Dr. Reaven said. “This held true when one examined high and lower glucose levels on average in the study. Those individuals that had A1c levels of 7.5% or above were the ones that appeared to show coronary calcium progression during the study following episodes of severe hypoglycemia, whereas it did not appear to be an issue among those with good glucose control. Another finding was that severe hypoglycemia is associated with increased glucose variability from office visit to office visit.”
He concluded his remarks by noting that being “glucose centric” is not the right approach to treating patients with diabetes. “Other risk factors may offer bigger and more rapid benefits,” he said. “The benefits of glucose lowering are likely most relevant in type 1 diabetes and in early type 2 diabetes, and the benefits of glucose lowering on vascular disease appear to take a long time. Avoid severe hypoglycemia, especially in older patients with type 2 diabetes. This last point may be particularly relevant for those in poor control.”
Dr. Reaven reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM WCIRDC 2017
LOS ANGELES – If you think the link between glucose control and cardiovascular disease is complicated, you’re not alone.
“Glucose is not the only risk factor for CVD, and it may not be the most important risk factor,” Peter Reaven, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Controlling blood pressure and lipids is also quite important. In current studies, patients with diabetes are aggressively treated for other risk factors with many vascular-acting medications, so it’s difficult to show the benefits of glucose lowering on its own. That is pertinent because it’s becoming clear that the benefits of glucose lowering may take a long time. How, and in whom, one controls glucose may influence the outcome.
Medications, hypoglycemia, glucose variation, and extent of disease all may influence vascular responses to glucose lowering.”
Dr. Reaven, an endocrinologist who directs the Diabetes Research Program at the University of Arizona and VA Health Care System, Phoenix, noted that, while a consistent body of evidence supports an association between higher levels of glucose and increased risk for CVD, it’s not as clear that tight control efforts decrease a patient’s risk for CVD at the microvascular and macrovascular level. “We also appreciate that complications from intensive glucose lowering – such as hypoglycemia, weight gain, time and cost, and increased mortality – are not minimal,” he said.
A meta-analysis of 27,049 patients with type 2 diabetes enrolled in four major trials found that those who were allocated to more-intensive, compared with less-intensive, glucose control had a reduced risk of major cardiovascular events by 9% (hazard ratio, 0.91), primarily because of a 15% reduced risk of myocardial infarction (Diabetologia 2009;52[11] 2288-98). “None of these studies actually achieved statistical significance, but they all showed a modest trend,” said Dr. Reaven, who was not involved in the meta-analysis. At the same time, interim data from the Veterans Affairs Diabetes Trial follow-up study (VADT-F) showed that, after about 10 years, the median HbA1c levels were similar between patients who had received either intensive or standard glucose for a median of 5.6 years in the initial VADT trial (N Engl J Med. 2009;360[2]:129-39). Other risk factors between the two groups were similar, including LDL and systolic and diastolic blood pressures.
In this extended follow-up of the VADT, a 17% reduction in CVD was observed among patients who were treated more intensively, compared with those on standard therapy, after about 12 years of treatment (P = .04; N Engl J Med. 2015;372:2197-206). “Why does it take so long?” he asked. “Why does it take 10-plus years of mean follow-up with an HbA1c separation of 1.5% to start to lead to cardiovascular events? The reality is, we don’t know the answer.”
It’s possible that many years of hyperglycemia created enough vascular injury and long-term consequences that are not easily turned around in short intervals, but Dr. Reaven noted that advanced glycation and oxidation products might also be contributing to long-term vascular legacy events. In an analysis of patients from the VADT-F, he and his associates found that specific advanced glycation end products and oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the “negative metabolic memory” of macrovascular complications in people with long-standing type 2 diabetes mellitus (Diabetes Care 2017;40[4]:591-8). In particular, the combination of 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone and 2-aminoadipic acid was strongly associated with all measures of subclinical atherosclerosis.
In the initial VADT trial, severe hypoglycemia occurred nearly three times more commonly in the intensively treated group, compared with the standard therapy group. Severe hypoglycemia was defined as an episode of low blood glucose that was accompanied by confusion requiring assistance from another person or loss of consciousness. In related analyses, the hazard ratio for CV events, CV mortality, and overall mortality with severe hypoglycemia within the preceding 3 months was also increased. “So this is a consistent finding across multiple studies of the danger of severe hypoglycemia occurring during your efforts to improve glucose lowering,” Dr. Reaven said. “Interestingly, it appears that the risk for CVD events following severe hypoglycemia increases with higher baseline CV risk, based on the United Kingdom Prospective Diabetes Study 10-year CV risk score. So, how great your risk is begins to influence how well you do after severe hypoglycemia.”
In a separate stratified analysis of VADT data, the risk for CVD after severe hypoglycemia was more prominent in the standard treatment group, compared with the intensive treatment group. “There’s nearly a sevenfold increased risk for all-cause mortality following severe hypoglycemia in the preceding 3 months,” he said. “The same pattern is present for cardiovascular mortality and, somewhat, for cardiovascular events, although not statistically significant. The association between symptomatic, severe hypoglycemia and mortality in type 2 diabetes was seen in the ACCORD [Action to Control Cardiovascular Risk in Diabetes] population as well.”
A subset of patients in the VADT study showed that individuals in the standard therapy group who had a prior serious hypoglycemic episode actually had greater coronary calcium progression during the study, compared with the intensively treated group (P = .02; Diabetes Care 2016;39[3]:448-54). “One possibility is that serious hypoglycemia contributed to the development of atherosclerosis in this group,” Dr. Reaven said. “This held true when one examined high and lower glucose levels on average in the study. Those individuals that had A1c levels of 7.5% or above were the ones that appeared to show coronary calcium progression during the study following episodes of severe hypoglycemia, whereas it did not appear to be an issue among those with good glucose control. Another finding was that severe hypoglycemia is associated with increased glucose variability from office visit to office visit.”
He concluded his remarks by noting that being “glucose centric” is not the right approach to treating patients with diabetes. “Other risk factors may offer bigger and more rapid benefits,” he said. “The benefits of glucose lowering are likely most relevant in type 1 diabetes and in early type 2 diabetes, and the benefits of glucose lowering on vascular disease appear to take a long time. Avoid severe hypoglycemia, especially in older patients with type 2 diabetes. This last point may be particularly relevant for those in poor control.”
Dr. Reaven reported having no relevant financial disclosures.
Early intervention key to treating substance use disorders
SAN DIEGO – Intervening early can positively affect outcomes for patients struggling with substance use disorders, regardless of their current stage of development and place in the life cycle, speaker after speaker said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
The prenatal/perinatal period represents a high-risk window for the kindling and precipitation of substance use disorders (SUDs), because of the stress of pregnancy, delivery, recovery, and the newly assumed parenting role. “Offspring who are exposed in utero have an earlier age of initiation of substance use, as well as a greater risk of substance use disorders later on in life,” said Justine Wittenaur Welsh, MD, director of the Emory Adolescent Substance Use Treatment Services, Atlanta. “We as treatment providers need to start to think about how to screen for these individuals. What types of early intervention can we provide, and how do we integrate this into our treatment planning?”
According to data on current illicit drug use among pregnant women from the Substance Abuse and Mental Health Services Administration, the risk is highest among those aged 15-17 years (14.6%), followed by those aged 18-25 years (8.6%), and 26-44 years (3.2%). “We also know that rates of substance use are higher in the first trimester, compared with the second and the third,” said Dr. Welsh, who holds a faculty position in the department of psychiatry and behavioral sciences at Emory University. “But unfortunately, a significant number of pregnant women return to substance use after they deliver. This is really important for treatment providers, to intervene early before a return to substance use. We know that improving the postnatal environment does reduce the risk of substance use, even in individuals who have in utero exposures.”
SUDs confer a host of adverse effects to both the baby and the mother. “With tobacco, although there are a significant number of poisonous chemicals in cigarettes that the baby would be exposed to, we believe it’s the carbon monoxide and the nicotine exposure that confers the most known damage,” Dr. Welsh said. In utero exposure to cigarettes increases the likelihood to initiate smoking during adolescence by twofold (Neurotoxicol Teratol. 2005;27[2]:267-77), and a dose-response relationship has been observed between prenatal smoking and psychiatric hospitalization for substance abuse in offspring (Am J Psychiatry. 2002;159[1]:48-54). In utero exposure to cigarettes also increases the risk for offspring cigarette use. “The exposure to greater than a half-pack of cigarettes per day has a 5.5-fold increased risk for early cigarette experimentation, while exposure to one pack per day or more is associated with twice the risk of developing nicotine dependence,” she said.
As for in utero alcohol exposure, consuming greater than or equal to three drinks is associated with an alcohol disorder at age 21 (odds ratio, 2.95) if the exposure occurred in early pregnancy; Arch Gen Psychiatry. 2006;63[9]:1009-16). In utero alcohol exposure also has been more predictive of adolescent alcohol use than family history. “It’s also been associated with an increased number of abuse/dependency symptoms in offspring, for nicotine, alcohol, and illicit drugs,” Dr. Welsh said. “It has also been associated with an increased risk of cigarette use and substance use disorders in offspring.”
In utero cannabis exposure has been associated with a twofold increased risk of tobacco and marijuana use later in life (Addiction 2006;101[9]:1313-22), as well as with a twofold increased risk of smoking cigarettes daily and of using marijuana during adolescence. In utero cocaine exposure has been associated with a twofold increased risk of using tobacco, a 2.2-fold increased risk of using alcohol, and a 1.8-fold risk of using marijuana, as well as a 2.1-fold increased risk of having an SUD by age 17. “Prenatal exposure and postnatal parent/caregiver cocaine use is uniquely related to teen use of cocaine at age 14,” Dr. Welsh said. “In addition, exposure in the first trimester is associated with earlier marijuana and alcohol initiation.”
Real-world barriers to SUD treatment in adolescents include a lack of coordination between treatment resources, fear of losing custody of children, shame and stigma, concerns about criminal prosecution, domestic violence, and other obstacles such as transportation, finances, and child care. Dr. Welsh pointed out that pregnant women with SUDs usually receive prenatal care and addiction treatment from different providers. “We should be thinking about an integrated treatment model to improve maternal and prenatal care for patients using substances prior to or during pregnancy,” she said. “Some sites have developed combined maternity care units as a way to reduce some of these barriers to treatment. We also need to be thinking about the infants themselves. In order to counter the drug-exposed child’s early disadvantages, service providers must be prepared to intervene early, focusing on things like nutrition, psychomotor assessments, early educational needs assessments, as well as modification of existing treatment services for people with in utero exposures. This can be a difficult population to treat.”
One resource for addressing fetal alcohol spectrum disorders that she recommended is Treatment Improvement Protocol 58, published by Substance Abuse and Mental Health Services Administration. She described one young adult with significant substance use issues who was diagnosed with fetal alcohol syndrome as a child. “This young adult didn’t know about the FAS diagnosis,” Dr. Welsh said. “I expressed to the mother that, ‘this is an ethical dilemma. I’m treating someone and I know this directly impacts my treatment planning. They have a real-world diagnosis that I feel they have a right to know about.’ It made me think: If I think it’s so important that this young adult knows the diagnosis, why are we not screening for it in our general patient populations more often?
“As child psychiatrists we often ask, ‘Were there any in utero exposures?’ When treating adults, I’m asking about family history, but I’m not asking about in utero exposures. This may not be information that they’re privy to, but it’s worth starting a conversation about.”
, a 14-session, evidence-based curriculum that addresses parenting skills, children’s social skills, and family life skills training, are among the treatment options aimed at decreasing the risk of substance use progression in offspring.
‘Adolescents indeed care about their health’
During a separate presentation, Peter Jackson, MD, a psychiatrist at the University of Vermont Medical Center, Burlington, noted that an estimated 3.4 million adolescents in the United States meet criteria for an SUD, but fewer than 10% enter treatment each year. Of those who do enter treatment, 50% relapse within 6 months.
“It’s not the same story for illicit drugs, unfortunately, and that’s largely due to marijuana,” Dr. Jackson said. He noted that adolescent cannabis use is inversely proportional to how dangerous they perceive it to be. “This is evidence that adolescents indeed care about their health,” he said. “They use when they think it’s safe, and they use less when they think it’s unsafe.” Recent Monitoring the Future data also demonstrate that e-cigarette use is outpacing cigarette use among 8th, 10th, and 12th graders, while the past-year misuse of acetaminophen/hydrocodone (Vicodin) among 12th graders has dropped dramatically in the past 5 years. So has misuse of all prescription opioids among 12th graders despite high opioid overdose rates among adults.
Adolescents are more likely to be secretive about their substance use, compared with older adults. “Also, with many substances, especially alcohol, they are more likely to use in a binge pattern,” Dr. Jackson said. “They haven’t accumulated as many negative consequences from their use, so voluntarily seeking treatment is less common than in adults. They’re most often referred through the justice department or legal channels.”
Screening instruments to consider using include the CRAFFT (Car, Relax, Alone, Forget, Friends, Trouble), which has been validated as an adolescent-specific screening instrument. A score of two or more has a strong correlation with meeting criteria for an SUD. The American Academy of Pediatrics recommends the Screening, Brief Intervention, and Referral to Treatment (SBIRT), though this intervention has not been as rigorously evaluated in adolescents, compared with adults.
Dr. Jackson frowned on the notion perpetuated by some parents and caregivers that novelty seeking behavior involving alcohol and other substances is okay if it’s controlled somehow, with statements such as, “I just make sure they’ve given up their car keys and make sure it stays in my own basement. That way nobody leaves here drunk.”
“I think we can do better than that,” Dr. Jackson said.
Well-validated behavioral treatment approaches for adolescent patients include the adolescent community reinforcement approach (A-CRA); cognitive-behavioral therapy (particularly in groups); motivational enhancement therapy (MET); contingency management, and 12-step facilitation.
“Colloquially, in pop culture, we’ve been pressed on this message at times that adolescents don’t care what their parents think; they only care what their peers think,” Dr. Jackson said. “That’s not true from literature we’ve seen, so we need to put the family back in its important place.”
In a meta-analysis of promising behavioral approaches for adolescent SUD, five out of six found to have promising to excellent empirical support were family-based therapies: multidimensional family therapy, functional family therapy, multisystemic family therapy, behavioral strategic family therapy, and family behavior therapy (J Child and Adolesc Psychology. 2008;37[1]:236-59). “That’s a huge take-home point when working with adolescents: Involve the family,” Dr. Jackson said. “As providers, do we have a tendency to side only with the parent or side only with the adolescent? If we do, we should be cautious and thoughtful, because we can very effectively work with both parties. If you have an adolescent who shows up [for counseling] but then walks right out the door, you still have a parent, maybe two parents or other concerned loved ones sitting there. You still have a target for intervention.”
Even if the adolescent never returns to your office, he continued, clinicians can do an intervention with the family to statistically decrease the SUD for the adolescent. “That’s really promising,” he said. In adults, the best evidence for treatment engagement of a loved one following these family-specific interventions is for the Community Reinforcement and Family Training (CRAFT) method (64%-74%), followed by the Johnson Intervention (23%-30%) and Al-Anon/Nar-Anon facilitation (13%-29%). These interventions are being studied more specifically in adolescents and young adults.
A key tip for parents of teens coping with substance abuse is the old adage actions speak louder than words. “You can tell your child not to smoke marijuana until you’re blue in the face, but then if you go out on the back porch and smoke marijuana, that’s a really bad message for behavior change,” Dr. Jackson said. “Words also speak louder than no words. Some parents have never told their adolescent children what their opinion is, and that they’re concerned. Maybe those parents have been convinced that adolescents don’t care what they think. In fact, they do care what they think.”
Once engaged, older adults do well
Among older adults, triggers for SUDs vary considerably from that of their younger counterparts. “We tend to think of this as a population that carries a lot of wisdom and has the coping skills to deal with life,” Olivera J. Bogunovic, MD, a psychiatrist who is medical director of ambulatory services in the division of alcohol and drug abuse at McClean Hospital, Belmont, Mass., said during a separate presentation. “In fact, this is a very vulnerable population at increased risk of mood disorders. For example, many men spend their careers working 60 or 80 hours a week, then they stop working. What is there for them? They sometimes turn to substance abuse. Similarly, older women who lose a loved one may turn to drinking. There’s a lot of room for prevention. The good news is that this group of patients is very responsive to treatment. Once engaged, they do very well.”
Nicotine is the chief addictive substance affecting older adults (17%), followed by alcohol (12% in a binge capacity, dependence 1%), illicit drugs (1.8%), and medications (1.6% for pain medications and 12% on benzodiazepines). Alcohol use disorders encompass a spectrum of problems for this patient population, including at-risk drinking, problem drinking, and dependence. Presentations, complications, and consequences are wide-ranging. “We sometimes miss the symptoms of alcohol use disorders when patients present in emergency rooms,” Dr. Bogunovic said. “Unfortunately, if it’s not treated initially it results in serious medical comorbidities and complications.”
The National Institute on Drug Abuse recommends that adults consume no more than two drinks per day, but the quantity is even lower for elderly. “For men it is no more than one drink per day, while for women it’s questionable if that one drink per day is even recommended,” Dr. Bogunovic said. The prevalence of at-risk drinking among older adults ranges from 3% to 25% and the rates for problem drinking range from 2.2% to 9.6%. Alcohol dependence rates, meanwhile, range from 2% to 3% among men and less than 1% among women.
Cross-sectional data indicate a low prevalence of illicit drug use in older adults, but longitudinal data from the National Survey on Drug Abuse and others suggest an increased use of cannabis and prescription opioids. “A lot of people do not think about opioid use disorders in the elderly,” she said. “The prevalence rate in methadone clinics is less than 2%. However, with the epidemic crisis we’re seeing opioid use disorders in the elderly. What’s important to know is that they also respond to medications for treatment, more so with suboxone than with naltrexone, as we know those patients sometimes have complications that need to be treated with pain medication.”
Elderly patients constitute 13% of the population yet they account for 30% of prescriptions, mainly benzodiazepines and prescription opioids. “Two-thirds of patients who are struggling with SUDs struggled with an SUD at some point in their youth,” said Dr. Bogunovic, who holds a faculty position in the department of psychiatry at Harvard Medical School, Boston. “They continue to use for longer periods of time, with some intermittent periods of sobriety. Of those 15% who do have an alcohol use problem, they are prescribed benzodiazepines. That can be a lethal combination, because there is a combined effect of both alcohol and benzodiazepines that can result in hip fractures, subdural hematomas, and other medical comorbidity.”
Risk factors for development of alcohol use disorder in elderly include physiologic changes in the way alcohol is metabolized; gender, family history, or prior personal history of alcohol use disorder; having a concomitant psychiatric disorder; and having a chronic medical illness, such as severe arthritis. Compared with their male peers, older women generally drink less often and less heavily, but they are more likely to start drinking heavily later in life. Older men face an increased risk of alcohol-related problems tied to cumulative use over the years.
“Social factors also play a role, so it’s important to perform a skilled diagnostic interview and a psychiatric evaluation but also to evaluate the motivational stage of change, because that’s the right moment to do the intervention, knowing what the patient’s values are,” she said. Recommended screenings include the Short Michigan Alcoholism Screening Instrument–Geriatric Version (SMAST-G), the SBIRT, the CAGE-AID, and the Opioid Risk Tool. Compliance with treatment tends to be greater in older adults, compared with their younger counterparts. “They don’t like a confrontational approach, so it’s important to communicate with empathy in a straightforward manner and pay attention to what is important to patients and motivate them,” she noted. “Involve family members or other social support whenever possible.”
Relapses are common, but clinicians should encourage patients to continue treatment, “because they can do very well,” Dr. Bogunovic emphasized. “And we can offer them a good life after that.”
Dr. Welsh disclosed that she has consulted for GW Pharmaceuticals and that she has received training fees from Chestnut Health Systems. Dr. Jackson and Dr. Bogunovic reported having no financial disclosures.
SAN DIEGO – Intervening early can positively affect outcomes for patients struggling with substance use disorders, regardless of their current stage of development and place in the life cycle, speaker after speaker said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
The prenatal/perinatal period represents a high-risk window for the kindling and precipitation of substance use disorders (SUDs), because of the stress of pregnancy, delivery, recovery, and the newly assumed parenting role. “Offspring who are exposed in utero have an earlier age of initiation of substance use, as well as a greater risk of substance use disorders later on in life,” said Justine Wittenaur Welsh, MD, director of the Emory Adolescent Substance Use Treatment Services, Atlanta. “We as treatment providers need to start to think about how to screen for these individuals. What types of early intervention can we provide, and how do we integrate this into our treatment planning?”
According to data on current illicit drug use among pregnant women from the Substance Abuse and Mental Health Services Administration, the risk is highest among those aged 15-17 years (14.6%), followed by those aged 18-25 years (8.6%), and 26-44 years (3.2%). “We also know that rates of substance use are higher in the first trimester, compared with the second and the third,” said Dr. Welsh, who holds a faculty position in the department of psychiatry and behavioral sciences at Emory University. “But unfortunately, a significant number of pregnant women return to substance use after they deliver. This is really important for treatment providers, to intervene early before a return to substance use. We know that improving the postnatal environment does reduce the risk of substance use, even in individuals who have in utero exposures.”
SUDs confer a host of adverse effects to both the baby and the mother. “With tobacco, although there are a significant number of poisonous chemicals in cigarettes that the baby would be exposed to, we believe it’s the carbon monoxide and the nicotine exposure that confers the most known damage,” Dr. Welsh said. In utero exposure to cigarettes increases the likelihood to initiate smoking during adolescence by twofold (Neurotoxicol Teratol. 2005;27[2]:267-77), and a dose-response relationship has been observed between prenatal smoking and psychiatric hospitalization for substance abuse in offspring (Am J Psychiatry. 2002;159[1]:48-54). In utero exposure to cigarettes also increases the risk for offspring cigarette use. “The exposure to greater than a half-pack of cigarettes per day has a 5.5-fold increased risk for early cigarette experimentation, while exposure to one pack per day or more is associated with twice the risk of developing nicotine dependence,” she said.
As for in utero alcohol exposure, consuming greater than or equal to three drinks is associated with an alcohol disorder at age 21 (odds ratio, 2.95) if the exposure occurred in early pregnancy; Arch Gen Psychiatry. 2006;63[9]:1009-16). In utero alcohol exposure also has been more predictive of adolescent alcohol use than family history. “It’s also been associated with an increased number of abuse/dependency symptoms in offspring, for nicotine, alcohol, and illicit drugs,” Dr. Welsh said. “It has also been associated with an increased risk of cigarette use and substance use disorders in offspring.”
In utero cannabis exposure has been associated with a twofold increased risk of tobacco and marijuana use later in life (Addiction 2006;101[9]:1313-22), as well as with a twofold increased risk of smoking cigarettes daily and of using marijuana during adolescence. In utero cocaine exposure has been associated with a twofold increased risk of using tobacco, a 2.2-fold increased risk of using alcohol, and a 1.8-fold risk of using marijuana, as well as a 2.1-fold increased risk of having an SUD by age 17. “Prenatal exposure and postnatal parent/caregiver cocaine use is uniquely related to teen use of cocaine at age 14,” Dr. Welsh said. “In addition, exposure in the first trimester is associated with earlier marijuana and alcohol initiation.”
Real-world barriers to SUD treatment in adolescents include a lack of coordination between treatment resources, fear of losing custody of children, shame and stigma, concerns about criminal prosecution, domestic violence, and other obstacles such as transportation, finances, and child care. Dr. Welsh pointed out that pregnant women with SUDs usually receive prenatal care and addiction treatment from different providers. “We should be thinking about an integrated treatment model to improve maternal and prenatal care for patients using substances prior to or during pregnancy,” she said. “Some sites have developed combined maternity care units as a way to reduce some of these barriers to treatment. We also need to be thinking about the infants themselves. In order to counter the drug-exposed child’s early disadvantages, service providers must be prepared to intervene early, focusing on things like nutrition, psychomotor assessments, early educational needs assessments, as well as modification of existing treatment services for people with in utero exposures. This can be a difficult population to treat.”
One resource for addressing fetal alcohol spectrum disorders that she recommended is Treatment Improvement Protocol 58, published by Substance Abuse and Mental Health Services Administration. She described one young adult with significant substance use issues who was diagnosed with fetal alcohol syndrome as a child. “This young adult didn’t know about the FAS diagnosis,” Dr. Welsh said. “I expressed to the mother that, ‘this is an ethical dilemma. I’m treating someone and I know this directly impacts my treatment planning. They have a real-world diagnosis that I feel they have a right to know about.’ It made me think: If I think it’s so important that this young adult knows the diagnosis, why are we not screening for it in our general patient populations more often?
“As child psychiatrists we often ask, ‘Were there any in utero exposures?’ When treating adults, I’m asking about family history, but I’m not asking about in utero exposures. This may not be information that they’re privy to, but it’s worth starting a conversation about.”
, a 14-session, evidence-based curriculum that addresses parenting skills, children’s social skills, and family life skills training, are among the treatment options aimed at decreasing the risk of substance use progression in offspring.
‘Adolescents indeed care about their health’
During a separate presentation, Peter Jackson, MD, a psychiatrist at the University of Vermont Medical Center, Burlington, noted that an estimated 3.4 million adolescents in the United States meet criteria for an SUD, but fewer than 10% enter treatment each year. Of those who do enter treatment, 50% relapse within 6 months.
“It’s not the same story for illicit drugs, unfortunately, and that’s largely due to marijuana,” Dr. Jackson said. He noted that adolescent cannabis use is inversely proportional to how dangerous they perceive it to be. “This is evidence that adolescents indeed care about their health,” he said. “They use when they think it’s safe, and they use less when they think it’s unsafe.” Recent Monitoring the Future data also demonstrate that e-cigarette use is outpacing cigarette use among 8th, 10th, and 12th graders, while the past-year misuse of acetaminophen/hydrocodone (Vicodin) among 12th graders has dropped dramatically in the past 5 years. So has misuse of all prescription opioids among 12th graders despite high opioid overdose rates among adults.
Adolescents are more likely to be secretive about their substance use, compared with older adults. “Also, with many substances, especially alcohol, they are more likely to use in a binge pattern,” Dr. Jackson said. “They haven’t accumulated as many negative consequences from their use, so voluntarily seeking treatment is less common than in adults. They’re most often referred through the justice department or legal channels.”
Screening instruments to consider using include the CRAFFT (Car, Relax, Alone, Forget, Friends, Trouble), which has been validated as an adolescent-specific screening instrument. A score of two or more has a strong correlation with meeting criteria for an SUD. The American Academy of Pediatrics recommends the Screening, Brief Intervention, and Referral to Treatment (SBIRT), though this intervention has not been as rigorously evaluated in adolescents, compared with adults.
Dr. Jackson frowned on the notion perpetuated by some parents and caregivers that novelty seeking behavior involving alcohol and other substances is okay if it’s controlled somehow, with statements such as, “I just make sure they’ve given up their car keys and make sure it stays in my own basement. That way nobody leaves here drunk.”
“I think we can do better than that,” Dr. Jackson said.
Well-validated behavioral treatment approaches for adolescent patients include the adolescent community reinforcement approach (A-CRA); cognitive-behavioral therapy (particularly in groups); motivational enhancement therapy (MET); contingency management, and 12-step facilitation.
“Colloquially, in pop culture, we’ve been pressed on this message at times that adolescents don’t care what their parents think; they only care what their peers think,” Dr. Jackson said. “That’s not true from literature we’ve seen, so we need to put the family back in its important place.”
In a meta-analysis of promising behavioral approaches for adolescent SUD, five out of six found to have promising to excellent empirical support were family-based therapies: multidimensional family therapy, functional family therapy, multisystemic family therapy, behavioral strategic family therapy, and family behavior therapy (J Child and Adolesc Psychology. 2008;37[1]:236-59). “That’s a huge take-home point when working with adolescents: Involve the family,” Dr. Jackson said. “As providers, do we have a tendency to side only with the parent or side only with the adolescent? If we do, we should be cautious and thoughtful, because we can very effectively work with both parties. If you have an adolescent who shows up [for counseling] but then walks right out the door, you still have a parent, maybe two parents or other concerned loved ones sitting there. You still have a target for intervention.”
Even if the adolescent never returns to your office, he continued, clinicians can do an intervention with the family to statistically decrease the SUD for the adolescent. “That’s really promising,” he said. In adults, the best evidence for treatment engagement of a loved one following these family-specific interventions is for the Community Reinforcement and Family Training (CRAFT) method (64%-74%), followed by the Johnson Intervention (23%-30%) and Al-Anon/Nar-Anon facilitation (13%-29%). These interventions are being studied more specifically in adolescents and young adults.
A key tip for parents of teens coping with substance abuse is the old adage actions speak louder than words. “You can tell your child not to smoke marijuana until you’re blue in the face, but then if you go out on the back porch and smoke marijuana, that’s a really bad message for behavior change,” Dr. Jackson said. “Words also speak louder than no words. Some parents have never told their adolescent children what their opinion is, and that they’re concerned. Maybe those parents have been convinced that adolescents don’t care what they think. In fact, they do care what they think.”
Once engaged, older adults do well
Among older adults, triggers for SUDs vary considerably from that of their younger counterparts. “We tend to think of this as a population that carries a lot of wisdom and has the coping skills to deal with life,” Olivera J. Bogunovic, MD, a psychiatrist who is medical director of ambulatory services in the division of alcohol and drug abuse at McClean Hospital, Belmont, Mass., said during a separate presentation. “In fact, this is a very vulnerable population at increased risk of mood disorders. For example, many men spend their careers working 60 or 80 hours a week, then they stop working. What is there for them? They sometimes turn to substance abuse. Similarly, older women who lose a loved one may turn to drinking. There’s a lot of room for prevention. The good news is that this group of patients is very responsive to treatment. Once engaged, they do very well.”
Nicotine is the chief addictive substance affecting older adults (17%), followed by alcohol (12% in a binge capacity, dependence 1%), illicit drugs (1.8%), and medications (1.6% for pain medications and 12% on benzodiazepines). Alcohol use disorders encompass a spectrum of problems for this patient population, including at-risk drinking, problem drinking, and dependence. Presentations, complications, and consequences are wide-ranging. “We sometimes miss the symptoms of alcohol use disorders when patients present in emergency rooms,” Dr. Bogunovic said. “Unfortunately, if it’s not treated initially it results in serious medical comorbidities and complications.”
The National Institute on Drug Abuse recommends that adults consume no more than two drinks per day, but the quantity is even lower for elderly. “For men it is no more than one drink per day, while for women it’s questionable if that one drink per day is even recommended,” Dr. Bogunovic said. The prevalence of at-risk drinking among older adults ranges from 3% to 25% and the rates for problem drinking range from 2.2% to 9.6%. Alcohol dependence rates, meanwhile, range from 2% to 3% among men and less than 1% among women.
Cross-sectional data indicate a low prevalence of illicit drug use in older adults, but longitudinal data from the National Survey on Drug Abuse and others suggest an increased use of cannabis and prescription opioids. “A lot of people do not think about opioid use disorders in the elderly,” she said. “The prevalence rate in methadone clinics is less than 2%. However, with the epidemic crisis we’re seeing opioid use disorders in the elderly. What’s important to know is that they also respond to medications for treatment, more so with suboxone than with naltrexone, as we know those patients sometimes have complications that need to be treated with pain medication.”
Elderly patients constitute 13% of the population yet they account for 30% of prescriptions, mainly benzodiazepines and prescription opioids. “Two-thirds of patients who are struggling with SUDs struggled with an SUD at some point in their youth,” said Dr. Bogunovic, who holds a faculty position in the department of psychiatry at Harvard Medical School, Boston. “They continue to use for longer periods of time, with some intermittent periods of sobriety. Of those 15% who do have an alcohol use problem, they are prescribed benzodiazepines. That can be a lethal combination, because there is a combined effect of both alcohol and benzodiazepines that can result in hip fractures, subdural hematomas, and other medical comorbidity.”
Risk factors for development of alcohol use disorder in elderly include physiologic changes in the way alcohol is metabolized; gender, family history, or prior personal history of alcohol use disorder; having a concomitant psychiatric disorder; and having a chronic medical illness, such as severe arthritis. Compared with their male peers, older women generally drink less often and less heavily, but they are more likely to start drinking heavily later in life. Older men face an increased risk of alcohol-related problems tied to cumulative use over the years.
“Social factors also play a role, so it’s important to perform a skilled diagnostic interview and a psychiatric evaluation but also to evaluate the motivational stage of change, because that’s the right moment to do the intervention, knowing what the patient’s values are,” she said. Recommended screenings include the Short Michigan Alcoholism Screening Instrument–Geriatric Version (SMAST-G), the SBIRT, the CAGE-AID, and the Opioid Risk Tool. Compliance with treatment tends to be greater in older adults, compared with their younger counterparts. “They don’t like a confrontational approach, so it’s important to communicate with empathy in a straightforward manner and pay attention to what is important to patients and motivate them,” she noted. “Involve family members or other social support whenever possible.”
Relapses are common, but clinicians should encourage patients to continue treatment, “because they can do very well,” Dr. Bogunovic emphasized. “And we can offer them a good life after that.”
Dr. Welsh disclosed that she has consulted for GW Pharmaceuticals and that she has received training fees from Chestnut Health Systems. Dr. Jackson and Dr. Bogunovic reported having no financial disclosures.
SAN DIEGO – Intervening early can positively affect outcomes for patients struggling with substance use disorders, regardless of their current stage of development and place in the life cycle, speaker after speaker said at the annual meeting and scientific symposium of the American Academy of Addiction Psychiatry.
The prenatal/perinatal period represents a high-risk window for the kindling and precipitation of substance use disorders (SUDs), because of the stress of pregnancy, delivery, recovery, and the newly assumed parenting role. “Offspring who are exposed in utero have an earlier age of initiation of substance use, as well as a greater risk of substance use disorders later on in life,” said Justine Wittenaur Welsh, MD, director of the Emory Adolescent Substance Use Treatment Services, Atlanta. “We as treatment providers need to start to think about how to screen for these individuals. What types of early intervention can we provide, and how do we integrate this into our treatment planning?”
According to data on current illicit drug use among pregnant women from the Substance Abuse and Mental Health Services Administration, the risk is highest among those aged 15-17 years (14.6%), followed by those aged 18-25 years (8.6%), and 26-44 years (3.2%). “We also know that rates of substance use are higher in the first trimester, compared with the second and the third,” said Dr. Welsh, who holds a faculty position in the department of psychiatry and behavioral sciences at Emory University. “But unfortunately, a significant number of pregnant women return to substance use after they deliver. This is really important for treatment providers, to intervene early before a return to substance use. We know that improving the postnatal environment does reduce the risk of substance use, even in individuals who have in utero exposures.”
SUDs confer a host of adverse effects to both the baby and the mother. “With tobacco, although there are a significant number of poisonous chemicals in cigarettes that the baby would be exposed to, we believe it’s the carbon monoxide and the nicotine exposure that confers the most known damage,” Dr. Welsh said. In utero exposure to cigarettes increases the likelihood to initiate smoking during adolescence by twofold (Neurotoxicol Teratol. 2005;27[2]:267-77), and a dose-response relationship has been observed between prenatal smoking and psychiatric hospitalization for substance abuse in offspring (Am J Psychiatry. 2002;159[1]:48-54). In utero exposure to cigarettes also increases the risk for offspring cigarette use. “The exposure to greater than a half-pack of cigarettes per day has a 5.5-fold increased risk for early cigarette experimentation, while exposure to one pack per day or more is associated with twice the risk of developing nicotine dependence,” she said.
As for in utero alcohol exposure, consuming greater than or equal to three drinks is associated with an alcohol disorder at age 21 (odds ratio, 2.95) if the exposure occurred in early pregnancy; Arch Gen Psychiatry. 2006;63[9]:1009-16). In utero alcohol exposure also has been more predictive of adolescent alcohol use than family history. “It’s also been associated with an increased number of abuse/dependency symptoms in offspring, for nicotine, alcohol, and illicit drugs,” Dr. Welsh said. “It has also been associated with an increased risk of cigarette use and substance use disorders in offspring.”
In utero cannabis exposure has been associated with a twofold increased risk of tobacco and marijuana use later in life (Addiction 2006;101[9]:1313-22), as well as with a twofold increased risk of smoking cigarettes daily and of using marijuana during adolescence. In utero cocaine exposure has been associated with a twofold increased risk of using tobacco, a 2.2-fold increased risk of using alcohol, and a 1.8-fold risk of using marijuana, as well as a 2.1-fold increased risk of having an SUD by age 17. “Prenatal exposure and postnatal parent/caregiver cocaine use is uniquely related to teen use of cocaine at age 14,” Dr. Welsh said. “In addition, exposure in the first trimester is associated with earlier marijuana and alcohol initiation.”
Real-world barriers to SUD treatment in adolescents include a lack of coordination between treatment resources, fear of losing custody of children, shame and stigma, concerns about criminal prosecution, domestic violence, and other obstacles such as transportation, finances, and child care. Dr. Welsh pointed out that pregnant women with SUDs usually receive prenatal care and addiction treatment from different providers. “We should be thinking about an integrated treatment model to improve maternal and prenatal care for patients using substances prior to or during pregnancy,” she said. “Some sites have developed combined maternity care units as a way to reduce some of these barriers to treatment. We also need to be thinking about the infants themselves. In order to counter the drug-exposed child’s early disadvantages, service providers must be prepared to intervene early, focusing on things like nutrition, psychomotor assessments, early educational needs assessments, as well as modification of existing treatment services for people with in utero exposures. This can be a difficult population to treat.”
One resource for addressing fetal alcohol spectrum disorders that she recommended is Treatment Improvement Protocol 58, published by Substance Abuse and Mental Health Services Administration. She described one young adult with significant substance use issues who was diagnosed with fetal alcohol syndrome as a child. “This young adult didn’t know about the FAS diagnosis,” Dr. Welsh said. “I expressed to the mother that, ‘this is an ethical dilemma. I’m treating someone and I know this directly impacts my treatment planning. They have a real-world diagnosis that I feel they have a right to know about.’ It made me think: If I think it’s so important that this young adult knows the diagnosis, why are we not screening for it in our general patient populations more often?
“As child psychiatrists we often ask, ‘Were there any in utero exposures?’ When treating adults, I’m asking about family history, but I’m not asking about in utero exposures. This may not be information that they’re privy to, but it’s worth starting a conversation about.”
, a 14-session, evidence-based curriculum that addresses parenting skills, children’s social skills, and family life skills training, are among the treatment options aimed at decreasing the risk of substance use progression in offspring.
‘Adolescents indeed care about their health’
During a separate presentation, Peter Jackson, MD, a psychiatrist at the University of Vermont Medical Center, Burlington, noted that an estimated 3.4 million adolescents in the United States meet criteria for an SUD, but fewer than 10% enter treatment each year. Of those who do enter treatment, 50% relapse within 6 months.
“It’s not the same story for illicit drugs, unfortunately, and that’s largely due to marijuana,” Dr. Jackson said. He noted that adolescent cannabis use is inversely proportional to how dangerous they perceive it to be. “This is evidence that adolescents indeed care about their health,” he said. “They use when they think it’s safe, and they use less when they think it’s unsafe.” Recent Monitoring the Future data also demonstrate that e-cigarette use is outpacing cigarette use among 8th, 10th, and 12th graders, while the past-year misuse of acetaminophen/hydrocodone (Vicodin) among 12th graders has dropped dramatically in the past 5 years. So has misuse of all prescription opioids among 12th graders despite high opioid overdose rates among adults.
Adolescents are more likely to be secretive about their substance use, compared with older adults. “Also, with many substances, especially alcohol, they are more likely to use in a binge pattern,” Dr. Jackson said. “They haven’t accumulated as many negative consequences from their use, so voluntarily seeking treatment is less common than in adults. They’re most often referred through the justice department or legal channels.”
Screening instruments to consider using include the CRAFFT (Car, Relax, Alone, Forget, Friends, Trouble), which has been validated as an adolescent-specific screening instrument. A score of two or more has a strong correlation with meeting criteria for an SUD. The American Academy of Pediatrics recommends the Screening, Brief Intervention, and Referral to Treatment (SBIRT), though this intervention has not been as rigorously evaluated in adolescents, compared with adults.
Dr. Jackson frowned on the notion perpetuated by some parents and caregivers that novelty seeking behavior involving alcohol and other substances is okay if it’s controlled somehow, with statements such as, “I just make sure they’ve given up their car keys and make sure it stays in my own basement. That way nobody leaves here drunk.”
“I think we can do better than that,” Dr. Jackson said.
Well-validated behavioral treatment approaches for adolescent patients include the adolescent community reinforcement approach (A-CRA); cognitive-behavioral therapy (particularly in groups); motivational enhancement therapy (MET); contingency management, and 12-step facilitation.
“Colloquially, in pop culture, we’ve been pressed on this message at times that adolescents don’t care what their parents think; they only care what their peers think,” Dr. Jackson said. “That’s not true from literature we’ve seen, so we need to put the family back in its important place.”
In a meta-analysis of promising behavioral approaches for adolescent SUD, five out of six found to have promising to excellent empirical support were family-based therapies: multidimensional family therapy, functional family therapy, multisystemic family therapy, behavioral strategic family therapy, and family behavior therapy (J Child and Adolesc Psychology. 2008;37[1]:236-59). “That’s a huge take-home point when working with adolescents: Involve the family,” Dr. Jackson said. “As providers, do we have a tendency to side only with the parent or side only with the adolescent? If we do, we should be cautious and thoughtful, because we can very effectively work with both parties. If you have an adolescent who shows up [for counseling] but then walks right out the door, you still have a parent, maybe two parents or other concerned loved ones sitting there. You still have a target for intervention.”
Even if the adolescent never returns to your office, he continued, clinicians can do an intervention with the family to statistically decrease the SUD for the adolescent. “That’s really promising,” he said. In adults, the best evidence for treatment engagement of a loved one following these family-specific interventions is for the Community Reinforcement and Family Training (CRAFT) method (64%-74%), followed by the Johnson Intervention (23%-30%) and Al-Anon/Nar-Anon facilitation (13%-29%). These interventions are being studied more specifically in adolescents and young adults.
A key tip for parents of teens coping with substance abuse is the old adage actions speak louder than words. “You can tell your child not to smoke marijuana until you’re blue in the face, but then if you go out on the back porch and smoke marijuana, that’s a really bad message for behavior change,” Dr. Jackson said. “Words also speak louder than no words. Some parents have never told their adolescent children what their opinion is, and that they’re concerned. Maybe those parents have been convinced that adolescents don’t care what they think. In fact, they do care what they think.”
Once engaged, older adults do well
Among older adults, triggers for SUDs vary considerably from that of their younger counterparts. “We tend to think of this as a population that carries a lot of wisdom and has the coping skills to deal with life,” Olivera J. Bogunovic, MD, a psychiatrist who is medical director of ambulatory services in the division of alcohol and drug abuse at McClean Hospital, Belmont, Mass., said during a separate presentation. “In fact, this is a very vulnerable population at increased risk of mood disorders. For example, many men spend their careers working 60 or 80 hours a week, then they stop working. What is there for them? They sometimes turn to substance abuse. Similarly, older women who lose a loved one may turn to drinking. There’s a lot of room for prevention. The good news is that this group of patients is very responsive to treatment. Once engaged, they do very well.”
Nicotine is the chief addictive substance affecting older adults (17%), followed by alcohol (12% in a binge capacity, dependence 1%), illicit drugs (1.8%), and medications (1.6% for pain medications and 12% on benzodiazepines). Alcohol use disorders encompass a spectrum of problems for this patient population, including at-risk drinking, problem drinking, and dependence. Presentations, complications, and consequences are wide-ranging. “We sometimes miss the symptoms of alcohol use disorders when patients present in emergency rooms,” Dr. Bogunovic said. “Unfortunately, if it’s not treated initially it results in serious medical comorbidities and complications.”
The National Institute on Drug Abuse recommends that adults consume no more than two drinks per day, but the quantity is even lower for elderly. “For men it is no more than one drink per day, while for women it’s questionable if that one drink per day is even recommended,” Dr. Bogunovic said. The prevalence of at-risk drinking among older adults ranges from 3% to 25% and the rates for problem drinking range from 2.2% to 9.6%. Alcohol dependence rates, meanwhile, range from 2% to 3% among men and less than 1% among women.
Cross-sectional data indicate a low prevalence of illicit drug use in older adults, but longitudinal data from the National Survey on Drug Abuse and others suggest an increased use of cannabis and prescription opioids. “A lot of people do not think about opioid use disorders in the elderly,” she said. “The prevalence rate in methadone clinics is less than 2%. However, with the epidemic crisis we’re seeing opioid use disorders in the elderly. What’s important to know is that they also respond to medications for treatment, more so with suboxone than with naltrexone, as we know those patients sometimes have complications that need to be treated with pain medication.”
Elderly patients constitute 13% of the population yet they account for 30% of prescriptions, mainly benzodiazepines and prescription opioids. “Two-thirds of patients who are struggling with SUDs struggled with an SUD at some point in their youth,” said Dr. Bogunovic, who holds a faculty position in the department of psychiatry at Harvard Medical School, Boston. “They continue to use for longer periods of time, with some intermittent periods of sobriety. Of those 15% who do have an alcohol use problem, they are prescribed benzodiazepines. That can be a lethal combination, because there is a combined effect of both alcohol and benzodiazepines that can result in hip fractures, subdural hematomas, and other medical comorbidity.”
Risk factors for development of alcohol use disorder in elderly include physiologic changes in the way alcohol is metabolized; gender, family history, or prior personal history of alcohol use disorder; having a concomitant psychiatric disorder; and having a chronic medical illness, such as severe arthritis. Compared with their male peers, older women generally drink less often and less heavily, but they are more likely to start drinking heavily later in life. Older men face an increased risk of alcohol-related problems tied to cumulative use over the years.
“Social factors also play a role, so it’s important to perform a skilled diagnostic interview and a psychiatric evaluation but also to evaluate the motivational stage of change, because that’s the right moment to do the intervention, knowing what the patient’s values are,” she said. Recommended screenings include the Short Michigan Alcoholism Screening Instrument–Geriatric Version (SMAST-G), the SBIRT, the CAGE-AID, and the Opioid Risk Tool. Compliance with treatment tends to be greater in older adults, compared with their younger counterparts. “They don’t like a confrontational approach, so it’s important to communicate with empathy in a straightforward manner and pay attention to what is important to patients and motivate them,” she noted. “Involve family members or other social support whenever possible.”
Relapses are common, but clinicians should encourage patients to continue treatment, “because they can do very well,” Dr. Bogunovic emphasized. “And we can offer them a good life after that.”
Dr. Welsh disclosed that she has consulted for GW Pharmaceuticals and that she has received training fees from Chestnut Health Systems. Dr. Jackson and Dr. Bogunovic reported having no financial disclosures.
EXPERT ANALYSIS FROM AAAP
Elevated CRP and mortality risk differs by gender, race
LOS ANGELES – The relationship between elevated C-reactive protein concentrations and increased all-cause mortality risk varies by gender and by race/ethnicity, an analysis of national data showed.
“Opportunities exist to discuss the importance of this marker and the relationship with mortality risk,” study author M. Ryan Richardson said in an interview following the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Although we do not fully understand all of the mechanisms that underlie this harmful relationship, our results add to the limited evidence available to those working within the clinical setting.”
A total of 4,383 adults between the ages of 30 and 79 years were included in the analysis. After the researchers adjusted for age, race, education, smoking, alcohol consumption, cardiovascular disease, waist circumference, and aerobic physical activity, they observed a significantly higher risk for all-cause mortality in non-Hispanic black males (hazard ratio, 2.04) and Mexican-American females (HR, 2.24). “We were surprised that this relationship was also independent of measured waist circumference and any volume of reported aerobic physical activity, which are both acknowledged as strong mediator variables in this relationship,” Mr. Richardson said. The HR in non-Hispanic white males approached but did not reach statistical significance (HR, 1.32).
He acknowledged certain limitations of the study, including its cross-sectional design. “We cannot make causal inferences based on this data,” he said.
The researchers reported having no financial disclosures.
SOURCE: M. Ryan Richardson et al.
LOS ANGELES – The relationship between elevated C-reactive protein concentrations and increased all-cause mortality risk varies by gender and by race/ethnicity, an analysis of national data showed.
“Opportunities exist to discuss the importance of this marker and the relationship with mortality risk,” study author M. Ryan Richardson said in an interview following the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Although we do not fully understand all of the mechanisms that underlie this harmful relationship, our results add to the limited evidence available to those working within the clinical setting.”
A total of 4,383 adults between the ages of 30 and 79 years were included in the analysis. After the researchers adjusted for age, race, education, smoking, alcohol consumption, cardiovascular disease, waist circumference, and aerobic physical activity, they observed a significantly higher risk for all-cause mortality in non-Hispanic black males (hazard ratio, 2.04) and Mexican-American females (HR, 2.24). “We were surprised that this relationship was also independent of measured waist circumference and any volume of reported aerobic physical activity, which are both acknowledged as strong mediator variables in this relationship,” Mr. Richardson said. The HR in non-Hispanic white males approached but did not reach statistical significance (HR, 1.32).
He acknowledged certain limitations of the study, including its cross-sectional design. “We cannot make causal inferences based on this data,” he said.
The researchers reported having no financial disclosures.
SOURCE: M. Ryan Richardson et al.
LOS ANGELES – The relationship between elevated C-reactive protein concentrations and increased all-cause mortality risk varies by gender and by race/ethnicity, an analysis of national data showed.
“Opportunities exist to discuss the importance of this marker and the relationship with mortality risk,” study author M. Ryan Richardson said in an interview following the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “Although we do not fully understand all of the mechanisms that underlie this harmful relationship, our results add to the limited evidence available to those working within the clinical setting.”
A total of 4,383 adults between the ages of 30 and 79 years were included in the analysis. After the researchers adjusted for age, race, education, smoking, alcohol consumption, cardiovascular disease, waist circumference, and aerobic physical activity, they observed a significantly higher risk for all-cause mortality in non-Hispanic black males (hazard ratio, 2.04) and Mexican-American females (HR, 2.24). “We were surprised that this relationship was also independent of measured waist circumference and any volume of reported aerobic physical activity, which are both acknowledged as strong mediator variables in this relationship,” Mr. Richardson said. The HR in non-Hispanic white males approached but did not reach statistical significance (HR, 1.32).
He acknowledged certain limitations of the study, including its cross-sectional design. “We cannot make causal inferences based on this data,” he said.
The researchers reported having no financial disclosures.
SOURCE: M. Ryan Richardson et al.
REPORTING FROM WCIRDC 2017
Key clinical point:
Major finding: The risk for all-cause mortality was significantly higher in non-Hispanic black men and in Mexican-American females (HR of 2.04 and 2.24, respectively).
Study details: An analysis of 4,383 adults who participated in NHANES 1999-2006.
Disclosures: The researchers reported having no financial disclosures.
Source: M. Ryan Richardson et al.
Expert discusses the role of salt and fructose in diabetes
LOS ANGELES – Sugar consumption has been implicated as a risk factor for the development of diabetes since at least the 1920s, but high salt intake may also increase the risk for obesity and prediabetes by stimulating fructose production in the liver.
“We think about high-salt diets as being associated with hypertension, but if you put people on a high-salt diet, you can induce insulin resistance within 5 or 10 days,” Richard J. Johnson, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “There is a fair amount of published data suggesting that a high salt intake, defined as greater than 150 mmol per day, is associated with hypertension, insulin resistance, obesity, and metabolic syndrome. In fact, it’s been reported that obese people are slightly hyperosmolar and tend to have elevated vasopressin levels. Interestingly, sugar stimulates vasopressin production.”
Furthermore, the mice on high-salt diets became insulin resistant. “Their fasting glucose went up, their fasting insulin went up, and they developed marked fatty liver, obesity, abdominal fat, and hypertension,” Dr. Johnson added. The discovery supports the notion that osmolality is the mechanism by which salt drives blood pressure, not volume expansion. “And I think that’s going to turn out to be important in obesity and metabolic syndrome as well,” he said.
Dr. Johnson, a professor of medicine in the department of renal diseases and hypertension at the University of Colorado at Denver, Aurora, discussed the role of role of sugar and fructose in the development of diabetes as well. He noted that annual sugar consumption in the United States rose from about 4 pounds per person in 1700 to about 150 pounds per person today. About one-third of current sugar intake comes from soft drinks.
“The reason why we think that fructose is a good candidate for playing a role in the diabetes epidemic is because, when you give an animal water drinking combined with fructose, they will rapidly start increasing their energy intake,” he said. “They become lethargic and less active, and they gain weight.”
He and his colleagues have demonstrated that when rats are fed fructose over time, they become leptin resistant (Am J Physiol. 2008 Nov;295:R1370-5). “Not only that, it’s been shown in animals and humans that, if you feed people fructose over time, fructose will decrease resting energy expenditure,” he said. “Our work and that of others has shown that fructose stimulates weight gain by stimulating energy intake. It does so by inducing leptin resistance. It also works in the brain to stimulate dopamine and to drive food intake that way as well.”
Fructose also impairs fatty acid oxidation and reduces energy expenditure, he continued. In one human trial, in which men consumed 200g of fructose for 2 weeks, Dr. Johnson and his associates found that 25% of them developed features of metabolic syndrome (Int J Obes. 2010;34[3]:454-61). “Just think about how long it takes to get obese or metabolic syndrome,” he said. “We think in terms of years, but this was a 2-week study! This means there’s something special about fructose that seems to drive metabolic syndrome.”
A key player in the process appears to be an enzyme in the liver known as fructokinase, which metabolizes fructose so rapidly that it causes ATP depletion. “Normally, when glucose is metabolized, ATP levels stay normal in the cell because if you start to consume too much ATP in the initial phosphorylation, there’s a feedback mechanism,” Dr. Johnson said. “But not so for fructose; it’s a runaway train, and it activates a nucleotide degradation pathway, which we call the energy depletion pathway. This seems to be what is critical for fructose effects.”
Further evaluation of that pathway led him and his associates to discover that lowering uric acid reduced fatty liver formation in fructose-fed rats (PLOS One 2012 Oct. 24. doi:10.1371/journal.pone.0047948). “We started looking at how this worked, and we found that, when we put uric acid on liver cells, that they actually stimulated fat accumulation,” he said. “We showed that in an in vitro system, and we found that both fructose and uric acid stimulate oxidative stress in the mitochondria. It’s very specific. You can actually block the production of oxidative stress with allopurinol, a drug that lowers uric acid. We’ve been building a case that this pathway is involved in a lot of mechanisms that lead to obesity, insulin resistance, and hypertension.”
Dr. Johnson concluded by noting that not all calories are created equal. “Some additives, like salt, might be playing a role in metabolic syndrome, obesity, and diabetes,” he said. “We think that sugar and high fructose corn sugar are the major causes driving metabolic syndrome. High-glycemic carbs are working primarily through fructose to induce [insulin resistance]. We think that salt may accelerate this pathway as well.”
He disclosed that he holds patents and patent applications related to this work and that he has launched a start-up company trying to develop inhibitors of fructose metabolism.
Dr. Johnson reported having no conflicts of interest related to this article.
LOS ANGELES – Sugar consumption has been implicated as a risk factor for the development of diabetes since at least the 1920s, but high salt intake may also increase the risk for obesity and prediabetes by stimulating fructose production in the liver.
“We think about high-salt diets as being associated with hypertension, but if you put people on a high-salt diet, you can induce insulin resistance within 5 or 10 days,” Richard J. Johnson, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “There is a fair amount of published data suggesting that a high salt intake, defined as greater than 150 mmol per day, is associated with hypertension, insulin resistance, obesity, and metabolic syndrome. In fact, it’s been reported that obese people are slightly hyperosmolar and tend to have elevated vasopressin levels. Interestingly, sugar stimulates vasopressin production.”
Furthermore, the mice on high-salt diets became insulin resistant. “Their fasting glucose went up, their fasting insulin went up, and they developed marked fatty liver, obesity, abdominal fat, and hypertension,” Dr. Johnson added. The discovery supports the notion that osmolality is the mechanism by which salt drives blood pressure, not volume expansion. “And I think that’s going to turn out to be important in obesity and metabolic syndrome as well,” he said.
Dr. Johnson, a professor of medicine in the department of renal diseases and hypertension at the University of Colorado at Denver, Aurora, discussed the role of role of sugar and fructose in the development of diabetes as well. He noted that annual sugar consumption in the United States rose from about 4 pounds per person in 1700 to about 150 pounds per person today. About one-third of current sugar intake comes from soft drinks.
“The reason why we think that fructose is a good candidate for playing a role in the diabetes epidemic is because, when you give an animal water drinking combined with fructose, they will rapidly start increasing their energy intake,” he said. “They become lethargic and less active, and they gain weight.”
He and his colleagues have demonstrated that when rats are fed fructose over time, they become leptin resistant (Am J Physiol. 2008 Nov;295:R1370-5). “Not only that, it’s been shown in animals and humans that, if you feed people fructose over time, fructose will decrease resting energy expenditure,” he said. “Our work and that of others has shown that fructose stimulates weight gain by stimulating energy intake. It does so by inducing leptin resistance. It also works in the brain to stimulate dopamine and to drive food intake that way as well.”
Fructose also impairs fatty acid oxidation and reduces energy expenditure, he continued. In one human trial, in which men consumed 200g of fructose for 2 weeks, Dr. Johnson and his associates found that 25% of them developed features of metabolic syndrome (Int J Obes. 2010;34[3]:454-61). “Just think about how long it takes to get obese or metabolic syndrome,” he said. “We think in terms of years, but this was a 2-week study! This means there’s something special about fructose that seems to drive metabolic syndrome.”
A key player in the process appears to be an enzyme in the liver known as fructokinase, which metabolizes fructose so rapidly that it causes ATP depletion. “Normally, when glucose is metabolized, ATP levels stay normal in the cell because if you start to consume too much ATP in the initial phosphorylation, there’s a feedback mechanism,” Dr. Johnson said. “But not so for fructose; it’s a runaway train, and it activates a nucleotide degradation pathway, which we call the energy depletion pathway. This seems to be what is critical for fructose effects.”
Further evaluation of that pathway led him and his associates to discover that lowering uric acid reduced fatty liver formation in fructose-fed rats (PLOS One 2012 Oct. 24. doi:10.1371/journal.pone.0047948). “We started looking at how this worked, and we found that, when we put uric acid on liver cells, that they actually stimulated fat accumulation,” he said. “We showed that in an in vitro system, and we found that both fructose and uric acid stimulate oxidative stress in the mitochondria. It’s very specific. You can actually block the production of oxidative stress with allopurinol, a drug that lowers uric acid. We’ve been building a case that this pathway is involved in a lot of mechanisms that lead to obesity, insulin resistance, and hypertension.”
Dr. Johnson concluded by noting that not all calories are created equal. “Some additives, like salt, might be playing a role in metabolic syndrome, obesity, and diabetes,” he said. “We think that sugar and high fructose corn sugar are the major causes driving metabolic syndrome. High-glycemic carbs are working primarily through fructose to induce [insulin resistance]. We think that salt may accelerate this pathway as well.”
He disclosed that he holds patents and patent applications related to this work and that he has launched a start-up company trying to develop inhibitors of fructose metabolism.
Dr. Johnson reported having no conflicts of interest related to this article.
LOS ANGELES – Sugar consumption has been implicated as a risk factor for the development of diabetes since at least the 1920s, but high salt intake may also increase the risk for obesity and prediabetes by stimulating fructose production in the liver.
“We think about high-salt diets as being associated with hypertension, but if you put people on a high-salt diet, you can induce insulin resistance within 5 or 10 days,” Richard J. Johnson, MD, said at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. “There is a fair amount of published data suggesting that a high salt intake, defined as greater than 150 mmol per day, is associated with hypertension, insulin resistance, obesity, and metabolic syndrome. In fact, it’s been reported that obese people are slightly hyperosmolar and tend to have elevated vasopressin levels. Interestingly, sugar stimulates vasopressin production.”
Furthermore, the mice on high-salt diets became insulin resistant. “Their fasting glucose went up, their fasting insulin went up, and they developed marked fatty liver, obesity, abdominal fat, and hypertension,” Dr. Johnson added. The discovery supports the notion that osmolality is the mechanism by which salt drives blood pressure, not volume expansion. “And I think that’s going to turn out to be important in obesity and metabolic syndrome as well,” he said.
Dr. Johnson, a professor of medicine in the department of renal diseases and hypertension at the University of Colorado at Denver, Aurora, discussed the role of role of sugar and fructose in the development of diabetes as well. He noted that annual sugar consumption in the United States rose from about 4 pounds per person in 1700 to about 150 pounds per person today. About one-third of current sugar intake comes from soft drinks.
“The reason why we think that fructose is a good candidate for playing a role in the diabetes epidemic is because, when you give an animal water drinking combined with fructose, they will rapidly start increasing their energy intake,” he said. “They become lethargic and less active, and they gain weight.”
He and his colleagues have demonstrated that when rats are fed fructose over time, they become leptin resistant (Am J Physiol. 2008 Nov;295:R1370-5). “Not only that, it’s been shown in animals and humans that, if you feed people fructose over time, fructose will decrease resting energy expenditure,” he said. “Our work and that of others has shown that fructose stimulates weight gain by stimulating energy intake. It does so by inducing leptin resistance. It also works in the brain to stimulate dopamine and to drive food intake that way as well.”
Fructose also impairs fatty acid oxidation and reduces energy expenditure, he continued. In one human trial, in which men consumed 200g of fructose for 2 weeks, Dr. Johnson and his associates found that 25% of them developed features of metabolic syndrome (Int J Obes. 2010;34[3]:454-61). “Just think about how long it takes to get obese or metabolic syndrome,” he said. “We think in terms of years, but this was a 2-week study! This means there’s something special about fructose that seems to drive metabolic syndrome.”
A key player in the process appears to be an enzyme in the liver known as fructokinase, which metabolizes fructose so rapidly that it causes ATP depletion. “Normally, when glucose is metabolized, ATP levels stay normal in the cell because if you start to consume too much ATP in the initial phosphorylation, there’s a feedback mechanism,” Dr. Johnson said. “But not so for fructose; it’s a runaway train, and it activates a nucleotide degradation pathway, which we call the energy depletion pathway. This seems to be what is critical for fructose effects.”
Further evaluation of that pathway led him and his associates to discover that lowering uric acid reduced fatty liver formation in fructose-fed rats (PLOS One 2012 Oct. 24. doi:10.1371/journal.pone.0047948). “We started looking at how this worked, and we found that, when we put uric acid on liver cells, that they actually stimulated fat accumulation,” he said. “We showed that in an in vitro system, and we found that both fructose and uric acid stimulate oxidative stress in the mitochondria. It’s very specific. You can actually block the production of oxidative stress with allopurinol, a drug that lowers uric acid. We’ve been building a case that this pathway is involved in a lot of mechanisms that lead to obesity, insulin resistance, and hypertension.”
Dr. Johnson concluded by noting that not all calories are created equal. “Some additives, like salt, might be playing a role in metabolic syndrome, obesity, and diabetes,” he said. “We think that sugar and high fructose corn sugar are the major causes driving metabolic syndrome. High-glycemic carbs are working primarily through fructose to induce [insulin resistance]. We think that salt may accelerate this pathway as well.”
He disclosed that he holds patents and patent applications related to this work and that he has launched a start-up company trying to develop inhibitors of fructose metabolism.
Dr. Johnson reported having no conflicts of interest related to this article.
EXPERT ANALYSIS AT WCIRDC 2017
Intranasal insulin, ketogenic diet may benefit Alzheimer’s patients
LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that
In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.
When that process goes awry, several pathologic processes linking insulin resistance (IR) and Alzheimer’s disease occur, including impaired proteostasis (oligomeric beta amyloid, microtubule-associated tau, and oligomeric insulin); hyperglycemia-induced toxicity and reduced glucose utilization; mitochondrial dysfunction; and vascular dysfunction, Dr. Craft continued.
In the past 5 years, researchers have developed ways to measure expression levels of insulin resistance markers like insulin receptor substrate 1 (IRS-1) pSer–positive neurons, Dr. Craft said. Others have found that increased IRS-1 pSer is associated with paired helical filaments (PHFs) tau in mild cognitive impairment (MCI) and AD, and that increased IRS-1 pSer in neutrally derived plasma exomes increased in AD years before onset and in type 2 diabetes. “We can look at the neurons themselves and what we see is that this IR marker colocalizes with tau,” Dr. Craft said. “It’s not very common in normal folks, but as you progress through the stages of MCI to AD, it becomes more common. So there’s a progressive increase in IR markers that associates with neurons in tau.” Other imaging studies have shown that homeostatic model assessment IR predicts gray matter atrophy, reduced blood flow, and amyloid deposition in middle-aged adults.
One way to overcome IR in AD is to increase insulin availability in the brain. Intranasal administration of insulin is a novel method being tested by Dr. Craft and her associates. “This is not inhaled insulin; it does not target the lungs,” she explained. “It’s insulin administered with a very specialized device that targets the olfactory cleft in the upper nasal passages. Virtually none of the insulin is deposited in the lungs or nasopharyngeally.” The approach is modeled on the notion that there are pathways from the olfactory perivascular spaces to the brain by which peptides can travel readily by bulk flow. “They reach the brain within minutes,” she said. “It’s a way of delivering peptides to the brain that bypasses the blood-brain barrier.”
In a published study, she and her associates randomized 104 adults with MCI or AD to receive 20 IU insulin, 40 IU insulin, or placebo twice daily for 4 months (Arch Neurol. 2012;61[1]:29-38). Tests performed at baseline and at 4 months included cognitive evaluation based on story recall and the ADAS-Cog (Alzheimer’s Disease Assessment Scale–Cognitive subscale); function based on the Dementia Rating Severity Scale, FDG-PET (positron emission tomography with 18fluorodeoxyglucose), and cerebrospinal fluid biomarkers. “We showed that the 20-IU dose of intranasal insulin improved memory quite substantially (P less than .05),” Dr. Craft said. “It also improved glucose utilization as assessed by FDG-PET. We also saw changes in spinal fluid biomarkers of amyloid in a favorable direction. Most recently, we looked at the exosomal indicator of IR (IRS-1 pSer), and what we saw quite remarkably was a reduction in the same condition that the memory improved. This gives us hope that we have a marker of whether or not we’re having a positive impact.”
She and her research team recently finished a phase 2 pilot study of regular insulin vs. long-acting insulin detemir, to determine if a longer-acting agent with longer exposure would have greater efficacy (J Alzheimers Dis. 2017;57[4]:1325–34). In all, 36 participants were randomized to receive placebo, 40 IU of insulin detemir, or 40 IU of regular insulin daily for 4 months, administered with a nasal delivery device. The investigators found that only the group treated with 40 IU regular insulin had better memory after 2 and 4 months, compared with placebo (P less than .03). Regular insulin treatment was also associated with preserved volume on MRI. “The normal pattern is for AD patients to lose brain volume rather rapidly,” Dr. Craft commented. “We see that abolished by the insulin treatment, which suggests to us that we’re able to stave off this disease-related mechanism.” She and her associates are currently conducting a phase 3 clinical trial with regular insulin and a phase 3 trial with rapid-acting insulin that are expected to be completed in the summer of 2018.
Dr. Craft spent the last few minutes of her presentation discussing the ketogenic diet as a nonpharmacologic approach to preventing or treating brain insulin resistance and AD. “I think the power of diet is underestimated, both in terms of causing disease and potentially modulating it,” she said. Her research team just completed a study of 87 middle-aged adults who were randomized to a Western diet or a healthy diet. The Western diet was high in saturated fat, sugar, and salt. The healthy diet was low in saturated fat, sugar, and salt, but the macronutrient composition of both diets was the same. “It was a eucaloric diet with normal calorie intake; no weight change, so trying to understand the integrated effect of the Western diet,” she said. “All food was prepared by us and delivered to the patients two times per week.” Patients with type 2 diabetes, patients with hypertension, and those who were on statins were excluded from the study.
The researchers observed pronounced diet-induced changes in cerebral blood flow, all which favored the healthy diet group. “The Western diet reduced blood flow, and the healthy diet increased blood blow in the hippocampus, which is critical for memory, as in some other regions that are known to be affected in AD,” Dr. Craft said. “We saw an effect on memory as well, with the healthy diet improving memory and the Western diet reducing it. Both of these effects were significant, so 4 weeks on a diet such as this is sufficient to modulate key aspects of brain function.”
More recently, Dr. Craft and her colleagues have been evaluating the effects of what they term the modified Mediterranean ketogenic diet (MMKD). “It does allow for higher carbohydrate consumption, compared with a traditional ketogenic diet, but they still have to stay under 10% a day,” she said. “We have an emphasis on healthy fats. We send everybody home with extra virgin olive oil. We think it gives us extra compliance and the potential for long-term nutrition.” She explained that the diet increases plasma and CNS ketone bodies, beta-hydroxybutyrate, acetoacetate, and acetone, which serves as preferred alternative fuel for the brain. “If the brain has a choice between glucose and ketones, it will choose ketones,” Dr. Craft said. “It can use them more easily.”
Ketone bodies are derived from hepatic fatty acid oxidation and readily diffuse across the blood-brain barrier into the brain. They are also synthesized in the brain by astrocytes, and they appear to have direct neuroprotective effects. “Ketone bodies may be beneficial because they may correct the hyperglycemic state and reduce glucose utilization in the brain in AD years prior to symptom onset,” Dr. Craft said. “They may correct neuronal hyperexcitability and preclinical seizures in presymptomatic and early stages of AD; they restore the balance between inhibitory and excitatory neurotransmitters like GABA [gamma-aminobutyric acid] and glutamate.”
In an unpublished, 16-week study, Dr. Craft and her associates randomized 16 patients to a Mediterranean ketogenic diet or to an American Heart Association low-fat diet. Lumbar punctures and brain imaging were performed before and after diet intervention. By the end of 6 weeks, they observed significant increases in ketones and in HDL cholesterol level in the MMKD group, compared with the AHA diet group, as well as significant decreases in trigylcerides and HbA1c level. “I would say that we improved the peripheral metabolic profile with the ketogenic diet,” Dr. Craft said. They also observed significant improvements from baseline in memory, spinal fluid AD biomarkers, and mitochondrial respiration.
“One of the things we’re appreciating is the role of insulin in a host of activities in the brain,” she concluded. “Disrupting those activities can have dire consequences on brain function that may lead to a neurological milieu that lends itself to pathological aging conditions like Alzheimer’s. Several large ongoing trials are poised to validate results of smaller studies, elucidate underlying mechanisms, and provide new therapeutic targets. It’s an exciting time.”
Dr. Craft’s research is supported by the National Institute on Aging and the Alzheimer’s Association Zenith Program. Intranasal delivery devices were provided by Kurve Technology.
LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that
In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.
When that process goes awry, several pathologic processes linking insulin resistance (IR) and Alzheimer’s disease occur, including impaired proteostasis (oligomeric beta amyloid, microtubule-associated tau, and oligomeric insulin); hyperglycemia-induced toxicity and reduced glucose utilization; mitochondrial dysfunction; and vascular dysfunction, Dr. Craft continued.
In the past 5 years, researchers have developed ways to measure expression levels of insulin resistance markers like insulin receptor substrate 1 (IRS-1) pSer–positive neurons, Dr. Craft said. Others have found that increased IRS-1 pSer is associated with paired helical filaments (PHFs) tau in mild cognitive impairment (MCI) and AD, and that increased IRS-1 pSer in neutrally derived plasma exomes increased in AD years before onset and in type 2 diabetes. “We can look at the neurons themselves and what we see is that this IR marker colocalizes with tau,” Dr. Craft said. “It’s not very common in normal folks, but as you progress through the stages of MCI to AD, it becomes more common. So there’s a progressive increase in IR markers that associates with neurons in tau.” Other imaging studies have shown that homeostatic model assessment IR predicts gray matter atrophy, reduced blood flow, and amyloid deposition in middle-aged adults.
One way to overcome IR in AD is to increase insulin availability in the brain. Intranasal administration of insulin is a novel method being tested by Dr. Craft and her associates. “This is not inhaled insulin; it does not target the lungs,” she explained. “It’s insulin administered with a very specialized device that targets the olfactory cleft in the upper nasal passages. Virtually none of the insulin is deposited in the lungs or nasopharyngeally.” The approach is modeled on the notion that there are pathways from the olfactory perivascular spaces to the brain by which peptides can travel readily by bulk flow. “They reach the brain within minutes,” she said. “It’s a way of delivering peptides to the brain that bypasses the blood-brain barrier.”
In a published study, she and her associates randomized 104 adults with MCI or AD to receive 20 IU insulin, 40 IU insulin, or placebo twice daily for 4 months (Arch Neurol. 2012;61[1]:29-38). Tests performed at baseline and at 4 months included cognitive evaluation based on story recall and the ADAS-Cog (Alzheimer’s Disease Assessment Scale–Cognitive subscale); function based on the Dementia Rating Severity Scale, FDG-PET (positron emission tomography with 18fluorodeoxyglucose), and cerebrospinal fluid biomarkers. “We showed that the 20-IU dose of intranasal insulin improved memory quite substantially (P less than .05),” Dr. Craft said. “It also improved glucose utilization as assessed by FDG-PET. We also saw changes in spinal fluid biomarkers of amyloid in a favorable direction. Most recently, we looked at the exosomal indicator of IR (IRS-1 pSer), and what we saw quite remarkably was a reduction in the same condition that the memory improved. This gives us hope that we have a marker of whether or not we’re having a positive impact.”
She and her research team recently finished a phase 2 pilot study of regular insulin vs. long-acting insulin detemir, to determine if a longer-acting agent with longer exposure would have greater efficacy (J Alzheimers Dis. 2017;57[4]:1325–34). In all, 36 participants were randomized to receive placebo, 40 IU of insulin detemir, or 40 IU of regular insulin daily for 4 months, administered with a nasal delivery device. The investigators found that only the group treated with 40 IU regular insulin had better memory after 2 and 4 months, compared with placebo (P less than .03). Regular insulin treatment was also associated with preserved volume on MRI. “The normal pattern is for AD patients to lose brain volume rather rapidly,” Dr. Craft commented. “We see that abolished by the insulin treatment, which suggests to us that we’re able to stave off this disease-related mechanism.” She and her associates are currently conducting a phase 3 clinical trial with regular insulin and a phase 3 trial with rapid-acting insulin that are expected to be completed in the summer of 2018.
Dr. Craft spent the last few minutes of her presentation discussing the ketogenic diet as a nonpharmacologic approach to preventing or treating brain insulin resistance and AD. “I think the power of diet is underestimated, both in terms of causing disease and potentially modulating it,” she said. Her research team just completed a study of 87 middle-aged adults who were randomized to a Western diet or a healthy diet. The Western diet was high in saturated fat, sugar, and salt. The healthy diet was low in saturated fat, sugar, and salt, but the macronutrient composition of both diets was the same. “It was a eucaloric diet with normal calorie intake; no weight change, so trying to understand the integrated effect of the Western diet,” she said. “All food was prepared by us and delivered to the patients two times per week.” Patients with type 2 diabetes, patients with hypertension, and those who were on statins were excluded from the study.
The researchers observed pronounced diet-induced changes in cerebral blood flow, all which favored the healthy diet group. “The Western diet reduced blood flow, and the healthy diet increased blood blow in the hippocampus, which is critical for memory, as in some other regions that are known to be affected in AD,” Dr. Craft said. “We saw an effect on memory as well, with the healthy diet improving memory and the Western diet reducing it. Both of these effects were significant, so 4 weeks on a diet such as this is sufficient to modulate key aspects of brain function.”
More recently, Dr. Craft and her colleagues have been evaluating the effects of what they term the modified Mediterranean ketogenic diet (MMKD). “It does allow for higher carbohydrate consumption, compared with a traditional ketogenic diet, but they still have to stay under 10% a day,” she said. “We have an emphasis on healthy fats. We send everybody home with extra virgin olive oil. We think it gives us extra compliance and the potential for long-term nutrition.” She explained that the diet increases plasma and CNS ketone bodies, beta-hydroxybutyrate, acetoacetate, and acetone, which serves as preferred alternative fuel for the brain. “If the brain has a choice between glucose and ketones, it will choose ketones,” Dr. Craft said. “It can use them more easily.”
Ketone bodies are derived from hepatic fatty acid oxidation and readily diffuse across the blood-brain barrier into the brain. They are also synthesized in the brain by astrocytes, and they appear to have direct neuroprotective effects. “Ketone bodies may be beneficial because they may correct the hyperglycemic state and reduce glucose utilization in the brain in AD years prior to symptom onset,” Dr. Craft said. “They may correct neuronal hyperexcitability and preclinical seizures in presymptomatic and early stages of AD; they restore the balance between inhibitory and excitatory neurotransmitters like GABA [gamma-aminobutyric acid] and glutamate.”
In an unpublished, 16-week study, Dr. Craft and her associates randomized 16 patients to a Mediterranean ketogenic diet or to an American Heart Association low-fat diet. Lumbar punctures and brain imaging were performed before and after diet intervention. By the end of 6 weeks, they observed significant increases in ketones and in HDL cholesterol level in the MMKD group, compared with the AHA diet group, as well as significant decreases in trigylcerides and HbA1c level. “I would say that we improved the peripheral metabolic profile with the ketogenic diet,” Dr. Craft said. They also observed significant improvements from baseline in memory, spinal fluid AD biomarkers, and mitochondrial respiration.
“One of the things we’re appreciating is the role of insulin in a host of activities in the brain,” she concluded. “Disrupting those activities can have dire consequences on brain function that may lead to a neurological milieu that lends itself to pathological aging conditions like Alzheimer’s. Several large ongoing trials are poised to validate results of smaller studies, elucidate underlying mechanisms, and provide new therapeutic targets. It’s an exciting time.”
Dr. Craft’s research is supported by the National Institute on Aging and the Alzheimer’s Association Zenith Program. Intranasal delivery devices were provided by Kurve Technology.
LOS ANGELES – Growing evidence from basic science and preclinical studies demonstrates that
In addition, brain insulin resistance in Alzheimer’s disease (AD) is associated with increased cerebral hyperglycemia, reduced cerebral glucose utilization, reduced blood flow, and reduced accumulation of amyloid and tau.
When that process goes awry, several pathologic processes linking insulin resistance (IR) and Alzheimer’s disease occur, including impaired proteostasis (oligomeric beta amyloid, microtubule-associated tau, and oligomeric insulin); hyperglycemia-induced toxicity and reduced glucose utilization; mitochondrial dysfunction; and vascular dysfunction, Dr. Craft continued.
In the past 5 years, researchers have developed ways to measure expression levels of insulin resistance markers like insulin receptor substrate 1 (IRS-1) pSer–positive neurons, Dr. Craft said. Others have found that increased IRS-1 pSer is associated with paired helical filaments (PHFs) tau in mild cognitive impairment (MCI) and AD, and that increased IRS-1 pSer in neutrally derived plasma exomes increased in AD years before onset and in type 2 diabetes. “We can look at the neurons themselves and what we see is that this IR marker colocalizes with tau,” Dr. Craft said. “It’s not very common in normal folks, but as you progress through the stages of MCI to AD, it becomes more common. So there’s a progressive increase in IR markers that associates with neurons in tau.” Other imaging studies have shown that homeostatic model assessment IR predicts gray matter atrophy, reduced blood flow, and amyloid deposition in middle-aged adults.
One way to overcome IR in AD is to increase insulin availability in the brain. Intranasal administration of insulin is a novel method being tested by Dr. Craft and her associates. “This is not inhaled insulin; it does not target the lungs,” she explained. “It’s insulin administered with a very specialized device that targets the olfactory cleft in the upper nasal passages. Virtually none of the insulin is deposited in the lungs or nasopharyngeally.” The approach is modeled on the notion that there are pathways from the olfactory perivascular spaces to the brain by which peptides can travel readily by bulk flow. “They reach the brain within minutes,” she said. “It’s a way of delivering peptides to the brain that bypasses the blood-brain barrier.”
In a published study, she and her associates randomized 104 adults with MCI or AD to receive 20 IU insulin, 40 IU insulin, or placebo twice daily for 4 months (Arch Neurol. 2012;61[1]:29-38). Tests performed at baseline and at 4 months included cognitive evaluation based on story recall and the ADAS-Cog (Alzheimer’s Disease Assessment Scale–Cognitive subscale); function based on the Dementia Rating Severity Scale, FDG-PET (positron emission tomography with 18fluorodeoxyglucose), and cerebrospinal fluid biomarkers. “We showed that the 20-IU dose of intranasal insulin improved memory quite substantially (P less than .05),” Dr. Craft said. “It also improved glucose utilization as assessed by FDG-PET. We also saw changes in spinal fluid biomarkers of amyloid in a favorable direction. Most recently, we looked at the exosomal indicator of IR (IRS-1 pSer), and what we saw quite remarkably was a reduction in the same condition that the memory improved. This gives us hope that we have a marker of whether or not we’re having a positive impact.”
She and her research team recently finished a phase 2 pilot study of regular insulin vs. long-acting insulin detemir, to determine if a longer-acting agent with longer exposure would have greater efficacy (J Alzheimers Dis. 2017;57[4]:1325–34). In all, 36 participants were randomized to receive placebo, 40 IU of insulin detemir, or 40 IU of regular insulin daily for 4 months, administered with a nasal delivery device. The investigators found that only the group treated with 40 IU regular insulin had better memory after 2 and 4 months, compared with placebo (P less than .03). Regular insulin treatment was also associated with preserved volume on MRI. “The normal pattern is for AD patients to lose brain volume rather rapidly,” Dr. Craft commented. “We see that abolished by the insulin treatment, which suggests to us that we’re able to stave off this disease-related mechanism.” She and her associates are currently conducting a phase 3 clinical trial with regular insulin and a phase 3 trial with rapid-acting insulin that are expected to be completed in the summer of 2018.
Dr. Craft spent the last few minutes of her presentation discussing the ketogenic diet as a nonpharmacologic approach to preventing or treating brain insulin resistance and AD. “I think the power of diet is underestimated, both in terms of causing disease and potentially modulating it,” she said. Her research team just completed a study of 87 middle-aged adults who were randomized to a Western diet or a healthy diet. The Western diet was high in saturated fat, sugar, and salt. The healthy diet was low in saturated fat, sugar, and salt, but the macronutrient composition of both diets was the same. “It was a eucaloric diet with normal calorie intake; no weight change, so trying to understand the integrated effect of the Western diet,” she said. “All food was prepared by us and delivered to the patients two times per week.” Patients with type 2 diabetes, patients with hypertension, and those who were on statins were excluded from the study.
The researchers observed pronounced diet-induced changes in cerebral blood flow, all which favored the healthy diet group. “The Western diet reduced blood flow, and the healthy diet increased blood blow in the hippocampus, which is critical for memory, as in some other regions that are known to be affected in AD,” Dr. Craft said. “We saw an effect on memory as well, with the healthy diet improving memory and the Western diet reducing it. Both of these effects were significant, so 4 weeks on a diet such as this is sufficient to modulate key aspects of brain function.”
More recently, Dr. Craft and her colleagues have been evaluating the effects of what they term the modified Mediterranean ketogenic diet (MMKD). “It does allow for higher carbohydrate consumption, compared with a traditional ketogenic diet, but they still have to stay under 10% a day,” she said. “We have an emphasis on healthy fats. We send everybody home with extra virgin olive oil. We think it gives us extra compliance and the potential for long-term nutrition.” She explained that the diet increases plasma and CNS ketone bodies, beta-hydroxybutyrate, acetoacetate, and acetone, which serves as preferred alternative fuel for the brain. “If the brain has a choice between glucose and ketones, it will choose ketones,” Dr. Craft said. “It can use them more easily.”
Ketone bodies are derived from hepatic fatty acid oxidation and readily diffuse across the blood-brain barrier into the brain. They are also synthesized in the brain by astrocytes, and they appear to have direct neuroprotective effects. “Ketone bodies may be beneficial because they may correct the hyperglycemic state and reduce glucose utilization in the brain in AD years prior to symptom onset,” Dr. Craft said. “They may correct neuronal hyperexcitability and preclinical seizures in presymptomatic and early stages of AD; they restore the balance between inhibitory and excitatory neurotransmitters like GABA [gamma-aminobutyric acid] and glutamate.”
In an unpublished, 16-week study, Dr. Craft and her associates randomized 16 patients to a Mediterranean ketogenic diet or to an American Heart Association low-fat diet. Lumbar punctures and brain imaging were performed before and after diet intervention. By the end of 6 weeks, they observed significant increases in ketones and in HDL cholesterol level in the MMKD group, compared with the AHA diet group, as well as significant decreases in trigylcerides and HbA1c level. “I would say that we improved the peripheral metabolic profile with the ketogenic diet,” Dr. Craft said. They also observed significant improvements from baseline in memory, spinal fluid AD biomarkers, and mitochondrial respiration.
“One of the things we’re appreciating is the role of insulin in a host of activities in the brain,” she concluded. “Disrupting those activities can have dire consequences on brain function that may lead to a neurological milieu that lends itself to pathological aging conditions like Alzheimer’s. Several large ongoing trials are poised to validate results of smaller studies, elucidate underlying mechanisms, and provide new therapeutic targets. It’s an exciting time.”
Dr. Craft’s research is supported by the National Institute on Aging and the Alzheimer’s Association Zenith Program. Intranasal delivery devices were provided by Kurve Technology.
AT WCIRDC 2017
Blisibimod shows mixed results for lupus in phase 3 trial
SAN DIEGO – While use of the investigational agent blisibimod did not meet the primary endpoint in a phase 3 trial in systemic lupus erythematosus (SLE), it was associated with steroid sparing, decreased urine protein, a trend toward decreased anti–double-stranded DNA antibodies, and significant decreases in anticardiolipin antibodies and immunoglobulin levels.
Those results were reported from CHABLIS-SC1 trial, a randomized (5:4), double-blind, placebo-controlled phase 3 study of 442 patients, and were presented by Joan T. Merrill, MD, at the annual meeting of the American College of Rheumatology. Blisibimod is a subcutaneously injected inhibitor of B-cell activating factor.
The SRI-6 primary endpoint at 52 weeks was met by 44% of patients on blisibimod, compared with 42% on placebo. But the SRI-6 endpoint widened when the most common features at entry were excluded (mucocutaneous and musculoskeletal), suggesting the possibility that blisibimod affects the more objective and potentially organ-threatening renal endpoint.
To be eligible for the trial, patients had to have a Safety of Estrogen in Lupus Erythematosus National Assessment Group–SLE Disease Activity Index (SELENA-SLEDAI) score of 10 or greater and be receiving steroids. The SRI-6 primary endpoint also required no worsening on the British Isles Lupus Assessment Group (BILAG) disease activity index or Physician Global Assessment. Key secondary endpoints included proteinuria and achievement of steroid taper.
Patients in the study were required to be receiving stable doses of prednisone or an equivalent steroid at less than or equal to 0.5 mg/kg or 40 mg daily for at least 28 days prior to randomization. Other permitted standard-of-care oral medications included methotrexate up to 25 mg weekly, azathioprine up to 300 mg daily, mycophenolate mofetil or sodium salt up to 3 mg daily, leflunomide up to 40 mg daily, hydroxychloroquine up to 400 mg daily, and nonsteroidal drugs within locally approved dose ranges.
Of the 442 patients enrolled, 245 received blisibimod, and 197 received placebo. They were well matched in demographics and baseline disease characteristics. “There were very few patients of African descent in this trial,” Dr. Merrill noted. “Also, about 30% of patients had some renal involvement. In fact, patients with stable, active renal disease were encouraged to participate in this trial.” The mean prednisone dose at entry was between 15 and 16 mg daily, and about 60% of patients were taking an antimalarial. An equal proportion of patients in both groups discontinued the study (22%). “A few more patients withdrew due to adverse events in the blisibimod group, and a few more patients withdrew due to lack of efficacy in the placebo group,” she said.
Of 135 patients with a baseline urine protein-to-creatinine ratio equal to or greater than 0.5, blisibimod treatment led to significantly greater improvement in proteinuria at several time points than did treatment with placebo, which also showed improvement in proteinuria.
Treatment with blisibimod also was associated with a reduction in anti–double-stranded DNA antibodies, as well as significant reductions in peripheral B-cell lineages, anticardiolipin antibodies, and immunoglobulins, and with significant increases in complement C3 and C4. “The expected pharmacodynamic markers were [also] met ... and more patients treated with blisibimod were able to achieve a prednisone milestone of reduction to less than or equal to 7.5 mg/day, compared with those in the placebo group,” she said. “This was statistically significant over time at multiple time points.”
Adverse events were balanced between treatment arms except for injection site reactions, which occurred in 7.3% of blisibimod-treated patients versus 2.6% of placebo patients. There were no major safety issues in the study.
Dr. Merrill hypothesized that the higher mean doses of corticosteroid at baseline could have contributed to the higher-than-usual placebo response rates and failure to meet the primary SRI-6 endpoint.
The study was supported by Anthera. Dr. Merrill disclosed that she has received research support from Anthera, Amgen, EMD Serono, GlaxoSmithKline. and Novartis.
SAN DIEGO – While use of the investigational agent blisibimod did not meet the primary endpoint in a phase 3 trial in systemic lupus erythematosus (SLE), it was associated with steroid sparing, decreased urine protein, a trend toward decreased anti–double-stranded DNA antibodies, and significant decreases in anticardiolipin antibodies and immunoglobulin levels.
Those results were reported from CHABLIS-SC1 trial, a randomized (5:4), double-blind, placebo-controlled phase 3 study of 442 patients, and were presented by Joan T. Merrill, MD, at the annual meeting of the American College of Rheumatology. Blisibimod is a subcutaneously injected inhibitor of B-cell activating factor.
The SRI-6 primary endpoint at 52 weeks was met by 44% of patients on blisibimod, compared with 42% on placebo. But the SRI-6 endpoint widened when the most common features at entry were excluded (mucocutaneous and musculoskeletal), suggesting the possibility that blisibimod affects the more objective and potentially organ-threatening renal endpoint.
To be eligible for the trial, patients had to have a Safety of Estrogen in Lupus Erythematosus National Assessment Group–SLE Disease Activity Index (SELENA-SLEDAI) score of 10 or greater and be receiving steroids. The SRI-6 primary endpoint also required no worsening on the British Isles Lupus Assessment Group (BILAG) disease activity index or Physician Global Assessment. Key secondary endpoints included proteinuria and achievement of steroid taper.
Patients in the study were required to be receiving stable doses of prednisone or an equivalent steroid at less than or equal to 0.5 mg/kg or 40 mg daily for at least 28 days prior to randomization. Other permitted standard-of-care oral medications included methotrexate up to 25 mg weekly, azathioprine up to 300 mg daily, mycophenolate mofetil or sodium salt up to 3 mg daily, leflunomide up to 40 mg daily, hydroxychloroquine up to 400 mg daily, and nonsteroidal drugs within locally approved dose ranges.
Of the 442 patients enrolled, 245 received blisibimod, and 197 received placebo. They were well matched in demographics and baseline disease characteristics. “There were very few patients of African descent in this trial,” Dr. Merrill noted. “Also, about 30% of patients had some renal involvement. In fact, patients with stable, active renal disease were encouraged to participate in this trial.” The mean prednisone dose at entry was between 15 and 16 mg daily, and about 60% of patients were taking an antimalarial. An equal proportion of patients in both groups discontinued the study (22%). “A few more patients withdrew due to adverse events in the blisibimod group, and a few more patients withdrew due to lack of efficacy in the placebo group,” she said.
Of 135 patients with a baseline urine protein-to-creatinine ratio equal to or greater than 0.5, blisibimod treatment led to significantly greater improvement in proteinuria at several time points than did treatment with placebo, which also showed improvement in proteinuria.
Treatment with blisibimod also was associated with a reduction in anti–double-stranded DNA antibodies, as well as significant reductions in peripheral B-cell lineages, anticardiolipin antibodies, and immunoglobulins, and with significant increases in complement C3 and C4. “The expected pharmacodynamic markers were [also] met ... and more patients treated with blisibimod were able to achieve a prednisone milestone of reduction to less than or equal to 7.5 mg/day, compared with those in the placebo group,” she said. “This was statistically significant over time at multiple time points.”
Adverse events were balanced between treatment arms except for injection site reactions, which occurred in 7.3% of blisibimod-treated patients versus 2.6% of placebo patients. There were no major safety issues in the study.
Dr. Merrill hypothesized that the higher mean doses of corticosteroid at baseline could have contributed to the higher-than-usual placebo response rates and failure to meet the primary SRI-6 endpoint.
The study was supported by Anthera. Dr. Merrill disclosed that she has received research support from Anthera, Amgen, EMD Serono, GlaxoSmithKline. and Novartis.
SAN DIEGO – While use of the investigational agent blisibimod did not meet the primary endpoint in a phase 3 trial in systemic lupus erythematosus (SLE), it was associated with steroid sparing, decreased urine protein, a trend toward decreased anti–double-stranded DNA antibodies, and significant decreases in anticardiolipin antibodies and immunoglobulin levels.
Those results were reported from CHABLIS-SC1 trial, a randomized (5:4), double-blind, placebo-controlled phase 3 study of 442 patients, and were presented by Joan T. Merrill, MD, at the annual meeting of the American College of Rheumatology. Blisibimod is a subcutaneously injected inhibitor of B-cell activating factor.
The SRI-6 primary endpoint at 52 weeks was met by 44% of patients on blisibimod, compared with 42% on placebo. But the SRI-6 endpoint widened when the most common features at entry were excluded (mucocutaneous and musculoskeletal), suggesting the possibility that blisibimod affects the more objective and potentially organ-threatening renal endpoint.
To be eligible for the trial, patients had to have a Safety of Estrogen in Lupus Erythematosus National Assessment Group–SLE Disease Activity Index (SELENA-SLEDAI) score of 10 or greater and be receiving steroids. The SRI-6 primary endpoint also required no worsening on the British Isles Lupus Assessment Group (BILAG) disease activity index or Physician Global Assessment. Key secondary endpoints included proteinuria and achievement of steroid taper.
Patients in the study were required to be receiving stable doses of prednisone or an equivalent steroid at less than or equal to 0.5 mg/kg or 40 mg daily for at least 28 days prior to randomization. Other permitted standard-of-care oral medications included methotrexate up to 25 mg weekly, azathioprine up to 300 mg daily, mycophenolate mofetil or sodium salt up to 3 mg daily, leflunomide up to 40 mg daily, hydroxychloroquine up to 400 mg daily, and nonsteroidal drugs within locally approved dose ranges.
Of the 442 patients enrolled, 245 received blisibimod, and 197 received placebo. They were well matched in demographics and baseline disease characteristics. “There were very few patients of African descent in this trial,” Dr. Merrill noted. “Also, about 30% of patients had some renal involvement. In fact, patients with stable, active renal disease were encouraged to participate in this trial.” The mean prednisone dose at entry was between 15 and 16 mg daily, and about 60% of patients were taking an antimalarial. An equal proportion of patients in both groups discontinued the study (22%). “A few more patients withdrew due to adverse events in the blisibimod group, and a few more patients withdrew due to lack of efficacy in the placebo group,” she said.
Of 135 patients with a baseline urine protein-to-creatinine ratio equal to or greater than 0.5, blisibimod treatment led to significantly greater improvement in proteinuria at several time points than did treatment with placebo, which also showed improvement in proteinuria.
Treatment with blisibimod also was associated with a reduction in anti–double-stranded DNA antibodies, as well as significant reductions in peripheral B-cell lineages, anticardiolipin antibodies, and immunoglobulins, and with significant increases in complement C3 and C4. “The expected pharmacodynamic markers were [also] met ... and more patients treated with blisibimod were able to achieve a prednisone milestone of reduction to less than or equal to 7.5 mg/day, compared with those in the placebo group,” she said. “This was statistically significant over time at multiple time points.”
Adverse events were balanced between treatment arms except for injection site reactions, which occurred in 7.3% of blisibimod-treated patients versus 2.6% of placebo patients. There were no major safety issues in the study.
Dr. Merrill hypothesized that the higher mean doses of corticosteroid at baseline could have contributed to the higher-than-usual placebo response rates and failure to meet the primary SRI-6 endpoint.
The study was supported by Anthera. Dr. Merrill disclosed that she has received research support from Anthera, Amgen, EMD Serono, GlaxoSmithKline. and Novartis.
AT ACR 2017
Key clinical point:
Major finding: The primary endpoint of CHABLIS-SC1 was not met, but expected pharmacodynamic markers were.
Study details: A phase 3 study in which 245 SLE patients received blisibimod and 197 received placebo.
Disclosures: The study was supported by Anthera Pharmaceuticals. Dr. Merrill disclosed that she has received research support from Anthera, Amgen, EMD Serono, GlaxoSmithKline, and Novartis.
December 2017: Click for Credit
Here are 5 articles in the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. When Is It Really Recurrent Strep Throat?
To take the posttest, go to: http://bit.ly/2lHFh8i
Expires September 21, 2018
2. Revised Bethesda System Resets Thyroid Malignancy Risks
To take the posttest, go to: http://bit.ly/2iSLOvM
Expires August 10, 2018
3. Tips for Avoiding Potentially Dangerous Patients
To take the posttest, go to: http://bit.ly/2lH1Fi7
Expires August 10, 2018
4. Study Findings Support Uncapping MELD Score
To take the posttest, go to: http://bit.ly/2xOA7sI
Expires September 12, 2018
5. 'Motivational Pharmacotherapy' Engages Latino Patients With Depression
To take the posttest, go to: http://bit.ly/2zs2ly4
Expires August 14, 2018
Here are 5 articles in the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. When Is It Really Recurrent Strep Throat?
To take the posttest, go to: http://bit.ly/2lHFh8i
Expires September 21, 2018
2. Revised Bethesda System Resets Thyroid Malignancy Risks
To take the posttest, go to: http://bit.ly/2iSLOvM
Expires August 10, 2018
3. Tips for Avoiding Potentially Dangerous Patients
To take the posttest, go to: http://bit.ly/2lH1Fi7
Expires August 10, 2018
4. Study Findings Support Uncapping MELD Score
To take the posttest, go to: http://bit.ly/2xOA7sI
Expires September 12, 2018
5. 'Motivational Pharmacotherapy' Engages Latino Patients With Depression
To take the posttest, go to: http://bit.ly/2zs2ly4
Expires August 14, 2018
Here are 5 articles in the December issue of Clinician Reviews (individual articles are valid for one year from date of publication—expiration dates below):
1. When Is It Really Recurrent Strep Throat?
To take the posttest, go to: http://bit.ly/2lHFh8i
Expires September 21, 2018
2. Revised Bethesda System Resets Thyroid Malignancy Risks
To take the posttest, go to: http://bit.ly/2iSLOvM
Expires August 10, 2018
3. Tips for Avoiding Potentially Dangerous Patients
To take the posttest, go to: http://bit.ly/2lH1Fi7
Expires August 10, 2018
4. Study Findings Support Uncapping MELD Score
To take the posttest, go to: http://bit.ly/2xOA7sI
Expires September 12, 2018
5. 'Motivational Pharmacotherapy' Engages Latino Patients With Depression
To take the posttest, go to: http://bit.ly/2zs2ly4
Expires August 14, 2018
